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Sample records for agonist propyl pyrazole

  1. 3-Substituted pyrazole analogs of the cannabinoid type 1 (CB₁) receptor antagonist rimonabant: cannabinoid agonist-like effects in mice via non-CB₁, non-CB₂ mechanism.

    PubMed

    Wiley, Jenny L; Selley, Dana E; Wang, Pinglang; Kottani, Rudresha; Gadthula, Srinivas; Mahadeven, Anu

    2012-02-01

    The prototypic cannabinoid type 1 (CB₁) receptor antagonist/inverse agonist, rimonabant, is comprised of a pyrazole core surrounded by a carboxyamide with terminal piperidine group (3-substituent), a 2,4-dichlorophenyl group (1-substituent), a 4-chlorophenyl group (5-substituent), and a methyl group (4-substituent). Previous structure-activity relationship (SAR) analysis has suggested that the 3-position may be involved in receptor recognition and agonist activity. The goal of the present study was to develop CB₁-selective compounds and explore further the SAR of 3-substitution on the rimonabant template. 3-Substituted analogs with benzyl and alkyl amino, dihydrooxazole, and oxazole moieties were synthesized and evaluated in vitro and in vivo. Several notable patterns emerged. First, most of the analogs exhibited CB₁ selectivity, with many lacking affinity for the CB₂ receptor. Affinity tended to be better when [³H]5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (SR141716), rather than [³H](-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol (CP55,940), was used as the binding radioligand. Second, many of the analogs produced an agonist-like profile of effects in mice (i.e., suppression of activity, antinociception, hypothermia, and immobility); however, their potencies were not well correlated with their CB₁ binding affinities. Further assessment of selected analogs showed that none were effective antagonists of the effects of Δ⁹-tetrahydrocannabinol in mice, their agonist-like effects were not blocked by rimonabant, they were active in vivo in CB₁⁻/⁻ mice, and they failed to stimulate guanosine-5'-O-(3-[³⁵S]thio)-triphosphate binding. Several analogs were inverse agonists in the latter assay. Together, these results suggest that this series of 3-substituted pyrazole analogs represent a novel class of CB₁-selective cannabinoids that produce agonist

  2. 3-Substituted Pyrazole Analogs of the Cannabinoid Type 1 (CB1) Receptor Antagonist Rimonabant: Cannabinoid Agonist-Like Effects in Mice via Non-CB1, Non-CB2 Mechanism

    PubMed Central

    Selley, Dana E.; Wang, Pinglang; Kottani, Rudresha; Gadthula, Srinivas; Mahadeven, Anu

    2012-01-01

    The prototypic cannabinoid type 1 (CB1) receptor antagonist/inverse agonist, rimonabant, is comprised of a pyrazole core surrounded by a carboxyamide with terminal piperidine group (3-substituent), a 2,4-dichlorophenyl group (1-substituent), a 4-chlorophenyl group (5-substituent), and a methyl group (4-substituent). Previous structure-activity relationship (SAR) analysis has suggested that the 3-position may be involved in receptor recognition and agonist activity. The goal of the present study was to develop CB1-selective compounds and explore further the SAR of 3-substitution on the rimonabant template. 3-Substituted analogs with benzyl and alkyl amino, dihydrooxazole, and oxazole moieties were synthesized and evaluated in vitro and in vivo. Several notable patterns emerged. First, most of the analogs exhibited CB1 selectivity, with many lacking affinity for the CB2 receptor. Affinity tended to be better when [3H]5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (SR141716), rather than [3H](−)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol (CP55,940), was used as the binding radioligand. Second, many of the analogs produced an agonist-like profile of effects in mice (i.e., suppression of activity, antinociception, hypothermia, and immobility); however, their potencies were not well correlated with their CB1 binding affinities. Further assessment of selected analogs showed that none were effective antagonists of the effects of Δ9-tetrahydrocannabinol in mice, their agonist-like effects were not blocked by rimonabant, they were active in vivo in CB1(−/−) mice, and they failed to stimulate guanosine-5′-O-(3-[35S]thio)-triphosphate binding. Several analogs were inverse agonists in the latter assay. Together, these results suggest that this series of 3-substituted pyrazole analogs represent a novel class of CB1-selective cannabinoids that produce agonist-like effects in mice

  3. (-)-N-[(11)C]propyl-norapomorphine: a positron-labeled dopamine agonist for PET imaging of D(2) receptors.

    PubMed

    Hwang, D R; Kegeles, L S; Laruelle, M

    2000-08-01

    Imaging neuroreceptors with radiolabeled agonists might provide valuable information on the in vivo agonist affinity states of receptors of interest. We report here the radiosynthesis, biodistribution in rodents, and imaging studies in baboons of [(11)C]-labeled (-)-N-propyl-norapomorphine [(-)-NPA]. (-)-[(11)C]NPA was prepared by reacting norapomorphine with [(11)C]propionyl chloride and a lithium aluminum hydride reduction. [(11)C]Propionyl chloride was prepared by reacting [(11)C]CO(2) with ethylmagnesium bromide, followed by reacting with phthaloyl chloride. The radiochemical yield of (-)-[(11)C]NPA was 2.5% at end of synthesis (EOS), and the synthesis time was 60 min. The specific activity was 1700+/-1900 mCi/micromol ( N=7; ranged 110-5200 mCi/micromol at EOS). Rodent biodistribution studies showed high uptake of [(11)C](-)-NPA in D(2) receptor-rich areas, and the striatum/cerebellum ratios were 1.7, 3.4, and 4.4 at 5 min, 30 min, and 60 min postinjection, respectively. Pretreating the animals with haloperidol (1 mg/kg) decreased the striatum/cerebellum ratio at 30 min postinjection to 1.3. (-)-[(11)C]NPA was also evaluated via baboon positron emission tomography (PET) studies. Under control conditions ( N=4), rapid uptake of the tracer was observed and the striatum/cerebellum ratio reached 2.86+/-0.15 at 45 min postinjection. Following haloperidol pretreatment (0.2 mg/kg IV), the striatum/cerebellum ratio was 1.29 at 45 min postinjection. The result demonstrated the existence of specific binding of this new tracer to the D(2) receptor. To our knowledge, the current finding of a striatum/cerebellum ratio of 2.8 in baboon was the highest reported with a radiolabeled D(2) agonist. (-)-[(11)C]NPA is a promising new D(2) agonist PET tracer for probing D(2) receptors in vivo using PET.

  4. Synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of PPARγ partial agonists

    PubMed Central

    Qvortrup, Katrine; Jensen, Jakob F.; Sørensen, Mikael S.; Kouskoumvekaki, Irene; Petersen, Rasmus K.; Taboureau, Olivier; Kristiansen, Karsten; Nielsen, Thomas E.

    2017-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a well-known target for thiazolidinedione antidiabetic drugs. In this paper, we present the synthesis and biological evaluation of a series of dihydropyrano[2,3-c]pyrazole derivatives as a novel family of PPARγ partial agonists. Two analogues were found to display high affinity for PPARγ with potencies in the micro molar range. Both of these hits were selective against PPARγ, since no activity was measured when tested against PPARα, PPARδ and RXRα. In addition, a novel modelling approach based on multiple individual flexible alignments was developed for the identification of ligand binding interactions in PPARγ. In combination with cell-based transactivation experiments, the flexible alignment model provides an excellent analytical tool to evaluate and visualize the effect of ligand chemical structure with respect to receptor binding mode and biological activity. PMID:28245241

  5. Denatonium and 6-n-Propyl-2-thiouracil, Agonists of Bitter Taste Receptor, Inhibit Contraction of Various Types of Smooth Muscles in the Rat and Mouse.

    PubMed

    Sakai, Hiroyasu; Sato, Ken; Kai, Yuki; Chiba, Yoshihiko; Narita, Minoru

    2016-01-01

    Recently the global expression of taste 2 receptors (TAS2Rs) on smooth muscle cells in human airways was demonstrated. Here, the effects of agonists of taste receptor, type 2, denatonium and 6-n-propyl-2-thiouracil, on smooth-muscle contraction were examined in the rat and mouse. Contractions induced by carbachol (CCh), high K(+), and sodium fluoride, but not calyculin-A, were inhibited significantly in the presence of a TAS2R agonist in the bronchial smooth muscle of mice. The contraction induced by CCh was inhibited by TAS2R agonists in ileal smooth muscle. Phenylephrine-induced contraction was also inhibited by TAS2R agonists in aortic smooth muscle. Gastrointestinal motility and blood pressure were attenuated by administration of TAS2R agonists in vivo. These findings suggest that TAS2R may be receptor for endogenous biologically active substances as well as for bitter tastes on the tongue. TAS2R signaling could be employed in the development of anti-asthmatic, anti-spasmodic, and anti-hypertensive drugs.

  6. Denatonium and 6-n-Propyl-2-thiouracil, Agonists of Bitter Taste Receptor, Inhibit Contraction of Various Types of Smooth Muscles in the Rat and Mouse.

    PubMed

    Sakai, Hiroyasu; Sato, Ken; Kai, Yuki; Chiba, Yoshihiko; Narita, Minoru

    2016-01-01

    Recently the global expression of taste 2 receptors (TAS2Rs) on smooth muscle cells in human airways was demonstrated. Here, the effects of agonists of taste receptor, type 2, denatonium and 6-n-propyl-2-thiouracil, on smooth-muscle contraction were examined in the rat and mouse. Contractions induced by carbachol (CCh), high K, and sodium fluoride, but not calyculin-A, were inhibited significantly in the presence of a TAS2R agonist in the bronchial smooth muscle of mice. The contraction induced by CCh was inhibited by TAS2R agonists in ileal smooth muscle. Phenylephrine-induced contraction was also inhibited by TAS2R agonists in aortic smooth muscle. Gastrointestinal motility and blood pressure were attenuated by administration of TAS2R agonists in vivo. These findings suggest that TAS2R may be receptor for endogenous biologically active substances as well as for bitter tastes on the tongue. TAS2R signaling could be employed in the development of anti-asthmatic, anti-spasmodic, and anti-hypertensive drugs.

  7. A novel synthesis and pharmacological evaluation of a potential dopamine D1/D2 agonist: 1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol.

    PubMed

    Liu, Danyang; Dijkstra, Durk; de Vries, Jan B; Wikström, Håkan V

    2008-03-15

    Previously, we have demonstrated that enone prodrugs of dopaminergic catecholamines represent a new type of dopamine (DA) agonist. Trans-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-6,7-diol (TL-334), the active form of trans-1-propyl-2,3,4,4a,5,7,8,9,10,10a-decahydro-1H-benzo[g]quinolin-6-one (GMC-6650), in vivo showed an extremely potent dopaminergic activity. Here, we report a novel synthesis and a pharmacological evaluation of TL-334 by means of microdialysis.

  8. In vivo vulnerability to competition by endogenous dopamine: comparison of the D2 receptor agonist radiotracer (-)-N-[11C]propyl-norapomorphine ([11C]NPA) with the D2 receptor antagonist radiotracer [11C]-raclopride.

    PubMed

    Narendran, Rajesh; Hwang, Dah-Ren; Slifstein, Mark; Talbot, Peter S; Erritzoe, David; Huang, Yiyun; Cooper, Thomas B; Martinez, Diana; Kegeles, Lawrence S; Abi-Dargham, Anissa; Laruelle, Marc

    2004-06-01

    (-)-N-Propyl-norapomorphine (NPA) is a full dopamine (DA) D2 receptor agonist and [11C]NPA is a suitable radiotracer to image D2 receptors configured in a state of high affinity for agonists with positron emission tomography (PET). In this study the vulnerability of the in vivo binding of [11C]NPA to acute fluctuation in synaptic DA was assessed with PET in baboons and compared to that of the reference D2 receptor antagonist radiotracer [11C]raclopride. Three male baboons were studied with [11C]raclopride and [11C]NPA under baseline conditions and following administration of the potent DA releaser amphetamine (0.3, 0.5, and 1.0 mg kg(-1) i.v.). Kinetic modeling with an arterial input function was used to derive the striatal specific-to-nonspecific equilibrium partition coefficient (V3"). [11C]Raclopride V3" was reduced by 24 +/- 10%, 32 +/- 6%, and 44 +/- 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg(-1), respectively. [11C]NPA V3" was reduced by 32 +/- 2%, 45 +/- 3%, and 53 +/- 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg(-1), respectively. Thus, endogenous DA was more effective at competing with [11C]NPA binding compared to [11C]raclopride binding, a finding consistent with the pharmacology of these tracers (agonist vs. antagonist). These results also suggest that 71% of D2 receptors are configured in a state of high affinity for agonists in vivo. In conclusion, [11C]NPA might provide a superior radiotracer to probe presynaptic DA function with PET in health and disease.

  9. A comparative evaluation of the dopamine D(2/3) agonist radiotracer [11C](-)-N-propyl-norapomorphine and antagonist [11C]raclopride to measure amphetamine-induced dopamine release in the human striatum.

    PubMed

    Narendran, Rajesh; Mason, N Scott; Laymon, Charles M; Lopresti, Brian J; Velasquez, Natalie D; May, Maureen A; Kendro, Steve; Martinez, Diana; Mathis, Chester A; Frankle, W Gordon

    2010-05-01

    (-)-N-Propyl-norapomorphine (NPA) is a full dopamine D(2/3) receptor agonist, and [(11)C]NPA is a suitable radiotracer to image D(2/3) receptors configured in a state of high affinity for agonists with positron emission tomography (PET). In this study, the vulnerability of the in vivo binding of [11C]NPA to acute fluctuation in synaptic dopamine was assessed with PET in healthy humans and compared with that of the reference D(2/3) receptor antagonist radiotracer [11C]raclopride. Ten subjects (eight females and two males) were studied on two separate days, a minimum of 1 week apart, both with [11C]raclopride and [11C]NPA at baseline and after the administration of 0.5 mg x kg(-1) oral d-amphetamine. Kinetic modeling with an arterial input function was used to derive the binding potential relative to nonspecific uptake (BPND) in the ventral striatum (VST), caudate (CAD), and putamen (PUT). [11C]Raclopride BPND was significantly reduced by 9.7 +/- 4.4, 8.4 +/- 4.2, and 14.7 +/- 4.8% after amphetamine administration in the VST, CAD, and PUT. [11C]NPA BPND was also reduced significantly, by 16.0 +/- 7.0, 16.1 +/- 6.1, and 21.9 +/- 4.9% after the same dose of amphetamine in the VST, CAD, and PUT. Although these results suggest that [11C]NPA is more vulnerable to endogenous competition by dopamine compared with [11C]raclopride by a factor of 1.49 to 1.90, the same data for a related outcome measure, binding potential relative to plasma concentration, was not significant. Nevertheless, these data add to the growing literature that suggests D(2/3) agonist radiotracers are more vulnerable to endogenous competition by dopamine than existing D(2/3) antagonist radiotracers.

  10. Both estrogen receptor alpha and estrogen receptor beta agonists enhance cell proliferation in the dentate gyrus of adult female rats.

    PubMed

    Mazzucco, C A; Lieblich, S E; Bingham, B I; Williamson, M A; Viau, V; Galea, L A M

    2006-09-15

    This study investigated the involvement of estrogen receptors alpha and beta in estradiol-induced enhancement of hippocampal neurogenesis in the adult female rat. Subtype selective estrogen receptor agonists, propyl-pyrazole triol (estrogen receptor alpha agonist) and diarylpropionitrile (estrogen receptor beta agonist) were examined for each receptor's contribution, individual and cooperative, for estradiol-enhanced hippocampal cell proliferation. Estradiol increases hippocampal cell proliferation within 4 h [Ormerod BK, Lee TT, Galea LA (2003) Estradiol initially enhances but subsequently suppresses (via adrenal steroids) granule cell proliferation in the dentate gyrus of adult female rats. J Neurobiol 55:247-260]. Therefore, animals received s.c. injections of estradiol (10 microg), propyl-pyrazole triol and diarylpropionitrile alone (1.25, 2.5, 5.0 mg/0.1 ml dimethylsulfoxide) or in combination (2.5 mg propyl-pyrazole triol+2.5 mg diarylpropionitrile/0.1 ml dimethylsulfoxide) and 4 h later received an i.p. injection of the cell synthesis marker, bromodeoxyuridine (200 mg/kg). Diarylpropionitrile enhanced cell proliferation at all three administered doses (1.25 mg, P<0.008; 2.5 mg, P<0.003; 5 mg, P<0.005), whereas propyl-pyrazole triol significantly increased cell proliferation (P<0.0002) only at the dose of 2.5 mg. Our results demonstrate both estrogen receptor alpha and estrogen receptor beta are individually involved in estradiol-enhanced cell proliferation. Furthermore both estrogen receptor alpha and estrogen receptor beta mRNA was found co-localized with Ki-67 expression in the hippocampus albeit at low levels, indicating a potential direct influence of each receptor subtype on progenitor cells and their progeny. Dual receptor activation resulted in reduced levels of cell proliferation, supporting previous studies suggesting that estrogen receptor alpha and estrogen receptor beta may modulate each other's activity. Our results also suggest that a component

  11. PET Imaging of D2/3 agonist binding in healthy human subjects with the radiotracer [11C]-N-propyl-nor-apomorphine (NPA): preliminary evaluation and reproducibility studies

    PubMed Central

    Narendran, Rajesh; Frankle, W. Gordon; Mason, N. Scott; Laymon, Charles M.; Lopresti, Brian J; Price, Julie C.; Kendro, Steve; Vora, Shivangi; Litschge, Maralee; Mountz, James M.; Mathis, Chester A.

    2009-01-01

    Objective (-)-N-[11C]-Propyl-norapomorphine (NPA) is a full dopamine D2/3 receptor agonist radiotracer suitable for imaging D2/3 receptors configured in a state of high affinity for agonists using Positron Emission Tomography (PET). The aim of the present study was to define the optimal analytic method to derive accurate and reliable D2/3 receptor parameters with [11C]NPA. Methods Six healthy subjects (4 females/2 males) underwent two [11C]NPA scans in the same day. D2/3 receptor binding parameters were estimated using kinetic analysis (using 1- and 2- tissue compartment models) as well as simplified reference tissue method in the three functional subdivisions of the striatum (associative striatum, AST; limbic striatum LST and sensorimotor striatum SMST). The test-retest variability and intraclass correlation coefficient were assessed for distribution volume (VT), binding potential relative to plasma concentration (BPP), and binding potential relative to nondisplaceable uptake (BPND) Results A two-tissue compartment kinetic model adequately described the functional subdivisions of the striatum as well as cerebellum time-activity data. The reproducibility of VT was excellent (≤ 10%) in all regions, for this approach. The reproducibility of both BPP (≤ 12%) and BPND (≤ 10%) was also excellent. The intraclass correlation coefficient of BPP and BPND were acceptable as well (> 0.75) in the three functional subdivisions of the striatum. Although SRTM led to an underestimation of BPND values relative to that estimated by kinetic analysis by 8 to 13%, the values derived using both the methods were reasonably well correlated (r2 = 0.89, n = 84). Both methods were similarly effective at detecting the differences in [11C]NPA BPND between subjects. Conclusion The results of this study indicate that [11C]NPA can be used to measure D2/3 receptors configured in a state of high affinity for the agonists with high reliability and reproducibility in the functional subdivisions

  12. FT-IR SOLUTION SPECTRA OF PROPYL SULFIDE, PROPYL SULFOXIDE, AND PROPYL SULFONE

    EPA Science Inventory

    FT-IR spectra were obtained of 0.5% volumetric solutions of propyl sulfide, propyl sulfoxide, and propyl sulfone in hexane, CCl4, CS2, and CHCl3 to assist in the assignment of FT-IR-PAS spectra of propyl sulfoxide sorbed within the structure of several peats and onto cellulose. T...

  13. Relaxant Effects of the Selective Estrogen Receptor Modulator, Bazedoxifene, and Estrogen Receptor Agonists in Isolated Rabbit Basilar Artery.

    PubMed

    Castelló-Ruiz, María; Salom, Juan B; Fernández-Musoles, Ricardo; Burguete, María C; López-Morales, Mikahela A; Arduini, Alessandro; Jover-Mengual, Teresa; Hervás, David; Torregrosa, Germán; Alborch, Enrique

    2016-10-01

    We have previously shown that the selective estrogen receptor modulator, bazedoxifene, improves the consequences of ischemic stroke. Now we aimed to characterize the effects and mechanisms of action of bazedoxifene in cerebral arteries. Male rabbit isolated basilar arteries were used for isometric tension recording and quantitative polymerase chain reaction. Bazedoxifene relaxed cerebral arteries, as 17-β-estradiol, 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol [estrogen receptor (ER) α agonist], and G1 [G protein-coupled ER (GPER) agonist] did it (4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol > bazedoxifene = G1 > 17-β-estradiol). 2,3-Bis(4-hydroxyphenyl)-propionitrile (ERβ agonist) had no effect. Expression profile of genes encoding for ERα (ESR1), ERβ (ESR2), and GPER was GPER > ESR1 > ESR2. As to the endothelial mechanisms, endothelium removal, N-nitro-L-arginine methyl ester, and indomethacin, did not modify the relaxant responses to bazedoxifene. As to the K channels, both a high-K medium and the Kv blocker, 4-aminopyridine, inhibited the bazedoxifene-induced relaxations, whereas tetraethylammonium (nonselective K channel blocker), glibenclamide (selective KATP blocker) or iberiotoxin (selective KCa blocker) were without effect. Bazedoxifene also inhibited both Ca- and Bay K8644-elicited contractions. Therefore, bazedoxifene induces endothelium-independent relaxations of cerebral arteries through (1) activation of GPER and ERα receptors; (2) increase of K conductance through Kv channels; and (3) inhibition of Ca entry through L-type Ca channels. Such a profile is compatible with the beneficial effects of estrogenic compounds (eg, SERMs) on vascular function and, specifically, that concerning the brain. Therefore, bazedoxifene could be useful in the treatment of cerebral disorders in which the cerebrovascular function is compromised (eg, stroke).

  14. Identification of a novel selective peroxisome proliferator-activated receptor alpha agonist, 2-methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]propyl}phenoxy)propanoic acid (LY518674), that produces marked changes in serum lipids and apolipoprotein A-1 expression.

    PubMed

    Singh, Jai Pal; Kauffman, Raymond; Bensch, William; Wang, Guoming; McClelland, Pam; Bean, James; Montrose, Chahrzad; Mantlo, Nathan; Wagle, Asavari

    2005-09-01

    Low high-density lipoprotein-cholesterol (HDL-c) is an important risk factor of coronary artery disease (CAD). Optimum therapy for raising HDL-c is still not available. Identification of novel HDL-raising agents would produce a major impact on CAD. In this study, we have identified a potent (IC50 approximately 24 nM) and selective peroxisome proliferator-activated receptor alpha (PPARalpha) agonist, 2-methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]propyl}phenoxy)propanoic acid (LY518674). In human apolipoprotein A-1 (apoA-1) transgenic mice, LY518674 produced a dose-dependent increase in serum HDL-c, resulting in 208 +/- 15% elevation at optimum dose. A new synthesis of apoA-1 contributed to the increase in HDL-c. LY518674 increased apoA-1 mRNA levels in liver. Moreover, liver slices from animals treated with LY518674 secreted 3- to 6-fold more apoA-1 than control liver slices. In cultured hepatocytes, LY518674 produced 50% higher apoA-1 secretion, which was associated with increase in radiolabeled methionine incorporation in apoA-1. Thus, LY518674 is a potent and selective PPARalpha agonist that produced a much greater increase in serum HDL-c than the known fibrate drugs. The increase in HDL-c was associated with de novo synthesis of apoA-1.

  15. (6aR)-11-amino-N-propyl-noraporphine, a new dopamine D2 and serotonin 5-HT1A dual agonist, elicits potent antiparkinsonian action and attenuates levodopa-induced dyskinesia in a 6-OHDA-lesioned rat model of Parkinson's disease.

    PubMed

    Zhao, Rui; Lu, Weijian; Fang, Xing; Guo, Lin; Yang, Zhi; Ye, Na; Zhao, Jiahao; Liu, Zhili; Jia, Jia; Zheng, Longtai; Zhao, Bin; Zhang, Ao; Zhen, Xuechu

    2014-09-01

    Parkinson's disease (PD) drug therapy remains a challenge. Dual modulation of dopamine and 5-HT receptors has emerged as a promising approach in anti-PD drug development. Taking advantage of the newly discovered aporphine analogue(s), (6aR)-11-amino-N-propyl-noraporphine (SOMCL-171), which exhibited dual D2/5-HT1A receptor agonistic activity, we studied the effects of the compound on levodopa-induced dyskinesia (LID) in a PD animal model. The results demonstrated that SOMCL-171 elicited a potent anti-PD effect in a 6-OHDA-lesioned rat model. Chronic use of SOMCL-171 reduced LID without compromising the antiparkinsonian efficacy. Furthermore, we found that the antidyskinesia effect of SOMCL-171 is associated with its 5-HT1A agonistic activity and the up-regulation of the striatal 5-HT1A receptor. The present data indicated that chronic SOMCL-171 alone produced potent antiparkinsonian effects with weak dyskinesia, compared with that of levodopa. In addition, chronic SOMCL-171 application attenuated the development of levodopa-induced LID at no expense to the antiparkinsonian efficacy. Taken together, our data suggested that dual modulation of D2/5-HT1A receptors may provide a novel approach for drug development in PD and LID.

  16. Discovery of 2-[5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazol-3-yl]-1,5,5-trimethyl-1,5-dihydro-imidazol-4-thione (BPR-890) via an active metabolite. A novel, potent and selective cannabinoid-1 receptor inverse agonist with high antiobesity efficacy in DIO mice.

    PubMed

    Wu, Chien-Huang; Hung, Ming-Shiu; Song, Jen-Shin; Yeh, Teng-Kuang; Chou, Ming-Chen; Chu, Cheng-Ming; Jan, Jiing-Jyh; Hsieh, Min-Tsang; Tseng, Shi-Liang; Chang, Chun-Ping; Hsieh, Wan-Ping; Lin, Yinchiu; Yeh, Yen-Nan; Chung, Wan-Ling; Kuo, Chun-Wei; Lin, Chin-Yu; Shy, Horng-Shing; Chao, Yu-Sheng; Shia, Kak-Shan

    2009-07-23

    By using the active metabolite 5 as an initial template, further structural modifications led to the identification of the titled compound 24 (BPR-890) as a highly potent CB1 inverse agonist possessing an excellent CB2/1 selectivity and remarkable in vivo efficacy in diet-induced obese mice with a minimum effective dose as low as 0.03 mg/kg (po qd) at the end of the 30-day chronic study. Current SAR studies along with those of many existing rimonabant-mimicking molecules imply that around the pyrazole C3-position, a rigid and deep binding pocket should exist for CB1 receptor. In addition, relative to the conventional carboxamide carbonyl, serving as a key hydrogen-bond acceptor during ligand-CB1 receptor interaction, the corresponding polarizable thione carbonyl might play a more critical role in stabilizing the Asp366-Lys192 salt bridge in the proposed CB1-receptor homology model and inducing significant selectivity for CB1R over CB2R.

  17. H-atom elimination of n-propyl and iso-propyl radicals: a photodissociation study

    NASA Astrophysics Data System (ADS)

    Zhang, Jingsong; Zhou, Weidong; Yuan, Yan

    2006-03-01

    The H-atom elimination channels in the UV photodissociation of jet-cooled n-propyl and iso-propyl radicals are studied in the region of 237 nm using the high-n Rydberg-atom time-of-flight technique. Upon excitation to the 3p state by the UV photolysis radiation, n-propyl radical and iso-propyl radical dissociate into the H atom and propene products. The product center-of-mass translational energy release of both n-propyl and iso-propyl radicals have bimodal distributions. The H-atom product angular distribution in n-propyl is anisotropic (with β ˜ 0.5), and that in iso-propyl is isotropic. The overall average translational energy release is ˜ 0.27Eavail for n-propyl and ˜ 0.21Eavail for iso-propyl. The bimodal translational energy distributions indicate two dissociation pathways: (i) a unimolecular dissociation pathway from the ground-state propyl after internal conversion from the 3p state, and (ii) a repulsive pathway directly connected with the excited state of the propyl radical. Isotope labeling has also been carried out. The possible photodissociation mechanisms will be discussed.

  18. Structure-activity relationship study of N⁶-(2-(4-(1H-Indol-5-yl)piperazin-1-yl)ethyl)-N⁶-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine analogues: development of highly selective D3 dopamine receptor agonists along with a highly potent D2/D3 agonist and their pharmacological characterization.

    PubMed

    Johnson, Mark; Antonio, Tamara; Reith, Maarten E A; Dutta, Aloke K

    2012-06-28

    In our effort to develop multifunctional drugs against Parkinson's disease, a structure-activity-relationship study was carried out based on our hybrid molecular template targeting D2/D3 receptors. Competitive binding with [(3)H]spiroperidol was used to evaluate affinity (K(i)) of test compounds. Functional activity of selected compounds in stimulating [(35)S]GTPγS binding was assessed in CHO cells expressing either human D2 or D3 receptors. Our results demonstrated development of highly selective compounds for D3 receptor (for (-)-40K(i), D3 = 1.84 nM, D2/D3 = 583.2; for (-)-45K(i), D3 = 1.09 nM, D2/D3 = 827.5). Functional data identified (-)-40 (EC(50), D2 = 114 nM, D3 = 0.26 nM, D2/D3 = 438) as one of the highest D3 selective agonists known to date. In addition, high affinity, nonselective D3 agonist (-)-19 (EC(50), D2 = 2.96 nM and D3 = 1.26 nM) was also developed. Lead compounds with antioxidant activity were evaluated using an in vivo PD animal model.

  19. Pyrazole complexes as anion receptors.

    PubMed

    Nieto, Sonia; Pérez, Julio; Riera, Lucía; Riera, Víctor; Miguel, Daniel

    2006-03-01

    The behavior of the receptors [Re(CO)3(Hdmpz)3]BAr'4 (Hdmpz = 3,5-dimethylpyrazole) (1) and [Re(CO)3(HtBupz)3]BAr'4 (HtBupz = 3(5)-tert-butylpyrazole) (2; Ar' = 3,5-bis(trifluoromethyl)phenyl) toward the anions fluoride, chloride, bromide, iodide, hydrogensulfate, dihydrogenphosphate, nitrate, and perrhenate was studied in CD3CN solution. In most cases, the receptors were stable. Anion exchange was fast, and binding constants were calculated from the NMR titration profiles. The structure of the adduct [Re(CO)3(HtBupz)3] x NO3 (3) was determined by X-ray diffraction. Two pyrazole moieties are hydrogen-bonded to one nitrate oxygen atom, and the third pyrazole moiety is hydrogen-bonded to an oxygen atom of an adjacent nitrate, leading to infinite chains. The structure of the adduct [Re(CO)3(Hdmpz)3]BAr'4acetone (4), also determined by X-ray diffraction, showed a similar interaction of two pyrazole N-H groups with the acetone oxygen atom. F- and H2PO4(-) deprotonate the receptors, and HSO4(-) decomposed 1. The structure of one of the decomposition products (5), determined by X-ray diffraction, is consistent with pyrazole protonation and substitution by sulfate.

  20. Ultraviolet photodissociation dynamics of the n-propyl and i-propyl radicals

    SciTech Connect

    Song, Yu; Zheng, Xianfeng; Zhou, Weidong; Lucas, Michael; Zhang, Jingsong

    2015-06-14

    Ultraviolet (UV) photodissociation dynamics of jet-cooled n-propyl (n-C{sub 3}H{sub 7}) radical via the 3s Rydberg state and i-propyl (i-C{sub 3}H{sub 7}) radical via the 3p Rydberg states are studied in the photolysis wavelength region of 230–260 nm using high-n Rydberg atom time-of-flight and resonance enhanced multiphoton ionization techniques. The H-atom photofragment yield spectra of the n-propyl and i-propyl radicals are broad and in good agreement with the UV absorption spectra. The H + propene product translational energy distributions, P(E{sub T})’s, of both n-propyl and i-propyl are bimodal, with a slow component peaking around 5-6 kcal/mol and a fast one peaking at ∼50 kcal/mol (n-propyl) and ∼45 kcal/mol (i-propyl). The fraction of the average translational energy in the total excess energy, 〈f{sub T}〉, is 0.3 for n-propyl and 0.2 for i-propyl, respectively. The H-atom product angular distributions of the slow components of n-propyl and i-propyl are isotropic, while that of the fast component of n-propyl is anisotropic (with an anisotropy parameter ∼0.8) and that of i-propyl is nearly isotropic. Site-selective loss of the β hydrogen atom is confirmed using the partially deuterated CH{sub 3}CH{sub 2}CD{sub 2} and CH{sub 3}CDCH{sub 3} radicals. The bimodal translational energy and angular distributions indicate two dissociation pathways to the H + propene products in the n-propyl and i-propyl radicals: (i) a unimolecular dissociation pathway from the hot ground-state propyl after internal conversion from the 3s and 3p Rydberg states and (ii) a direct, prompt dissociation pathway coupling the Rydberg excited states to a repulsive part of the ground-state surface, presumably via a conical intersection.

  1. Ultraviolet photodissociation dynamics of the n-propyl and i-propyl radicals

    NASA Astrophysics Data System (ADS)

    Song, Yu; Zheng, Xianfeng; Zhou, Weidong; Lucas, Michael; Zhang, Jingsong

    2015-06-01

    Ultraviolet (UV) photodissociation dynamics of jet-cooled n-propyl (n-C3H7) radical via the 3s Rydberg state and i-propyl (i-C3H7) radical via the 3p Rydberg states are studied in the photolysis wavelength region of 230-260 nm using high-n Rydberg atom time-of-flight and resonance enhanced multiphoton ionization techniques. The H-atom photofragment yield spectra of the n-propyl and i-propyl radicals are broad and in good agreement with the UV absorption spectra. The H + propene product translational energy distributions, P(ET)'s, of both n-propyl and i-propyl are bimodal, with a slow component peaking around 5-6 kcal/mol and a fast one peaking at ˜50 kcal/mol (n-propyl) and ˜45 kcal/mol (i-propyl). The fraction of the average translational energy in the total excess energy, , is 0.3 for n-propyl and 0.2 for i-propyl, respectively. The H-atom product angular distributions of the slow components of n-propyl and i-propyl are isotropic, while that of the fast component of n-propyl is anisotropic (with an anisotropy parameter ˜0.8) and that of i-propyl is nearly isotropic. Site-selective loss of the β hydrogen atom is confirmed using the partially deuterated CH3CH2CD2 and CH3CDCH3 radicals. The bimodal translational energy and angular distributions indicate two dissociation pathways to the H + propene products in the n-propyl and i-propyl radicals: (i) a unimolecular dissociation pathway from the hot ground-state propyl after internal conversion from the 3s and 3p Rydberg states and (ii) a direct, prompt dissociation pathway coupling the Rydberg excited states to a repulsive part of the ground-state surface, presumably via a conical intersection.

  2. Ultraviolet photodissociation dynamics of the n-propyl and i-propyl radicals.

    PubMed

    Song, Yu; Zheng, Xianfeng; Zhou, Weidong; Lucas, Michael; Zhang, Jingsong

    2015-06-14

    Ultraviolet (UV) photodissociation dynamics of jet-cooled n-propyl (n-C3H7) radical via the 3s Rydberg state and i-propyl (i-C3H7) radical via the 3p Rydberg states are studied in the photolysis wavelength region of 230-260 nm using high-n Rydberg atom time-of-flight and resonance enhanced multiphoton ionization techniques. The H-atom photofragment yield spectra of the n-propyl and i-propyl radicals are broad and in good agreement with the UV absorption spectra. The H + propene product translational energy distributions, P(E(T))'s, of both n-propyl and i-propyl are bimodal, with a slow component peaking around 5-6 kcal/mol and a fast one peaking at ∼50 kcal/mol (n-propyl) and ∼45 kcal/mol (i-propyl). The fraction of the average translational energy in the total excess energy, 〈f(T)〉, is 0.3 for n-propyl and 0.2 for i-propyl, respectively. The H-atom product angular distributions of the slow components of n-propyl and i-propyl are isotropic, while that of the fast component of n-propyl is anisotropic (with an anisotropy parameter ∼0.8) and that of i-propyl is nearly isotropic. Site-selective loss of the β hydrogen atom is confirmed using the partially deuterated CH3CH2CD2 and CH3CDCH3 radicals. The bimodal translational energy and angular distributions indicate two dissociation pathways to the H + propene products in the n-propyl and i-propyl radicals: (i) a unimolecular dissociation pathway from the hot ground-state propyl after internal conversion from the 3s and 3p Rydberg states and (ii) a direct, prompt dissociation pathway coupling the Rydberg excited states to a repulsive part of the ground-state surface, presumably via a conical intersection.

  3. SWELLING OF PEATS IN LIQUID METHYL, TETRAMETHYLENE AND PROPYL SULFOXIDES AND IN LIQUID PROPYL SULFONE

    EPA Science Inventory

    The interactions of methyl, tetramethylene, and propyl sulfoxides and propyl sulfone during sorption onto four de-waxed, acid-form peats have been studied by means of swelling measurements. The results for sulfoxides are displayed as het-eromolecular sorption isotherms, which plo...

  4. Modulation of mitochondrial Ca2+ uptake by estrogen receptor agonists and antagonists

    PubMed Central

    Lobatón, Carmen D; Vay, Laura; Hernández-SanMiguel, Esther; SantoDomingo, Jaime; Moreno, Alfredo; Montero, Mayte; Alvarez, Javier

    2005-01-01

    Ca2+ uptake by mitochondria is a key element in the control of cellular Ca2+ homeostasis and Ca2+-dependent phenomena. It has been known for many years that this Ca2+ uptake is mediated by the mitochondrial Ca2+ uniporter, a specific Ca2+ channel of the inner mitochondrial membrane. We have shown previously that this channel is strongly activated by a series of natural phytoestrogenic flavonoids. We show here that several agonists and antagonists of estrogen receptors (ERs) also modulate the activity of the uniporter. The specific α-ER agonist 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) was the strongest activator, increasing the rate of mitochondrial Ca2+ uptake in permeabilized HeLa cells by 10-fold at 2 μM. Consistently, PPT largely increased the histamine-induced mitochondrial [Ca2+] peak and reduced the cytosolic one. Diethylstilbestrol and 17-β-estradiol (but not 17-α-estradiol) were active at pharmacological concentrations while the β-estrogen-receptor agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) was little effective. The ER modulators tamoxifen and 4-hydroxy-tamoxifen inhibited mitochondrial Ca2+ uptake (IC50 2.5±1.5 and 2.5±1.4 μM, mean±s.d., respectively) both in the presence and in the absence of PPT, but raloxifene and the pure estrogen antagonist ICI 182,780 produced no effect. Activation by PPT was immediate and inhibition by tamoxifen or 4-hydroxy-tamoxifen required only 5 min to reach maximum. Tamoxifen did not modify mitochondrial membrane potential and PPT induced a slow mitochondrial depolarization at higher concentrations than those required to activate mitochondrial Ca2+ uptake. These results suggest that some kind of ER or related protein located in mitochondria controls the activity of the Ca2+ uniporter by a nongenomic mechanism. This novel mechanism of action of estrogen agonists and antagonists can provide a new interpretation for several previously reported effects of these compounds. PMID

  5. Modulation of mitochondrial Ca(2+) uptake by estrogen receptor agonists and antagonists.

    PubMed

    Lobatón, Carmen D; Vay, Laura; Hernández-Sanmiguel, Esther; Santodomingo, Jaime; Moreno, Alfredo; Montero, Mayte; Alvarez, Javier

    2005-08-01

    Ca(2+) uptake by mitochondria is a key element in the control of cellular Ca(2+) homeostasis and Ca(2+)-dependent phenomena. It has been known for many years that this Ca(2+) uptake is mediated by the mitochondrial Ca(2+) uniporter, a specific Ca(2+) channel of the inner mitochondrial membrane. We have shown previously that this channel is strongly activated by a series of natural phytoestrogenic flavonoids. We show here that several agonists and antagonists of estrogen receptors (ERs) also modulate the activity of the uniporter. The specific alpha-ER agonist 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) was the strongest activator, increasing the rate of mitochondrial Ca(2+) uptake in permeabilized HeLa cells by 10-fold at 2 microM. Consistently, PPT largely increased the histamine-induced mitochondrial [Ca(2+)] peak and reduced the cytosolic one. Diethylstilbestrol and 17-beta-estradiol (but not 17-alpha-estradiol) were active at pharmacological concentrations while the beta-estrogen-receptor agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) was little effective. The ER modulators tamoxifen and 4-hydroxy-tamoxifen inhibited mitochondrial Ca(2+) uptake (IC(50) 2.5+/-1.5 and 2.5+/-1.4 microM, mean+/-s.d., respectively) both in the presence and in the absence of PPT, but raloxifene and the pure estrogen antagonist ICI 182,780 produced no effect. Activation by PPT was immediate and inhibition by tamoxifen or 4-hydroxy-tamoxifen required only 5 min to reach maximum. Tamoxifen did not modify mitochondrial membrane potential and PPT induced a slow mitochondrial depolarization at higher concentrations than those required to activate mitochondrial Ca(2+) uptake. These results suggest that some kind of ER or related protein located in mitochondria controls the activity of the Ca(2+) uniporter by a nongenomic mechanism. This novel mechanism of action of estrogen agonists and antagonists can provide a new interpretation for several previously reported

  6. The first X-ray crystal structure of the glucocorticoid receptor bound to a non-steroidal agonist

    SciTech Connect

    Madauss, Kevin P.; Bledsoe, Randy K.; Mclay, Iain; Stewart, Eugene L.; Uings, Iain J.; Weingarten, Gordon; Williams, Shawn P.

    2009-07-23

    The amino-pyrazole 2,6-dichloro-N-ethyl benzamide 1 is a selective GR agonist with dexamethasone-like in vitro potency. Its X-ray crystal structure in the GR LBD (Glucocorticoid ligand-binding domain) is described and compared to other reported structures of steroidal GR agonists in the GR LBD (3E7C).

  7. MiR-7-1 potentiated estrogen receptor agonists for functional neuroprotection in VSC4.1 motoneurons.

    PubMed

    Chakrabarti, M; Banik, N L; Ray, S K

    2014-01-03

    Protection of motoneurons is an important goal in the treatment of spinal cord injury (SCI). We tested whether neuroprotective microRNAs (miRs) like miR-206, miR-17, miR-21, miR-7-1, and miR-106a could enhance efficacy of estrogen receptor (ER) agonists such as 1,3,5-tris (4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT, ERα agonist), Way200070 (WAY, ERβ agonist), and estrogen (EST, ERα and ERβ agonist) in preventing apoptosis in the calcium ionophore (CI)-insulted ventral spinal cord 4.1 (VSC4.1) motoneurons. We determined that 200 nM CI induced 70% cell death. Treatment with 50 nM PPT, 100 nM WAY, and 150 nM EST induced overexpression of ERα, ERβ, and both receptors, respectively, at mRNA and protein levels. Treatment with ER agonists significantly upregulated miR-206, miR-17, and miR-7-1 in the CI-insulted VSC4.1 motoneurons. Transfection with miR-206, miR-17, or miR-7-1 mimic potentiated WAY or EST to inhibit apoptosis in the CI-insulted VSC4.1 motoneurons. Overexpression of miR-7-1 maximally increased efficacy of WAY and EST for down regulation of pro-apoptotic Bax and upregulation of anti-apoptotic Bcl-2. A search using microRNA database (miRDB) indicated that miR-7-1 could inhibit the expression of L-type Ca(2+) channel protein alpha 1C (CPα1C). miR-7-1 overexpression and WAY or EST treatment down regulated CPα1C but upregulated p-Akt to trigger cell survival signaling. The same therapeutic strategy increased expression of the Ca(2+)/calmodulin-dependent protein kinase II beta (CaMKIIβ) and the phosphorylated cAMP response element binding protein (p-CREB) so as to promote Bcl-2 transcription. Whole cell membrane potential and mitochondrial membrane potential studies indicated that miR-7-1 highly potentiated EST to preserve functionality in the CI-insulted VSC4.1 motoneurons. In conclusion, our data indicated that miR-7-1 most significantly potentiated efficacy of EST for functional neuroprotection and this therapeutic strategy could be used in the future

  8. 21 CFR 573.880 - Normal propyl alcohol.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Normal propyl alcohol. 573.880 Section 573.880 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Additive Listing § 573.880 Normal propyl alcohol. Normal propyl alcohol may be safely used in feeds...

  9. 21 CFR 573.880 - Normal propyl alcohol.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Normal propyl alcohol. 573.880 Section 573.880 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Additive Listing § 573.880 Normal propyl alcohol. Normal propyl alcohol may be safely used in feeds...

  10. 21 CFR 573.880 - Normal propyl alcohol.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Normal propyl alcohol. 573.880 Section 573.880 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Additive Listing § 573.880 Normal propyl alcohol. Normal propyl alcohol may be safely used in feeds...

  11. 21 CFR 573.880 - Normal propyl alcohol.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Normal propyl alcohol. 573.880 Section 573.880 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Additive Listing § 573.880 Normal propyl alcohol. Normal propyl alcohol may be safely used in feeds...

  12. 21 CFR 573.880 - Normal propyl alcohol.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Normal propyl alcohol. 573.880 Section 573.880 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Additive Listing § 573.880 Normal propyl alcohol. Normal propyl alcohol may be safely used in feeds...

  13. Chemical consequences of pyrazole orientation in Ru(II) complexes of unsymmetric quinoline-pyrazole ligands.

    PubMed

    Hedberg Wallenstein, Joachim; Fredin, Lisa A; Jarenmark, Martin; Abrahamsson, Maria; Persson, Petter

    2016-08-07

    A series of homoleptic Ru(II) complexes including the tris-bidentate complexes of a new bidentate ligand 8-(1-pyrazol)-quinoline (Q1Pz) and bidentate 8-(3-pyrazol)-quinoline (Q3PzH), as well as the bis-tridentate complex of bis(quinolinyl)-1,3-pyrazole (DQPz) was studied. Together these complexes explore the orientation of the pyrazole relative to the quinoline. By examining the complexes structurally, photophysically, photochemically, electrochemically, and computationally by DFT and TD-DFT, it is shown that the pyrazole orientation has a significant influence on key properties. In particular, its orientation has noticeable effects on oxidation and reduction potentials, photostability and proton sensitivity, indicating that [Ru(Q3PzH)3](2+) is a particularly good local environment acidity-probe candidate.

  14. Current status of pyrazole and its biological activities

    PubMed Central

    Naim, Mohd Javed; Alam, Ozair; Nawaz, Farah; Alam, Md. Jahangir; Alam, Perwaiz

    2016-01-01

    Pyrazole are potent medicinal scaffolds and exhibit a full spectrum of biological activities. This review throws light on the detailed synthetic approaches which have been applied for the synthesis of pyrazole. This has been followed by an in depth analysis of the pyrazole with respect to their medical significance. This follow-up may help the medicinal chemists to generate new leads possessing pyrazole nucleus with high efficacy. PMID:26957862

  15. Current status of pyrazole and its biological activities.

    PubMed

    Naim, Mohd Javed; Alam, Ozair; Nawaz, Farah; Alam, Md Jahangir; Alam, Perwaiz

    2016-01-01

    Pyrazole are potent medicinal scaffolds and exhibit a full spectrum of biological activities. This review throws light on the detailed synthetic approaches which have been applied for the synthesis of pyrazole. This has been followed by an in depth analysis of the pyrazole with respect to their medical significance. This follow-up may help the medicinal chemists to generate new leads possessing pyrazole nucleus with high efficacy.

  16. Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.

    PubMed

    Sams, Anette G; Hentzer, Morten; Mikkelsen, Gitte K; Larsen, Krestian; Bundgaard, Christoffer; Plath, Niels; Christoffersen, Claus T; Bang-Andersen, Benny

    2010-09-09

    The discovery and structure-activity relationship (SAR) of a series of allosteric muscarinic M(1) receptor agonists are described. Compound 17 (Lu AE51090) was identified as a representative compound from the series, based on its high selectivity as an agonist at the muscarinic M(1) receptor across a panel of muscarinic receptor subtypes. Furthermore, 17 displayed a high degree of selectivity when tested in a broad panel of G-protein-coupled receptors, ion channels, transporters, and enzymes, and 17 showed an acceptable pharmacokinetic profile and sufficient brain exposure in rodents in order to characterize the compound in vivo. Hence, in a rodent model of learning and memory, 17 reversed delay-induced natural forgetting, suggesting a procognitive potential of 17.

  17. Novel pyrazole derivatives as neutral CB₁ antagonists with significant activity towards food intake.

    PubMed

    Manca, Ilaria; Mastinu, Andrea; Olimpieri, Francesca; Falzoi, Matteo; Sani, Monica; Ruiu, Stefania; Loriga, Giovanni; Volonterio, Alessandro; Tambaro, Simone; Bottazzi, Mirko Emilio Heiner; Zanda, Matteo; Pinna, Gérard Aimè; Lazzari, Paolo

    2013-04-01

    In spite of rimonabant's withdrawal from the European market due to its adverse effects, interest in the development of drugs based on CB1 antagonists is revamping on the basis of the peculiar properties of this class of compounds. In particular, new strategies have been proposed for the treatment of obesity and/or related risk factors through CB1 antagonists, i.e. by the development of selectively peripherally acting agents or by the identification of neutral CB1 antagonists. New compounds based on the lead CB1 antagonist/inverse agonist rimonabant have been synthesized with focus on obtaining neutral CB1 antagonists. Amongst the new derivatives described in this paper, the mixture of the two enantiomers (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-(2-cyclohexyl-1-hydroxyethyl)-4-methyl-1H-pyrazole ((±)-5), and compound 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-[(Z)-2-cyclohexyl-1-fluorovinyl]-4-methyl-1H-pyrazole ((Z)-6), showed interesting pharmacological profiles. According to the preliminary pharmacological evaluation, these novel pyrazole derivatives showed in fact both neutral CB1 antagonism behaviour and significant in vivo activity towards food intake.

  18. Therapeutic outlook of pyrazole analogs: A mini review.

    PubMed

    Ganguly, Swastika; Sony Jacob, K

    2015-11-19

    Pyrazole is one of the excellent structural motifs in medicinal chemistry. Various physiological and therapeutic possibilities have been exploited by incorporating different pharmacophoric groups in the pyrazole moiety. This has opened a new arena of pyrazole analogs that can be developed into medicinal agents such as anti-inflammatory, analgesic, antipyretic, antiviral, antibacterial, anticancer, anticonvulsant, hypoglycemic, carbonic anhydrase inhibitors, mono amino oxidase (MAO) inhibitors, etc. Though, pyrazole analogs have proven their clinical efficacy as different pharmacological agents, a few of them have been withdrawn from the market due to their side effects. Thus, research on potential new drug candidates bearing the pyrazole moiety with lesser side effects has fairly increased over the last few years. This review explores diverse pharmacological activities exhibited by pyrazole analogs reported recently, which may be of great help for researchers in the area of drug discovery to understand the current scenario of pyrazole based compounds and to design and develop newer drug candidates with improved efficacy.

  19. The antiangiogenic and antinociceptive activities of n-propyl gallate.

    PubMed

    Jung, H-J; Lim, C-J

    2011-10-01

    n-Propyl gallate dose-dependently displayed an inhibitory effect on chick chorioallantoic membrane (CAM) angiogenesis. It markedly increased the endostatin level in both isolated CAM tissues and human umbilical vein endothelial cells (HUVECs). n-Propyl gallate was also able to enhance the endostatin mRNA level in HUVECs. Antinociceptive activity of n-propyl gallate was assessed using an acetic acid-induced writhing test in mice. In brief, n-propyl gallate possesses antiangiogenic activity via up-regulation of endostatin.

  20. Synthesis and antifungal activity of the derivatives of novel pyrazole carboxamide and isoxazolol pyrazole carboxylate.

    PubMed

    Sun, Jialong; Zhou, Yuanming

    2015-03-09

    A series of pyrazole carboxamide and isoxazolol pyrazole carboxylate derivatives were designed and synthesized in this study. The structures of the compounds were elucidated based on spectral data (infrared, proton nuclear magnetic resonance and mass spectroscopy). Then, all of the compounds were bioassayed in vitro against four types of phytopathogenic fungi (Alternaria porri, Marssonina coronaria, Cercospora petroselini and Rhizoctonia solani) using the mycelium growth inhibition method. The results showed that some of the synthesized pyrazole carboxamides displayed notable antifungal activity. The isoxazole pyrazole carboxylate 7ai exhibited significant antifungal activity against R. solani, with an EC50 value of 0.37 μg/mL. Nonetheless, this value was lower than that of the commercial fungicide, carbendazol.

  1. Interaction of D₃ preferring agonist (-)-N⁶-(2-(4-(biphenyl-4-yl)piperazin-1-yl)ethyl)-N⁶-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (D-264) with cloned human D₂L, D₂S, and D₃ receptors: potent stimulation of mitogen-activated protein kinases and G protein-coupled inward rectifier potassium channels.

    PubMed

    Kuzhikandathil, Eldo V; Cote, Samantha; Santra, Soumava; Dutta, Aloke K

    2013-02-01

    This study aims to determine the effect of the novel D(3) dopamine receptor agonist, D-264, on activation of D(3) and D(2) dopamine receptor signal transduction pathways and cell proliferation. AtT-20 neuroendocrine cells stably expressing human D(2S), D(2L), and D(3) dopamine receptors were treated with D-264 and the coupling of the receptors to mitogen-activated protein kinase (MAPK) and G protein-coupled inward rectifier potassium (GIRK) channels was determined using Western blotting and whole-cell voltage clamp recording, respectively. D-264 potently activated MAPK signaling pathway coupled to D(2S), D(2L), and D(3) dopamine receptors. The activation of MAPK was more pronounced than the reference agonist quinpirole and was longer lasting. D-264 also activated GIRK channels coupled to D(2S), D(2L), and D(3) receptors. In addition, D-264 dose-dependently induced cell proliferation in AtT-D(2L) and AtT-D(3) cells. These results indicate that D-264 robustly activates GIRK channels and MAPK coupled to D(2) and D(3) dopamine receptors in AtT-20 cells. D-264 is also a potent inducer of cell proliferation.

  2. Discovery of 4-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)-ethyl)piperazin-1-yl)quinolin-8-ol and its analogues as highly potent dopamine D2/D3 agonists and as iron chelator: In vivo activity indicates potential application in symptomatic and neuroprotective therapy for Parkinson’s Disease

    PubMed Central

    Ghosh, Balaram; Antonio, Tamara; Reith, Maarten E. A.; Dutta, Aloke K.

    2010-01-01

    The role of iron in the pathogenesis of Parkinson’s disease (PD) has been implicated strongly due to generation of oxidative stress leading to dopamine cell death. In our overall goal to develop bifunctional/multifunctional drugs, we designed dopamine D2/D3 agonist molecules with a capacity to bind to iron. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors with tritiated spiperone to evaluate inhibition constants (Ki). Functional activity of selected compounds was carried out with GTPγS binding assay. SAR results identified compounds (+)-19a and (−)-19b as two potent agonists for both D2 and D3 receptors (EC50 (GTPγS); D2 = 4.51 and 1.69 nM and D3 = 1.58 and 0.74 nM for (−)-19b and (+)-19a, respectively). In vitro complexation studies with 19b demonstrated efficient chelation with iron. Furthermore, the deoxyribose assay with 19b demonstrated potent antioxidant activity. In PD animal model study, (−)-19b exhibited potent in vivo activity in reversing locomotor activity in reserpinized rats and also in producing potent rotational activity in 6-OHDA lesioned rats. This reports initial development of unique lead molecules which might find potential use in symptomatic and neuroprotective treatment of PD. PMID:20146482

  3. Final report on the amended safety assessment of Propyl Gallate.

    PubMed

    2007-01-01

    Propyl Gallate is the n-propyl ester of gallic acid (3,4,5-trihydroxybenzoic acid). It is soluble in ethanol, ethyl ether, oil, lard, and aqueous solutions of polyethylene glycol (PEG) ethers of cetyl alcohol, but only slightly soluble in water. Propyl Gallate currently is used as an antioxidant in a reported 167 cosmetic products at maximum concentrations of 0.1%. Propyl Gallate is a generally recognized as safe (GRAS) antioxidant to protect fats, oils, and fat-containing food from rancidity that results from the formation of peroxides. Data on dermal absorption are not available, but Propyl Gallate is absorbed when ingested, then methylated, conjugated, and excreted in the urine. The biological activity of Propyl Gallate is consistent with its free-radical scavenging ability, with effects that include antimicrobial activity, enzyme inhibition, inhibition of biosynthetic processes, inhibition of the formation of nitrosamines, anesthesia, inhibition of neuromuscular response to chemicals, ionizing/ultraviolet (UV) radiation protection, chemoprotection, antimutagenesis, anticarcinogenesis and antitumorigenesis, antiteratogenesis, and anticariogenesis. Animal toxicity studies indicate that Propyl Gallate was slightly toxic when ingested, but no systemic effects were noted with dermal application. Propyl Gallate is a strong sensitizer when tested intradermally, less sensitizing when tested topically, and nonsensitizing topically at 0.1% in one study. In a second study, Propyl Gallate (15 mg dissolved in 8 ml vehicle) was sensitizing to guinea pigs. Acute eye irritation tests conducted on nine cosmetic formulations, each containing less than 1% Propyl Gallate, were negative. A phototoxicity study conducted on a cosmetic formulation containing 0.003% Propyl Gallate determined that the product was not phototoxic to guinea pigs. In one study, female rats fed 0.5 g Propyl Gallate had substantially increased fetal resorption rates when compared to controls, but in four

  4. Pyrazole derivatives as antitumor, anti-inflammatory and antibacterial agents.

    PubMed

    Liu, Jia-Jia; Zhao, Meng-Yue; Zhang, Xin; Zhao, Xin; Zhu, Hai-Liang

    2013-11-01

    Within the past years, many researches on the synthesis, structure-activity relationships (SAR), antitumor, antiinflammatory and anti-bacterial activities of the pyrazole derivatives have been reported. Several pyrazole derivatives possess important pharmacological activities and they have been proved useful materials in drug research. Pyrazole derivatives play an important role in antitumor agents because of their good inhibitory activity against BRAF(V600E), EGFR, telomerase, ROS Receptor Tyrosine Kinase and Aurora-A kinase. In addition, pyrazole derivatives also show good antiinflammatory and anti-bacterial activities. In this review, the bioactivities of the pyrazole derivatives mentioned above will be summarized in detail. We sincerely hope that increasing knowledge of the SAR and cellular processes underlying the bioactivity of pyrazole derivatives will be beneficial to the rational design of new generation of small molecule drugs.

  5. Propargyl hydrazides: synthesis and conversion into pyrazoles through hydroamination.

    PubMed

    Yoshimatsu, Mitsuhiro; Ohta, Katsuki; Takahashi, Nami

    2012-12-03

    Pyrazoles direct: propargyl alcohols undergo hydrazination when treated with p-tosyl hydrazide in the presence of catalytic amounts of either Sc(OTf)(3) or La(OTf)(3) (see scheme; Tf=trifluoromethanesulfonyl). Propargyl hydrazides are converted into either N-tosyl or N-H pyrazoles when treated with an acid or a base, respectively. The one-step acid-catalyzed hydrazination/cyclization of propargyl alcohols directly affords pyrazoles in high yields.

  6. Development of (S)-N6-(2-(4-(Isoquinolin-1-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]-thiazole-2,6-diamine and its analogue as a D3 receptor preferring agonist: Potent in vivo activity in Parkinson’s disease animal models

    PubMed Central

    Ghosh, Balaram; Antonio, Tamara; Zhen, Juan; Kharkar, Prashant; Reith, Maarten E. A.; Dutta, Aloke K.

    2010-01-01

    Here we report structure-activity relationship study of a novel hybrid series of compounds where structural alteration of aromatic hydrophobic moieties connected to the piperazine ring and bioisosteric replacement of the aromatic tetralin moieties were carried out. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors with tritiated spiperone to evaluate inhibition constants (Ki). Functional activity of selected compounds in stimulating GTPγS binding was assessed with CHO cells expressing human D2 receptors and AtT-20 cells expressing human D3 receptors. SAR results identified compound (−)-24c (D-301) as one of the lead molecules with preferential agonist activity for D3 receptor (EC50 (GTPγS); D3 = 0.52 nM; D2/D3 (EC50): 223). Compounds (−)-24b and (−)-24c exhibited potent radical scavenging activity. The two lead compounds (−)-24b and (−)-24c exhibited high in vivo activity in two Parkinson’s disease (PD) animal models, reserpinized rat model and 6-OH-DA induced unilaterally lesioned rat model. Future studies will explore potential use of these compounds in the neuroprotective therapy for PD. PMID:20038106

  7. Purification of the pyrazole-inducible cytochrome P-450 isozyme

    SciTech Connect

    Palakodety, R.; Clejan, L.; Krikun, G.; Feierman, D.; Cederbaum, A.I.

    1987-05-01

    The alcohol dehydrogenase inhibitor, pyrazole, appears to induce a cytochrome P-450 isozyme with properties similar to the ethanol-inducible P-450. The pyrazole-inducible P-450 isozyme was purified from the liver microsomes of rats treated with pyrazole essentially by the procedure of Ryan et al and also by chromatofocussing. The final preparation appeared homogenous by SDS-PAGE with an apparent molecular weight of 52,000, had a specific content of 11 nmoles P-450 per mg protein, showed very high activity of low K/sub m/ dimethylnitrosamine demethylase and produced a type II binding spectrum with dimethylsulfoxide. The enzyme was also active with aniline and aminopyrine as substrates. Pyrazole itself served as an excellent substrate with 4-hydroxy pyrazole being the product. An antibody against the pyrazole-inducible P-450 raised in chickens recognized a protein with mol.wt of about 52,000 in control microsomes. This band was highly enriched in microsomes from rats treated with pyrazole, 4-methyl-pyrazole, ethanol or acetone, but not phenobarbital or 3-methylcholanthrene. In summary, the pyrazole-inducible P-450 has been purified and appears to be identical in its catalytic and immunological properties to the alcohol-inducible P-450.

  8. Pyrazole complexes as anion receptors: effects of changing the metal, the pyrazole substitution pattern, and the number of pyrazole ligands.

    PubMed

    Nieto, Sonia; Pérez, Julio; Riera, Lucía; Riera, Víctor; Miguel, Daniel; Golen, James A; Rheingold, Arnold L

    2007-04-16

    Compound cis,fac-[Mo(eta3-allyl)(CO)2(Hdmpz)3]BAr'4 (1) (Hdmpz = 3,5-dimethylpyrazole, Ar' = 3,5-bis(trifluoromethyl)phenyl) undergoes rapid substitution of one of the pyrazole ligands by anions, including the low nucleophilic ReO4-, a reaction that afforded [Mo(OReO3)(eta3-allyl)(CO)2(Hdmpz)2] (2), structurally characterized by X-ray diffraction. The new compounds fac-[Mn(CO)3(Hdmpz)3]BAr'4 (4a) and fac-[Mn(CO)3(HtBupz)3]BAr'4 (4b) (HtBupz = 3(5)-tert-butylpyrazole) also undergo pyrazole substitution with most anions, and the product from the reaction with nitrate was crystallographically characterized. Compounds 4a,b were found to be substitutionally stable toward perrhenate, and the adducts [Mn(CO)3(Hdmpz)3].[ReO4] (7a) and [Mn(CO)3(HtBupz)3].[ReO4].[Bu4N].[BAr'4] (7b), crystallographically characterized, display hydrogen bonds between one of the perrhenate oxygens and the N-H groups of two of the pyrazole ligands. The structurally similar adduct [Re(CO)3(Hdmpz)3].[ReO4] (8) was found to result from the interaction of [Re(CO)3(Hdmpz)3]BAr'4 with perrhenate. The reaction of [Re(OTf)(CO)5] with 3,5-dimethylpyrazole (Hdmpz) afforded [Re(CO)5(Hdmpz)]OTf (9). The reaction of 9 with Hdmpz and NaBAr'4 yielded [Re(CO)4(Hdmpz)2]BAr'4 (10), which was found to be unstable toward chloride anion. In contrast, the new compound fac,cis-[Re(CO)3(CNtBu)(Hdmpz)2]BAr'4 (11) is stable in solution in the presence of different anions. Binding constants for 11 with chloride, bromide, and nitrate are 1-2 orders of magnitude lower than those found for these anions and rhenium tris(pyrazole) hosts, indicating that the presence of the third pyrazole ligand is crucial. Compounds fac-[Re(CO)3(HPhpz)3]BAr'4 (14) (HPhpz = 3(5)-phenylpyrazole) and fac-[Re(CO)3(HIndz)3]BAr'4 (15) (HIndz = indazole) are, in terms of anion binding strength and selectivity, inferior to those with dimethylpyrazole or tert-butylpyrazole ligands.

  9. Preparation and Investigation of Monodentate and Bridging Pyrazole Complexes

    ERIC Educational Resources Information Center

    Evans, Wynne

    2004-01-01

    Complexes of pyrazole-derived ligands are very popular due to the ability of the pyrazolato anion to form bridged polymetallic compounds in which the metals are held close enough to react with small molecules or facilitate magnetic exchange. The preparation of monodentate pyrazole and 3,5-dimethylpyrazole (DMHpz) nickel species and the…

  10. H-Atom Elimination Channel in UV Photodissociation of N-Propyl and Iso-Propyl Radicals: the Role of Conical Intersections

    NASA Astrophysics Data System (ADS)

    Zheng, Xianfeng; Zhou, Weidong; Song, Yu; Zhang, Jingsong

    2009-06-01

    The H-atom elimination channels in the UV photodissociation of jet-cooled n-propyl and iso-propyl radicals are studied in the region of 237 nm using the high-n Rydberg-atom time-of-flight technique. Upon excitation to the 3p state by the UV photolysis radiation, n-propyl radical and iso-propyl radical dissociate into the H atom and propene products. The product center-of-mass translational energy release of both n-propyl and iso-propyl radicals have bimodal distributions. The H-atom product angular distribution in n-propyl is anisotropic (with beta ˜0.5), and that in iso-propyl is isotropic. The overall average translational energy release is E_{trans} ˜0.27E_{avail} for n-propyl and E_{trans} ˜0.21E_{avail} for iso-propyl. The bimodal translational energy distributions indicate two dissociation pathways: (i) a unimolecular dissociation pathway from the ground-state propyl after internal conversion from the 3p state, and (ii) a repulsive pathway directly connected with the excited state of the propyl radical. Isotope labeling experiments have also been carried out. The possible photodissociation mechanisms and the role of conical intersections will be discussed.

  11. Identification of Trisubstituted-pyrazol Carboxamide Analogs as Novel and Potent Antagonists of Farnesoid X Receptor

    PubMed Central

    Yu, Donna D.; Lin, Wenwei; Forman, Barry M.; Chen, Taosheng

    2014-01-01

    Farnesoid X receptor (FXR, NRIH4) plays a major role in the control of cholesterol metabolism. This suggests that antagonizing the transcriptional activity of FXR is a potential means to treat cholestasis and related metabolic disorders. Here we describe the synthesis, biological evaluation, and structure-activity relationship (SAR) studies of trisubstituted-pyrazol carboxamides as novel and potent FXR antagonists. One of these novel FXR antagonists, 4j has an IC50 of 7.5 nM in an FXR binding assay and 468.5 nM in a cell-based FXR antagonistic assay. Compound 4j has no detectable FXR agonistic activity or cytotoxicity. Notably, 4j is the most potent FXR antagonist identified to date; it has a promising in vitro profile and could serve as an excellent chemical tool to elucidate the biological function of FXR. PMID:24775917

  12. Pyrazole antagonists of the CB1 receptor with reduced brain penetration.

    PubMed

    Fulp, Alan; Zhang, Yanan; Bortoff, Katherine; Seltzman, Herbert; Snyder, Rodney; Wiethe, Robert; Amato, George; Maitra, Rangan

    2016-03-01

    Type 1 cannabinoid receptor (CB1) antagonists might be useful for treating obesity, liver disease, metabolic syndrome, and dyslipidemias. Unfortunately, inhibition of CB1 in the central nervous system (CNS) produces adverse effects, including depression, anxiety and suicidal ideation in some patients, which led to withdrawal of the pyrazole inverse agonist rimonabant (SR141716A) from European markets. Efforts are underway to produce peripherally selective CB1 antagonists to circumvent CNS-associated adverse effects. In this study, novel analogs of rimonabant (1) were explored in which the 1-aminopiperidine group was switched to a 4-aminopiperidine, attached at the 4-amino position (5). The piperidine nitrogen was functionalized with carbamates, amides, and sulfonamides, providing compounds that are potent inverse agonists of hCB1 with good selectivity for hCB1 over hCB2. Select compounds were further studied using in vitro models of brain penetration, oral absorption and metabolic stability. Several compounds were identified with predicted minimal brain penetration and good metabolic stability. In vivo pharmacokinetic testing revealed that inverse agonist 8c is orally bioavailable and has vastly reduced brain penetration compared to rimonabant.

  13. Novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives: synthesis and anticancer activity.

    PubMed

    Shi, Jing Bo; Tang, Wen Jian; Qi, Xing Bao; Li, Rong; Liu, Xin Hua

    2015-01-27

    A series of novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives were designed and synthesized. All compounds have been screened for their antiproliferative activity against MGC-803, SGC-7901 and Bcap-37 cell lines in vitro. The results revealed that compounds 8a, 8c and 8e exhibited strong inhibitory activity against MGC-803 cell line. The flow cytometric analysis result showed that compound 8e could inhibit MGC-803 proliferation. Some title compounds were tested against telomerase, and compound 8e showed the most potent inhibitory activity with IC50 value at 1.02 ± 0.08 μM. The docking simulation of compound 8e was performed to get the probable binding model, among them, LYS 189, LYS 372, LYS 249 and ASP 254 may be the key residues for the telomerase activity.

  14. The therapeutic voyage of pyrazole and its analogs: A review.

    PubMed

    Khan, Mohemmed Faraz; Alam, Mohammad Mumtaz; Verma, Garima; Akhtar, Wasim; Akhter, Mymoona; Shaquiquzzaman, Mohammad

    2016-09-14

    Pyrazole, a five membered heteroaromatic ring with two nitrogen atoms is of immense significance. Presence of this nucleus in the pharmacological agents of diverse therapeutic categories viz. antianxiety, anti-inflammatory, antipsychotic, anticancer, antiobesity, analgesic, antipyretic etc. has made it an indispensable anchor for design and development of new pharmacological agents. Owing to the development of novel and new pyrazole based therapeutic agents at a faster pace, there is a need to couple the latest information with previously available information to understand status of this moiety in medicinal chemistry research. The review herein highlights the therapeutic worth of pyrazole derivatives. Several therapeutically active pyrazole based derivatives developed by numerous scientists across the globe are reported here.

  15. New pyrazolic compounds as cytotoxic agents.

    PubMed

    Bouabdallah, Ibrahim; M'Barek, Lahcen Ait; Zyad, Abdelmajid; Ramdani, Abdelkrim; Zidane, Ismail; Melhaoui, Ahmed

    2007-04-01

    The evaluation of the in vitro cytotoxic properties of two pyrazole compounds: 1-(4-nitrophényl)-3,5-diméthylpyrazole (1) and 1,1'-di(4-nitrophényl)-5,5'-diisopropyl-3,3'-bipyrazole (2) was investigated against Hep cell line (Human laryngeal carcinoma). These two compounds showed an important cytotoxic activity on the Hep cell line, with IC(50): 8.25 microg mL(-1) for the compound 1; IC(50): 10.20 microg mL(-1) for the compound 2 while the IC(50) for adriamycine used as positive control was 3.62 microg mL(-1).

  16. Convenient synthesis of 18F-radiolabeled R-(-)-N-n-propyl-2-(3-fluoropropanoxy-11-hydroxynoraporphine.

    PubMed

    Sromek, Anna W; Zhang, Shaohui; Akurathi, Vamsidhar; Packard, Alan B; Li, Wei; Alagille, David; Morley, Thomas J; Baldwin, Ronald; Tamagnan, Gilles; Neumeyer, John L

    2014-12-01

    Aporphines are attractive candidates for imaging D2 receptor function because, as agonists rather than antagonists, they are selective for the receptor in the high affinity state. In contrast, D2 antagonists do not distinguish between the high and low affinity states, and in vitro data suggests that this distinction may be important in studying diseases characterized by D2 dysregulation, such as schizophrenia and Parkinson's disease. Accordingly, MCL-536 (R-(-)-N-n-propyl-2-(3-[(18)F]fluoropropanoxy-11-hydroxynoraporphine) was selected for labeling with (18)F based on in vitro data obtained for the non-radioactive ((19)F) compound. Fluorine-18-labeled MCL-536 was synthesized in 70% radiochemical yield, >99% radiochemical purity, and specific activity of 167 GBq/µmol (4.5 Ci/µmol) using p-toluenesulfonyl (tosyl) both as a novel protecting group for the phenol and a leaving group for the radiofluorination.

  17. Convenient Synthesis of 18F-Radiolabeled R-(−)-N-n-propyl-2-(3-fluoropropanoxy-11-hydroxynoraporphine

    PubMed Central

    Sromek, Anna W.; Zhang, Shaohui; Akurathi, Vamsidar; Packard, Alan B.; Li, Wei; Alagille, David; Morley, Thomas J.; Baldwin, Ronald; Tamagnan, Gilles; Neumeyer, John L.

    2014-01-01

    Aporphines are attractive candidates for imaging D2 receptor function because, as agonists rather than antagonists, they are selective for the receptor in the high affinity state. In contrast, D2 antagonists do not distinguish between the high and low affinity states, and in vitro data suggests that this distinction may be important in studying diseases characterized by D2 dysregulation, such as schizophrenia and Parkinson’s disease. Accordingly, MCL-536 (R-(−)-N-n-propyl-2-(3-[18F]fluoropropanoxy-11-hydroxynoraporphine) was selected for labeling with 18F based on in vitro data obtained for the non-radioactive (19F) compound. Fluorine-18-labeled MCL-536 was synthesized in 70% radiochemical yield, >99% radiochemical purity and specific activity of 167 GBq/μmol (4.5 Ci/μmol) using p-toluenesulfonyl (tosyl) both as a novel protecting group for the phenol and a leaving group for the radiofluorination. PMID:25400260

  18. Effects of propyl paraben on the male reproductive system.

    PubMed

    Oishi, S

    2002-12-01

    Parabens are p-hydroxybenzoic acid ester compounds widely used as preservatives in foods, cosmetics, toiletries and pharmaceuticals. These compounds exert a weak estrogenic activity as determined by in vitro estrogen receptor assay and in vivo uterotrophic assay. In a previous study, it was demonstrated by the present author that exposure of post-weaning mammals to butyl paraben adversely affects the secretion of testosterone and the function of the male reproductive system. In the present study, it is shown that propyl paraben also adversely affects the hormonal secretion and the male reproductive functions. Propyl paraben was administered to 3-week-old rats which were divided into four groups of eight animals each, at doses of 0.00, 0.01, 0.10 and 1.00% with the AIN93G modified diet. At the end of 4 weeks, the rats were sacrificed by decapitation and the weights of testes, epididymides, prostates, seminal vesicles and preputial glands were determined. There were no treatment-related effects of propyl paraben on the organ weights in any of the study groups. The cauda epididymal sperm reserves and concentrations decreased in a dose-dependent manner and the difference was significant at dose of 0.10% and above. Daily sperm production and its efficiency in the testis of all groups receiving propyl paraben significantly decreased. The serum testosterone concentration decreased in a dose-dependent manner and the decrease was significant in the group that received the highest dose. The exposure level at which this effect was observed is the same as the upper-limit acceptable daily intake (10 mg/kg body weight/day) of parabens in the European Community and Japan.

  19. 4-Bromo-N-(di-n-propyl-carbamothioyl)-benzamide.

    PubMed

    Binzet, Gün; Flörke, Ulrich; Külcü, Nevzat; Arslan, Hakan

    2009-02-04

    The synthesis of the title compound, C(14)H(19)BrN(2)OS, involves the reaction of 4-bromo-benzoyl chloride with potassium thio-cyanate in acetone followed by condensation of the resulting 4-bromo-benzoyl isothio-cyanate with di-n-propyl-amine. Typical thio-urea carbonyl and thio-carbonyl double bonds, as well as shortened C-N bonds, are observed in the title compound. The short C-N bond lengths in the centre of the mol-ecule reveal the effects of resonance in this part of the mol-ecule. The asymmetric unit of the title compound contains two crystallographically independent mol-ecules, A and B. There is very little difference between the bond lengths and angles of these mol-ecules. In mol-ecule B, one di-n-propyl group is twisted in a -anti-periplanar conformation with C-C-C-H = -179.1 (3)° and the other adopts a -synclinal conformation with C-C-C-H = -56.7 (4)°; in mol-ecule A the two di-n-propyl groups are twisted in + and -anti-periplanar conformations, with C-C-C-H = -179.9 (3) and 178.2 (3)°, respectively. In the crystal, the mol-ecules are linked into dimeric pairs via pairs of N-H⋯S hydrogen bonds.

  20. Progress of the synthesis of condensed pyrazole derivatives (from 2010 to mid-2013).

    PubMed

    Li, Meng; Zhao, Bao-Xiang

    2014-10-06

    Condensed pyrazole derivatives are important heterocyclic compounds due to their excellent biological activities and have been widely applied in pharmaceutical and agromedical fields. In recent years, numerous condensed pyrazole derivatives have been synthesized and advanced to clinic studies with various biological activities. In this review, we summarized the reported synthesis methods of condensed pyrazole derivatives from 2010 until now. All compounds are divided into three parts according to the rings connected to pyrazole-ring, i.e. [5, 5], [5,F 6], and [5, 7]-condensed pyrazole derivatives. The biological activities and applications in pharmaceutical fields are briefly introduced to offer an orientation for the design and synthesis of condensed pyrazole derivatives with good biological activities.

  1. Synthetic routes to 3(5)-phosphonylated pyrazoles

    NASA Astrophysics Data System (ADS)

    Goulioukina, N. S.; Makukhin, N. N.; Beletskaya, I. P.

    2016-07-01

    This review comprehensively covers the currently available synthetic routes to 3(5)-phosphonylated pyrazoles. There are demonstrated significant advances in this field over the last 10-15 years caused by the use of the Bestmann-Ohira reagent [as well as (diazomethyl)phosphonates and phosphonylated hydrazonoyl halides] in reactions with diverse dipolarophiles. 1,3-Dipolar cycloaddition of diazo compounds to α,β-unsaturated phosphonates as well as intramolecular heterocyclization of (1-diazoallyl)phosphonates and (3--diazo-1-propenyl)phosphonates are discussed. Synthetic potential of cyclocondensation of organophosphorus 1,3-dielectrophilic compounds with hydrazines is shown. Ways to introduce a phosphonate group into the pyrazole ring are considered. Examples of chemical transformations of 3(5)-phosphonylated pyrazoles are reported. The bibliography includes 88 references.

  2. Effects of dopamine D1 receptor full agonists in rats trained to discriminate SKF 38393.

    PubMed

    Gleason, S D; Witkin, J M

    2004-02-01

    Although the dopaminergic pharmacology of the D1 receptor full agonists, dinapsoline, dihydrexidine and the prodrug ABT-431 have been studied, no information is available on the ability of these agonists to substitute for the D1 agonist SKF 38393 in rats trained to discriminate this compound from vehicle. The present study was designed to characterize the potential D1 discriminative stimulus effects of these compounds. The selective dopamine D1-receptor agonists dihydrexidine [(+/-)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a] phenanthridine hydrochloride], ABT-431 [(-)-trans-9,10-diacetyloxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride], the diacetyl prodrug derivative of A-86929, and dinapsoline [9-dihydroxy-2,3,7,11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline] were studied in rats trained to discriminate racemic SKF 38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol], a selective D1 receptor partial agonist from vehicle. All of the agonists substituted fully for the discriminative stimulus effects of SKF 38393. The rank order of potency for substitution was ABT-431 > dinapsoline > dihydrexidine > SKF 38393. The D1 receptor antagonist, SCH 23390, blocked the discriminative stimulus effects of SKF 38393. The D3/D2-receptor agonist PD 128,907 [S(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]-benzopyrano[4,3-b]-1,4-oxazin-9-ol] did not substitute up to doses that produced profound rate-suppressant effects. Thus, consistent with their D1 receptor pharmacology, the full D1-receptor agonists substituted completely for the discriminative stimulus of SKF 38393.

  3. Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. II. Chronic effects of ethanol

    SciTech Connect

    Buck, K.J.; Harris, R.A. )

    1990-05-01

    Mice were made tolerant to and dependent on ethanol by administration of a liquid diet. Gamma-aminobutyric acid (GABA) receptor-dependent uptake of 36Cl- by mouse cortical microsacs was used to study the actions of benzodiazepine (BZ) agonists and inverse agonists. Chronic exposure to ethanol attenuated the ability of a BZ agonist, flunitrazepam, to augment muscimol-stimulated uptake of 36Cl- and enhanced the actions of BZ inverse agonists, Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,4)-benzodiazepine - 3-carboxylate) and DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate), to inhibit GABAA receptor-operated chloride channels. Augmentation of chloride flux by pentobarbital was not reduced by chronic ethanol exposure. Attenuation of flunitrazepam efficacy was transient and returned to control levels within 6 to 24 hr after withdrawal from ethanol, but increased sensitivity to Ro15-4513 was observed as long as 8 days after withdrawal. Chronic exposure to ethanol did not alter (3H)SR 95531 (2-(3'-carbethoxy-2'propyl)-3-amino-6-p-methoxyphenylpyridazinium bromide) binding to low-affinity GABAA receptors or muscimol stimulation of chloride flux; and did not alter (3H)Ro15-4513 or (3H)flunitrazepam binding to central BZ receptors or allosteric modulation of this binding by muscimol (i.e., muscimol-shift). These results suggest that chronic exposure to ethanol reduces coupling between BZ agonist sites and the chloride channel, and may be responsible for the development of cross-tolerance between ethanol and BZ agonists. In contrast, coupling between BZ inverse agonist sites and the chloride channel is increased.

  4. NMR and theoretical study on interactions between diperoxovanadate complex and pyrazole-like ligands.

    PubMed

    Yu, Xianyong; Liu, Ronghua; Peng, Hongliang; Huang, Haowen; Li, Xiaofang; Zheng, Baishu; Yi, Pinggui; Chen, Zhong

    2010-03-01

    To understand the effects of pyrazole substitution on reaction equilibrium, the interactions between a series of pyrazole-like ligands and [OV(O(2))(2)(D(2)O)](-)/[OV(O(2))(2)(HOD)](-) were explored by using multinuclear ((1)H, (13)C, and (51)V) magnetic resonance, HSQC, and variable temperature NMR in 0.15 mol/L NaCl ionic medium mimicking physiological conditions. These results show that the relative reactivities among the pyrazole-like ligands are 3-methyl-1H-pyrazole approximately 4-methyl-1H-pyrazole approximately 1H-pyrazole>1-methyl-1H-pyrazole. As a result, the main factor which affects the reaction equilibrium is the steric effect instead of the electronic effect of the methyl group of these ligands. A pair of isomers has been formed resulting from the coordination of 3-methyl-1H-pyrazole and a vanadium complex, which is attributed to different types of coordination between the vanadium atom and the ligands. Thus, the competitive coordination leads to the formation of a series of six-coordinate peroxovanadate species [OV(O(2))(2)L](-) (L, pyrazole-like ligands). Moreover, the results of density functional calculations provided a reasonable explanation on the relative reactivity of the pyrazole-like ligands as well as the important role of solvation in these reactions.

  5. Pharmacophore modeling, comprehensive 3D-QSAR, and binding mode analysis of TGR5 agonists.

    PubMed

    Sindhu, Thangaraj; Srinivasan, Pappu

    2017-04-01

    Takeda G-protein-coupled receptor 5 (TGR5) is emerging as an important and promising target for the development of anti-diabetic drugs. Pharmacophore modeling and atom-based 3D-QSAR studies were carried out on a new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as highly potent agonists of TGR5. The generated best six featured pharmacophore model AAHHRR consists of two hydrogen bond acceptors (A): two hydrophobic groups (H) and two aromatic rings (R). The constructed 3D-QSAR model acquired excellent correlation coefficient value (R(2 )=( )0.9018), exhibited good predictive power (Q(2 )=( )0.8494) and high Fisher ratio (F = 61.2). The pharmacophore model was validated through Guner-Henry (GH) scoring method. The GH value of 0.5743 indicated that the AAHHRR model was statistically valuable and reliable in the identification of TGR5 agonists. Furthermore, the combined approach of molecular docking and binding free energy calculations were carried out for the 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides to explore the binding mode and interaction pattern. The generated contour maps revealed the important structural insights for the activity of the compounds. The results obtained from this study could be helpful in the development of novel and more potent agonists of TGR5.

  6. Pyrazoles as potential anti-angiogenesis agents: a contemporary overview

    PubMed Central

    Kasiotis, Konstantinos M.; Tzanetou, Evangelia N.; Haroutounian, Serkos A.

    2014-01-01

    Angiogenesis is a mulit-step process by which new blood vessels are formed from preexisting vasculature. It is a key rate limiting factor in tumor growth since new blood vessels are necessary to increase tumor size. In this context it has been shown that anti-angiogenic factors can be used in cancer therapy. Among the plethora of heterocyclic compounds administered as anti-angiogenesis agents, pyrazoles constitute one of the bottlenecks of this category. Currently, several pyrazole based compounds are administered or are in Phase II and III trials and new targets emerge. It is highly possible that the advent of the next two decades will lead to the discovery and use of additional pyrazoles whose anti-angiogenic profile will position them in the forefront of the battle of various malignancies. The present review is an attempt to focus on those pyrazoles that arise as anti-angiogenesis agents commenting both on the chemistry and bioactivity that these exhibit aiming to contribute to the perspectives that they hold for future research. PMID:25250310

  7. Cationic fac-tris(pyrazole) complexes as anion receptors.

    PubMed

    Nieto, Sonia; Pérez, Julio; Riera, Víctor; Miguel, Daniel; Alvarez, Celedonio

    2005-01-28

    New receptors fac-[Re(CO)3(pz)3]BAr'4 (pz = 3,5-dimethylpyrazole or 3(5)-tert-butylpyrazole, Ar' = 3,5-(CF3)2C6H3), synthesized from [Re(OTf)(CO)5] and the pyrazoles, have been found to show a high affinity for chloride.

  8. Pyrazoles as potential anti-angiogenesis agents: A contemporary overview

    NASA Astrophysics Data System (ADS)

    Kasiotis, Konstantinos; Tzanetou, Evangelia; Haroutounian, Serkos

    2014-09-01

    Angiogenesis is a mulit-step process by which new blood vessels are formed from preexisting vasculature. It is a key rate limiting factor in tumor growth since new blood vessels are necessary to increase tumor size. In this context it has been shown that anti-angiogenic factors can be used in cancer therapy. Among the plethora of heterocyclic compounds administered as anti-angiogenesis agents, pyrazoles constitute one of the bottlenecks of this category. Currently several pyrazole based compounds are administered or are in Phase II and III trials and new targets emerge. It is highly possible that the advent of the next two decades will lead to the discovery and use of additional pyrazoles whose anti-angiogenic profile will position them in the forefront of the battle of various malignancies. The present review is an attempt to focus on those pyrazoles that arise as anti-angiogenesis agents commenting both on the chemistry and bioactivity that these exhibit aiming to contribute to the perspectives that they hold for future research.

  9. Recent progress on pyrazole scaffold-based antimycobacterial agents.

    PubMed

    Keri, Rangappa S; Chand, Karam; Ramakrishnappa, Thippeswamy; Nagaraja, Bhari Mallanna

    2015-05-01

    New and reemerging infectious diseases will continue to pose serious global health threats well into the 21st century and according to the World Health Organization report, these are still the leading cause of death among humans worldwide. Among infectious diseases, tuberculosis claims approximately 2 million deaths per year worldwide. Also, agents that reduce the duration and complexity of the current therapy would have a major impact on the overall cure rate. Due to the development of resistance to conventional antibiotics there is a need for new therapeutic strategies to combat Mycobacterium tuberculosis. Subsequently, there is an urgent need for the development of new drug candidates with newer targets and alternative mechanism of action. In this perspective, pyrazole, one of the most important classes of heterocycles, has been the topic of research for thousands of researchers all over the world because of its wide spectrum of biological activities. To pave the way for future research, there is a need to collect the latest information in this promising area. In the present review, we have collated published reports on the pyrazole core to provide an insight so that its full therapeutic potential can be utilized for the treatment of tuberculosis. In this article, the possible structure-activity relationship of pyrazole analogs for designing better antituberculosis (anti-TB) agents has been discussed and is also helpful for new thoughts in the quest for rational designs of more active and less toxic pyrazole-based anti-TB drugs.

  10. Mutagenicity study on pyrazole, seven pyrazole derivatives, and two nitroimidazoles with the L-arabinose resistance test of Salmonella typhimurium

    SciTech Connect

    Alejandre-Duran, E.; Ruiz-Rubio, M.; Claramunt, R.M.; Lopez, C.; Pueyo, C.

    1986-01-01

    The mutagenicity of pyrazole and seven pyrazole derivatives (4-nitropyrazole, 4-bromopyrazole, 1-methyl-4-nitropyrazole, 3,5-dimethyl-4-nitropyrazole, 1-methyl-4-bromopyrazole, 4,4'-dinitro-1, 1'-methylene-dipyrazole and 4,4'-dibromo-1,1'-methylene-dipyrazole) has been investigated with the L-arabinose forward mutation assay of Salmonella typhimurium. Two nitroimidazoles (1-methyl-5-nitroimidazole and metronidazole) were included as reference drugs. The mutagenicity of each chemical was determined by both preincubation and liquid tests, in the presence or absence of S9 microsomal fraction. The mutagenic responses was expressed as the absolute number of L-arabinose resistant mutants growing in selective plates, supplemented with traces of D-glucose. Strain BA13 with a wild-type lipopolysaccharide barrier was used as a comparison to the deep rough derivative BA9. No mutagenic effect was detected with pyrazole and two of its derivatives, 1-methyl-4-bromopyrazole and 4,4'-dibromo-1,1'-methylene-dipyrazole. The other five pyrazole derivatives were mutagenic to different degrees, although their mutagenic potencies were always considerably lower than those of the two nitroimidazoles. The results suggest that 4-nitropyrazoles, as well as 4,4'-dinitro-1, 1'-methylene-dipyrazoles, should be investigated further as alternatives to, or even substitutes for, the currently used nitroimidazoles.

  11. Psychotomimetic opiate receptors labeled and visualized with (+)-(/sup 3/H)3-(3-hydroxyphenyl)-N-(1-propyl)piperidine

    SciTech Connect

    Largent, B.L.; Gundlach, A.L.; Snyder, S.H.

    1984-08-01

    3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP) has been proposed as a selective dopamine autoreceptor agonist in the central nervous system. This report describes the pharmacology and localization of specific high-affinity binding sites for (+)-(/sup 3/H)3-PPP in brain. The drug specificity of (+)-(/sup 3/H)3-PPP binding is identical to that of sigma receptors, which may mediate psychotomimetic effects of some opiates. Haloperidol and the opioid derivatives, pentazocine, cyclazocine, and SKF 10,047 are potent inhibitors of (+)-(/sup 3/H)3-PPP binding. Stereoselectivity is exhibited for the (+) isomers of cyclazocine and SKF 10.047 at the sigma site, opposite to the stereoselectivity seen at ..mu.., sigma, and k opiate receptors. (+)-(/sup 3/H)3-PPP does not label dopamine receptors, as potent dopamine agonists and antagonists are weak inhibitors of binding and the localization of specific (+)-(/sup 3/H)3-PPP binding sites does not parallel that of dopamine neurons. Discrete localizations of (+)-(/sup 3/H)3-PPP binding sites in many brain areas including limbic, midbrain, brainstem, and cerebellar regions may explain psychotomimetic actions of opiates and behavior effects of 3-PPP. 41 references, 2 figures, 1 table.

  12. [Study on derivatives of 5-amino-4-acylamino-1H-pyrazole as inhibitors of furin].

    PubMed

    Kibirev, V K; Osadchuk, T V; Vadziuk, O B; Shablykin, O V; Kozachenko, A P; Chumachenko, S A; Popil'nichenko, S V; Brovarets, V S

    2011-01-01

    A series of 5-amino-1H-pyrazoles was synthesized and studied as inhibitors of furin. The most potent compound, 5-amino-4-acetylamino-3-(4-methylphenylamino)1H-pyrazole, was found to retard the activity of furin by mixed-type inhibition with K = 288 microM. These findings permit to plan new ways for chemical modifications of the 5-amino-1H-pyrazole structure and design more potent furin inhibitors of non-peptide nature.

  13. Infrared Laser Spectroscopy of the n-PROPYL and i-PROPYL Radicals in Helium Droplets: Significant Bend-Stretch Coupling Revealed in the CH Stretch Region

    NASA Astrophysics Data System (ADS)

    Moradi, Christopher P.; Douberly, Gary E.; Tabor, Daniel P.; Sibert, Edwin

    2016-06-01

    The n-propyl and i-propyl radicals were generated in the gas phase via pyrolysis of n-butyl nitrite (CH3(CH2)3ONO) and i-butyl nitrite (CH3CH(CH3)CH2ONO) precursors, respectively. Nascent radicals were promptly solvated by a beam of He nanodroplets, and the infrared spectra of the radicals were recorded in the C-H stretching region. In addition to three vibrations of n-propyl previously measured in an Ar matrix, we observe many unreported bands between 2800 and 3150 wn, which we attribute to propyl radicals. The C-H stretching modes observed above 2960 wn for both radicals are in excellent agreement with anharmonic frequencies computed using VPT2. Between 2800 and 2960 wn, however, the spectra of n-propyl and i-propyl radicals become quite congested and difficult to assign due to the presence of multiple anharmonic resonances. Computations employing a local mode Hamiltonian reveal the origin of the spectral congestion to be strong coupling between the high frequency C-H stretching modes and the lower frequency bending/scissoring motions. The only significant local coupling is between stretches and bends on the same CH2/CH3 group.

  14. The dopamine D(1) receptor agonist SKF-82958 serves as a discriminative stimulus in the rat.

    PubMed

    Haile, C N; Carey, G; Varty, G B; Coffin, V L

    2000-01-28

    We examined the discriminative stimulus effects of the high-efficacy dopamine D(1) receptor agonist (+/-)6-chloro-7, 8-dihydroxy-3-ally1-phenyl-2,3,4,5-tetrahydro-1H-3benzazepine++ + hydrobromide (SKF-82958) in rats trained to discriminate SKF-82958 (0.03 mg/kg) from vehicle in a two-lever food-reinforced drug discrimination task. SKF-82958 produced dose-related increases in responding to the SKF-82958 appropriate lever with full substitution occurring at the training dose. Pretreatment with the dopamine D(1)/D(5) receptor antagonist (-)-trans-6,7,7a,8,9, 13b-hexahydro-3-chloro-2hydroxy-N-methyl-5H-benzo-[d]naphtho -¿2, 1-b¿azepine (SCH-39166) (0.01 mg/kg) attenuated the discriminative stimulus effects of SKF-82958. Pretreatment with the dopamine D(2) receptor antagonist raclopride (0.03 mg/kg) had no effect. The high-efficacy dopamine D(1) receptor agonist R(+)6chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-81297) fully substituted for SKF-82958, whereas the low-efficacy dopamine D(1) receptor agonist (+/-)1-phenyl-2,3,4, 5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393) produced only partial substitution. The dopamine D(2) receptor agonist trans-(+/-)-4,4a,5,6,7,8,8a, 9-octahydro-5-propyl-1H-propyl-1H-pyrazolo[3,4-g]quinoline dihydrochloride (quinpirole) and the indirect dopamine agonist cocaine did not substitute fully for the SKF-82958 discriminative stimulus cue. These results demonstrate that the high-efficacy dopamine D(1) receptor agonist SKF-82958 can serve as an effective discriminative stimulus in the rat, and that these effects are mediated by a dopamine D(1)-like receptor mechanism.

  15. Synthesis, characterization, and anticancer activity of ruthenium-pyrazole complexes.

    PubMed

    David, Solene; Perkins, Richard S; Fronczek, Frank R; Kasiri, Sahba; Mandal, Subhrangsu S; Srivastava, Radhey S

    2012-06-01

    A series of new water soluble Ru(III) pyrazole complexes mer-[RuCl(3)(DMSO-S)(pyz)(2)] 1, mer-[RuCl(3)(DMSO-S)(DMSO-O)(pyz)] 2, mer-[RuCl(3)(bpy)(dmpyz)] 3, and mer-[RuCl(3)(DMSO-S)(dmpyz)(2)] 4 (pyz=pyrazole; dmpyz=3,5-dimethylpyrazole, bpy=2,2'-bipyridine) have been synthesized and characterized by use of a combination of spectroscopy (IR and UV-visible), X-ray diffraction, and cyclic voltammetry. The molecular X-ray structure of all reported compounds (1-4) revealed distorted octahedral coordination around ruthenium. The cytotoxicity assay on human breast cancer cells (MCF7) demonstrated that compounds 1 and 4 affect cell viability, whereas compounds 2 and 3 do not show appreciable activity. The IC(50) values for 1 and 4 lie within the range of 71-32μM in MCF7 cells.

  16. New pyrazole derivative 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole: synthesis and assessment of some biological activities.

    PubMed

    de Oliveira, Lanussy Porfiro; da Silva, Daiany Priscilla Bueno; Florentino, Iziara Ferreira; Fajemiroye, James Oluwagbamigbe; de Oliveira, Thiago Sardinha; Marcelino, Renato Ivan de Ávila; Pazini, Francine; Lião, Luciano Morais; Ghedini, Paulo César; de Moura, Soraia Santana; Valadares, Marize Campos; de Carvalho, Verônica Vale; Vaz, Boniek Gontijo; Menegatti, Ricardo; Costa, Elson Alves

    2017-01-01

    The molecular modification and synthesis of compounds is vital to discovering drugs with desirable pharmacological and toxicity profiles. In response to pyrazole compounds' antipyretic, analgesic, and anti-inflammatory effects, this study sought to evaluate the analgesic, anti-inflammatory, and vasorelaxant effects, as well as the mechanisms of action, of a new pyrazole derivative, 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole. During the acetic acid-induced abdominal writhing test, treatments with 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole reduced abdominal writhing, while during the formalin test, 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole reduced licking times in response to both neurogenic pain and inflammatory pain, all without demonstrating any antinociceptive effects, as revealed during the tail flick test. 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole also reduced carrageenan-induced paw edema and cell migration during the carrageenan-induced pleurisy test. As demonstrated by the model of the isolated organ, 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole exhibits a vasorelaxant effect attenuated by Nω-nitro-l-arginine methyl ester, 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one, tetraethylammonium or glibenclamide. 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole also blocked CaCl2 -induced contraction in a dose-dependent manner. Suggesting a safe toxicity profile, 5-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]-2H-tetrazole reduced the viability of 3T3 cells at higher concentrations and was orally tolerated, despite signs of toxicity in doses of 2000 mg/kg. Lastly, the compounds' analgesic activity might be attributed to the involvement of the NO/cGMP pathway and K(+) channels observed in the vasorelaxant effect.

  17. New Potential Antitumor Pyrazole Derivatives: Synthesis and Cytotoxic Evaluation

    PubMed Central

    Nitulescu, George Mihai; Draghici, Constantin; Olaru, Octavian Tudorel

    2013-01-01

    New pyrazole derivatives were designed and synthesized as potential protein kinase inhibitors in the view to develop specific antitumor therapies. The structures of the compounds were elucidated using spectral and elemental analyses. The antitumor potential was estimated using wheat seeds and the general toxicity was evaluated by alternative methods, using invertebrate animals. One 3-aminopyrazole derivative emerged as a potential candidate for the development of future cytotoxic compounds. PMID:24192822

  18. Derivation of an occupational exposure limit (OEL) for n-propyl bromide using an improved methodology.

    PubMed

    Rozman, Karl K; Doull, John

    2002-10-01

    n-Propyl bromide is an industrial solvent with increasing production volume due to its use as a replacement for fluorohydrocarbons. Therefore, the number of occupationally exposed workers is growing accordingly. This manuscript presents a thorough evaluation of available animal and human data to derive an occupational exposure limit (OEL) for n-propyl bromide. In addition, structure activity relationship within the homologous series of methyl, ethyl, and n-propyl bromide and an identical spectrum of effects caused by similar doses of 2-propyl bromide are used to increase the confidence of the analysis. The structure activity relationship was entirely consistent for acute and subchronic (neurologic, reproductive, and hematopoietic) toxicities and for mutagenic potency in that CH3Br was more toxic than CH3CH2Br, which in turn was more toxic than CH3CH2CH2Br in every case in all species studied, including humans. Animals appeared to be similarly susceptible as, or slightly more susceptible than, humans to n-propyl bromide's toxicity. An OEL (60-90 ppm) was derived from a limited human study and supported by an across-the-toxic-spectrum comparison of animal and human data for both n-propyl and 2-propyl bromide. A carcinogenic classification was not deemed necessary at the recommended OEL based on very low mutagenic potency and the consistent structure activity relationship across the homologous series of these alkyl bromides.

  19. An iron(III) complex salt containing pyrazole as both ligand and counter-ion: bis(1H-pyrazol-2-ium) pentacyanido(1H-pyrazole-κN(2))ferrate(III).

    PubMed

    Wang, Yu-Feng; Yu, Chun-Hua; Zhu, Run-Qiang

    2014-05-01

    The title compound, (C3H5N2)2[Fe(CN)5(C3H4N2)], is composed of a mononuclear [Fe(CN)5(pyrazole)](2-) dianion and two 1H-pyrazol-2-ium cations. A three-dimensional supramolecular network is formed through a rich scheme of N-H...N hydrogen bonds and C-H...π interactions among the cations and anions.

  20. Molecular structure, vibrational spectral studies of pyrazole and 3,5-dimethyl pyrazole based on density functional calculations.

    PubMed

    Krishnakumar, V; Jayamani, N; Mathammal, R

    2011-09-01

    In this work, the experimental and theoretical vibrational spectra of pyrazole (PZ) and 3,5-dimethyl pyrazole (DMP) have been studied. FTIR and FT-Raman spectra of the title compounds in the solid phase are recorded in the region 4000-400 cm(-1) and 4000-50 cm(-1), respectively. The structural and spectroscopic data of the molecules in the ground state are calculated using density functional methods (B3LYP) with 6-311+G** basis set. The vibrational frequencies are calculated and scaled values are compared with experimental FTIR and FT-Raman spectra. The observed and calculated frequencies are found to be in good agreement. The complete vibrational assignments are performed on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanical (SM) method. 13C and 1H NMR chemical shifts results are compared with the experimental values.

  1. 40 CFR 721.987 - Dialkylaminophenyl imino pyrazole acid ester (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... ester (generic). 721.987 Section 721.987 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.987 Dialkylaminophenyl imino pyrazole acid ester (generic). (a) Chemical... as dialkylaminophenyl imino pyrazole acid ester (PMN P-98-45) is subject to reporting under...

  2. 40 CFR 721.987 - Dialkylaminophenyl imino pyrazole acid ester (generic).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... ester (generic). 721.987 Section 721.987 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.987 Dialkylaminophenyl imino pyrazole acid ester (generic). (a) Chemical... as dialkylaminophenyl imino pyrazole acid ester (PMN P-98-45) is subject to reporting under...

  3. 40 CFR 721.987 - Dialkylaminophenyl imino pyrazole acid ester (generic).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... ester (generic). 721.987 Section 721.987 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.987 Dialkylaminophenyl imino pyrazole acid ester (generic). (a) Chemical... as dialkylaminophenyl imino pyrazole acid ester (PMN P-98-45) is subject to reporting under...

  4. 40 CFR 721.987 - Dialkylaminophenyl imino pyrazole acid ester (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... ester (generic). 721.987 Section 721.987 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.987 Dialkylaminophenyl imino pyrazole acid ester (generic). (a) Chemical... as dialkylaminophenyl imino pyrazole acid ester (PMN P-98-45) is subject to reporting under...

  5. 40 CFR 721.987 - Dialkylaminophenyl imino pyrazole acid ester (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... ester (generic). 721.987 Section 721.987 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.987 Dialkylaminophenyl imino pyrazole acid ester (generic). (a) Chemical... as dialkylaminophenyl imino pyrazole acid ester (PMN P-98-45) is subject to reporting under...

  6. Palladium-catalyzed phosphonylation: synthesis of C3-, C4-, and C5-phosphonylated pyrazoles.

    PubMed

    Tran, Gaël; Gomez Pardo, Domingo; Tsuchiya, Tomoki; Hillebrand, Stefan; Vors, Jean-Pierre; Cossy, Janine

    2013-11-01

    A palladium-catalyzed cross-coupling between 3-, 4-, and 5-halo-pyrazoles and H-phosphonates, H-phosphinates, and secondary phosphine oxides has been developed. This coupling reaction constitutes the first general method allowing the introduction of a great diversity of phosphorus substituents on the different carbons of the pyrazole ring in a one-step process.

  7. [Melatonin receptor agonist].

    PubMed

    Uchiyama, Makoto

    2015-06-01

    Melatonin is a hormone secreted by the pineal gland and is involved in the regulation of human sleep-wake cycle and circadian rhythms. The melatonin MT1 and MT2 receptors located in the suprachiasmatic nucleus in the hypothalamus play a pivotal role in the sleep-wake regulation. Based on the fact that MT1 receptors are involved in human sleep onset process, melatonin receptor agonists have been developed to treat insomnia. In this article, we first reviewed functions of melatonin receptors with special reference to MT1 and MT2, and properties and clinical application of melatonin receptor agonists as hypnotics.

  8. In Vitro Transformation of Chlorinated Parabens by the Liver S9 Fraction: Kinetics, Metabolite Identification, and Aryl Hydrocarbon Receptor Agonist Activity.

    PubMed

    Terasaki, Masanori; Wada, Takeshi; Nagashima, Satoshi; Makino, Masakazu; Yasukawa, Hiro

    2016-01-01

    We investigated the kinetics of in vitro transformation of a dichlorinated propyl paraben (2-propyl 3,5-dichloro-4-hydroxybenzoate; Cl2PP) by the rat liver S9 fraction and assessed the aryl hydrocarbon receptor (AhR) agonist activity of the metabolite products identified in HPLC and GC/MS analysis and by metabolite syntheses. The results indicated that the chlorination of Cl2PP reduced its degradation rate by approximately 40-fold. Two hydroxylated metabolite products showed AhR agonist activity of up to 39% of that of the parent Cl2PP when assessed in a yeast (YCM3) reporter gene assay. The determination of the metabolic properties of paraben bioaccumulation presented here provides further information on the value of risk assessments of chlorinated parabens as a means to ensure human health and environmental safety.

  9. Melatonin agonists and insomnia.

    PubMed

    Ferguson, Sally A; Rajaratnam, Shantha M W; Dawson, Drew

    2010-02-01

    The ability of melatonin to shift biological rhythms is well known. As a result, melatonin has been used in the treatment of various circadian rhythm sleep disorders, such as advanced and delayed sleep phase disorders, jet lag and shiftwork disorder. The current evidence for melatonin being efficacious in the treatment of primary insomnia is less compelling. The development of agents that are selective for melatonin receptors provides opportunity to further elucidate the actions of melatonin and its receptors and to develop novel treatments for specific types of sleep disorders. The agonists reviewed here - ramelteon, tasimelteon and agomelatine - all appear to be efficacious in the treatment of circadian rhythm sleep disorders and some types of insomnia. However, further studies are required to understand the mechanisms of action, particularly for insomnia. Clinical application of the agonists requires a good understanding of their phase-dependent properties. Long-term effects of melatonin should be evaluated in large-scale, independent randomized controlled trials.

  10. Beta-Adrenergic Agonists

    PubMed Central

    Barisione, Giovanni; Baroffio, Michele; Crimi, Emanuele; Brusasco, Vito

    2010-01-01

    Inhaled β2-adrenoceptor (β2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the β2-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of β2-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and β-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled β2-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised. PMID:27713285

  11. Complete assignment of NMR data of 22 phenyl-1H-pyrazoles' derivatives.

    PubMed

    de Oliveira, Aline Lima; Alves de Oliveira, Carlos Henrique; Mairink, Laura Maia; Pazini, Francine; Menegatti, Ricardo; Lião, Luciano Morais

    2011-08-01

    Complete assignment of (1)H and (13)C NMR chemical shifts and J((1)H/(1)H and (1)H/(19)F) coupling constants for 22 1-phenyl-1H-pyrazoles' derivates were performed using the concerted application of (1)H 1D and (1)H, (13)C 2D gs-HSQC and gs-HMBC experiments. All 1-phenyl-1H-pyrazoles' derivatives were synthesized as described by Finar and co-workers. The formylated 1-phenyl-1H-pyrazoles' derivatives were performed under Duff's conditions.

  12. Synthesis of diversely 1,3,5-trisubstituted pyrazoles via 5-exo-dig cyclization.

    PubMed

    Borkin, Dmitry A; Puscau, Mirela; Carlson, Alena; Solan, Agnes; Wheeler, Kraig A; Török, Béla; Dembinski, Roman

    2012-06-21

    5-Exo-dig cyclocondensation of alk-3-yn-1-ones with hydrazines, in the presence of montmorillonite K-10, provides an effective method with a high atom economy for the synthesis of diversely 1,3,5-trisubstituted pyrazoles. The microwave-accelerated reaction proceeds in the absence of solvent and leads to 5-benzyl substituted pyrazoles with good yields (72-91%). The regiochemistry of the process was confirmed by the X-ray crystallographic structure determination of 1-(2-fluorophenyl)-5-(4-methylbenzyl)-3-phenyl-1H-pyrazole.

  13. Surface, morphology and X-ray diffraction studies of Co (II) complexes of pyrazole ligands

    NASA Astrophysics Data System (ADS)

    Mishra, A.; Jain, Garima; Ninama, S.

    2014-09-01

    Pyrazole based complexes of the cobalt (II) Bis-(diethyl 4-amino-1-(P-nitrophenyl) 1H-pyrazole-3,5dicarboxylate) [Co (D4A1(P-N)1HP35D)] and cobalt (II) Bis-(diethyl 4- amino-1-(3-chlorophenyl) 1H-pyrazole-3,5dicarboxylate) [Co (D4A1(3-Cl)1HP35D)] were synthesized by chemical root method and characterized by different method viz. X-ray diffraction, Fourier transform infrared spectroscopy and Transmission electron microscopy studies. All these studies were in good agreement with the synthesized complexes.

  14. Design and Synthesis of Pyrazole-3-one Derivatives as Hypoglycaemic Agents

    PubMed Central

    Datar, Prasanna A.; Jadhav, Sonali R.

    2015-01-01

    Pyrazole-3-one compounds were designed on the basis of docking studies of previously reported antidiabetic pyrazole compounds. The amino acid residues found during docking studies were used as guidelines for the modification of aromatic substitutions on pyrazole-3-one structure. Depending on the docking score, the designed compounds were selectively prioritized for synthesis. The synthesized compounds were subjected to in vivo hypoglycemic activity using alloxan induced diabetic rats and metformin as a standard. Compound 4 having sulphonamide derivative was found to be the most potent compound among the series. PMID:25734015

  15. Coordination chemistry in the solid state: synthesis and interconversion of pyrazolium salts, pyrazole complexes, and pyrazolate MOFs.

    PubMed

    Adams, Christopher J; Kurawa, Mukhtar A; Orpen, A Guy

    2010-08-14

    Solid pyrazole reacts with HCl gas to form pyrazolium chloride [H2pz]Cl, which reacts in the solid state, under grinding, with metal chlorides MCl2 (M = Co, Zn, Cu) to form the pyrazolium tetrachlorometallate salts [H2pz]2[MCl4] (M = Co 1, Zn 3, Cu 5). Salt 5 cannot be made in solution, and upon standing at room temperature spontaneously emits HCl to give the coordination compound [CuCl2(Hpz)2] (6). Compounds 1 and 3 do not exhibit this behaviour, but can be ground together with bases such as KOH or K2CO3 to effect the elimination of HCl and afford their respective [MCl2(Hpz)2] compounds (M = Co 2, Zn 4). 2, 4 and 6 can also be synthesised in the solid-state by direct reaction of the appropriate metal chloride with pyrazole, or by reaction of a basic metal salt such as the carbonate or hydroxide with pyrazolium chloride. 4 and 6 {and their nickel analogue [NiCl2(Hpz)2]} can be ground with a further two equivalents of base to make the known polymeric metal pyrazolates [M(pz)2]n (M = Ni 7, Cu 8, Zn 9); the same reaction appears to work for the cobalt analogue 2, but the presumed product [Co(pz)2]n10 then decomposes by oxidation. The imidazolate complexes [M(im)2] (M = Ni, 11; Cu, 12; Zn, 13; Co, 14) were similarly prepared by grinding the appropriate [M(Him)2Cl2] precursor with KOH.

  16. The action of n-propyl gallate on gluconeogenesis and oxygen uptake in the rat liver.

    PubMed

    Eler, Gabrielle Jacklin; Peralta, Rosane Marina; Bracht, Adelar

    2009-10-30

    In the present study the metabolic actions of n-propyl gallate on hepatic gluconeogenesis, oxygen uptake and related parameters were investigated. Experiments were done in the isolated perfused rat liver. n-Propyl gallate inhibited gluconeogenesis and stimulated oxygen uptake at concentrations up to 200 microM. The inhibitory effects on lactate gluconeogenesis (ED(50) 86.4 microM) and alanine gluconeogenesis were considerably more pronounced than those on glycerol and fructose gluconeogenesis. n-Propyl gallate also stimulated oxygen uptake in both the mitochondrial (63%) and microsomal (37%) electron transport chains. The first one is due mainly to the oxidation of n-propanol, as a metabolite of the first step of n-propyl gallate transformation. The second one results from a direct stimulation of the microsomal electron transport chain. n-Propyl gallate inhibited pyruvate carboxylation (ED(50) 142.2 microM) in consequence of an inhibition of pyruvate transport into the mitochondria an effect not found for gallic acid. This is probably the main cause for glucose output inhibition. Secondary causes are (1) deviation of intermediates for the production of NADPH to be used in microsomal electron transport; (2) deviation of glucose 6-phosphate for glucuronidation reactions; (3) gluconeogenesis inhibition by n-propanol, produced intracellularly from n-propyl gallate. Inhibition of mitochondrial energy metabolism is not significant in the range up to 200 microM, as indicated by the very small effect on the cellular ATP levels (5% decreased). n-Propyl gallate can be considered a kind of metabolic effector, whose actions on the liver metabolism are relatively mild although they can become harmful for the organ and the whole organism at high doses and concentrations.

  17. Pyrazole scaffold: a remarkable tool in the development of anticancer agents.

    PubMed

    Kumar, Harish; Saini, Deepika; Jain, Sandeep; Jain, Neelam

    2013-01-01

    Pyrazole has been the topic of interest for thousands of researchers across the world because of its wide spectrum pharmacological activities. Various structural modifications of the pyrazole nucleus have been made to explore its characteristics and biological potential. The present work aims to review the use of molecular modeling in the designing of novel pyrazole analogs that may target various receptors such as protein kinase inhibitor, tyrosine kinase, Aurora-A kinase, tumor growth factor (TGF), cyclin dependent kinase (CDK) and fibroblast growth factor (FGF), which are significant for the management of cancer. An insight has been given in this article for the importance of pyrazoles in the treatment of cancer and the perspectives that they hold for future research.

  18. Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening.

    PubMed

    Miller, Zachary; Kim, Keun-Sik; Lee, Do-Min; Kasam, Vinod; Baek, Si Eun; Lee, Kwang Hyun; Zhang, Yan-Yan; Ao, Lin; Carmony, Kimberly; Lee, Na-Ra; Zhou, Shou; Zhao, Qingquan; Jang, Yujin; Jeong, Hyun-Young; Zhan, Chang-Guo; Lee, Wooin; Kim, Dong-Eun; Kim, Kyung Bo

    2015-02-26

    We performed a virtual screen of ∼340 000 small molecules against the active site of proteasomes followed by in vitro assays and subsequent optimization, yielding a proteasome inhibitor with pyrazole scaffold. The pyrazole-scaffold compound displayed excellent metabolic stability and was highly effective in suppressing solid tumor growth in vivo. Furthermore, the effectiveness of this compound was not negatively impacted by resistance to bortezomib or carfilzomib.

  19. Synthesis of Fluorescent Indazoles by Palladium-Catalyzed Benzannulation of Pyrazoles with Alkynes.

    PubMed

    Kim, Og Soon; Jang, Jin Hyeok; Kim, Hyun Tae; Han, Su Jin; Tsui, Gavin Chit; Joo, Jung Min

    2017-03-17

    The synthesis of indazoles from pyrazoles and internal alkynes is described. Instead of complex benzenoid compounds, readily available pyrazoles were used for the preparation of indazoles by reaction of the C-H bonds of the heterocyclic ring. Oxidative benzannulation was also applied to imidazoles, providing benzimidazoles. This convergent strategy enabled alteration of the photochemical properties of benzo-fused diazoles by varying the substituents at the benzene ring, thus leading to the development of tetraarylindazoles as new fluorophores.

  20. Photodissociation dynamics of the 2-propyl radical, C3H7

    NASA Astrophysics Data System (ADS)

    Noller, Bastian; Fischer, Ingo

    2007-04-01

    The photodissociation of 2-propyl leading to propene+H was investigated with nanosecond time resolution. A supersonic beam of isolated 2-propyl radicals was produced by pyrolysis of 2-bromopopane. The kinetic energy release of the H-atom photofragment was monitored as a function of excitation wavelength by photofragment Doppler spectroscopy via the Lyman-α transition. The loss of hydrogen atoms after excitation proceeds in α position to the radical center with a rate constant of 5.8×107s-1 at 254nm. Approximately 20% of the excess energy is deposited as translation in the H-atom photofragment. In contrast 1-propyl does not lose H atoms to a significant extent. The experimental results are compared to simple Rice-Ramsperger-Kassel-Marcus calculations. The possible reaction pathways are examined in hybrid density functional theory calculations.

  1. Design, synthesis and structure-activity relationship study of novel pyrazole-based heterocycles as potential antitumor agents.

    PubMed

    Farag, Ahmad M; Ali, Korany A K; El-Debss, Taha M A; Mayhoub, Abdelrahman S; Amr, Abdel-Galil E; Abdel-Hafez, Naglaa A; Abdulla, Mohamed M

    2010-12-01

    The versatile hitherto unreported 3-[(E)-3-(dimethylamino)acryloyl]-1,5-diphenyl-1H-pyrazole-4-carbonitrile (3) was prepared via the reaction of 3-acetyl-1,5-diphenyl-1H-pyrazole-4-carbonitrile (1) with dimethylformamid-dimethylacetal (DMF-DMA). The latter product and 3-((E)-3-morpholin-4-yl-acryloyl)-1,5-diphenyl-1H-pyrazole-4-carbonitrile (4) underwent regioselective 1,3-dipolar cycloaddition with nitrilimines to afford the corresponding pyrazole derivatives. In vivo anti-estrogenic activity and acute toxicity after single oral dose of the newly synthesized compounds were evaluated. In vitro disease-oriented primary antitumor screening utilizing 14 cell lines of breast and ovarian tumor subpanels has been also carried out. All tested compounds showed anti-estrogenic properties equipotent or superior to the reference drug, letrozole. 3-[3-(4-Cyano-1,5-diphenyl-1H-pyrazole-3-yl)-1-(4-methylphenyl)-1H-pyrazole-4-carbonyl]-1,5-diphenyl-1H-pyrazole-4-carbonitrile (27c) and 3-(3-acetyl-1-phenyl-1H-pyrazole-4-carbonyl)-1,5-diphenyl-1H-pyrazole-4-carbonitrile (8a) showed a significant cytotoxic activity in a nanomolar range against certain types of breast and ovarian tumors with tolerable toxicity.

  2. Ecotoxicological effects of the antioxidant additive propyl gallate in five aquatic systems.

    PubMed

    Zurita, Jorge L; Jos, Angeles; del Peso, Ana; Salguero, Manuel; López-Artíguez, Miguel; Repetto, Guillermo

    2007-06-01

    Propyl gallate is an antioxidant widely used in foods, cosmetics and pharmaceuticals. The occurrence and fate of additives in the aquatic environment is an emerging issue in environmental chemistry. To date, there is little available information about the adverse effects of propyl gallate on aquatic organisms. Therefore, the toxic effects were investigated, using five model systems from four trophic levels. The most sensitive system was the hepatoma fish cell line PLHC-1 according to total protein content, with an EC(50) of 10 microM and a NOAEL of 1 microM at 72 h, followed by the immobilization of Daphnia magna, the inhibition of bioluminescence of Vibrio fischeri, the salmonid fish cell line RTG-2 and the inhibition of the growth of Chlorella vulgaris. Although protein content, neutral red uptake, methylthiazol metabolization and acetylcholinesterase activity were reduced in PLHC-1 cells, stimulations were observed for lysosomal function, succinate dehydrogenase, glucose-6-phosphate dehydrogenase and ethoxyresorufin-O-deethylase activities. No changes were observed in metallothionein levels. The main morphological observations were the loss of cells and the induction of cell death mainly by necrosis but also by apoptosis. The protective and toxic effects of propyl gallate were evaluated. General antioxidants and calcium chelators did not modify the toxicity of propyl gallate, but an iron-dependent lipid peroxidation inhibitor gave 22% protection. The results also suggest that propyl gallate cytotoxicity is dependent on glutathione levels, which were modulated by malic acid diethyl ester and 2-oxothiazolidine-4-carboxylic acid. According to the results, propyl gallate should be classified as toxic to aquatic organisms.

  3. Synthesis and Characterization of Mixed Substituent P-n-Propyl-N-trimethylphosphoranimines

    SciTech Connect

    Klaehn, John Ray; Luther, Thomas Alan; Harrup, Mason Kurt; Stewart, Frederick Forrest

    2003-07-01

    One approach to the synthesis of polyphosphazenes is the condensation polymerization of phosphoranimines. In this work, several novel P-n-propyl-N-trimethylsilylphosphoranimines have been synthesized and characterized. Modifications to the literature synthetic routes were required to obtain the precursor phosphines. The N-trimethylsilylphosphoranimines were obtained though oxidation of the phosphine with bromine and then subsequent nucleophilic displacement using lithium phenoxide. These phosphoranimines were stable for long periods of time under dry inert conditions. NMR analyses revealed complex splitting patterns beyond typical coupling due to the stereocenter at phosphorus. We report several approaches to the n-propyl containing phosphines

  4. Excited state tautomerization of 7-azaindole catalyzed by pyrazole

    NASA Astrophysics Data System (ADS)

    Karmakar, Shreetama; Mukherjee, Moitrayee; Chakraborty, Tapas

    2013-03-01

    Pyrazole, a five member cyclic azole, is reported here as an efficient catalyst for excited state tautomeric conversion of 7-azaindole. In hydrocarbon solution the two compounds efficiently form a doubly hydrogen-bonded 1:1 cyclic complex whose association constant value is found comparable with 7-azaindole dimerization constant, and according to B3LYP/6-311G++∗∗ calculation the binding energies of the complex and dimer are nearly same. In the excited state (S1), the TDDFT calculation predicts tautomer of the complex to be 13.4 kcal/mol more stable than normal form. Fluorescence spectra reveal that upon UV excitation the complex emits exclusively from the tautomeric form.

  5. The β2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis.

    PubMed

    Wills, Lauren P; Trager, Richard E; Beeson, Gyda C; Lindsey, Christopher C; Peterson, Yuri K; Beeson, Craig C; Schnellmann, Rick G

    2012-07-01

    Mitochondrial dysfunction is a common mediator of disease and organ injury. Although recent studies show that inducing mitochondrial biogenesis (MB) stimulates cell repair and regeneration, only a limited number of chemicals are known to induce MB. To examine the impact of the β-adrenoceptor (β-AR) signaling pathway on MB, primary renal proximal tubule cells (RPTC) and adult feline cardiomyocytes were exposed for 24 h to multiple β-AR agonists: isoproterenol (nonselective β-AR agonist), (±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL 37344) (selective β(3)-AR agonist), and formoterol (selective β(2)-AR agonist). The Seahorse Biosciences (North Billerica, MA) extracellular flux analyzer was used to quantify carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled oxygen consumption rate (OCR), a marker of maximal electron transport chain activity. Isoproterenol and BRL 37244 did not alter mitochondrial respiration at any of the concentrations examined. Formoterol exposure resulted in increases in both FCCP-uncoupled OCR and mitochondrial DNA (mtDNA) copy number. The effect of formoterol on OCR in RPTC was inhibited by the β-AR antagonist propranolol and the β(2)-AR inverse agonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol hydrochloride (ICI-118,551). Mice exposed to formoterol for 24 or 72 h exhibited increases in kidney and heart mtDNA copy number, peroxisome proliferator-activated receptor γ coactivator 1α, and multiple genes involved in the mitochondrial electron transport chain (F0 subunit 6 of transmembrane F-type ATP synthase, NADH dehydrogenase subunit 1, NADH dehydrogenase subunit 6, and NADH dehydrogenase [ubiquinone] 1β subcomplex subunit 8). Cheminformatic modeling, virtual chemical library screening, and experimental validation identified nisoxetine from the Sigma Library of Pharmacologically Active Compounds and two compounds from the ChemBridge DIVERSet

  6. 78 FR 57285 - 2,5-Furandione, Polymer With Ethenylbenzene, Hydrolyzed, 3-(Dimethylamino)propyl Imide, Imide...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-18

    ... AGENCY 40 CFR Part 180 2,5-Furandione, Polymer With Ethenylbenzene, Hydrolyzed, 3- (Dimethylamino)propyl...-furandione, polymer with ethenylbenzene, hydrolyzed, 3-(dimethylamino)propyl imide, imide with polyethylene... permissible level for residues of 2,5-furandione, polymer with ethenylbenzene, hydrolyzed, 3- ]...

  7. The Glycine Transport Inhibitor Sarcosine Is an Inhibitory Glycine Receptor Agonist

    PubMed Central

    Zhang, Hai Xia; Lyons-Warren, Ariel; Thio, Liu Lin

    2009-01-01

    Summary Sarcosine is an endogenous amino acid that is a competitive inhibitor of the type I glycine transporter (GlyT1), an N-methyl-D-aspartate receptor (NMDAR) co-agonist, and an important intermediate in one-carbon metabolism. Its therapeutic potential for schizophrenia further underscores its clinical importance. The structural similarity between sarcosine and glycine and sarcosine's ability to serve as an NMDAR co-agonist led us to examine whether sarcosine is also an agonist at the inhibitory glycine receptor (GlyR). We examined this possibility using whole-cell recordings from cultured embryonic mouse hippocampal neurons and found that sarcosine evoked a dose-dependent, strychnine sensitive, Cl- current that cross-inhibited glycine currents. Sarcosine evoked this current with Li+ in the extracellular solution to block GlyT1, in neurons treated with the essentially irreversible GlyT1 inhibitor N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine (NFPS), and in neurons plated in the absence of glia. These results indicate that the sarcosine currents did not result from GlyT1 inhibition or heteroexchange. We conclude that sarcosine is a GlyR agonist. PMID:19619564

  8. Infrared laser spectroscopy of the n-propyl and i-propyl radicals: Stretch-bend Fermi coupling in the alkyl CH stretch region.

    PubMed

    Franke, Peter R; Tabor, Daniel P; Moradi, Christopher P; Douberly, Gary E; Agarwal, Jay; Schaefer, Henry F; Sibert, Edwin L

    2016-12-14

    The n-propyl and i-propyl radicals were generated in the gas phase via pyrolysis of n-butyl nitrite [CH3(CH2)3ONO] and i-butyl nitrite [(CH3)2CHCH2ONO], respectively. Nascent radicals were promptly solvated by a beam of He nanodroplets, and the infrared spectra of the radicals were recorded in the CH stretching region. Several previously unreported bands are observed between 2800 and 3150 cm(-1). The CH stretching modes observed above 3000 cm(-1) are in excellent agreement with CCSD(T) anharmonic frequencies computed using second-order vibrational perturbation theory. However, between 2800 and 3000 cm(-1), the spectra of n- and i-propyl radicals become congested and difficult to assign due to the presence of multiple anharmonic resonance polyads. To model the spectrally congested region, Fermi and Darling-Dennison resonances are treated explicitly using "dressed" Hamiltonians and CCSD(T) quartic force fields in the normal mode representation, and the agreement with experiment is less than satisfactory. Computations employing local mode effective Hamiltonians reveal the origin of the spectral congestion to be strong coupling between the high frequency CH stretching modes and the lower frequency CHn bending/scissoring motions. The most significant coupling is between stretches and bends localized on the same CH2/CH3 group. Spectral simulations using the local mode approach are in excellent agreement with experiment.

  9. Infrared laser spectroscopy of the n-propyl and i-propyl radicals: Stretch-bend Fermi coupling in the alkyl CH stretch region

    NASA Astrophysics Data System (ADS)

    Franke, Peter R.; Tabor, Daniel P.; Moradi, Christopher P.; Douberly, Gary E.; Agarwal, Jay; Schaefer, Henry F.; Sibert, Edwin L.

    2016-12-01

    The n-propyl and i-propyl radicals were generated in the gas phase via pyrolysis of n-butyl nitrite [CH3(CH2)3ONO] and i-butyl nitrite [(CH3)2CHCH2ONO], respectively. Nascent radicals were promptly solvated by a beam of He nanodroplets, and the infrared spectra of the radicals were recorded in the CH stretching region. Several previously unreported bands are observed between 2800 and 3150 cm-1. The CH stretching modes observed above 3000 cm-1 are in excellent agreement with CCSD(T) anharmonic frequencies computed using second-order vibrational perturbation theory. However, between 2800 and 3000 cm-1, the spectra of n- and i-propyl radicals become congested and difficult to assign due to the presence of multiple anharmonic resonance polyads. To model the spectrally congested region, Fermi and Darling-Dennison resonances are treated explicitly using "dressed" Hamiltonians and CCSD(T) quartic force fields in the normal mode representation, and the agreement with experiment is less than satisfactory. Computations employing local mode effective Hamiltonians reveal the origin of the spectral congestion to be strong coupling between the high frequency CH stretching modes and the lower frequency CHn bending/scissoring motions. The most significant coupling is between stretches and bends localized on the same CH2/CH3 group. Spectral simulations using the local mode approach are in excellent agreement with experiment.

  10. Kinetics of the transformation of n-propyl gallate and structural analogs in the perfused rat liver

    SciTech Connect

    Eler, Gabrielle Jacklin; Santos, Israel Souza; Giaretta de Moraes, Amarilis; Mito, Márcio Shigueaki; Comar, Jurandir Fernando; Peralta, Rosane Marina; Bracht, Adelar

    2013-11-15

    n-Propyl gallate and its analogs are used in foods and other products to prevent oxidation. In the liver the compound exerts several harmful effects, especially gluconeogenesis inhibition. The mode of transport and distribution of n-propyl gallate and its kinetics of biotransformation have not yet been investigated. To fill this gap the transformation, transport and distribution of n-propyl gallate and two analogs were investigated in the rat liver. Isolated perfused rat liver was used. n-Propyl gallate, methyl gallate, n-octyl gallate and transformation products were quantified by high pressure-liquid chromatography coupled to fluorescence detection. The interactions of n-propyl gallate and analogs with the liver presented three main characteristics: (1) the hydrolytic release of gallic acid from n-propyl gallate and methyl gallate was very fast compared with the subsequent transformations of the gallic acid moiety; (2) transport of the esters was very fast and flow-limited in contrast to the slow and barrier-limited transport of gallic acid; (3) the apparent distribution volume of n-propyl gallate, but probably also of methyl gallate and n-octyl gallate, greatly exceeded the water space in the liver, contrary to the gallic acid space which is smaller than the water space. It can be concluded that at low portal concentrations (< 50 μM) the gallic acid esters are 100% extracted during a single passage through the liver, releasing mainly gallic acid into the systemic circulation. For the latter a considerable time is required until complete biotransformation. The exposure of the liver to the esters, however, is quite prolonged due to extensive intracellular binding. - Highlights: • The liver binds very strongly n-propyl gallate and releases basically gallic acid. • n-propyl gallate and analogs undergo concentrative flow-limited distribution. • Gallic acid undergoes barrier-limited distribution and is slowly transformed. • The long residence time of n-propyl

  11. Studies on the Food Additive Propyl Gallate: Synthesis, Structural Characterization, and Evaluation of the Antioxidant Activity

    ERIC Educational Resources Information Center

    Garrido, Jorge; Garrido, E. Manuela; Borges, Fernanda

    2012-01-01

    Antioxidants are additives largely used in industry for delaying, retarding, or preventing the development of oxidative deterioration. Propyl gallate (E310) is a phenolic antioxidant extensively used in the food, cosmetics, and pharmaceutical industries. A series of lab experiments have been developed to teach students about the importance and…

  12. Rotational spectra of methyl ethyl and methyl propyl nitrosamines. Conformational assignment, internal rotation and quadrupole coupling

    NASA Astrophysics Data System (ADS)

    Walker, A. R. Hight; Lou, Qi; Bohn, Robert K.; Novick, Stewart E.

    1995-02-01

    A structural determination of two carcinogenic nitrosamines, methyl ethyl and methyl propyl nitrosamine, was performed. Microwave spectra were gathered from both a Stark cell spectrometer and a pulsed jet Fabry-Perot Fourier transform microwave spectrometer. Each rotational transition is split into quadrupole hyperfine components by two nitrogen nuclei. This quadrupole pattern is doubled by a low barrier methyl rotor which produces resolvable A and E states. Rotational spectra were assigned for one conformer of methyl ethyl nitrosamine and two conformers of methyl propyl nitrosamine. The lowest energy conformers of each compound, according to empirical force field calculations, were assigned. The structure found for methyl ethyl nitrosamine has the nitrosyl oxygen on the methyl side with the terminal methyl group of the ethyl chain in the gauche position (OMG). Both conformers of methyl propyl nitrosamine have the same skeletal structure as the methyl ethyl compound; one conformer has the terminal methyl of the propyl group in the anti position (OMGA) while the other conformer has this methyl in the gauche position (OMGG -). Rotational constants and quadrupole coupling constants are reported for each assigned species. A barrier to internal rotation of the N-methyl group in each compound is also reported.

  13. Synthesis of 3-Methyl-4-(4-methylbenzoyl)-1-phenyl-pyrazol-5-One: How to Avoid O-Acylation

    ERIC Educational Resources Information Center

    Kurteva, Vanya B.; Petrova, Maria A.

    2015-01-01

    In this laboratory experiment, students synthesize 3-methyl-4-(4-methylbenzoyl)-1-phenyl-pyrazol-5-one by selective C-acylation of 3-methyl-1-phenyl-1H-pyrazol-5-one. Calcium hydroxide is used to push the tautomeric equilibrium toward the enol form, to protect the hydroxyl functionality as a complex, to trap the liberated hydrogen chloride, and to…

  14. Safety assessment of propyl paraben: a review of the published literature.

    PubMed

    Soni, M G; Burdock, G A; Taylor, S L; Greenberg, N A

    2001-06-01

    Propyl paraben (CAS no. 94-13-3) is a stable, non-volatile compound used as an antimicrobial preservative in foods, drugs and cosmetics for over 50 years. It is an ester of p-hydroxybenzoate. Propyl paraben is readily absorbed via the gastrointestinal tract and dermis. It is hydrolyzed to p-hydroxybenzoic acid, conjugated and the conjugates are rapidly excreted in the urine. There is no evidence of accumulation. Acute toxicity studies in animals indicate that propyl paraben is relatively non-toxic by both oral and parenteral routes, although it is mildly irritating to the skin. Following chronic administration, no-observed-effect levels (NOEL) as high as 1200-4000 mg/kg have been reported and a no-observed-adverse-effect level (NOAEL) in the rat of 5500 mg/kg is posited. Propyl paraben is not carcinogenic, mutagenic or clastogenic. It is not cytogenic in vitro in the absence of carboxyesterase inhibitors. The mechanism of propyl paraben may be linked to mitochondrial failure dependent on induction of membrane permeability transition accompanied by the mitochondrial depolarization and depletion of cellular ATP through uncoupling of oxidative phosphorylation. Sensitization has occurred when medications containing parabens have been applied to damaged or broken skin. Parabens have been implicated in numerous cases of contact sensitivity associated with cutaneous exposure, but high concentrations of 5-15% in patch testing are needed to elicit reaction in susceptible individuals. Allergic reactions to ingested parabens have been reported, although rigorous evidence of the allergenicity of ingested paraben is lacking.

  15. Pyrazole-substituted Near-infrared Cyanine Dyes Exhibit pH-dependent Fluorescence Lifetime Properties

    PubMed Central

    Lee, Hyeran; Berezin, Mikhail Y.; Tang, Rui; Zhegalova, Natalia; Achilefu, Samuel

    2012-01-01

    Near-infrared heptamethine cyanine dye is functionalized with pyrazole derivatives at the meso-position to induce pH-dependent photophysical properties. The presence of pyrazole unsubstituted at 1-position is essential to induce pH-dependent fluorescence intensity and lifetime changes of these dyes. Replacement of meso-chloro group of cyanine dye IR820 with 1N-unsubstituted pyrazole resulted in the pH-dependent fluorescence lifetime changes from 0.93 ns in neutral media to 1.27 ns in acidic media in DMSO. Time resolved emission spectra (TRES) revealed that at lower pH, the pyrazole consists of fluorophores with two distinct lifetimes, which corresponds to pH sensitive and non-pH sensitive species. In contrast, 1N-substituted pyrazoles do not exhibit pH response, suggesting excited state electron transfer as the mechanism of pH-dependent fluorescence lifetime sensitivity for this class of compounds. PMID:23094959

  16. Electronic Configuration of Five-Coordinate High-Spin Pyrazole-Ligated Iron(II) Porphyrinates

    PubMed Central

    Hu, Chuanjiang; Noll, Bruce C.; Schulz, Charles E.; Scheidt, W. Robert

    2010-01-01

    Pyrazole, a neutral nitrogen ligand and an isomer of imidazole, has been used as a fifth ligand to prepare two new species, [Fe(TPP)(Hdmpz)] and [Fe(Tp-OCH3PP)(Hdmpz)] (Hdmpz = 3,5-dimethylpyrazole), the first structurally characterized examples of five-coordinate iron(II) porphyrinates with a nonimidazole neutral ligand. Both complexes are characterized by X-ray crystallography, and structures show common features for five-coordinate iron(II) species, such as an expanded porphinato core, large equatorial Fe–Np bond distances and a significant out-of-plane displacement of the iron(II) atom. The Fe–N(pyrazole) and Fe–Np bond distances are similar to those in imidazole-ligated species. These suggest that the coordination abilities to iron(II) for imidazole and pyrazole are very similar even though pyrazole is less basic than imidazole. Mössbauer studies reveal that [Fe(TPP)(Hdmpz)] has the same behavior as those of imidazole-ligated species, such as negative quadrupole splitting values and relative large asymmetry parameters. Both the structures and Mössbauer spectra suggest pyrazole-ligated five-coordinate iron(II) porphyrinates have the same electronic configuration as imidazole-ligated species. PMID:21047081

  17. Electronic configuration of five-coordinate high-spin pyrazole-ligated iron(II) porphyrinates.

    PubMed

    Hu, Chuanjiang; Noll, Bruce C; Schulz, Charles E; Scheidt, W Robert

    2010-12-06

    Pyrazole, a neutral nitrogen ligand and an isomer of imidazole, has been used as a fifth ligand to prepare two new species, [Fe(TPP)(Hdmpz)] and [Fe(Tp-OCH(3)PP)(Hdmpz)] (Hdmpz = 3,5-dimethylpyrazole), the first structurally characterized examples of five-coordinate iron(II) porphyrinates with a nonimidazole neutral ligand. Both complexes are characterized by X-ray crystallography, and structures show common features for five-coordinate iron(II) species, such as an expanded porphyrinato core, large equatorial Fe-N(p) bond distances, and a significant out-of-plane displacement of the iron(II) atom. The Fe-N(pyrazole) and Fe-N(p) bond distances are similar to those in imidazole-ligated species. These suggest that the coordination abilities to iron(II) for imidazole and pyrazole are very similar even though pyrazole is less basic than imidazole. Mössbauer studies reveal that [Fe(TPP)(Hdmpz)] has the same behavior as those of imidazole-ligated species, such as negative quadrupole splitting values and relative large asymmetry parameters. Both the structures and the Mössbauer spectra suggest pyrazole-ligated five-coordinate iron(II) porphyrinates have the same electronic configuration as imidazole-ligated species.

  18. Inhibition of the mitochondrial permeability transition by cyclosporin A prevents pyrazole plus lipopolysaccharide-induced liver injury in mice.

    PubMed

    Zhuge, Jian; Cederbaum, Arthur I

    2009-02-01

    Previous results showed that pyrazole potentiates lipopolysaccharide (LPS)-induced liver injury in mice. Mechanisms involved the overexpression of cytochrome P450 2E1 (CYP2E1), oxidative stress, and activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). The current study was carried out to test the hypothesis that the mitochondria permeability transition (MPT) plays a role in this pyrazole plus LPS toxicity. Mice were injected intraperitoneally with pyrazole for 2 days, followed by a challenge with LPS with or without treatment with cyclosporin A (CsA), an inhibitor of the MPT. Serum alanine aminotransferase and aspartate aminotransferase were increased by pyrazole plus LPS treatment, and CsA treatment could attenuate these increases. CsA also prevented pyrazole plus LPS-induced hepatocyte necrosis. Formation of 4-hydroxynonenal protein adducts and 3-nitrotyrosine protein adducts in liver tissue was increased by the pyrazole plus LPS treatment, and CsA treatment blunted these increases. Swelling, cytochrome c release from mitochondria to the cytosol, and lipid peroxidation were increased in mitochondria isolated from the pyrazole plus LPS-treated mice, and CsA treatment prevented these changes. CsA did not prevent the increased levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-alpha), pp38 MAPK, and p-JNK2. In conclusion, although CsA does not prevent elevations in upstream mediators of the pyrazole plus LPS toxicity (iNOS, TNF-alpha, CYP2E1, MAPK), it does protect mice from the pyrazole plus LPS-induced liver toxicity by preventing the MPT and release of cytochrome c and decreasing mitochondrial oxidative stress. These results indicate that mitochondria are the critical targets of pyrazole plus LPS in mediating liver injury.

  19. Agonist-activated ion channels

    PubMed Central

    Colquhoun, David

    2006-01-01

    This paper looks at ion channels as an example of the pharmacologist's stock in trade, the action of an agonist on a receptor to produce a response. Looked at in this way, ion channels have been helpful because they are still the only system which is simple enough for quantitative investigation of transduction mechanisms. A short history is given of attempts to elucidate what happens between the time when agonist first binds, and the time when the channel opens. PMID:16402101

  20. Reactions of OH and Cl with isopropyl formate, isobutyl formate, n-propyl isobutyrate and isopropyl isobutyrate

    NASA Astrophysics Data System (ADS)

    Zhang, Y. J.; Liang, P.; Jiang, Z. H.; Cazaunau, M.; Daële, V.; Mu, Y. J.; Mellouki, A.

    2014-05-01

    The rate coefficients for the reactions of OH with isopropyl formate, isobutyl formate, n-propyl isobutyrate and isopropyl isobutyrate have been determined using both absolute and relative methods. The relative rate method has been also used to measure the room temperature rate coefficient for the reaction of Cl with the same esters. In addition, a series of runs conducted on the OH-initiated oxidation of isopropyl formate, isobutyl formate and n-propyl isobutyrate showed the formation of acetone from the three reactions. The formation of propanal was also observed for n-propyl isobutyrate.

  1. Synthesis and biological evaluation of pyrazole derivatives containing thiourea skeleton as anticancer agents.

    PubMed

    Lv, Peng-Cheng; Li, Huan-Qiu; Sun, Juan; Zhou, Yang; Zhu, Hai-Liang

    2010-07-01

    Two series of pyrazole derivatives designing for potential EGFR kinase inhibitors have been discovered. Some of them exhibited significant EGFR inhibitory activity. Compound 3-(3,4-dimethylphenyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (C5) displayed the most potent EGFR inhibitory activity with IC₅₀ of 0.07 μM, which was comparable to the positive control erlotinib. Docking simulation was performed to position compound C5 into the EGFR active site to determine the probable binding model. Antiproliferative assay results indicating that some of the pyrazole derivatives own high antiproliferative activity against MCF-7. Compound C5 showed significant antiproliferative activity against MCF-7 with IC₅₀ of 0.08 μM. Therefore, compound C5 with potent inhibitory activity in tumor growth inhibition would be a potential anticancer agent.

  2. Hydrogen bonding in the crystal structure of the molecular salt of pyrazole-pyrazolium picrate.

    PubMed

    Su, Ping; Song, Xue-Gang; Sun, Ren-Qiang; Xu, Xing-Man

    2016-06-01

    The asymmetric unit of the title organic salt [systematic name: 1H-pyrazol-2-ium 2,4,6-tri-nitro-phenolate-1H-pyrazole (1/1)], H(C3H4N2)2 (+)·C6H2N3O7 (-), consists of one picrate anion and one hydrogen-bonded dimer of a pyrazolium monocation. The H atom involved in the dimer N-H⋯N hydrogen bond is disordered over both symmetry-unique pyrazole mol-ecules with occupancies of 0.52 (5) and 0.48 (5). In the crystal, the component ions are linked into chains along [100] by two different bifurcated N-H⋯(O,O) hydrogen bonds. In addition, weak C-H⋯O hydrogen bonds link inversion-related chains, forming columns along [100].

  3. Efficient ultrasound-assisted synthesis, spectroscopic, crystallographic and biological investigations of pyrazole-appended quinolinyl chalcones

    NASA Astrophysics Data System (ADS)

    Prasath, R.; Bhavana, P.; Sarveswari, S.; Ng, Seik Weng; Tiekink, Edward R. T.

    2015-02-01

    Two series of new quinolinyl chalcones containing a pyrazole group, 3a-f and 4a-r, have been synthesized by Claisen-Schmidt condensation of the derivatives of 2-methyl-3-acetylquinoline with either substituted 1,3-diphenyl-1H-pyrazole-4-carbaldehyde or 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde in 76-93% yield under ultrasonic method. The compounds were characterized using IR, 1H NMR and ESI-MS spectroscopic methods and, for representative compounds, by X-ray crystallography. An E-configuration about the Cdbnd C ethylene bond has been established via 1H NMR spectroscopy and X-ray crystallography. These compounds show promising anti-microbial properties, with 4a and 3e being the most potent against bacterial and fungal strains, respectively and the methoxy substituted compounds showed moderate anti-oxidant activity.

  4. Histamine H1 receptors mediate vasodilation in guinea-pig ileum resistance vessels: characterization with computer-assisted videomicroscopy and new selective agonists.

    PubMed

    Bungardt, E; Buschauer, A; Moser, U; Schunack, W; Lambrecht, G; Mutschler, E

    1992-10-06

    Histamine receptors on guinea-pig ileum submucosal arterioles (outside diameter 40-80 microns) were studied in vitro using a computer-assisted videomicroscopy system (Diamtrak). Histamine receptor agonists investigated in this study were histamine, the H1 receptor-selective compound, 2-[2-(3-fluorophenyl)-4-imidazolyl]ethanamine (VZ 20), the H2 receptor-selective compounds, dimaprit, impromidine, (+/-)-N1-[3-(4-fluorophenyl)-3-(pyridin-2-yl)propyl]- N2-[3-(1H-imidazol-4-yl)propyl]guanidine (arpromidine) and (+/-)-N1-[3-(3,4-difluorophenyl)-3-(pyridin-2-yl)propyl]- N2-[3-(1H-imidazol-4-yl)propyl]guanidine (BU-E-75), as well as the H3 receptor-selective drug, (R)-alpha-methylhistamine ((R)-alpha-MeHA). Applied to vessels at resting tone, the agonists (1 nM-300 microM) did not change arteriolar diameter. Vessels preconstricted by 10 microM noradrenaline showed similar concentration-dependent vasodilations with histamine and VZ 20 (pD2 = 5.38 and 5.36, respectively). This histamine-induced vasodilation was not affected by tetrodotoxin (0.5 microM) or indomethacin (1 microM), but was completely abolished in the presence of 1 microM of the H1 receptor antagonist, mepyramine. Calculation of the antagonist affinity of mepyramine for the histamine receptors in submucosal arterioles yielded a pA2 of 9.46. In contrast to histamine and VZ 20, the H2 receptor agonist, dimaprit, and the H3 receptor agonist, (R)-alpha-MeHA, were ineffective at preconstricted arterioles. The guanidine-type H2 receptor agonists, impromidine, apromidine and BU-E-75, produced vasodilation at noradrenaline-preconstricted arterioles (-log EC50 = 4.47, 5.30 and 5.39, respectively) but, in contrast to histamine, were ineffective at arterioles preconstricted by U-46619 (300 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Curcumin-derived pyrazoles and isoxazoles: Swiss army knives or blunt tools for Alzheimer's disease?

    PubMed

    Narlawar, Rajeshwar; Pickhardt, Marcus; Leuchtenberger, Stefanie; Baumann, Karlheinz; Krause, Sabine; Dyrks, Thomas; Weggen, Sascha; Mandelkow, Eckhard; Schmidt, Boris

    2008-01-01

    Curcumin binds to the amyloid beta peptide (Abeta) and inhibits or modulates amyloid precursor protein (APP) metabolism. Therefore, curcumin-derived isoxazoles and pyrazoles were synthesized to minimize the metal chelation properties of curcumin. The decreased rotational freedom and absence of stereoisomers was predicted to enhance affinity toward Abeta(42) aggregates. Accordingly, replacement of the 1,3-dicarbonyl moiety with isosteric heterocycles turned curcumin analogue isoxazoles and pyrazoles into potent ligands of fibrillar Abeta(42) aggregates. Additionally, several compounds are potent inhibitors of tau protein aggregation and depolymerized tau protein aggregates at low micromolar concentrations.

  6. Diethyl 2-[phen­yl(pyrazol-1-yl)meth­yl]propane­dioate

    PubMed Central

    Meskini, Ihssan; Daoudi, Maria; Daran, Jean-Claude; Zouihri, Hafid; Ben Hadda, Taibi

    2010-01-01

    There are two independent mol­ecules in the asymmetric unit of the title compound, C17H20N2O4, which differ slightly in the orientation of the phenyl ring and carbonyl groups with respect to the pyrazole unit. In the first mol­ecule, the dihedral angle between the phenyl and pyrazole rings is 68.99 (13)° while the two carbonyl groups make a dihedral angle of 72.1 (4)°. The corresponding values in the second mol­ecule are 68.54 (14) and 71.5 (4)°, respectively. PMID:21579078

  7. 5-Amino-pyrazoles as potent and selective p38[alpha] inhibitors

    SciTech Connect

    Das, Jagabandhu; Moquin, Robert V.; Dyckman, Alaric J.; Li, Tianle; Pitt, Sidney; Zhang, Rosemary; Shen, Ding Ren; McIntyre, Kim W.; Gillooly, Kathleen; Doweyko, Arthur M.; Newitt, John A.; Sack, John S.; Zhang, Hongjian; Kiefer, Susan E.; Kish, Kevin; McKinnon, Murray; Barrish, Joel C.; Dodd, John H.; Schieven, Gary L.; Leftheris, Katerina

    2012-02-07

    The synthesis and structure-activity relationships (SAR) of p38{alpha} MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38{alpha} MAP kinase with excellent cellular potency toward the inhibition of TNF{alpha} production. Compound 2j was highly efficacious in vivo in inhibiting TNF{alpha} production in an acute murine model of TNF{alpha} production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38{alpha} is also disclosed.

  8. Recent advanced in bioactive systems containing pyrazole fused with a five membered heterocycle.

    PubMed

    Raffa, Demetrio; Maggio, Benedetta; Raimondi, Maria Valeria; Cascioferro, Stella; Plescia, Fabiana; Cancemi, Gabriella; Daidone, Giuseppe

    2015-06-05

    In this review we report the recent advances in bioactive system containing pyrazole fused with a five membered heterocycle, covering the time span of the last decade. All of them are represented around the common structure of the pyrazole ring fused with another five membered heterocycle containing the nitrogen, sulfur and oxygen atoms in all their possible combinations. The classification we have used is based in terms of the therapeutic area providing, when possible, some general conclusions on the targets and mechanisms of action as well as the structure-activity relationships of the molecules.

  9. Positron-labeled dopamine agonists for probing the high affinity states of dopamine subtype 2 receptors.

    PubMed

    Hwang, Dah-Ren; Narendran, Raj; Laruelle, Marc

    2005-01-01

    It is well documented that guanidine nucleotide-coupled dopamine subtype 2 receptors (D2) are configured in high and low affinity states for the dopamine agonist in vitro. However, it is still unclear whether these functional states exist in vivo. We hypothesized that positron-labeled D2 agonist and Positron Emission Tomography can be used to probe these functional states noninvasively. Recently, we demonstrated in nonhuman primates that N-[11C]propyl-norapomorphine (NPA), a full D2 agonist, is a suitable tracer for imaging the high affinity states of D2 receptors in vivo. We also developed kinetic modeling method to derive receptor parameters, such as binding potential (BP) and specific uptake ratios (V3''). When coupled with a dopamine releasing drug, amphetamine, NPA was found to be more sensitive than antagonist tracers, such as [11C]raclopride (RAC), to endogenous dopamine concentration changes (by about 42%). This finding suggests that NPA is a superior tracer for reporting endogenous DA concentration. In addition, the difference of the BP or V3'' of NPA and RAC under control and amphetamine challenge conditions could be used to estimate the functional states of D2 receptors in vivo. On the basis of our findings and the assumptions that NPA binds only to the high affinity states and RAC binds equally to both affinity states, we proposed that about 70% of the D2 receptors are configured in the high affinity states in vivo.

  10. Interaction of single-walled carbon nanotubes with poly(propyl ether imine) dendrimers

    SciTech Connect

    Jayamurugan, G.; Rajesh, Y. B. R. D.; Jayaraman, N.; Vasu, K. S.; Kumar, S.; Sood, A. K.; Vasumathi, V.; Maiti, P. K.

    2011-03-14

    We study the complexation of nontoxic, native poly(propyl ether imine) dendrimers with single-walled carbon nanotubes (SWNTs). The interaction was monitored by measuring the quenching of inherent fluorescence of the dendrimer. The dendrimer-nanotube binding also resulted in the increased electrical resistance of the hole doped SWNT, due to charge-transfer interaction between dendrimer and nanotube. This charge-transfer interaction was further corroborated by observing a shift in frequency of the tangential Raman modes of SWNT. We also report the effect of acidic and neutral pH conditions on the binding affinities. Experimental studies were supplemented by all atom molecular dynamics simulations to provide a microscopic picture of the dendrimer-nanotube complex. The complexation was achieved through charge transfer and hydrophobic interactions, aided by multitude of oxygen, nitrogen, and n-propyl moieties of the dendrimer.

  11. Structure and internal dynamics of n-propyl acetate studied by microwave spectroscopy and quantum chemistry

    NASA Astrophysics Data System (ADS)

    Sutikdja, Lilian W.; Stahl, Wolfgang; Sironneau, Vincent; Nguyen, Ha Vinh Lam; Kleiner, Isabelle

    2016-10-01

    The gas phase structure of n-propyl acetate was determined using molecular beam Fourier transform microwave spectroscopy from 2 to 40 GHz supplemented by quantum chemical calculations. The experimental spectrum revealed only one conformer with trans configuration and C1 symmetry. Torsional splittings occurred for each rotational transition due to the internal rotation of the acetyl methyl group with a barrier height of approximately 100 cm-1. The XIAM and BELGI-C1 codes were applied to reproduce the spectrum within the measurement accuracy. This investigation on n-propyl acetate has accomplished our studies on saturated linear aliphatic acetates CH3COOCnH2n+1 (n = 1-6).

  12. Interaction of single-walled carbon nanotubes with poly(propyl ether imine) dendrimers

    NASA Astrophysics Data System (ADS)

    Jayamurugan, G.; Vasu, K. S.; Rajesh, Y. B. R. D.; Kumar, S.; Vasumathi, V.; Maiti, P. K.; Sood, A. K.; Jayaraman, N.

    2011-03-01

    We study the complexation of nontoxic, native poly(propyl ether imine) dendrimers with single-walled carbon nanotubes (SWNTs). The interaction was monitored by measuring the quenching of inherent fluorescence of the dendrimer. The dendrimer-nanotube binding also resulted in the increased electrical resistance of the hole doped SWNT, due to charge-transfer interaction between dendrimer and nanotube. This charge-transfer interaction was further corroborated by observing a shift in frequency of the tangential Raman modes of SWNT. We also report the effect of acidic and neutral pH conditions on the binding affinities. Experimental studies were supplemented by all atom molecular dynamics simulations to provide a microscopic picture of the dendrimer-nanotube complex. The complexation was achieved through charge transfer and hydrophobic interactions, aided by multitude of oxygen, nitrogen, and n-propyl moieties of the dendrimer.

  13. Detection of a branched alkyl molecule in the interstellar medium: iso-propyl cyanide

    NASA Astrophysics Data System (ADS)

    Belloche, Arnaud; Garrod, Robin T.; Müller, Holger S. P.; Menten, Karl M.

    2014-09-01

    The largest noncyclic molecules detected in the interstellar medium (ISM) are organic with a straight-chain carbon backbone. We report an interstellar detection of a branched alkyl molecule, iso-propyl cyanide (i-C3H7CN), with an abundance 0.4 times that of its straight-chain structural isomer. This detection suggests that branched carbon-chain molecules may be generally abundant in the ISM. Our astrochemical model indicates that both isomers are produced within or upon dust grain ice mantles through the addition of molecular radicals, albeit via differing reaction pathways. The production of iso-propyl cyanide appears to require the addition of a functional group to a nonterminal carbon in the chain. Its detection therefore bodes well for the presence in the ISM of amino acids, for which such side-chain structure is a key characteristic.

  14. Laboratory Evaluation of Drop-in Solvent Alternatives to n-Propyl Bromide for Vapor Degreasing

    NASA Technical Reports Server (NTRS)

    Mitchell, Mark A.; Lowrey, Nikki M.

    2012-01-01

    Based on this limited laboratory study, solvent blends of trans-1,2 dichloroethylene with HFEs, HFCs, or PFCs appear to be viable alternatives to n-propyl bromide for vapor degreasing. The lower boiling points of these blends may lead to greater solvent loss during use. Additional factors must be considered when selecting a solvent substitute, including stability over time, VOC, GWP, toxicity, and business considerations.

  15. 1,5-Bis(4-iso­propyl­benzyl­idene)thio­carbonohydrazide

    PubMed Central

    Han, Yan-Hua; Zhao, Qiao; Wang, Yong

    2013-01-01

    The title compound, C21H26N4S, was synthesized by the condensation reaction of 4-iso­propyl­benzaldehyde with thio­carbohydrazide in ethanol. The planes of the two benzene rings in the mol­ecule are inclined at 22.6 (1)°. In the crystal, pairs of inter­molecular N—H⋯S hydrogen bonds link the mol­ecules into inversion dimers. PMID:24454099

  16. Spectroscopic Study and Astronomical Detection of Vibrationally Excited n-PROPYL Cyanide

    NASA Astrophysics Data System (ADS)

    Müller, Holger S. P.; Wehres, Nadine; Wilkins, Olivia H.; Lewen, Frank; Schlemmer, Stephan; Walters, Adam; Vicente, Rémi; Liu, Delong; Garrod, Robin T.; Belloche, Arnaud; Menten, Karl M.

    2016-06-01

    We have obtained ALMA data of Sagittarius (Sgr for short) B2(N) between 84.0 and 114.4 GHz in its Early Science Cycles 0 and 1. We have focused our analyses on the northern, secondary hot molecular core Sgr B2(N2) because of the smaller line widths. The survey led to the first detection of a branched alkyl compound, iso-propyl cyanide, i-C_3H_7CN, in space besides the ˜2.5 times more abundant straight chain isomer n-propyl cyanide, a molecule which we had detected in our IRAM 30 m survey. We suspected to be able to detect n-propyl cyanide in vibrationally excited states in our ALMA data. We have recorded laboratory rotational spectra of this molecule in three large frequency regions and identified several excited vibrational states. The analyses of these spectra have focused on the 36 to 70 GHz and 89 to 127 GHz regions and on the four lowest excited vibrational states of both the lower lying gauche- and the slightly higher lying anti-conformer for which rotational constants had been published. We will present results of our laboratory spectroscopic investigations and will report on the detection of these states toward Sgr B2(N2). A. Belloche et al., Science 345 (2014) 1584. A. Belloche et al., A&A 499 (2009) 215. E. Hirota, J. Chem. Phys. 37 (1962) 2918.

  17. Vibrational-Torsional Coupling Revealed in the Infrared Spectrum of He-Solvated n-PROPYL Radical

    NASA Astrophysics Data System (ADS)

    Moradi, Christopher P.; Broderick, Bernadette M.; Agarwal, Jay; Schaefer, Henry F., III.; Douberly, Gary E.

    2015-06-01

    The n-propyl and i-propyl radicals were generated in the gas phase via pyrolysis of n-butyl nitrite (CH3(CH2)3ONO) and i-butyl nitrite (CH3CH(CH3)CH2ONO) precursors, respectively. Nascent radicals were promptly solvated by a beam of He nanodroplets, and the infrared spectra of the radicals were recorded in the C-H stretching region. In addition to three vibrations of n-propyl previously measured in an Ar matrix, we observe many unreported bands between 2800 and 3150 wn, which we attribute to propyl radicals. The C-H stretching modes observed above 2960 wn for both radicals are in excellent agreement with anharmonic frequencies computed using VPT2. Between 2800 and 2960 wn, however, the spectra of n-propyl and i-propyl radicals become quite congested and difficult to assign due to the presence of multiple anharmonic resonances. Computations reveal the likely origin of the spectral congestion to be strong coupling between the high frequency C-H stretching modes and a lower frequency torsional motion, which modulates quite substantially a through-space hyperconjugation interaction. Pacansky, et. al., J. Phys. Chem. 1977, 81, 2149.

  18. Antinociceptive property of new 4-acyl-arylhydrazone pyrazole compounds.

    PubMed

    Matheus, M E; Oliveira, L F; Freitas, A C; Carvalho, A M; Barreiro, E J

    1991-01-01

    A series of new 4-acyl-arylhydrazone pyrazole compounds were tested for antinociceptive activity using the inhibition of abdominal contortions induced by acetylcholine (4 mg/kg, ip) in the mouse. Dipyrone was used for comparison of the antinociceptive potency of the compounds being tested. All drugs were administered po in saline (dipyrone) or in propylene glycol (4-acyl-arylhydrazones). The maximum response induced by dipyrone (86% inhibition) was assigned an efficacy index of 1.0. Although none of the compounds had an efficacy index greater than 1.0, all three reached 1.0. The two most potent compounds, W1d and W1g, which also had an efficacy similar to that of dipyrone, contain a p-N(CH3)2 and m-OH,p-OCH3 group in the aromatic ring of the acyl-hydrazone, respectively. W1d presented the lowest antinociceptive ED50 in the series (1.41 mg/kg) and was eleven times more potent than dipyrone (ED50 = 15.80 mg/kg). Other substitutions at the para position had lower potency than W1d. The present results indicate that the introduction of a group at the para position of the acyl-arylhydrazone ring increases the antinociceptive activity of these compounds to provide compounds of the same efficacy but greater potency than dipyrone to which these new compounds are structurally related. Other assays of nociceptive activity are being used to characterize the mechanism of action of the potential new drugs.

  19. Laboratory spectroscopic study and astronomical detection of vibrationally excited n-propyl cyanide

    NASA Astrophysics Data System (ADS)

    Müller, Holger S. P.; Walters, Adam; Wehres, Nadine; Belloche, Arnaud; Wilkins, Olivia H.; Liu, Delong; Vicente, Rémi; Garrod, Robin T.; Menten, Karl M.; Lewen, Frank; Schlemmer, Stephan

    2016-11-01

    Context. We performed a spectral line survey called Exploring Molecular Complexity with ALMA (EMoCA) toward Sagittarius B2(N) between 84.1 and 114.4 GHz with the Atacama Large Millimeter/submillimeter Array (ALMA) in its Cycles 0 and 1. We determined line intensities of n-propyl cyanide in the ground vibrational states of its gauche and anti conformers toward the hot molecular core Sagittarius B2(N2) which suggest that we should also be able to detect transitions pertaining to excited vibrational states. Aims: We wanted to determine spectroscopic parameters of low-lying vibrational states of both conformers of n-propyl cyanide to search for them in our ALMA data. Methods: We recorded laboratory rotational spectra of n-propyl cyanide in two spectral windows between 36 and 127 GHz. We searched for emission lines produced by these states in the ALMA spectrum of Sagittarius B2(N2). We modeled their emission and the emission of the ground vibrational states assuming local thermodynamic equilibrium (LTE). Results: We have made extensive assignments of a- and b-type transitions of the four lowest vibrational states of the gauche conformer which reach J and Ka quantum numbers of 65 and 20, respectively. We assigned mostly a-type transitions for the anti conformer with J and Ka quantum numbers up to 48 and 24, respectively. Rotational and Fermi perturbations between two anti states allowed us to determine their energy difference. The resulting spectroscopic parameters enabled us to identify transitions of all four vibrational states of each conformer in our ALMA data. The emission features of all states, including the ground vibrational state, are well-reproduced with the same LTE modeling parameters, which gives us confidence in the reliability of the identifications, even for the states with only one clearly detected line. Conclusions: Emission features pertaining to the highest excited vibrational states of n-propyl cyanide reported in this work have been identified just

  20. Optimization of a pyrazole hit from FBDD into a novel series of indazoles as ketohexokinase inhibitors

    SciTech Connect

    Zhang, Xuqing; Song, Fengbing; Kuo, Gee-Hong; Xiang, Amy; Gibbs, Alan C.; Abad, Marta C.; Sun, Weimei; Kuo, Lawrence C.; Sui, Zhihua

    2013-11-20

    A series of indazoles have been discovered as KHK inhibitors from a pyrazole hit identified through fragment-based drug discovery (FBDD). The optimization process guided by both X-ray crystallography and solution activity resulted in lead-like compounds with good pharmaceutical properties.

  1. Combining silver- and organocatalysis: an enantioselective sequential catalytic approach towards pyrano-annulated pyrazoles.

    PubMed

    Hack, Daniel; Chauhan, Pankaj; Deckers, Kristina; Mizutani, Yusuke; Raabe, Gerhard; Enders, Dieter

    2015-02-11

    A one-pot asymmetric Michael addition/hydroalkoxylation sequence, catalyzed by a sequential catalytic system consisting of a squaramide and a silver salt, provides a new series of chiral pyrano-annulated pyrazole derivatives in excellent yields (up to 95%) and high enantioselectivities (up to 97% ee).

  2. Non-covalent interactions at bis(pyrazole)silver(i) or -gold(i) cations.

    PubMed

    García-Pacios, Vanesa; Arroyo, Marta; Antón, Noelia; Miguel, Daniel; Villafañe, Fernando

    2009-03-28

    The reaction of AgBF(4) with two equivalents of pzH (pyrazole) or dmpzH (3,5-dimethylpyrazole) leads to [Ag(pzH)(2)]BF(4) or [Ag(dmpzH)(2)]BF(4). The reaction of [AuCl(tht)] with an equimolar amount of dmpzH in refluxing hexane leads to [Au(dmpzH)(2)][AuCl(2)]. Similar complexes [Au(dmpzH)(2)]A (A = BF(4) or NO(3)) are obtained from [AuCl(tht)], two equivalents of dmpzH, and AgBF(4) or AgNO(3). The complexes [Ag(dmpzH)(2)]BF(4) and [Au(dmpzH)(2)]A (A = [AuCl(2)], BF(4) or NO(3)) crystallize as ionic pairs where the NH groups of the pyrazoles are involved in short cation-anion interactions. The nitrate complex crystallizes as a dimer, where both molecules are supported by pi-stacking interactions between the pyrazole rings. The crystal structure of [Ag(pzH)(2)]BF(4) reveals a three dimensional array of cations and anions. In solution, [Ag(pzH)(2)]BF(4) and [Ag(dmpzH)(2)]BF(4) undergo intermolecular processes involving pyrazole decoordination, and behave as 1/1 electrolytes; whereas dimethylpyrazole gold complexes do not display any dynamic behavior, and show cation-anion association also in solution.

  3. Mixing with microwaves: solvent-free and catalyst-free synthesis of pyrazoles and diazepines

    EPA Science Inventory

    A simple and facile condensation of hydrazines/hydrazides and diamines with 1,3-diketones/β-ketoester leads to the preparation of pyrazoles and diazepines in high yields. This eco-friendly protocol is accelerated by microwave heating and efficiently carried out without any r...

  4. Role of Rydberg states in the photostability of heterocyclic dimers: the case of pyrazole dimer.

    PubMed

    Zilberg, Shmuel; Haas, Yehuda

    2012-11-26

    A new route for the nonradiative decay of photoexcited, H-bonded, nitrogen-containing, heterocyclic dimers is offered and exemplified by a study of the pyrazole dimer. In some of these systems the N(3s) Rydberg state is the lowest excited singlet state. This state is formed by direct light absorption or by nonradiative transition from the allowed ππ* state. An isomer of this Rydberg state is formed by H atom transfer to the other component of the dimer. The newly formed H-bonded radical pair is composed of two radicals (a H-adduct of pyrazole, a heterocyclic analogue of the NH(4) radical) and the pyrazolium π-radical. It is calculated to have a shallow local minimum and is the lowest point on the PES of the H-pyrazole/pyrazolium radical pair. This species can cross back to the ground state of the original dimer through a relatively small energy gap and compete with the H-atom loss channel, known for the monomer. In both Rydberg dimers, an electron occupies a Rydberg orbital centered mostly on one of the two components of the dimer. This Rydberg Center Shift (RCS) mechanism, proposed earlier (Zilberg, S.; Kahan, A.; Haas, Y. Phys. Chem. Chem. Phys. 2012, 14, 8836), leads to deactivation of the electronically excited dimer while keeping it intact. It, thus, may explain the high photostability of the pyrazole dimer as well as other heterocyclic dimers.

  5. N-Substituted pyrazole-3-carboxamides as inhibitors of human 15-lipoxygenase.

    PubMed

    Pelcman, Benjamin; Sanin, Andrei; Nilsson, Peter; Schaal, Wesley; Olofsson, Kristofer; Krog-Jensen, Christian; Forsell, Pontus; Hallberg, Anders; Larhed, Mats; Boesen, Thomas; Kromann, Hasse; Claesson, Hans-Erik

    2015-08-01

    High-throughput screening was used to find selective inhibitors of human 15-lipoxygenase-1 (15-LOX-1). One hit, a 1-benzoyl substituted pyrazole-3-carboxanilide (1a), was used as a starting point in a program to develop potent and selective 15-LOX-1 inhibitors.

  6. Dopamine agonist therapy in hyperprolactinemia.

    PubMed

    Webster, J

    1999-12-01

    Introduction of the dopamine agonist bromocriptine heralded a major advance in the management of hyperprolactinemic disorders. Although its side effects of nausea, dizziness and headache and its short elimination half-life are limiting factors, its efficacy established it as a reference compound against the activity of which several dopamine agonists, like pergolide, lysuride, metergoline, terguride and dihydroergocristine, fell by the wayside. More recently, two new agents, cabergoline and quinagolide, have been introduced and appear to offer considerable advantages over bromocriptine. Cabergoline, an ergoline D2 agonist, has a long plasma half-life that enables once- or twice-weekly administration. Quinagolide, in contrast, is a nonergot D2 agonist with an elimination half-life intermediate between those of bromocriptine and cabergoline, allowing the drug to be administered once daily. Comparative studies indicate that cabergoline is clearly superior to bromocriptine in efficacy (prolactin suppression, restoration of gonadal function) and in tolerability. In similar studies, quinagolide appeared to have similar efficacy and superior tolerability to that of bromocriptine. Results of a small crossover study indicate that cabergoline is better tolerated, with a trend toward activity superior to that of quinagolide. In hyperprolactinemic men and in women not seeking to become pregnant, cabergoline may be regarded as the treatment of choice.

  7. The structures of two scorpionates: thallium tetrakis(3-phenyl-1H-pyrazol-1-yl)borate and potassium tetrakis(3-cyclopropyl-1H-pyrazol-1-yl)borate.

    PubMed

    Infantes, Lourdes; Claramunt, Rosa M; Sanz, Dionisia; Alkorta, Ibon; Elguero, José

    2016-11-01

    The introduction of poly(1H-pyrazolyl)borate anions, better known as scorpionates, as negatively charged ligands for a great diversity of metal cations has had a tremendous influence in coordination chemistry. The structures of two salts of tetrakispyrazolylborate, namely [tetrakis(3-phenyl-1H-pyrazol-1-yl)borato]thallium(I), [Tl(C36H28BN8)], and catena-poly[potassium-[μ2-tetrakis(3-cyclopropyl-1H-pyrazol-1-yl)borato

  8. Room Temperature ICl-Induced Dehydration/Iodination of 1-Acyl-5-hydroxy-4,5-dihydro-1H-pyrazoles. A Selective Route to Substituted 1-Acyl-4-iodo-1H-pyrazoles

    PubMed Central

    Waldo, Jesse P.; Mehta, Saurabh

    2013-01-01

    A number of new functionally substituted 1-acyl-5-hydroxy-4,5-dihydro-1H-pyrazoles have been prepared in moderate to excellent yields from the corresponding 2-alkyn-1-ones. The resulting dihydropyrazoles undergo dehydration and iodination in the presence of ICl and Li2CO3 at room temperature to provide 1-acyl-4-iodo-1H-pyrazoles. PMID:18665643

  9. Supramolecular Columnar Liquid Crystals with Tapered-Shape Simple Pyrazoles Obtained by Efficient Henry/Michael Reactions.

    PubMed

    Blanco, Hugo; Iguarbe, Verónica; Barberá, Joaquín; Serrano, José Luis; Elduque, Anabel; Giménez, Raquel

    2016-03-24

    A straightforward synthesis of mesogenic pyrazoles starting from benzaldehydes by a combination of efficient Henry and Michael reactions led to novel supramolecular liquid crystals. The mesogens are fluorescent 3,5-dimethyl-4-(di or trialkoxyphenyl)pyrazoles and, in spite of the tapered shape of these molecules and their structural simplicity (only one phenyl ring), columnar liquid-crystal phases were formed that are stable at room temperature. The self-assembled structure was studied by XRD and the columnar cross section contains two molecules on average with an antiparallel arrangement of pyrazoles interacting through hydrogen bonds. In contrast, the single-crystal structure of a trimethoxy analog did not show hydrogen-bonded pyrazoles but chains of head-to-tail arranged molecules.

  10. Access to Silylated Pyrazole Derivatives by Palladium-Catalyzed C-H Activation of a TMS group.

    PubMed

    Mistico, Laetitia; Querolle, Olivier; Meerpoel, Lieven; Angibaud, Patrick; Durandetti, Muriel; Maddaluno, Jacques

    2016-07-04

    A simple and efficient approach to new silylated heterocycles of potential interest in medicinal chemistry is presented. A set of bromophenyl trimethylsilyl pyrazole intermediates can be transformed by direct organometallic routes into two families of regioisomeric iodoaryl substrates; using either arylzinc or aryllithium chemistry, the TMS group remains on the pyrazole ring or translocates to the aryl moiety. These two families can then be efficiently transformed into benzo silino pyrazoles thanks to a single-step cyclization relying on the Pd-catalyzed activation of a non-activated C(sp(3) )-H bond alpha to a silicon atom. The experimental conditions used, which are fully compatible with the pyrazole ring, suggest that this reaction evolves through a concerted metalation-deprotonation (CMD) mechanism.

  11. Kinetics of the transformation of n-propyl gallate and structural analogs in the perfused rat liver.

    PubMed

    Eler, Gabrielle Jacklin; Santos, Israel Souza; de Moraes, Amarilis Giaretta; Mito, Márcio Shigueaki; Comar, Jurandir Fernando; Peralta, Rosane Marina; Bracht, Adelar

    2013-11-15

    n-Propyl gallate and its analogs are used in foods and other products to prevent oxidation. In the liver the compound exerts several harmful effects, especially gluconeogenesis inhibition. The mode of transport and distribution of n-propyl gallate and its kinetics of biotransformation have not yet been investigated. To fill this gap the transformation, transport and distribution of n-propyl gallate and two analogs were investigated in the rat liver. Isolated perfused rat liver was used. n-Propyl gallate, methyl gallate, n-octyl gallate and transformation products were quantified by high pressure-liquid chromatography coupled to fluorescence detection. The interactions of n-propyl gallate and analogs with the liver presented three main characteristics: (1) the hydrolytic release of gallic acid from n-propyl gallate and methyl gallate was very fast compared with the subsequent transformations of the gallic acid moiety; (2) transport of the esters was very fast and flow-limited in contrast to the slow and barrier-limited transport of gallic acid; (3) the apparent distribution volume of n-propyl gallate, but probably also of methyl gallate and n-octyl gallate, greatly exceeded the water space in the liver, contrary to the gallic acid space which is smaller than the water space. It can be concluded that at low portal concentrations (<50μM) the gallic acid esters are 100% extracted during a single passage through the liver, releasing mainly gallic acid into the systemic circulation. For the latter a considerable time is required until complete biotransformation. The exposure of the liver to the esters, however, is quite prolonged due to extensive intracellular binding.

  12. 40 CFR 721.10565 - Ethanol, 2,2′-[[3-[(2-hydroxyethyl)amino]propyl]imino]bis-, N-(hydrogenated tallow alkyl) derivs.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Ethanol, 2,2â²- propyl]imino]bis-, N... Significant New Uses for Specific Chemical Substances § 721.10565 Ethanol, 2,2′- propyl]imino]bis-, N...) The chemical substance identified as ethanol, 2,2′- propyl]imino]bis-, N-(hydrogenated tallow...

  13. 40 CFR 721.10565 - Ethanol, 2,2′-[[3-[(2-hydroxyethyl)amino]propyl]imino]bis-, N-(hydrogenated tallow alkyl) derivs.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Ethanol, 2,2â²- propyl]imino]bis-, N... Significant New Uses for Specific Chemical Substances § 721.10565 Ethanol, 2,2′- propyl]imino]bis-, N...) The chemical substance identified as ethanol, 2,2′- propyl]imino]bis-, N-(hydrogenated tallow...

  14. Tailored design of ruthenium molecular catalysts with 2,2'-bypyridine-6,6'-dicarboxylate and pyrazole based ligands for water oxidation.

    PubMed

    Daniel, Quentin; Wang, Lei; Duan, Lele; Li, Fusheng; Sun, Licheng

    2016-10-07

    With the incorporation of pyrazole and DMSO as axial ligands, a series of tailor-designed Ru water oxidation catalysts [Ru(bda)(DMSO)(L)] (H2bda = 2,2'-bypyridine-6,6'-dicarboxylic acid; DMSO = dimethyl sulfoxide; L = pyrazole, A-1; 4-Br-3-methyl pyrazole, B-1) and [Ru(bda)(L)2] (L = pyrazole, A-2; 4-Br-3-methyl pyrazole, B-2) have been generated in situ from their corresponding precursors [Ru(κ3(O,N,N)-bda)(DMSO)x(L)3-x] which are in a zwitterionic form with an extra pyrazole based ligand in the equatorial position. Formation of the active catalyst has been investigated under pH 1.0 conditions. Electrochemistry and water oxidation activity of these catalysts were investigated. By fine tuning of the catalyst structure, the turnover frequency was increased up to 500 s(-1) and the stability over 6000 turnovers.

  15. Partial deletion of argininosuccinate synthase protects from pyrazole plus lipopolysaccharide-induced liver injury by decreasing nitrosative stress.

    PubMed

    Lu, Yongke; Leung, Tung Ming; Ward, Stephen C; Nieto, Natalia

    2012-02-01

    Argininosuccinate synthase (ASS) is the rate-limiting enzyme in the urea cycle. Along with nitric oxide synthase (NOS)-2, ASS endows cells with the L-citrulline/nitric oxide (NO·) salvage pathway to continually supply L-arginine from L-citrulline for sustained NO· generation. Because of the relevant role of NOS in liver injury, we hypothesized that downregulation of ASS could decrease the availability of intracellular substrate for NO· synthesis by NOS-2 and, hence, decrease liver damage. Previous work demonstrated that pyrazole plus LPS caused significant liver injury involving NO· generation and formation of 3-nitrotyrosine protein adducts; thus, wild-type (WT) and Ass+/- mice (Ass+/+ mice are lethal) were treated with pyrazole plus LPS, and markers of nitrosative stress, as well as liver injury, were analyzed. Partial ablation of Ass protected from pyrazole plus LPS-induced liver injury by decreasing nitrosative stress and hepatic and circulating TNFα. Moreover, apoptosis was prevented, since pyrazole plus LPS-treated Ass+/- mice showed decreased phosphorylation of JNK; increased MAPK phosphatase-1, which is known to deactivate JNK signaling; and lower cleaved caspase-3 than treated WT mice, and this was accompanied by less TdT-mediated dUTP nick end labeling-positive staining. Lastly, hepatic neutrophil accumulation was almost absent in pyrazole plus LPS-treated Ass+/- compared with WT mice. Partial Ass ablation prevents pyrazole plus LPS-mediated liver injury by reducing nitrosative stress, TNFα, apoptosis, and neutrophil infiltration.

  16. Thermodynamic functions of Ni(II) complexes with 5-(2-hydroxyphenyl)-pyrazole derivatives. A potentiometric study

    NASA Astrophysics Data System (ADS)

    Deosarkar, S. D.; Narwade, M. L.; Thakre, V. J.

    2013-10-01

    Proton-ligand dissociation constants of five biologically important pyrazole derivatives, viz. [5-(2-hydroxyphenyl)-3-(pyridin-3-yl)-4-benzoyl]-pyrazol (HPPBP), [5-(2-hydroxyphenyl)-3-(3-nitrophenyl)-4-(3-pyridinoyl)]-pyrazol (HPNPPP), [5-(2-hydroxyphenyl)-3-(3-nitrophenyl)-4-benzoyl]-pyrazol (HPNPBP), [5-(2-hydroxyphenyl)-3-phenyl-4-(3-pyridinoyl)]-pyrazol (HPPPP), and [5-(2-hydroxyphenyl)-3-(3-nitrophenyl)-4-(2-furoyl) pyrazol (HPNPFP) and metal ligand stability constants of their Ni(II) complexes in 70% (v/v) dioxane-water and 0.1 M KNO3 were determined at 298.15, 303.15, and 308.15 K by potentiometric method. Thermodynamic functions, such as, free energy change (Δ G ○), enthalpy change (Δ H ○) and entropy (Δ S ○) change for dissociation and complex formation have been estimated form temperature dependence of proton-ligand and metal-ligand stability constants and interpreted in terms of feasibility of these processes.

  17. Chromenopyrazoles: non-psychoactive and selective CB₁ cannabinoid agonists with peripheral antinociceptive properties.

    PubMed

    Cumella, Jose; Hernández-Folgado, Laura; Girón, Rocio; Sánchez, Eva; Morales, Paula; Hurst, Dow P; Gómez-Cañas, Maria; Gómez-Ruiz, Maria; Pinto, Diana C G A; Goya, Pilar; Reggio, Patricia H; Martin, María Isabel; Fernández-Ruiz, Javier; Silva, Artur M S; Jagerovic, Nadine

    2012-03-05

    The unwanted psychoactive effects of cannabinoid receptor agonists have limited their development as medicines. These CB₁-mediated side effects are due to the fact that CB₁ receptors are largely expressed in the central nervous system (CNS). As it is known that CB₁ receptors are also located peripherally, there is growing interest in targeting cannabinoid receptors located outside the brain. A library of chromenopyrazoles designed analogously to the classical cannabinoid cannabinol were synthesized, characterized, and tested for cannabinoid activity. Radioligand binding assays were used to determine their affinities at CB₁ and CB₂ receptors. Structural features required for CB₁/CB₂ affinity and selectivity were explored by molecular modeling. Some compounds in the chromenopyrazole series were observed to be selective CB₁ ligands. These modeling studies suggest that full CB₁ selectivity over CB₂ can be explained by the presence of a pyrazole ring in the structure. The functional activities of selected chromenopyrazoles were evaluated in isolated tissues. In vivo behavioral tests were then carried out on the most effective CB₁ cannabinoid agonist, 13 a. Chromenopyrazole 13 a did not induce modifications in any of the tested parameters on the mouse cannabinoid tetrad, thus discounting CNS-mediated effects. This lack of agonistic activity in the CNS suggests that this compound does not readily cross the blood-brain barrier. Moreover, 13 a can induce antinociception in a rat peripheral model of orofacial pain. Taking into account the negative results obtained with the hot-plate test, the antinociception induced by 13 a in the orofacial test could be mediated through peripheral mechanisms.

  18. Kinetics of tris (1-chloro-2-propyl) phosphate (TCIPP) metabolism in human liver microsomes and serum.

    PubMed

    Van den Eede, Nele; Tomy, Gregg; Tao, Fang; Halldorson, Thor; Harrad, Stuart; Neels, Hugo; Covaci, Adrian

    2016-02-01

    Tris(1-chloro-2-propyl) phosphate (TCIPP) is an emerging contaminant which is ubiquitous in the indoor and outdoor environment. Moreover, its presence in human body fluids and biota has been evidenced. Since no quantitative data exist on the biotransformation or stability of TCIPP in the human body, we performed an in vitro incubation of TCIPP with human liver microsomes (HLM) and human serum (HS). Two metabolites, namely bis(2-chloro-isopropyl) phosphate (BCIPP) and bis(1-chloro-2-propyl) 1-hydroxy-2-propyl phosphate (BCIPHIPP), were quantified in a kinetic study using HLM or HS (only BCIPP, the hydrolysis product) and LC-MS. The Michaelis-Menten model fitted best the NADPH-dependent formation of BCIPHIPP and BCIPP in HLM, with respective V(MAX) of 154 ± 4 and 1470 ± 110 pmol/min/mg protein and respective apparent K(m) of 80.2 ± 4.4 and 96.1 ± 14.5 μM. Hydrolases, which are naturally present in HLM, were also involved in the production of BCIPP. A HS paraoxonase assay could not detect any BCIPP formation above 38.6 ± 10.8 pmol/min/μL serum. Our data indicate that BCIPP is the major metabolite of TCIPP formed in the liver. To our knowledge, this is the first quantitative assessment of the stability of TCIPP in tissues of humans or any other species. Further research is needed to confirm whether these biotransformation reactions are associated with a decrease or increase in toxicity.

  19. Determination of rotary diffusivity of poly(n-propyl isocyanate) by molecular dynamics

    NASA Astrophysics Data System (ADS)

    Laso, M.; Jimeno, N.; Muneta, L. M.; Müller, M.

    2006-12-01

    The rotational dynamics of a nondilute solution of the rodlike polymer poly(n-propyl isocyanate) (PPIC) has been studied on an atomistic model by means of a large-scale classical molecular dynamics investigation. The rotary diffusivity of PPIC in toluene solution has been determined from the Einsteinian diffusion regime of the end-to-end vector on the surface of the unit sphere and has been found to be Dr=10.5×105(±2.7)s-1, which falls in the range of the experimental data available. A comparison of molecular dynamics predictions with theoretical and perturbation expansion predictions has also been performed.

  20. Determination of rotary diffusivity of poly(n-propyl isocyanate) by molecular dynamics.

    PubMed

    Laso, M; Jimeno, N; Muneta, L M; Müller, M

    2006-12-28

    The rotational dynamics of a nondilute solution of the rodlike polymer poly(n-propyl isocyanate) (PPIC) has been studied on an atomistic model by means of a large-scale classical molecular dynamics investigation. The rotary diffusivity of PPIC in toluene solution has been determined from the Einsteinian diffusion regime of the end-to-end vector on the surface of the unit sphere and has been found to be Dr=10.5x10(5)(+/-2.7) s-1, which falls in the range of the experimental data available. A comparison of molecular dynamics predictions with theoretical and perturbation expansion predictions has also been performed.

  1. Novel diazabicycloalkane delta opioid agonists.

    PubMed

    Loriga, Giovanni; Lazzari, Paolo; Manca, Ilaria; Ruiu, Stefania; Falzoi, Matteo; Murineddu, Gabriele; Bottazzi, Mirko Emilio Heiner; Pinna, Giovanni; Pinna, Gérard Aimè

    2015-09-01

    Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (δ) opioid agonists, as conformationally constrained homologues of the reference δ agonist (+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of δ opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3-7 showed δ agonism behaviour and remarkable affinity to δ receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved δ affinity and selectivity relative to SNC80.

  2. Conformational Change in Molecular Assembly of Nickel(II) Tetra(n-propyl)porphycene Triggered by Potential Manipulation.

    PubMed

    Yoshimoto, Soichiro; Kawamoto, Teppei; Okawara, Toru; Hisaeda, Yoshio; Abe, Masaaki

    2016-12-27

    Metal-coordinated porphyrin and related compounds are important for developing molecular architectures that mimic enzymes. Porphycene, a structural isomer of porphyrin, has shown unique properties in semiartificial myoglobin. To explore its potential as a molecular building block, we studied the molecular assembly of nickel(II) tetra(n-propyl)porphycene (NiTPrPc), a metalloporphycene with introduced tetra n-propyl moieties, on the Au(111) electrode surface using in situ scanning tunneling microscopy. Because of the low molecular symmetry of NiTPrPc, the molecular assembly undergoes unique phase transitions due to conformational change of the n-propyl moieties. The phase transitions can be precisely controlled by the electrode potential, demonstrating that the latter can play an important role in the porphycene molecular assembly on Au surface. This new discovery indicates possible uses of this porphycene framework in molecular engineering.

  3. Identification of a 2-phenyl-substituted octahydrobenzo[f]quinoline as a dopamine D3 receptor-selective full agonist ligand

    PubMed Central

    Clark, Alia H.; McCorvy, John D.; Conley, Jason M.; Williams, Whitney K.; Bekkam, Markondaiah; Watts, Val J.

    2012-01-01

    This work describes the identification of a novel class of octahydrobenzo[f]quinolines as dopamine D3-selective full agonists. We developed a facile method that utilizes Suzuki coupling for easy incorporations of various substituted pendant rings into the scaffold. A small focused library of octahydrobenzo[f]quinolines 5 was synthesized, and these compounds demonstrated at least 14-fold D2-like selectivity over D1 in native porcine striatal tissue. Furthermore, n-propyl analog 5f was found to be a high affinity (ki = 1.1 nM) D3 dopamine full agonist with 145-fold selectivity over the D2 receptor and about 840-fold selectivity over the D1 receptor. 1. PMID:23018094

  4. Dichlorido(3,5-dimethyl-1H-pyrazole)[(3,5-dimethyl-1H-pyrazol-1-yl)(o-tol­yl)methanone]palladium(II)

    PubMed Central

    Nelana, Simphiwe M.; Kruger, Gert J.; Darkwa, James

    2008-01-01

    In the title compound, [PdCl2(C5H8N2)(C12H12N2O)], the Pd atom adopts a slightly distorted trans-PdCl2N2 square-planar arrangement. The different Pd—N bond lengths can be related to the the electron-withdrawing effect of the o-toluoyl group on the substituted pyrazole ligand. The complex crystallizes as centrosymmetric hydrogen-bonded dimers through N—H⋯Cl linkages. PMID:21200554

  5. Regulation of membrane cholecystokinin-2 receptor by agonists enables classification of partial agonists as biased agonists.

    PubMed

    Magnan, Rémi; Masri, Bernard; Escrieut, Chantal; Foucaud, Magali; Cordelier, Pierre; Fourmy, Daniel

    2011-02-25

    Given the importance of G-protein-coupled receptors as pharmacological targets in medicine, efforts directed at understanding the molecular mechanism by which pharmacological compounds regulate their presence at the cell surface is of paramount importance. In this context, using confocal microscopy and bioluminescence resonance energy transfer, we have investigated internalization and intracellular trafficking of the cholecystokinin-2 receptor (CCK2R) in response to both natural and synthetic ligands with different pharmacological features. We found that CCK and gastrin, which are full agonists on CCK2R-induced inositol phosphate production, rapidly and abundantly stimulate internalization. Internalized CCK2R did not rapidly recycle to plasma membrane but instead was directed to late endosomes/lysosomes. CCK2R endocytosis involves clathrin-coated pits and dynamin and high affinity and prolonged binding of β-arrestin1 or -2. Partial agonists and antagonists on CCK2R-induced inositol phosphate formation and ERK1/2 phosphorylation did not stimulate CCK2R internalization or β-arrestin recruitment to the CCK2R but blocked full agonist-induced internalization and β-arrestin recruitment. The extreme C-terminal region of the CCK2R (and more precisely phosphorylatable residues Ser(437)-Xaa(438)-Thr(439)-Thr(440)-Xaa(441)-Ser(442)-Thr(443)) were critical for β-arrestin recruitment. However, this region and β-arrestins were dispensable for CCK2R internalization. In conclusion, this study allowed us to classify the human CCK2R as a member of class B G-protein-coupled receptors with regard to its endocytosis features and identified biased agonists of the CCK2R. These new important insights will allow us to investigate the role of internalized CCK2R·β-arrestin complexes in cancers expressing this receptor and to develop new diagnosis and therapeutic strategies targeting this receptor.

  6. Metal complexes with the quinolone antibacterial agent N-propyl-norfloxacin: synthesis, structure and bioactivity.

    PubMed

    Efthimiadou, Eleni K; Psomas, George; Sanakis, Yiannis; Katsaros, Nikos; Karaliota, Alexandra

    2007-03-01

    Nine new metal complexes of the quinolone antibacterial agent N-propyl-norfloxacin, pr-norfloxacin, with VO(2+), Mn(2+), Fe(3+), Co(2+), Ni(2+), Zn(2+), MoO(2)(2+), Cd(2+) and UO(2)(2+) have been prepared and characterized with physicochemical and spectroscopic techniques while molecular mechanics calculations for Fe(3+), VO(2+) and MoO(2)(2+) complexes have been performed. In all complexes, pr-norfloxacin acts as a bidentate deprotonated ligand bound to the metal through the pyridone and one carboxylate oxygen atoms. All complexes are six-coordinate with slightly distorted octahedral geometry. For the complex VO(N-propyl-norfloxacinato)(2)(H(2)O) the axial position, trans to the vanadyl oxygen, is occupied by one pyridone oxygen atom. The investigation of the interaction of the complexes with calf-thymus DNA has been performed with diverse spectroscopic techniques and has shown that the complexes can be bound to calf-thymus DNA resulting to a B-->A DNA transition. The antimicrobial activity of the complexes has been tested on three different microorganisms. The complexes show equal or decreased biological activity in comparison to the free pr-norfloxacin except UO(2)(pr-norf)(2) which shows better inhibition against S. aureus.

  7. Isoform-Specific Biased Agonism of Histamine H3 Receptor Agonists.

    PubMed

    Riddy, Darren M; Cook, Anna E; Diepenhorst, Natalie A; Bosnyak, Sanja; Brady, Ryan; Mannoury la Cour, Clotilde; Mocaer, Elisabeth; Summers, Roger J; Charman, William N; Sexton, Patrick M; Christopoulos, Arthur; Langmead, Christopher J

    2017-02-01

    The human histamine H3 receptor (hH3R) is subject to extensive gene splicing that gives rise to a large number of functional and nonfunctional isoforms. Despite the general acceptance that G protein-coupled receptors can adopt different ligand-induced conformations that give rise to biased signaling, this has not been studied for the H3R; further, it is unknown whether splice variants of the same receptor engender the same or differential biased signaling. Herein, we profiled the pharmacology of histamine receptor agonists at the two most abundant hH3R splice variants (hH3R445 and hH3R365) across seven signaling endpoints. Both isoforms engender biased signaling, notably for 4-[3-(benzyloxy)propyl]-1H-imidazole (proxyfan) [e.g., strong bias toward phosphorylation of glycogen synthase kinase 3β (GSK3β) via the full-length receptor] and its congener 3-(1H-imidazol-4-yl)propyl-(4-iodophenyl)-methyl ether (iodoproxyfan), which are strongly consistent with the former's designation as a "protean" agonist. The 80 amino acid IL3 deleted isoform hH3R365 is more permissive in its signaling than hH3R445: 2-(1H-imidazol-5-yl)ethyl imidothiocarbamate (imetit), proxyfan, and iodoproxyfan were all markedly biased away from calcium signaling, and principal component analysis of the full data set revealed divergent profiles for all five agonists. However, most interesting was the identification of differential biased signaling between the two isoforms. Strikingly, hH3R365 was completely unable to stimulate GSK3β phosphorylation, an endpoint robustly activated by the full-length receptor. To the best of our knowledge, this is the first quantitative example of differential biased signaling via isoforms of the same G protein-coupled receptor that are simultaneously expressed in vivo and gives rise to the possibility of selective pharmacological targeting of individual receptor splice variants.

  8. Design, synthesis, characterization and anti-inflammatory evaluation of novel pyrazole amalgamated flavones.

    PubMed

    Chavan, Hemant V; Bandgar, Babasaheb P; Adsul, Laxman K; Dhakane, Valmik D; Bhale, Pravin S; Thakare, Vishnu N; Masand, Vijay

    2013-03-01

    A series of novel pyrazole amalgamated flavones has been designed and synthesized from 1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole 6. The structures of regioisomers 6 and 7 were resolved by 2D (1)H-(1)H COSY, (1)H-(13)C HSQC and (1)H-(13)C HMBC experiments. The newly synthesized compounds were tested for their in vitro COX inhibition and in vivo carrageenan induced hind paw edema in rats and acetic acid induced vascular permeability in mice. Although the compounds have inhibitory profile against both COX-1 and COX-2, some of the compounds are found to be selective against COX-2, supported by inhibition of paw edema and vascular permeability. Docking studies were also carried out to determine the structural features which sway the anti-inflammatory activity of the tested compounds. The keto and phenolic -OH are major factors that are prominently involved in interaction with COX-2 active site.

  9. Experimental and theoretical investigation of optical nonlinearities in (nitrovinyl)-1H-pyrazole derivative

    NASA Astrophysics Data System (ADS)

    Dwivedi, Y.; de Boni, L.; Gonçalves, P. J.; Mairink, L. M.; Menegatti, R.; Fonseca, T. L.; Zilio, S. C.

    2013-03-01

    This work reports on the optical nonlinearities of a newly synthesized pyrazole derivative, namely (E)-1-(4-chlorophenyl)-4-(2-nitrovinyl)-1H-pyrazole. The Z-scan technique with femtosecond laser pulses was used to determine the two-photon absorption (2PA) cross-section spectrum, which presents a maximum of 67 GM at 690 nm. We have combined hyper-Rayleigh scattering (HRS) experiments and second-order Møller-Plesset perturbation theory (MP2) calculations to study the first hyperpolarizability (βHRS). It was found that the MP2/6-311+G(d) model, taking into account solvent and dispersion effects, provides the βHRS value of 40 × 10-30 cm5/esu for the compound, in good agreement with the experimental result of 45 ± 2 × 10-30 cm5/esu.

  10. Synthesis and bioevaluation of pyrazole-benzimidazolone hybrids as novel human 4-Hydroxyphenylpyruvate dioxygenase inhibitors.

    PubMed

    Xu, Yu-Ling; Lin, Hong-Yan; Ruan, Xu; Yang, Sheng-Gang; Hao, Ge-Fei; Yang, Wen-Chao; Yang, Guang-Fu

    2015-03-06

    4-Hydroxyphenylpyruvate dioxygenase (HPPD), an essential enzyme in tyrosine catabolism, is an important target for treating type I tyrosinemia. Inhibition of HPPD can effectively alleviate the symptoms of type I tyrosinemia. However, only one commercial HPPD inhibitor, 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione (NTBC), has been available for clinical use so far. In the present study, a series of novel pyrazole-benzimidazolone hybrids were designed, synthesized and evaluated as potent human HPPD inhibitors. Most of the new compounds displayed significant inhibitory activity against the recombinant human HPPD. Moreover, compound 9l was identified as the most potent candidate with IC50 value of 0.021 μM against recombinant human HPPD, about 3-fold more potent than NTBC. Thus the pyrazole-benzimidazolone hybrid has great potential to be further developed for the treatment of type I tyrosinemia.

  11. Design, Synthesis and Bioactivities of Novel Dichloro-Allyloxy-Phenol-Containing Pyrazole Oxime Derivatives.

    PubMed

    Dai, Hong; Ye, Linyu; Zhuang, Huiyang; Dai, Baojiang; Fang, Yuan; Shi, Yujun

    2015-12-08

    In this study, in order to find novel biologically active pyrazole oxime compounds, a number of dichloro-allyloxy-phenol-containing pyrazole oximes were designed and synthesized according to the method of active group combination. All of the target compounds were confirmed by ¹H-NMR, (13)C-NMR and elemental analysis. In addition, bioassays showed that all of the newly synthesized compounds had no acaricidal activity against Tetranychus cinnabarinus and low insecticidal activity against Aphis craccivora at tested concentrations. However, most of them displayed excellent insecticidal activity against Oriental armyworm at a concentration of 500 μg/mL, and some designed compounds still exhibited potent insecticidal activity against Oriental armyworm even at the dose of 20 μg/mL, especially compounds 7f, 7n and 7p had 100%, 90% and 90% inhibition rates, respectively, which were comparable to that of the control pyridalyl.

  12. Sulfate-bridged dimeric trinuclear copper(II)–pyrazolate complex with three different terminal ligands

    PubMed Central

    Mezei, Gellert

    2016-01-01

    The reaction of CuSO4·5H2O, 4-chloro­pyrazole (4-Cl-pzH) and tri­ethyl­amine (Et3N) in di­methyl­formamide (DMF) produced crystals of di­aqua­hexa­kis­(μ-4-chloro­pyrazolato-κ2 N:N′)bis­(N,N-di­methyl­formamide)di-μ3-hydroxido-bis­(μ4-sulfato-κ4 O:O′:O′′:O′′)hexa­copper(II) N,N-di­methyl­formamide tetra­solvate dihydrate, [Cu3(OH)(SO4)(C3H2ClN2)3(C3H7NO)(H2O)]2·4C3H7NO·2H2O. The centrosymmetric dimeric molecule consists of two trinuclear copper–pyrazolate units bridged by two sulfate ions. The title compound provides the first example of a trinuclear copper–pyrazolate complex with three different terminal ligands on the Cu atoms, and also the first example of such complex with a strongly binding basal sulfate ion. Within each trinuclear unit, the CuII atoms are bridged by μ-pyrazolate groups and a central μ3-OH group, and are coordinated by terminal sulfate, H2O and DMF ligands, respectively. Moreover, the sulfate O atoms coordinate at the apical position to the Cu atoms of the symmetry-related unit, providing square–pyramidal coordination geometry around each copper cation. The metal complex and solvent mol­ecules are involved in O—H⋯O hydrogen bonds, leading to a two-dimensional network parallel to (10-1). PMID:27536383

  13. Sulfate-bridged dimeric trinuclear copper(II)-pyrazolate complex with three different terminal ligands.

    PubMed

    Mezei, Gellert

    2016-08-01

    The reaction of CuSO4·5H2O, 4-chloro-pyrazole (4-Cl-pzH) and tri-ethyl-amine (Et3N) in di-methyl-formamide (DMF) produced crystals of di-aqua-hexa-kis-(μ-4-chloro-pyrazolato-κ(2) N:N')bis-(N,N-di-methyl-formamide)di-μ3-hydroxido-bis-(μ4-sulfato-κ(4) O:O':O'':O'')hexa-copper(II) N,N-di-methyl-formamide tetra-solvate dihydrate, [Cu3(OH)(SO4)(C3H2ClN2)3(C3H7NO)(H2O)]2·4C3H7NO·2H2O. The centrosymmetric dimeric molecule consists of two trinuclear copper-pyrazolate units bridged by two sulfate ions. The title compound provides the first example of a trinuclear copper-pyrazolate complex with three different terminal ligands on the Cu atoms, and also the first example of such complex with a strongly binding basal sulfate ion. Within each trinuclear unit, the Cu(II) atoms are bridged by μ-pyrazolate groups and a central μ3-OH group, and are coordinated by terminal sulfate, H2O and DMF ligands, respectively. Moreover, the sulfate O atoms coordinate at the apical position to the Cu atoms of the symmetry-related unit, providing square-pyramidal coordination geometry around each copper cation. The metal complex and solvent mol-ecules are involved in O-H⋯O hydrogen bonds, leading to a two-dimensional network parallel to (10-1).

  14. A novel, potent, oral active and safe antinociceptive pyrazole targeting kappa opioid receptors.

    PubMed

    Trevisan, Gabriela; Rossato, Mateus F; Walker, Cristiani I B; Oliveira, Sara M; Rosa, Fernanda; Tonello, Raquel; Silva, Cássia R; Machado, Pablo; Boligon, Aline A; Martins, Marcos A P; Zanatta, Nilo; Bonacorso, Hélio G; Athayde, Margareth L; Rubin, Maribel A; Calixto, João B; Ferreira, Juliano

    2013-10-01

    Pyrazole compounds are an intriguing class of compounds with potential analgesic activity; however, their mechanism of action remains unknown. Thus, the goal of this study was to explore the antinociceptive potential, safety and mechanism of action of novel 1-pyrazole methyl ester derivatives, which were designed by molecular simplification, using in vivo and in vitro methods in mice. First, tree 1-pyrazole methyl ester derivatives (DMPE, MPFE, and MPCIE) were tested in the capsaicin test and all presented antinociceptive effect; however the MPClE (methyl 5-trichloromethyl-3-methyl-1H-pyrazole-1-carboxylate) was the most effective. Thus, we selected this compound to assess the effects and mechanisms in subsequent pain models. MPCIE produced antinociception when administered by oral, intraperitoneal, intrathecal and intraplantar routes and was effective in the capsaicin and the acetic acid-induced nociception tests. Moreover, this compound reduced the hyperalgesia in diverse clinically-relevant pain models, including postoperative, inflammatory, and neuropathic nociception in mice. The antinociception produced by orally administered MPClE was mediated by κ-opioid receptors, since these effects were prevented by systemically pre-treatment with naloxone and the κ-opioid receptor antagonist nor-binaltorphimine. Moreover, MPCIE prevented binding of the κ-opioid ligand [(3)H]-CI-977 in vitro (IC₅₀ of 0.68 (0.32-1.4) μM), but not the TRPV1 ([(3)H]-resiniferatoxin) or the α₂-adrenoreceptor ([(3)H]-idazoxan) binding. Regarding the drug-induced side effects, oral administration of MPClE did not produce sedation, constipation or motor impairment at its active dose. In addition, MPCIE was readily absorbed after oral administration. Taken together, these results demonstrate that MPClE is a novel, potent, orally active and safe analgesic drug that targets κ-opioid receptors.

  15. Discovery of pyrazole as C-terminus of selective BACE1 inhibitors.

    PubMed

    Zou, Yiquan; Xu, Lei; Chen, Wuyan; Zhu, Yiping; Chen, Tiantian; Fu, Yan; Li, Li; Ma, Lanping; Xiong, Bing; Wang, Xin; Li, Jian; He, Jianhua; Zhang, Haiyan; Xu, Yechun; Li, Jia; Shen, Jingkang

    2013-10-01

    We recently discovered and reported dual inhibitor 5 of AChE and BACE1 with N-benzylpiperidine ethyl as C-terminus. Compound 5 showed potent inhibitory activities for BACE1, and could reduce endogenous Aβ1-40 production in APP transgenic mice. In present work, we rapidly identified substituted triazole as the C-terminus of compound 5 by replacing the benzylpiperidine ethyl group with click chemistry and tested these synthesized compounds by in situ screening assay. As revealed by the crystal structures of BACE1 in complex with our triazole compound 12, we found that Pro70 and Thr72 located in the flap region were the critical components for binding with these inhibitors. With the aid of the crystal structure, a new series of five-membered heterocyclic compounds was prepared in order to explore the structure-activity relationship (SAR) of this class of molecules. From these efforts, pyrazole was discovered as a novel C-terminus of BACE1 inhibitors. After further modification of pyrazole with variable substituents, compound 37 exhibited good potency in enzyme inhibition assay (IC50=0.025 μM) and compound 33 showed moderate inhibition effects on Aβ production of APP transfected HEK293 cells. Moreover, these pyrazole derivatives demonstrated good selectivity versus cathepsin D. Our results indicated that the vicinity of Pro70 and Thr72 might be utilized as a subsite, and the discovered pyrazole derivatives might provide useful hints for developing novel BACE1 inhibitors as anti-AD drugs.

  16. Toxic fluorine compounds. The use of the ω-fluorine atom in the study of the metabolism of fatty acids containing ethyl, n-propyl and isopropyl branches

    PubMed Central

    Pattison, F. L. M.; Peters, D. A. V.

    1966-01-01

    1. Some ω-fluoroalkanoic acids containing a branched ethyl, n-propyl or isopropyl group in the α- or β-position have been prepared. 2. A study of the toxicity of these acids revealed that the ethyl group partially inhibited, and the n-propyl and isopropyl groups completely inhibited, the normal processes of oxidative degradation. PMID:5911518

  17. Efficient catalytic phosphate ester cleavage by binuclear zinc(II) pyrazolate complexes as functional models of metallophosphatases.

    PubMed

    Penkova, Larysa V; Maciag, Anna; Rybak-Akimova, Elena V; Haukka, Matti; Pavlenko, Vadim A; Iskenderov, Turganbay S; Kozłowski, Henryk; Meyer, Franc; Fritsky, Igor O

    2009-07-20

    A series of dizinc(II) complexes based on the pyrazolate ligands 3-[(1E)-N-hydroxyethanimidoyl]-4-methyl-1H-pyrazole-5-carboxylic acid (H(3)L(1)), (1E,1'E)-1,1'-(4-methyl-1H-pyrazole-3,5-diyl)diethanone dihydrazone (HL(2)), (E,E)-(4-methyl-1H-pyrazole-3,5-diyl)bis(methylmethanone) dioxime (H(3)L(3)), (E,E)-(4-phenyl-1H-pyrazole-3,5-diyl)bis(phenylmethanone) dioxime (H(3)L(4)), and 1H-pyrazole-3,5-dicarboxylic acid (H(3)L(5)) have been synthesized and investigated as functional models of phosphoesterases, focusing on correlations between the hydrolytic activity and molecular parameters of the bimetallic core. Speciation of the various dizinc complexes in solution has been determined potentiometrically, and the structures in the solid state have been established by X-ray crystallography. The hydrolysis of two phosphoesters, an RNA model 2-hydroxypropyl-p-nitrophenyl phosphate (HPNP) and the pesticide paraoxon-ethyl (POE), promoted by the dinuclear phosphoesterase model complexes has been investigated in DMSO/buffered water (1:1) at 50 degrees C as a function of complex concentration, substrate concentration, and pH. Drastic differences in the hydrolytic activities of [Zn(2)(HL(1))(2)](0), [Zn(2)(L(2))(2)](2+), [Zn(2)(H(2)L(3))(2)](2+), and [Zn(2)(HL(5))(2)](2-) are observed and can be attributed to molecular peculiarities. Pyrazolate-bridged dinuclear zinc(II) complexes seem to provide a sufficient number of coordination sites for both activating the substrate and generating the nucleophile, where the phosphate esters are preferentially bound in a bidentate bridging fashion (in the case of HPNP) and in a monodentate fashion (in the case of POE).

  18. STRUCTURAL BASIS OF TRANSCRIPTION INHIBITION BY CBR HYDROXAMIDINES AND CBR PYRAZOLES

    PubMed Central

    Wang, Xinyue; Gigliotti, Matthew; Liu, Shuang; Zhang, Yu; Das, Deepankar; Michalchuk, Trevor; Ebright, Yon W.; Talaue, Meliza; Connell, Nancy; Ebright, Richard H.

    2015-01-01

    SUMMARY CBR hydroxamidines are small-molecule inhibitors of bacterial RNA polymerase (RNAP) discovered through high-throughput-screening of synthetic-compound libraries. CBR pyrazoles are structurally related RNAP inhibitors discovered through “scaffold hopping” from CBR hydroxamidines. CBR hydroxamidines and pyrazoles selectively inhibit Gram-negative bacterial RNAP and exhibit selective antibacterial activity against Gram-negative bacteria. Here, we report crystal structures of the prototype CBR hydroxamidine, CBR703, and two CBR pyrazoles in complex with E. coli RNAP holoenzyme. In addition, we define the full resistance determinant for CBR703, show that the binding site and resistance determinant for CBR703 do not overlap the binding sites and resistance determinants of other characterized RNAP inhibitors, show that CBR703 exhibits no or minimal cross-resistance with other characterized RNAP inhibitors, and show that co-administration of CBR703 with other RNAP inhibitors results in additive antibacterial activities. The results set the stage for structure-based optimization of CBR inhibitors as antibacterial drugs. PMID:26190576

  19. Supramolecular structures and columnar mesophase induction in nondiscoid pyrazoles by complexation to rhodium(I).

    PubMed

    Giménez, Raquel; Elduque, Anabel; López, José Antonio; Barbera, Joaquín; Cavero, Emma; Lantero, Ignacio; Oro, Luis A; Serrano, José Luis

    2006-12-11

    Several new cis-[RhCl(CO)2(Ln)] complexes have been prepared using different polycatenar pyrazole ligands (Ln) in order to obtain columnar liquid crystalline arrangements. The topology of the ligand plays an essential role, and a mesophase is induced at room temperature from a nonmesogenic pyrazole only when it is symmetrically substituted with six decyloxy chains. The single-crystal structure of a methoxy-substituted analogue, 3,5-bis(3,4,5-trimethoxyphenyl)pyrazole, is formed by globular tetrameric structures held together by H-bonding. However, parallel dimers are present in the corresponding cis-chlorodicarbonylrhodium(I) complex, a situation that explains the induction of a columnar mesophase in the decyloxy-substituted complex. The XRD pattern of the mesophase is consistent with a hexagonal symmetry in which the columns are formed by molecules assembled in an antiparallel mode. The crystal-to-mesophase transition was also detected by spectroscopic techniques as a shift in the IR carbonyl stretching bands and the appearance of a charge-transfer band in the absorption spectrum with thermochromic behavior.

  20. Synthesis and biofilm formation reduction of pyrazole-4-carboxamide derivatives in some Staphylococcus aureus strains.

    PubMed

    Cascioferro, Stella; Maggio, Benedetta; Raffa, Demetrio; Raimondi, Maria Valeria; Cusimano, Maria Grazia; Schillaci, Domenico; Manachini, Barbara; Plescia, Fabiana; Daidone, Giuseppe

    2016-11-10

    The ability of several N-phenyl-1H-pyrazole-4-carboxamide derivatives and other pyrazoles opportunely modified at the positions 3, 4 and 5, to reduce the formation of the biofilm in some Staphylococcus aureus strains (ATCC 29213, ATCC 25923 and ATCC 6538) were investigated. All the tested compounds were able, although to a different extent, to reduce the biofilm formation of the three bacterial strains considered. Among these, the 1-(2,5-dichlorophenyl)-5-methyl-N-phenyl-1H-pyrazole-4-carboxamide 14 resulted as the best inhibitor of biofilm formation showing an IC50 ranging from 2.3 to 32 μM, against all the three strains of S. aureus. Compound 14 also shows a good protective effect in vivo by improving the survival of wax moth larva (Galleria mellonella) infected with S. aureus ATCC 29213. These findings indicate that 14d is a potential lead compound for the development of new anti-virulence agents against S. aureus infections.

  1. Novel pyrazole integrated 1,3,4-oxadiazoles: synthesis, characterization and antimicrobial evaluation.

    PubMed

    Ningaiah, Srikantamurthy; Bhadraiah, Umesha K; Doddaramappa, Shridevi D; Keshavamurthy, Shubakara; Javarasetty, Chethan

    2014-01-01

    A novel series of 2-(5-methyl-1,3-diphenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazoles 7(a-m) were synthesized either by cyclization of N'-benzoyl-5-methyl-1,3-diphenyl-1H-pyrazole-4-carbohydrazide 4a using POCl3 at 120°C or by oxidative cyclization of hydrazones derived from various arylaldehyde and (E)-N'-benzylidene-5-methyl-1,3-diphenyl-1H-pyrazole-4-carbohydrazide 5(a-d) using chloramine-T as oxidant. Newly synthesized compounds were characterized by analytical and spectral (IR, (1)H NMR, (13)C NMR and LC-MS) methods. The synthesized compounds were evaluated for their antimicrobial activity and were compared with standard drugs. The compounds demonstrated potent to weak antimicrobial activity. Among the synthesized compounds, compound 7m emerged as an effective antimicrobial agent, while compounds 7d, 7f, 7i and 7l showed good to moderate activity. The minimum inhibitory concentration of the compounds was in the range of 20-50μgmL(-1) against bacteria and 25-55μgmL(-1) against fungi. The title compounds represent a novel class of potent antimicrobial agents.

  2. Discovery of N-benzoxazol-5-yl-pyrazole-4-carboxamides as nanomolar SQR inhibitors.

    PubMed

    Xiong, Li; Zhu, Xiao-Lei; Shen, Yan-Qing; Wishwajith, Wickramabahu Kandergama Wasala Mudiyanselage; Li, Kui; Yang, Guang-Fu

    2015-05-05

    Succinate-ubiquinone oxidoreductase (SQR, EC 1.3.5.1, complex II), an essential component of cellular respiratory chain and tricarboxylic acid (or Krebs) cycle, has been identified as one of the most significant targets for pharmaceutical and agrochemical. Herein, with the aim of discovery of new antibacterial lead structure, a series of N-benzoxazol-5-yl-pyrazole-4-carboxamides were designed, synthesized, and evaluated for their SQR inhibitory effects. Very promisingly, one candidate (Ki = 11 nM, porcine SQR) was successfully identified as the most potent synthetic SQR inhibitor so far. The further inhibitory kinetics studies revealed that the candidate is non-competitive with respect to the substrate cytochrome c and DCIP. Computational simulations revealed that the titled compounds have formed hydrogen bond with D_Y91 and B_W173 and the pyrazole ring formed cation-π interaction with C_R46. In addition, in R(1) position, -CHF2 group has increased the binding affinity and decreased the entropy contribution, while -CF3 group displayed completely opposite effect when bound with SQR. The results of the present work showed that N-benzoxazol-5-yl-pyrazole-4-carboxamide is a new scaffold for discovery of SQR inhibitors and worth further study.

  3. Structure-activity relationships of pyrazole derivatives as potential therapeutics for immune thrombocytopenias.

    PubMed

    Purohit, Meena K; Chakka, Sai Kumar; Scovell, Iain; Neschadim, Anton; Bello, Angelica M; Salum, Noruê; Katsman, Yulia; Bareau, Madeleine C; Branch, Donald R; Kotra, Lakshmi P

    2014-05-01

    Idiopathic or immune thrombocytopenia (ITP) is a serious clinical disorder involving the destruction of platelets by macrophages. Small molecule therapeutics are highly sought after to ease the burden on current therapies derived from human sources. Earlier, we discovered that dimers of five-membered heterocycles exhibited potential to inhibit phagocytosis of human RBCs by macrophages. Here, we reveal a structure-activity relationship of the bis-pyrazole class of molecules with -C-C-, -C-N- and -C-O- linkers, and their evaluation as inhibitors of phagocytosis of antibody-opsonized human RBCs as potential therapeutics for ITP. We have uncovered three potential candidates, 37, 47 and 50, all carrying a different linker connecting the two pyrazole moieties. Among these compounds, hydroxypyrazole derivative 50 is the most potent compound with an IC50 of 14 ± 9 μM for inhibiting the phagocytosis of antibody-opsonized human RBCs by macrophages. None of the compounds exhibited significant potential to induce apoptosis in peripheral blood mononuclear cells (PBMCs). Current study has revealed specific functional features, such as up to 2-atom spacer arm and alkyl substitution at one of the N(1) positions of the bivalent pyrazole core to be important for the inhibitory activity.

  4. Synthesis and apoptotic activity of new pyrazole derivatives in cancer cell lines.

    PubMed

    Nitulescu, George Mihai; Draghici, Constantin; Olaru, Octavian Tudorel; Matei, Lilia; Ioana, Aldea; Dragu, Laura Denisa; Bleotu, Coralia

    2015-09-01

    We designed and synthesized new pyrazole thiourea chimeric derivatives and confirmed their structures by NMR and IR spectra. Apoptotic effects were studied in human cancer cells. The N-[(1-methyl-1H-pyrazol-4-yl)carbonyl]-N'-(3-bromophenyl)-thiourea compound (4b) exhibited the highest apoptosis-inducing effect. Compound 4b and the thiazole derivatives, 5b and 6b, increased the expression of tumor necrosis factor receptors TRAIL-R2 and TRAIL-R1, accompanied by down-modulation of pro-caspase 3 levels, and the augmentation of cleaved caspase 3. They also reduced the levels of apoptosis inhibitory proteins and the expression of the heat-shock proteins Hsp27 and Hsp70. All the tested pyrazole derivatives induced a concentration-dependent increase of cells in G2/M phases. The analysis of the experimental data indicates the reduction of Akt phosphorylation as the most probable cellular mechanism of action for the tested compounds. The in vitro study indicated that compound 4b could be a promising anti-cancer drug, to be further developed in animal models of cancer.

  5. Dopaminergic D2-like agonists produce yawning in the myelin mutant taiep and Sprague-Dawley rats.

    PubMed

    Eguibar, Jose R; Cortes, Ma del Carmen; Lara-Lozano, Manuel; Mendiola, Diana M

    2012-07-01

    Systemic administration of D2-like dopaminergic-receptor agonists increases yawning behavior. However, only a few studies have been done in animals with pathological conditions. The taiep rat is a myelin mutant with an initial hypomyelination followed by progressive demyelination, being the brainstem one of the most affected areas. In our experiments, we analyzed the effects of systemic administration of the D2-family agonists and antagonists on yawning behavior, and correlated them with the lipid myelin content in the brainstem and other areas in the central nervous system (CNS) in 8 month old male taiep and Sprague-Dawley rats. Subjects were maintained under standard conditions in Plexiglas cages with a 12:12 light-dark cycle, lights on at 0700 and free access to rodent pellets and tap water. Drugs were freshly prepared injected ip at 0800 and subjects were observed for 60 min. When antagonists were used it was administered 15 min before the agonist. Sprague-Dawley and taiep rats significantly increased their yawning frequency after systemic injection of (-)-quinpirole hydrochloride, R(+)-7-Hydroxy-2-(dipropylamino)tetralin hydrobromide (7-OH-DPAT) or trans-(±)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano [4,3-b]-1,4-oxazin-9-ol hydrochloride ((±)-PD 128,907). Among D2-like agonists used higher effects are obtained with (-)-quinpirole. The effects caused by (-)-quinpirole can be reduced by (-)-sulpiride; and yawning caused by 7-OH-DPAT was decreased by tiapride only in taiep rats. In Sprague-Dawley only (-)-sulpiride is able to decrease (-)-quinpirole-caused yawning. In conclusion, dopaminergic D2-like agonists are still able to cause yawning despite the severe myelin loss in taiep rats. Similarly, patients with various CNS illnesses that affect myelin, such as stroke or multiple sclerosis, are able to yawn suggesting that trigger neurons are still able to command this innate behavior.

  6. Kappa Opioid Receptor Agonist and Brain Ischemia

    PubMed Central

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury. PMID:25574482

  7. One-pot synthesis of 1,4-disubstituted pyrazoles from arylglycines via copper-catalyzed sydnone-alkyne cycloaddition reaction.

    PubMed

    Specklin, Simon; Decuypere, Elodie; Plougastel, Lucie; Aliani, Soifia; Taran, Frédéric

    2014-08-15

    A robust method for constructing 1,4-pyrazoles from arylglycines was developed using the copper-catalyzed sydnone-alkyne cycloaddition reaction. The procedure offers a straightforward and general route to the pyrazole heterocycle through a three-step one-pot procedure.

  8. Copper-catalyzed aerobic C(sp2)-H functionalization for C-N bond formation: synthesis of pyrazoles and indazoles.

    PubMed

    Li, Xianwei; He, Li; Chen, Huoji; Wu, Wanqing; Jiang, Huanfeng

    2013-04-19

    A simple, practical, and highly efficient synthesis of pyrazoles and indazoles via copper-catalyzed direct aerobic oxidative C(sp(2))-H amination has been reported herein. This process tolerated a variety of functional groups under mild conditions. Further diversification of pyrazoles was also investigated, which provided its potential for drug discovery.

  9. Synthesis of 1H-indazoles and 1H-pyrazoles via FeBr3/O2 mediated intramolecular C-H amination.

    PubMed

    Zhang, Tianshui; Bao, Weiliang

    2013-02-01

    A new synthesis of substituted 1H-indazoles and 1H-pyrazoles from arylhydrazones via FeBr(3)/O(2) mediated C-H activation/C-N bond formation reactions is reported. The corresponding 1,3-diaryl-substituted indazoles and trisubstituted pyrazoles were obtained in moderate to excellent yields under mild conditions.

  10. Food restriction alters N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole)-induced yawning, hypothermia, and locomotor activity in rats: evidence for sensitization of dopamine D2 receptor-mediated effects.

    PubMed

    Collins, Gregory T; Calinski, Diane M; Newman, Amy Hauck; Grundt, Peter; Woods, James H

    2008-05-01

    Food restriction enhances sensitivity to the reinforcing effects of a variety of drugs of abuse including opiates, nicotine, and psychostimulants. Food restriction has also been shown to alter a variety of behavioral and pharmacological responses to dopaminergic agonists, including an increased sensitivity to the locomotor stimulatory effects of direct- and indirect-dopamine agonists, elevated extracellular dopamine levels in responses to psychostimulants, as well as suppression of agonist-induced yawning. Behavioral and molecular studies suggest that augmented dopaminergic responses observed in food-restricted animals result from a sensitization of the dopamine D2 receptor; however, little is known about how food restriction affects dopamine D3 receptor function. The current studies were aimed at better defining the effects of food restriction on D2 and D3 receptor function by assessing the capacity of N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole) to induce yawning, penile erection (PE), hypothermia, and locomotor activity in free-fed and food-restricted rats. Food restriction resulted in a suppression of pramipexole-induced yawning, a sensitized hypothermic response, and an enhanced locomotor response to pramipexole, effects that are suggestive of an enhanced D2 receptor activity; no effect on pramipexole-induced PE was observed. Antagonist studies further supported a food restriction-induced enhancement of the D2 receptor activity because the D2 antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole (L741,626) recovered pramipexole-induced yawning to free-fed levels, whereas yawning and PE were suppressed following pretreatment with the D3 antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride (PG01037). The results of the current studies suggest that food restriction sensitized rats to the D2-mediated effects of pramipexole while having no effect

  11. Discovery of a novel series of phenyl pyrazole inner salts based on fipronil as potential dual-target insecticides.

    PubMed

    Jiang, Dingxin; Zheng, Xiaohua; Shao, Guang; Ling, Zhang; Xu, Hanhong

    2014-04-23

    A series of novel phenyl pyrazole inner salt derivatives based on fipronil were designed and synthesized in the search for dual-target insecticides. These compounds were designed to target two families of nicotinic acetylcholine receptors and γ-aminobutyric acid receptors. The insecticidal activities of the new compounds against diamondback moth (Plutella xylostella) were evaluated. The results of bioassays indicated that most of the inner salts showed moderate to high activities, of which the phenyl pyrazole inner salts containing quinoline had excellent biological activity. Previous structure-activity relationship studies revealed that a suitable structure of the quaternary ammonium salts was critical for the bioactivity of phenyl pyrazole inner salts, which contribute to exposing the cationic nitrogen to bind to the receptor (for instance, nicotinic acetylcholine receptors) and possibly interact with the receptor via hydrogen bonding and cooperative π-π interaction. The present work demonstrates that the insecticidal potency of phenyl pyrazole inner salts holds promise for the development new dual-target phenyl pyrazole insecticides.

  12. Protic N-Heterocyclic Carbene Versus Pyrazole: Rigorous Comparison of Proton- and Electron-Donating Abilities in a Pincer-Type Framework.

    PubMed

    Toda, Tatsuro; Yoshinari, Akihiro; Ikariya, Takao; Kuwata, Shigeki

    2016-11-07

    Evaluation of the acidity of proton-responsive ligands such as protic N-heterocyclic carbenes (NHCs) bearing an NH-wingtip provides a key to understanding the metal-ligand cooperation in enzymatic and artificial catalysis. Here, we design a CNN pincer-type ruthenium complex 2 bearing protic NHC and isoelectronic pyrazole units in a symmetrical skeleton, to compare their acidities and electron-donating abilities. The synthesis is achieved by direct C-H metalation of 2-(imidazol-1-yl)-6-(pyrazol-3-yl)pyridine with [RuCl2 (PPh3 )3 ]. (15) N-Labeling experiments confirm that deprotonation of 2 occurs first at the pyrazole side, indicating clearly that the protic pyrazole is more acidic than the NHC group. The electrochemical measurements as well as derivatization to carbonyl complexes demonstrate that the protic NHC is more electron-donating than pyrazole in both protonated and deprotonated forms.

  13. Novel thiol-based histone deacetylase inhibitors bearing 3-phenyl-1H-pyrazole-5-carboxamide scaffold as surface recognition motif: Design, synthesis and SAR study.

    PubMed

    Wen, Jiachen; Niu, Qun; Liu, Jiang; Bao, Yu; Yang, Jinyu; Luan, Shenglin; Fan, Yinbo; Liu, Dan; Zhao, Linxiang

    2016-01-15

    A series of novel thiol-based histone deacetylase (HDAC) inhibitors bearing 3-phenyl-1H-pyrazole-5-carboxamide scaffold as surface recognition motif was designed, synthesized, and evaluated for their HDAC inhibition activity. Among them, 15j (IC50=0.08μM) was identified as a better inhibitor than Vorinostat (IC50=0.25μM) against total HDACs. In addition, Structure-activity relationships (SAR) analyses indicated that (i) compounds with different substituents on pyrazole N-1 position exhibited superior activities than those on pyrazole N-2 position, (ii) variation of functional groups on N-1'-alkyl chain terminus followed the trends of carboxyl group>hydroxyl group≫alkyl group, and (iii) methylation on pyrazole C-4 position diminished the HDAC inhibition activity. The SAR will guide us to further refine compounds bearing 3-phenyl-1H-pyrazole-5-carboxamide scaffold to achieve better HDAC inhibitors.

  14. Low cost brine tolerant sulfonate and sulfate surfactants having 1,3-dyhydrocharboxy-2-propyl hydrophobic tails

    SciTech Connect

    Hoskin, D. H.

    1985-05-07

    Novel sulfonate and sulfate surfactants which have low interfacial tension at high salinity, and their use in enhanced oil recovery are disclosed. These surfactants may be made from relatively inexpensive intermediates, such as monohydric alcohols and epichlorohydrin. These surfactants have 1,3-dihydrocarboxy-2-propyl hydrophobic tails linked by ethoxy linkages to sulfate or alkyl sulfonate moieties.

  15. Study of hydroxy propyl guar derivative for its gelling property and it's use in the formulation of tenoxicam gels.

    PubMed

    Swamy, N G N; Dharmarajan, T S; Paranjothi, K L K

    2007-01-01

    Gels of tenoxicam 1% w/w were formulated using 2% w/w hydroxy propyl guar derivative and 3% w/w sodium carboxy methyl cellulose as gelling agents. A detailed rheological investigation was carried out to study the influence of preservative, drug and preservative, solvent system and the preservative, drug, solvent system and the preservative on the pseudoplastic behaviour of polymers. Hydroxy propyl guar derivative in 2% w/w strength resulted in gels with a higher pseudoplastic index value of 3.383 in contrast to an index value of 1.797 for a 3% w/w sodium carboxy methyl cellulose gels of a similar composition. The gels were stored at different temperatures and variations in pH values were recorded. Hydroxy propyl guar derivative based gels revealed variations in pH values over a narrow range in contrast to sodium carboxy methyl cellulose gels. The gels were subjected to short term stability studies by storing gels at refrigerated temperature, lab temperature, at 37 degrees C and at 45 degrees C. Gels based on hydroxy propyl guar derivative revealed better drug keeping qualities in contrast to sodium carboxy methyl cellulose stabilized gels. Release studies of tenoxicam from formulations across hairless albino mice skin revealed a zero order drug release pattern from both the formulations.

  16. Dopamine receptor agonists, partial agonists and psychostimulant addiction.

    PubMed

    Pulvirenti, L; Koob, G F

    1994-10-01

    Despite the epidemic growth of psychostimulant addiction over the past years, few pharmacological means of intervention are available to date for clinical treatment. This is of importance since the withdrawal syndrome that follows abstinence from drugs such as cocaine and the amphetamines is characterized, among other symptoms, by intense craving for the abused drug, and this is considered a critical factor leading into relapse of drug use. In this article, Luigi Pulvirenti and George Koob focus on the modulatory role shown by drugs acting at the dopamine receptor on the various phases of psychostimulant dependence in preclinical models and in human studies, and suggest that a class of compounds with partial agonist properties at the dopamine receptor may have therapeutic potential.

  17. Pyrazole induced oxidative liver injury independent of CYP2E1/2A5 induction due to Nrf2 deficiency.

    PubMed

    Lu, Yongke; Gong, Pengfei; Cederbaum, Arthur I

    2008-10-30

    Pyrazole can induce CYP2E1 and 2A5, which produce reactive oxygen species (ROS). Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates important antioxidant enzymes to remove ROS. In this study, we applied Nrf2 knockout mice to test the hypothesis that pyrazole will cause hepatotoxicity and elevate oxidative stress to a greater extent in Nrf2 knockout mice compared to wild type mice. Pyrazole induced severe oxidative liver damage in Nrf2 knockout mice but not in wild type mice. Activities and levels of CYP2E1 and 2A5 were elevated by pyrazole in the wild type mice but not in the Nrf2 knockout mice. However, expression or activity of Nrf2-regulated antioxidant enzymes, such as gamma-glutamylcysteine synthetase (GCS), heme oxygenase-1 (HO-1) and glutathione-S-transferase (GST), were upregulated in the pyrazole-treated wild type mice, but to a lesser extent or not at all in the pyrazole-treated Nrf2 knockout mice. Treatment with antioxidants such as vitamin C or S-adenosyl-l-methionine (SAM) or an inhibitor of iNOS prevented the pyrazole-induced oxidative liver damage, thus validating the role of oxidative/nitrosative stress in the pyrazole induced liver injury to the Nrf2 knockout mice. In summary, even though ROS-producing CYP2E1/2A5 were not elevated by pyrazole, impaired antioxidant capacity resulting from Nrf2 deficiency appear to be sufficient to promote pyrazole-induced oxidative liver injury.

  18. Crystal structure of 3-amino-2-propyl­quinazolin-4(3H)-one

    PubMed Central

    El-Hiti, Gamal A.; Smith, Keith; Hegazy, Amany S.; Alanazi, Saud A.; Kariuki, Benson M.

    2015-01-01

    In the title mol­ecule, C11H13N3O, the propyl group is almost perpendicular to the quinazolin-4(3H)-one mean plane, making a dihedral angle of 88.98 (9)°. In the crystal, mol­ecules related by an inversion centre are paired via π–π overlap, indicated by the short distances of 3.616 (5) and 3.619 (5) Å between the centroids of the aromatic rings of neighbouring mol­ecules. Inter­molecular N—H⋯N and N—H⋯O hydrogen bonds form R 6 6(30) rings and C(5) chains, respectively, generating a three-dimensional network. Weak C—H⋯O inter­actions are also observed. PMID:26396813

  19. Control of laser induced molecular fragmentation of n-propyl benzene using chirped femtosecond laser pulses

    NASA Astrophysics Data System (ADS)

    Goswami, Tapas; Karthick Kumar, S. K.; Dutta, Aveek; Goswami, Debabrata

    2009-06-01

    We present the effect of chirping a femtosecond laser pulse on the fragmentation of n-propyl benzene. An enhancement of an order of magnitude for the relative yields of C3H 3 + and C5H 5 + in the case of negatively chirped pulses and C6H 5 + in the case of positively chirped pulses with respect to the transform-limited pulse indicates that in some fragmentation channel, coherence of the laser field plays an important role. For the relative yield of all other heavier fragment ions, resulting from the interaction of the intense laser field with the molecule, there is no such enhancement effect with the sign of chirp, within experimental errors. The importance of the laser phase is further reinforced through a direct comparison of the fragmentation results with the second harmonic of the chirped laser pulse with identical bandwidth.

  20. Physico-chemical studies and emulsifying properties of N-propyl-N-methylene phosphonic chitosan.

    PubMed

    Albertengo, Liliana; Farenzena, Sonia; Debbaudt, Adriana; Zuñiga, Adriana; Schulz, Pablo; Rodriguez, Maria Susana

    2013-02-15

    Chitosan is a modified, natural carbohydrate polymer derived by deacetylation of chitin. Due to the presence of two functional groups can undergo many chemical modifications. In a previous work we described the synthetic strategy and characterization of a novel soluble derivative: N-propyl-N-methylene phosphonic chitosan (PNMPC). In the study of some physicochemical properties, results showed that this modified chitosan aggregates in several steps when the concentration is increased. By addition of NaOH the initially coiled molecules stretch exposing more phosphonic acid groups to neutralization and finally give a cooperative reaction with OH((). PNMPC has emulsifying properties and gives O/W emulsions with quasi-monodisperse small droplets. Emulsions with 0.18% PNMPC and 30:70 o:w ratio exhibited the best emulsifying properties within the test range. This emulsion ratio showed high stability to long time storage and several successive freeze/thaw and heating/cooling cycles.

  1. Control of laser induced molecular fragmentation of n-propyl benzene using chirped femtosecond laser pulses.

    PubMed

    Goswami, Tapas; Karthick Kumar, S K; Dutta, Aveek; Goswami, Debabrata

    2009-06-12

    We present the effect of chirping a femtosecond laser pulse on the fragmentation of n-propyl benzene. An enhancement of an order of magnitude for the relative yields of C3H3+ and C5H5+ in the case of negatively chirped pulses and C6H5+ in the case of positively chirped pulses with respect to the transform-limited pulse indicates that in some fragmentation channel, coherence of the laser field plays an important role. For the relative yield of all other heavier fragment ions, resulting from the interaction of the intense laser field with the molecule, there is no such enhancement effect with the sign of chirp, within experimental errors. The importance of the laser phase is further reinforced through a direct comparison of the fragmentation results with the second harmonic of the chirped laser pulse with identical bandwidth.

  2. The Use of Chlorhexidine/n-Propyl Gallate (CPG) as an Ambient-Temperature Urine Preservative

    NASA Technical Reports Server (NTRS)

    Nillen, Jeannie L.; Smith, Scott M.

    2003-01-01

    A safe, effective ambient temperature urine preservative, chlorhexidine/n-propyl gallate (CPG), has been formulated for use during spacefli ght that reduces the effects of oxidation and bacterial contamination on sample integrity while maintaining urine pH. The ability of this preservative to maintain stability of nine key analytes was evaluated for a period of one year. CPG effectively maintained stability of a mmonia, total nitrogen, 3-methylhistidine, chloride, sodium, potassiu m, and urea; however, creatinine and osmolality were not preserved by CPG. These data indicate that CPG offers prolonged room-temperature storage for multiple urine analytes, reducing the requirements for f rozen urine storage on future spaceflights. Iii medical applications on Earth, this technology can allow urine samples to be collected in remote settings and eliminate the need to ship frozen samples.

  3. In Vivo Cardioprotective Effects and Pharmacokinetic Profile of N-Propyl Caffeamide Against Ischemia Reperfusion Injury.

    PubMed

    Cheng, Yuan-Yuan; Luo, Dan; Xia, Zhengyuan; Tse, Hung-Fat; Li, Xuechen; Rong, Jianhui

    2016-08-01

    Caffeic acid derivatives constitute a class of potent anti-inflammatory and cardioprotective drug candidates. We recently synthesized a new caffeic acid derivative N-propyl caffeamide (PCA). Our pilot experiments demonstrated that PCA enhanced the survival of rat cardiomyocyte H9c2 cells against oxygen glucose deprivation and reoxygenation challenge in a concentration-dependent manner. Interestingly, PCA exhibited better cardioprotective potential than caffeic acid phenethyl ester and propyl caffeate. Thus, we hypothesized that PCA could protect heart against ischemia reperfusion (I/R) injury in mice. We first determined the stability and pharmacokinetic profile of PCA in male Sprague-Dawley rats by ultra-performance liquid chromatography coupled with UV and MS/MS detections. The stability of PCA in rat plasma was defined by the half-life of 31.39, 7.19 and 1.37 h in rat plasma at 25, 37 and 60 °C, respectively. To study the pharmacokinetic profiles, PCA was injected into male SD rats at the dose of 15 mg/kg via intravenous bolus administration. PCA showed the elimination half-life of approximate 235 min in rats. We subsequently evaluated the cardioprotective potential of PCA in mice model of myocardial infarction. Our results demonstrated that PCA effectively reduced infarct size and release of myocardial enzymes (e.g., CK, CK-MB and LDH). Biochemical analyses suggested that PCA increased the activities of antioxidant enzymes (e.g., CAT and SOD) while attenuated lipid peroxidation. Moreover, PCA profoundly reduced the number of apoptotic cells in infarcted myocardium. Consistently, PCA increased the expression level of anti-apoptotic protein Bcl2 whereas suppressed the expression of pro-apoptotic protein Bax in cardiac tissues. Collectively, PCA appears to be a novel bioavailable and stable pharmacological treatment for myocardial infarction.

  4. Crystal structure of catena-poly[[aquadi-n-propyl-tin(IV)]-μ-oxalato].

    PubMed

    Reichelt, Martin; Reuter, Hans

    2014-08-01

    The title compound, [Sn(C3H7)2(H2O)(C2O4)] n , represents the first diorganotin(IV) oxalate hydrate to be structurally characterized. The tin(IV) atom of the one-dimensional coordination polymer is located on a twofold rotation axis and is coordinated by two chelating oxalate ligands with two slightly different Sn-O bond lengths of 2.290 (2) and 2.365 (2) Å, two symmetry-related n-propyl groups with a Sn-C bond lengths of 2.127 (3) Å, and a water mol-ecule with a Sn-O bond length of 2.262 (2) Å. The coordination polyhedron around the Sn(IV) atom is a slightly distorted penta-gonal bipyramid with a nearly linear axis between the trans-oriented n-propyl groups [C-Sn-C = 176.8 (1)°]. The bond angles between the oxygen atoms of the equatorial plane range from 70.48 (6)° to 76.12 (8)°. A one-dimensional coordination polymer results from the less asymmetric bilateral coordination of the centrosymmetric oxalate anion, inter-nally reflected by two slightly different C-O bond lengths of 1.248 (3) and 1.254 (3) Å. The chains of the polymer propagate parallel to [001] and are held together by hydrogen bonds between water mol-ecules and oxalate anions of neighboring chains, leading to a two-dimensional network parallel to (100).

  5. Determination of Six Pyrazole Fungicides in Grape Wine by Solid-Phase Extraction and Gas Chromatography-Tandem Mass Spectrometry.

    PubMed

    Shen, Yan; Li, Zhou; Ma, Qiang; Wang, Chuanxian; Chen, Xiangzhun; Miao, Qian; Han, Chao

    2016-05-18

    A gas chromatography-tandem mass spectrometry (GC-MS/MS) method was developed for the first simultaneous identification and quantification of six pyrazole fungicides (furametpyr, rabenzazole, fluxapyroxad, penflufen, bixafen, and isopyrazam) in grape wine samples. The grape wine samples were first diluted with water, then purified by solid-phase extraction, and finally examined by GC-MS/MS in multiple reaction monitoring (MRM) mode. Matrix-matched calibration curves were used to correct the matrix effects. The limits of quantification (LOQs), calculated as 10 times the standard deviation, were 0.2-0.8 μg kg(-1) for the six pyrazole fungicides. The average recoveries were in the range of 74.3-94.5%, with relative standard deviations (RSDs) below 5.8%, measured at three concentration levels. The proposed method is suitable for the simultaneous determination of six pyrazole fungicides in grape wine samples.

  6. Synthetic approaches, structure activity relationship and biological applications for pharmacologically attractive pyrazole/pyrazoline-thiazolidine-based hybrids.

    PubMed

    Havrylyuk, Dmytro; Roman, Olexandra; Lesyk, Roman

    2016-05-04

    The features of the chemistry of 4-thiazolidinone and pyrazole/pyrazolines as pharmacologically attractive scaffolds were described in a number of reviews in which the main approaches to the synthesis of mentioned heterocycles and their biological activity were analyzed. However, the pyrazole/pyrazoline-thiazolidine-based hybrids as biologically active compounds is poorly discussed in the context of pharmacophore hybrid approach. Therefore, the purpose of this review is to summarize the data about the synthesis and modification of heterocyclic systems with thiazolidine and pyrazoline or pyrazole fragments in molecules as promising objects of modern bioorganic and medicinal chemistry. The description of biological activity was focused on SAR analysis and mechanistic insights of mentioned hybrids.

  7. Beta-agonists and animal welfare

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  8. Small molecule fluoride toxicity agonists.

    PubMed

    Nelson, James W; Plummer, Mark S; Blount, Kenneth F; Ames, Tyler D; Breaker, Ronald R

    2015-04-23

    Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here, we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride.

  9. Small Molecule Fluoride Toxicity Agonists

    PubMed Central

    Nelson1, James W.; Plummer, Mark S.; Blount, Kenneth F.; Ames, Tyler D.; Breaker, Ronald R.

    2015-01-01

    SUMMARY Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch-reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride. PMID:25910244

  10. Synthesis and spectroscopy studies of the inclusion complex of 3-amino-5-methyl pyrazole with beta-cyclodextrin.

    PubMed

    Louiz, S; Labiadh, H; Abderrahim, R

    2015-01-05

    Amino pyrazole belongs to anti-inflammatory class, and is characterized by a low solubility in water. (In order to increase its solubility in water, inclusion complex of amino pyrazole with β-CD was obtained.) The inclusion complex obtained between AMP and β-cyclodextrin, was characterized by FT-IR, (1)H NMR, (1)H-(1)H NOESY, (13)C NMR, DEPT, XHCOR, spectra, through TG analysis, DTA, DSC and Scanning Electron Microscopy (SEM). The stoichiometry of inclusion complex is 1:1 (guest-host) and K stability is 1.1 × 10(4)M(-1).

  11. Synthesis and Biological Evaluation of Novel Aryl-2H-pyrazole Derivatives as Potent Non-purine Xanthine Oxidase Inhibitors.

    PubMed

    Sun, Zhi-Gang; Zhou, Xiao-Jing; Zhu, Ming-Li; Ding, Wen-Ze; Li, Zhen; Zhu, Hai-Liang

    2015-01-01

    A series of aryl-2H-pyrazole derivatives were synthesized and evaluated for inhibitory activity against xanthine oxidase in vitro as potent xanthine oxidase inhibitors. Among them, 2 aryl-2H-pyrazole derivatives showed significant inhibitory activities against xanthine oxidase. Compound 19 emerged as the most potent xanthine oxidase inhibitor (IC50=9.8 µM) in comparison with allopurinol (IC50=9.5 µM). The docking study revealed that compound 19 might have strong interactions with the active site of xanthine oxidase. This compound is thus a new candidate for further development for the treatment of gout.

  12. Synthesis and spectroscopy studies of the inclusion complex of 3-amino-5-methyl pyrazole with beta-cyclodextrin

    NASA Astrophysics Data System (ADS)

    Louiz, S.; Labiadh, H.; Abderrahim, R.

    2015-01-01

    Amino pyrazole belongs to anti-inflammatory class, and is characterized by a low solubility in water. (In order to increase its solubility in water, inclusion complex of amino pyrazole with β-CD was obtained.) The inclusion complex obtained between AMP and β-cyclodextrin, was characterized by FT-IR, 1H NMR, 1H-1H NOESY, 13C NMR, DEPT, XHCOR, spectra, through TG analysis, DTA, DSC and Scanning Electron Microscopy (SEM). The stoichiometry of inclusion complex is 1:1 (guest-host) and K stability is 1.1 × 104 M-1.

  13. Densities and vapor-liquid equilibria in binary mixtures formed by propyl methanoate + ethanol, + propan-1-ol, and + butan-1-ol at 160.0 kPa

    SciTech Connect

    Falcon, J.; Ortega, J.; Gonzalez, E.

    1996-07-01

    Densities and excess volumes were determined at 298.15 K for propyl methanoate + ethanol, + propan-1-ol, and + butan-1-ol. The results of those quantities were then correlated to get the concentrations of vapor-liquid equilibrium obtained isobarically at 160 kPa for the same mixtures. Two mixtures show azeotropes: for propyl methanoate (1) + ethanol (2), x{sub 1} = 0.443 at T = 358.7 K; and for propyl methanoate (1) + propan-1-ol (2), x{sub 1} = 0.762 at T = 368.2 K. The mixtures are thermodynamically consistent, and the predictions made using several group-contribution models are satisfactory.

  14. Pyrazolylamidino ligands from coupling of acetonitrile and pyrazoles: a systematic study.

    PubMed

    Gómez-Iglesias, Patricia; Arroyo, Marta; Bajo, Sonia; Strohmann, Carsten; Miguel, Daniel; Villafañe, Fernando

    2014-12-01

    Mixed pyrazole-acetonitrile complexes, both neutral fac-[ReBr(CO)3(NCMe)(pz*H)] (pz*H = pzH, pyrazole; dmpzH, 3,5-dimethylpyrazole; or indzH, indazole) and cationic fac-[Re(CO)3(NCMe)(pz*H)2]A (A = BF4, ClO4, or OTf), are described. Their role as the only starting products to obtain final pyrazolylamidino complexes fac-[ReBr(CO)3(NH═C(Me)pz*-κ(2)N,N)] and fac-[Re(CO)3(pz*H)(NH═C(Me)pz*-κ(2)N,N)]A, respectively, is examined. Other products involved in the processes, such as fac-[ReBr(CO)3(pz*H)2], fac-[Re(CO)3(NCMe)(NH═C(Me)pz*-κ(2)N,N)]A, and fac-[Re(CO)3(pz*H)2(OTf)] are also described. Warming CD3CN solutions of fac-[Re(CO)3(NCMe)(pz*H)2]A at 40 °C gives cleanly the pyrazolylamidino complexes [Re(CO)3(pz*H)(NH═C(Me)pz*-κ(2)N,N)]A as the only products, pointing to an intramolecular process. This is confirmed by carrying out reactions in the presence of one equivalent of a pyrazole different from that coordinated, which affords complexes where the pyrazolylamidino ligand contains only the pyrazole previously coordinated. When the reactions lead to an equilibrium mixture of the final and starting products, the reverse reaction gives the same equilibrium mixture, which indicates that the coupling reaction of pyrazoles and nitriles to obtain pyrazolylamidino ligands is a reversible intramolecular process. A systematic study of the possible factors which may affect the reaction gives the following results: (a) the yields of the direct reactions are higher for lower temperatures; (b) the tendency of the pyrazoles to give pyrazolylamidino complexes follows the sequence indzH > pzH > dmpzH; and (c) the reaction rates do not depend on the nature of the anion even when a large excess is added. The presence of a small amount of aqueous solution of NaOH catalyzes the reaction. Thus, addition of 0.5-1% of NaOH (aq) to solutions of fac-[ReBr(CO)3(NCMe)(pz*H)] (in CD3CN) or fac-[Re(CO)3(NCMe)(pz*H)2]A (in CD3CN, CD3NO2 or (CD3)2CO) allowed the syntheses of the

  15. Copper(II) complexes with pyrazole derivatives - Synthesis, crystal structure, DFT calculations and cytotoxic activity

    NASA Astrophysics Data System (ADS)

    Kupcewicz, Bogumiła; Ciolkowski, Michal; Karwowski, Boleslaw T.; Rozalski, Marek; Krajewska, Urszula; Lorenz, Ingo-Peter; Mayer, Peter; Budzisz, Elzbieta

    2013-11-01

    The series of pyrazole derivatives (1a-4a) were used as bidentate N,N' ligands to obtain neutral Cu(II) complexes of ML2Cl2 type (1b-4b). The molecular structures of ligand 1a and Cu(II) complex 4b were determined by X-ray crystallography and theoretical DFT calculations. In this study, three functionals B3LYP, BP86 and mPW1PW91 with different basis sets and two effective core potentials Los Alamos and Stuttgart/Dresden were performed. The DFT study disclosed the usefulness of BP86 functional with SDD-ECP for Cu(II) ion and dedicated D95 basis set for other non-transition metal atoms, with the exclusion of Cl for which 6-31++G(2df,2pd) were used. The structural analysis shows that the presence of phenyl substituent in a pyrazole ring contributed to Cu-N bond elongation, which can result in different reactivity of complexes 1b and 3b. The cytotoxicity of the obtained compounds was evaluated on three cancer cells lines: HL-60, NALM-6 and WM-115. The complexes have exhibited similar moderate antiproliferative activity. All the complexes, except for 1b, were found to be more active against three cancer cell lines than uncomplexed pyrazoles. The lipophilicity and electrochemical properties of ligands and complexes was also studied. For complexes with ligand 1a and 3a only one reduction process at the metal centre occurs (Cu(II) → Cu(I)) with oxidization of Cu(I)-Cu(II) in the backward step.

  16. Effects of dietary fat on alcohol-pyrazole hepatitis in rats: the pathogenetic role of the nonalcohol dehydrogenase pathway in alcohol-induced hepatic cell injury.

    PubMed

    Takada, A; Matsuda, Y; Takase, S

    1986-08-01

    Rats were fed with two different alcohol-containing (36% of total calories) liquid diets of high fat and low fat (35% and 15% of total calories) with or without 2 mM of pyrazole for 12 weeks. At the 12th week, the serum glutamic oxaloacetic transaminase level was significantly elevated in the alcohol-pyrazole high fat group, but not in the low fat group. Ballooning and necrotic changes of the hepatocytes in the centrolobular area were more prominent in the alcohol-pyrazole high fat group than in the low fat group and alcohol alone groups, indicating that high fat diet accelerates the development of alcohol-pyrazole hepatitis. In the alcohol-pyrazole high fat group, a decrease of hepatic microtubules content and an accumulation of hepatic export proteins in the hepatocytes were found. The protein accumulation was prominent only in the ballooned hepatocytes. Hepatic acetaldehyde levels were significantly higher in the alcohol-pyrazole high fat group than in the alcohol-pyrazole low fat group. These results suggest that the accelerated ethanol metabolism in the nonalcohol dehydrogenase pathway by a high fat diet may play an important role in the development of hepatocytic injuries, by impairing the microtubular function of the hepatocytes.

  17. Organocatalyzed enantioselective synthesis of 6-amino-5-cyanodihydropyrano[2,3-c]pyrazoles

    PubMed Central

    Gogoi, Sanjib; Zhao, Cong-Gui

    2009-01-01

    The first enantioselective synthesis of biologically active 6-amino-5-cyanodihydropyrano[2,3-c]pyrazoles has been achieved through a cinchona alkaloid-catalyzed tandem Michael addition and Thorpe-Ziegler type reaction between 2-pyrazolin-5-ones and benzylidenemalononitriles. The reaction may also be carried out in a three-component or a four-component fashion via the in situ formation of these two components from simple and readily available starting materials. The desired products were obtained in excellent yields with mediocre to excellent enantioselectivities (up to >99% ee). PMID:19915654

  18. Cascade multicomponent synthesis of indoles, pyrazoles, and pyridazinones by functionalization of alkenes.

    PubMed

    Matcha, Kiran; Antonchick, Andrey P

    2014-10-27

    The development of multicomponent reactions for indole synthesis is demanding and has hardly been explored. The present study describes the development of a novel multicomponent, cascade approach for indole synthesis. Various substituted indole derivatives were obtained from simple reagents, such as unfunctionalized alkenes, diazonium salts, and sodium triflinate, by using an established straightforward and regioselective method. The method is based on the radical trifluoromethylation of alkenes as an entry into Fischer indole synthesis. Besides indole synthesis, the application of the multicomponent cascade reaction to the synthesis of pyrazoles and pyridazinones is described.

  19. Coordination versus coupling of dicyanamide in molybdenum and manganese pyrazole complexes.

    PubMed

    Arroyo, Marta; Gómez-Iglesias, Patricia; Martín-Alvarez, Jose Miguel; Alvarez, Celedonio M; Miguel, Daniel; Villafañe, Fernando

    2012-06-04

    The reactions of cis-[MoCl(η(3)-methallyl)(CO)(2)(NCMe)(2)] (methallyl = CH(2)C(CH(3))CH(2)) with Na(NCNCN) and pz*H (pzH, pyrazole, or dmpzH, 3,5-dimethylpyrazole) lead to cis-[Mo(η(3)-methallyl)(CO)(2)(pz*H)(μ-NCNCN-κ(2)N,N)](2) (pzH, 1a; dmpzH, 1b), where dicyanamide is coordinated as bridging ligand. Similar reactions with fac-[MnBr(CO)(3)(NCMe)(2)] lead to the pyrazolylamidino complexes fac-[Mn(pz*H)(CO)(3)(NH═C(pz*)NCN-κ(2)N,N)] (pzH, 2a; dmpzH, 2b), resulting from the coupling of pyrazol with one of the CN bonds of dicyanamide. The second CN bond of dicyanamide in 2a undergoes a second coupling with pyrazole after addition of 1 equiv of fac-[MnBr(CO)(3)(pzH)(2)], yielding the dinuclear doubly coupled complex [{fac-Mn(pzH)(CO)(3)}(2)(μ-NH═C(pz)NC(pz)=NH-κ(4)N,N,N,N)]Br (3). The crystal structure of 3 reveals the presence of two isomers, cis or trans, depending on whether the terminal pyrazoles are coordinated at the same or at different sides of the approximate plane defined by the bridging bis-amidine ligand. Only the cis isomer is detected in the crystal structure of the perchlorate salt of the same bimetallic cation (4), obtained by metathesis with AgClO(4). All the N-bound hydrogen atoms of the cations in 3 or 4 are involved in hydrogen bonds. Some of the C-N bonds of the pyrazolylamidino ligand have a character intermediate between single and double, and theoretical studies were carried out on 2a and 3 to confirm its electronic origin and discard packing effects. Calculations also show the essential role of bromide in the planarity of the tetradentate ligand in the bimetallic complex 3.

  20. Dibromidobis(3,5-dimethyl-1H-pyrazole-κN 2)cobalt(II)

    PubMed Central

    Tomyn, Stefania; Pavlenko, Vadim A.; Gumienna-Kontecka, Elżbieta; Penkova, Larysa; Kotova, Natalia V.

    2011-01-01

    In the mononuclear title complex, [CoBr2(C5H8N2)2], the CoII atom is coordinated by two N atoms from two monodentate 3,5-dimethyl­pyrazole ligands and two Br atoms in a highly distorted tetra­hedral geometry. In the crystal, the complex mol­ecules are linked by inter­molecular N—H⋯Br hydrogen bonds into chains along [101]. An intra­molecular N—H⋯Br hydrogen bond is also present. PMID:22219744

  1. Synthesis and biological activity of pyrazole analogues of the staurosporine aglycon K252c.

    PubMed

    Esvan, Yannick J; Giraud, Francis; Pereira, Elisabeth; Suchaud, Virginie; Nauton, Lionel; Théry, Vincent; Dezhenkova, Lyubov G; Kaluzhny, Dmitry N; Mazov, Vsevolod N; Shtil, Alexander A; Anizon, Fabrice; Moreau, Pascale

    2016-07-15

    A derivative of the staurosporine aglycon (K252c), in which the lactam ring was replaced by a pyrazole moiety, was synthesized. The resulting indolopyrazolocarbazole (3) inhibited Pim isoforms 1-3 whereas it did not impair the activity of two known targets of K252c, protein kinase C isoforms α and γ. Compound 3 exhibited moderate cytotoxic activity toward human leukemia and colon carcinoma cell lines (K562 and HCT116), strongly suggesting that this new scaffold deserves further investigations for treatment of malignancies associated with Pim activity.

  2. Aryl Pyrazoles as Potent Inhibitors of Arginine Methyltransferases: Identification of the First PRMT6 Tool Compound

    PubMed Central

    2015-01-01

    A novel aryl pyrazole series of arginine methyltransferase inhibitors has been identified. Synthesis of analogues within this series yielded the first potent, selective, small molecule PRMT6 inhibitor tool compound, EPZ020411. PRMT6 overexpression has been reported in several cancer types suggesting that inhibition of PRMT6 activity may have therapeutic utility. Identification of EPZ020411 provides the field with the first small molecule tool compound for target validation studies. EPZ020411 shows good bioavailability following subcutaneous dosing in rats making it a suitable tool for in vivo studies. PMID:26101569

  3. Aryl Pyrazoles as Potent Inhibitors of Arginine Methyltransferases: Identification of the First PRMT6 Tool Compound.

    PubMed

    Mitchell, Lorna H; Drew, Allison E; Ribich, Scott A; Rioux, Nathalie; Swinger, Kerren K; Jacques, Suzanne L; Lingaraj, Trupti; Boriack-Sjodin, P Ann; Waters, Nigel J; Wigle, Tim J; Moradei, Oscar; Jin, Lei; Riera, Tom; Porter-Scott, Margaret; Moyer, Mikel P; Smith, Jesse J; Chesworth, Richard; Copeland, Robert A

    2015-06-11

    A novel aryl pyrazole series of arginine methyltransferase inhibitors has been identified. Synthesis of analogues within this series yielded the first potent, selective, small molecule PRMT6 inhibitor tool compound, EPZ020411. PRMT6 overexpression has been reported in several cancer types suggesting that inhibition of PRMT6 activity may have therapeutic utility. Identification of EPZ020411 provides the field with the first small molecule tool compound for target validation studies. EPZ020411 shows good bioavailability following subcutaneous dosing in rats making it a suitable tool for in vivo studies.

  4. Synthesis and crystal structure of tris(cyclopentadienyl)pyrazolatouranium. A new mode of pyrazolate bonding

    SciTech Connect

    Eigenbrot, Charles W.; Raymond, Kenneth N.

    1981-05-01

    For this research, the title compound has been prepared by the reaction of tris(cyclopentadienyl) uranium chloride (UCp3Cl) and sodium pyrazolate (NaC3H3N2) in tetrahydrofuran (THF). The compound has been characterized by its infrared, visible-near IR, pmr, and mass spectra; and by single crystal X-ray diffraction. The molecular structure consists of discrete UCp3(C3H3N2) molecules in which the uranium(IV) ion is coordinated by three η5-Cp rings in a nearly trigonal array similar to that of other lanthanide and actinide MCp3X structures. However, unlike these other structures, an eleven-coordinate geometry is achieved by having both the adjacent nitrogen atoms of the pyrazolate ring coordinate to the metal ion, such that the local twofold axis of the pyrazolate ring and the local threefold axis of the UCp3 fragment coincide. This is the first example of this type of endo-bidentate η2 coordination for the pyrazolate anion. Red-brown crystals from toluene conform to space group P21/a (an alternate setting of P21/c) with a = 14.295(1)Å, b = 8.383(1)Å, c = 14.282(1)Å, β = 112.80(1)⁰, and there are four molecules per unit cell. For the 3631 independent reflections collected by counter methods with F2 > 3σ(F2). the final weighted and unweighted R factors are both 3.14 percent. The U-N distances are 2.40(1) and 2.36(1)Å. The average U-C distance of 2.76 Å is consistent with that predicted for an eleven-coordinate uranium(IV) cyclopentadienyl complex. The 90 MHz proton resonances of the Cp rings occur at -9.51 (35°C), -11.59 (-10°C), -14.22 (-50°C), and -15.84 (-75°C) ppm. Finally, susceptibility studies from 5 to 80 K show a temperature-independent paramagnetism from 7.5 to 37.1 K; above this temperature μeff = 2.67 μB·

  5. Synthesis, in vitro and in vivo antitumor activity of pyrazole-fused 23-hydroxybetulinic acid derivatives.

    PubMed

    Zhang, Hengyuan; Zhu, Peiqing; Liu, Jie; Lin, Yan; Yao, Hequan; Jiang, Jieyun; Ye, Wencai; Wu, Xiaoming; Xu, Jinyi

    2015-02-01

    A collection of pyrazole-fused 23-hydroxybetulinic acid derivatives were designed, synthesized and evaluated for their antitumor activity. Most of the newly synthesized compounds exhibited significant antiproliferative activity. Especially compound 15e displayed the most potent activity with the IC50 values of 5.58 and 6.13μM against B16 and SF763 cancer cell lines, respectively. Furthermore, the significant in vivo antitumor activity of 15e was validated in H22 liver cancer and B16 melanoma xenograft mouse models. The structure-activity relationships of these 23-hydroxybetulinic acid derivatives were also discussed based on the present investigation.

  6. XRD, IR and XAFS studies of cobalt complexes having amino pyrazole dicarboxylate (APD) as ligand

    NASA Astrophysics Data System (ADS)

    Mishra, Ashutosh; Jain, Garima; Patil, H.

    2014-09-01

    X-ray absorption fine structure spectroscopic (XAFS) studies have been done on two cobalt complexes using APD (diethyl 4-amino-1-phenyl-1H-pyrazole-3,5 dicarboxylate) as ligand. The X-ray absorption spectra of the complexes have been recorded on beam line of synchrotron at Raja Ramanna Centre for Advanced Technology (RRCAT), Indore (India). The X-ray diffraction of the samples has also been carried out. FTIR studies of two samples were also reported in the present communication.

  7. Pyrazole phenylcyclohexylcarbamates as inhibitors of human fatty acid amide hydrolases (FAAH).

    PubMed

    Aghazadeh Tabrizi, Mojgan; Baraldi, Pier Giovanni; Ruggiero, Emanuela; Saponaro, Giulia; Baraldi, Stefania; Romagnoli, Romeo; Martinelli, Adriano; Tuccinardi, Tiziano

    2015-06-05

    Fatty acid amide hydrolase (FAAH) inhibitors have gained attention as potential therapeutic targets in the management of neuropathic pain. Here, we report a series of pyrazole phenylcyclohexylcarbamate derivatives standing on the known carbamoyl FAAH inhibitor URB597. Structural modifications led to the recognition of compound 22 that inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 nM). The most active compounds of this series showed significant selectivity toward monoacylglycerol lipase (MAGL) enzyme. In addition, molecular modeling and reversibility behavior of the new class of FAAH inhibitors are presented in this article.

  8. Pyrazole-based cathepsin S inhibitors with arylalkynes as P1 binding elements

    SciTech Connect

    Ameriks, Michael K.; Axe, Frank U.; Bembenek, Scott D.; Edwards, James P.; Gu, Yin; Karlsson, Lars; Randal, Mike; Sun, Siquan; Thurmond, Robin L.; Zhu, Jian

    2010-01-12

    A crystal structure of 1 bound to a Cys25Ser mutant of cathepsin S helped to elucidate the binding mode of a previously disclosed series of pyrazole-based CatS inhibitors and facilitated the design of a new class of arylalkyne analogs. Optimization of the alkyne and tetrahydropyridine portions of the pharmacophore provided potent CatS inhibitors (IC{sub 50} = 40-300 nM), and an X-ray structure of 32 revealed that the arylalkyne moiety binds in the S1 pocket of the enzyme.

  9. Investigation of the mechanism of agonist and inverse agonist action at D2 dopamine receptors.

    PubMed

    Roberts, David J; Lin, Hong; Strange, Philip G

    2004-05-01

    This study investigated, for the D2 dopamine receptor, the relation between the ability of agonists and inverse agonists to stabilise different states of the receptor and their relative efficacies. Ki values for agonists were determined in competition versus the binding of the antagonist [3H]spiperone. Competition data were fitted best by a two-binding site model (with the exception of bromocriptine, for which a one-binding site model provided the best fit) and agonist affinities for the higher (Kh) (G protein-coupled) and lower affinity (Kl) (G protein-uncoupled) sites determined. Ki values for agonists were also determined in competition versus the binding of the agonist [3H]N-propylnorapomorphine (NPA) to provide a second estimate of Kh. Maximal agonist effects (Emax) and their potencies (EC50) were determined from concentration-response curves for agonist stimulation of guanosine-5'-O-(3-[32S]thiotriphosphate) ([35S]GTPgammaS) binding. The ability of agonists to stabilise the G protein-coupled state of the receptor (Kl/Kh determined from ligand-binding assays) did not correlate with either of two measures of relative efficacy (relative Emax, Kl/EC50) of agonists determined in [35S]GTPgammaS-binding assays, when the data for all of the compounds tested were analysed. For a subset of compounds, however, there was a relation between Kl/Kh and Emax. Competition-binding data versus [3H]spiperone and [3H]NPA for a range of inverse agonists were fitted best by a one-binding site model. Ki values for the inverse agonists tested were slightly lower in competition versus [3H]NPA compared to [3H]spiperone. These data do not provide support for the idea that inverse agonists act by binding preferentially to the ground state of the receptor.

  10. Two tautomers in the same crystal: 3-(4-fluoro-phen-yl)-1H-pyrazole and 5-(4-fluoro-phen-yl)-1H-pyrazole.

    PubMed

    Yamuna, Thammarse S; Kaur, Manpreet; Jasinski, Jerry P; Anderson, Brian J; Yathirajan, H S

    2014-09-01

    The title co-crystal, 3-(4-fluoro-phen-yl)-1H-pyrazole-5-(4-fluoro-phen-yl)-1H-pyrazole (1/1), C9H7FN2, crystallizes with four independent mol-ecules (A, B, C and D) in the asymmetric unit exhibiting two tautomeric forms (A and D; B and C) due to N-H proton exchange between the two N atoms of the pyrazole ring. The dihedral angles between the mean planes of the pyrazole and benzene rings are 15.6 (1), 19.8 (9), 14.0 (1) and 10.7 (7)° in mol-ecules A, B, C and D, respectively. In the crystal, N-H⋯N hydrogen bonds link the four mol-ecules in the asymmetric unit into a ring with an R 4 (4)(12) motif. Furthermore, weak C-H⋯F inter-actions link the mol-ecules into a three-dimensional network.

  11. Synthesis of Functionalized Pyrazoles via Vanadium-Catalyzed C-N Dehydrogenative Cross-Coupling and Fluorescence Switch-On Sensing of BSA Protein.

    PubMed

    Sar, Dinabandhu; Bag, Raghunath; Yashmeen, Afsana; Bag, Subhendu Sekhar; Punniyamurthy, Tharmalingam

    2015-11-06

    Vanadium-catalyzed C-N dehydrogenative cross-coupling of alkenyl hydrazones leading to functionalized pyrazoles is described in a 1:1 mixture of toluene/H2O using air as the terminal oxidant. Significant practical features include use of the commercial nontoxic VOSO4 as a recyclable catalyst, mild reaction conditions, scalability, and the broad substrate scope. Some of the product pyrazoles exhibit interesting photophysical properties. Fluorescence light-up sensing of BSA protein by one of the pyrazoles is also highlighted.

  12. Energetic N-Nitramino/N-Oxyl-Functionalized Pyrazoles with Versatile π-π Stacking: Structure-Property Relationships of High-Performance Energetic Materials.

    PubMed

    Yin, Ping; Mitchell, Lauren A; Parrish, Damon A; Shreeve, Jean'ne M

    2016-11-07

    N-Nitramino/N-oxyl functionalization strategies were employed to investigate structure-property relationships of energetic materials. Based on single-crystal diffraction data, π-π stacking of pyrazole backbones can be tailored effectively by energetic functionalities, thereby resulting in diversified energetic compounds. Among them, hydroxylammonium 4-amino-3,5-dinitro-1H-pyrazol-1-olate and dipotassium N,N'-(3,5-dinitro-1H-pyrazol-1,4-diyl)dinitramidate, with unique face-to-face π-π stacking, can be potentially used as a high-performance explosive and an energetic oxidizer, respectively.

  13. Isolation and structural characterization of tetra-n-propyl zirconate in hydrocarbon solution and the solid state.

    PubMed

    Day, V W; Klemperer, W G; Pafford, M M

    2001-11-05

    Tetra-n-propyl zirconate has been purified by vacuum distillation and isolated as an extremely moisture sensitive, crystalline solid. According to a single-crystal X-ray diffraction study, crystalline tetra-n-propyl zirconate is composed of tetrameric Zr(4)(OPr(n))(16) (1) molecules whose Zr(4)O(16) metal-oxygen core structure has virtual C(2)(h) symmetry, the same structure observed previously for n-alkyl orthotitanates. Carbon-13 NMR spectroscopic data indicate that this core structure is retained in hydrocarbon solution. Molecule 1 has the same M(4)O(16) metal-oxygen core structure as [CH(3)C(CH(2)O)(3)](2)M(4)(OPr(i))(10), M = Ti, where the metal centers have octahedral coordination geometry, but a metal-oxygen core structure different from that of the M = Zr case, where trigonal metaprismatic coordination geometry is observed.

  14. Phase diagram of the iodine-sodium iodide-water-propyl alcohol system at 298.15 K

    NASA Astrophysics Data System (ADS)

    Rubtsova, E. M.; Varlamova, T. M.; Monakhova, Y. B.; Mushtakova, S. P.

    2015-06-01

    Phase equilibria in the cross sections of isothermal-isobaric sections of the phase diagram of four-component iodine-potassium iodide-water-propyl alcohol are investigated at 298.15 K and pressure of 101325 Pa. It is shown that a three-phase equilibrium of the eutonic type occurs in the cross sections containing (I) 10 and (II) 30 wt % of propyl alcohol, and two three-phase equilibria of the monotectic type are found in cross section II. It is shown that the solid phases of saturated solutions in the investigated cross sections are potassium iodide and crystalline iodine. The compositions of the mixed solvents with the strongest iodine dissolving ability relative to individual solvents are established.

  15. Pathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitin.

    PubMed

    Luo, Jialie; Li, Wenming; Zhao, Yuming; Fu, Hongjun; Ma, Dik-Lung; Tang, Jing; Li, Chaoying; Peoples, Robert W; Li, Fushun; Wang, Qinwen; Huang, Pingbo; Xia, Jun; Pang, Yuanping; Han, Yifan

    2010-06-25

    Uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and gamma-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate hydrophobic interaction between bis(propyl)-cognitin and the MK-801 binding region in the ion channel pore of the NMDA receptor. Bis(propyl)-cognitin was further found to compete with [(3)H]MK-801 with a K(i) value of 0.27 mum, and the mutation of NR1(N616R) significantly reduced its inhibitory potency. Under glutamate-mediated pathological conditions, bis(propyl)-cognitin, in contrast to bis(heptyl)-cognitin, prevented excitotoxicity with increasing effectiveness against escalating levels of glutamate and much more effectively protected against middle cerebral artery occlusion-induced brain damage than did memantine. More interestingly, under NMDA receptor-mediated physiological conditions, bis(propyl)-cognitin enhanced long-term potentiation in hippocampal slices, whereas MK-801 reduced and memantine did not alter this process. These results suggest that bis(propyl)-cognitin is a UFO antagonist of NMDA receptors with moderate affinity, which may provide a pathologically activated therapy for various neurodegenerative disorders associated with NMDA receptor dysregulation.

  16. Pyrazinoic acid and its n-propyl ester inhibit fatty acid synthase type I in replicating tubercle bacilli.

    PubMed

    Zimhony, Oren; Vilchèze, Catherine; Arai, Masayoshi; Welch, John T; Jacobs, William R

    2007-02-01

    The activity of different analogs of pyrazinamide on Mycobacterium tuberculosis fatty acid synthase type I (FASI) in replicating bacilli was studied. Palmitic acid biosynthesis was diminished by 96% in bacilli treated with n-propyl pyrazinoate, 94% in bacilli treated with 5-chloro-pyrazinamide, and 97% in bacilli treated with pyrazinoic acid, the pharmacologically active agent of pyrazinamide. We conclude that the minimal structure of pyrazine ring with an acyl group is sufficient for FASI inhibition and antimycobacterial activity.

  17. 3,3'-Di-n-propyl-1,1'-[p-phenyl-enebis(methyl-ene)]diimidazolium dibromide.

    PubMed

    Haque, Rosenani A; Nasri, S Fatimah; Hemamalini, Madhukar; Fun, Hoong-Kun

    2011-08-01

    The asymmetric unit of the title compound, C(20)H(28)N(4) (2+)·2Br(-), consists of half a 3,3'-di-n-propyl-1,1'-[p-phenyl-enenis(methyl-ene)]diimidazolium cation and a bromide anion. The cation is located on an inversion center and adopts an ⋯AAA⋯ trans conformation. In the crystal, the cation is linked to the anions via weak C-H⋯Br hydrogen bonds.

  18. GREENER AND RAPID ACCESS TO BIO-ACTIVE HETEROCYCLES: ROOM TEMPERATURE SYNTHESIS OF PYRAZOLES AND DIAZEPINES IN AQUEOUS MEDIUM

    EPA Science Inventory

    An expeditious room temperature synthesis of pyrazoles and diazepines by condensation of hydrazines/hydrazides and diamines with various 1,3-diketones is described. This greener protocol was catalyzed by polystyrene supported sulfonic acid (PSSA) and proceeded efficiently in wate...

  19. Design and synthesis of pyrazole/isoxazole linked arylcinnamides as tubulin polymerization inhibitors and potential antiproliferative agents.

    PubMed

    Kamal, Ahmed; Shaik, Anver Basha; Rao, Bala Bhaskara; Khan, Irfan; Bharath Kumar, G; Jain, Nishant

    2015-10-28

    As pyrazole and isoxazole based derivatives are well-known for displaying a considerable biological profile, an attempt has been made to unravel their cytotoxic potential. In this context, a number of pyrazole/isoxazole linked arylcinnamide conjugates (15a-o and 21a-n) have been synthesized by employing a straight forward route. The basic structure comprised three ring scaffolds (A, B and C): methoxyphenyl rings as A and C rings and a five membered heterocyclic ring (pyrazole or isoxazole) as the B-ring. To achieve clear understanding, these derivatives are categorized as pyrazole-phenylcinnamides (PP) and isoxazole-phenylcinnamides (IP). These compounds have been evaluated for their ability to inhibit the growth of various human cancer cell lines such as HeLa, DU-145, A549 and MDA-MB231 and most of them exhibit considerable cytotoxic effects. Some of them like 15a, 15b, 15e, 15i and 15l exhibit promising cytotoxicity in HeLa cells (IC50 = 0.4, 1.8, 1.2, 2.7 and 1.7 μM). Amongst them 15a, 15b and 15e were taken up for detailed biological studies, they were found to arrest the cells in the G2/M phase of the cell cycle. Moreover, they were investigated for their effect on the microtubular cytoskeletal system by using a tubulin polymerization assay, immunofluroscence and molecular docking studies; interestingly they demonstrate a significant inhibition of tubulin polymerization.

  20. [Safety of beta-agonists in asthma].

    PubMed

    Oscanoa, Teodoro J

    2014-01-01

    Beta 2 agonist bronchodilators (β2A) are very important part in the pharmacotherapy of bronchial asthma, a disease that progresses in the world in an epidemic way. The β2A are prescribed to millions of people around the world, therefore the safety aspects is of public interest. Short-Acting β2 Agonists (SABAs), such as albuterol inhaler, according to current evidence, confirming its safety when used as a quick-relief or rescue medication. The long-acting β2 agonists (LABAs) The long-acting bronchodilators β2A (Long acting β2 Agonists or LABAs) are used associated with inhaled corticosteroids as controller drugs for asthma exacerbationsaccess, for safety reasons LABAs are not recommended for use as monotherapy.

  1. Bis[3-methyl-5-(pyridin-2-yl)-1H-pyrazol-4-yl] selenide methanol hemisolvate.

    PubMed

    Seredyuk, Maksym; Sharkina, Natalia O; Gumienna-Kontecka, Elzbieta; Kapshuk, Anatoly A

    2014-02-01

    The asymmetric unit of the title compound, C18H16N6Se·0.5CH3OH, contains two independent mol-ecules of bis-[3-methyl-5-(pyridin-2-yl)-1H-pyrazol-4-yl] selenide with similar C-Se-C bond angles [99.30 (14) and 98.26 (13)°], and a methanol molecule of solvation. In one mol-ecule, the dihedral angles between pyrazole and neighbouring pyridine rings are 18.3 (2) and 15.8 (2)°, and the corresponding angles in the other mol-ecule are 13.5 (2) and 8.3 (2)°. In the crystal, the selenide and solvent mol-ecules are linked by classical O-H⋯N and N-H⋯N hydrogen bonds, as well as by weak C-H⋯O and C-H⋯π inter-actions, forming a three-dimensional supra-molecular architecture.

  2. Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds

    PubMed Central

    Niculescu-Duvaz, Dan; Niculescu-Duvaz, Ion; Suijkerbuijk, Bart M.J.M.; Ménard, Delphine; Zambon, Alfonso; Nourry, Arnaud; Davies, Lawrence; Manne, Helen A.; Friedlos, Frank; Ogilvie, Lesley; Hedley, Douglas; Takle, Andrew K.; Wilson, David M.; Pons, Jean-Francois; Coulter, Tom; Kirk, Ruth; Cantarino, Neus; Whittaker, Steven; Marais, Richard; Springer, Caroline J.

    2010-01-01

    V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a serine/threonine-specific protein kinase that is mutated with high frequency in cutaneous melanoma, and many other cancers. Inhibition of mutant BRAF is an attractive therapeutic approach for the treatment of melanoma. A triarylimidazole BRAF inhibitor bearing a phenylpyrazole group (dimethyl-[2-(4-{5-[4-(1H-pyrazol-3-yl)-phenyl]-4-pyridin-4-yl-1H-imidazol-2-yl}-phenoxy)-ethyl]-amine, 1a) was identified as an active BRAF inhibitor. Based on this starting point, we synthesized a series of analogues leading to the discovery of 6-{2-[4-(4-methyl-piperazin-1-yl)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-2,4-dihydro-indeno[1,2-c]pyrazole (1j), with nanomolar activity in three assays: inhibition of purified mutant BRAF activity in vitro; inhibition of oncogenic BRAF-driven extracellular regulated kinase (ERK) activation in BRAF mutant melanoma cell lines; and inhibition of proliferation in these cells. PMID:20667740

  3. Synthesis, Characterization, Antimicrobial Screening and Free-Radical Scavenging Activity of Some Novel Substituted Pyrazoles.

    PubMed

    Hamada, Nagwa Mohamed Mahrous; Abdo, Nadia Yousef Megally

    2015-06-08

    The present work deals with the synthesis of acetoxysulfonamide pyrazole derivatives, substituted 4,5-dihydropyrazole-1-carbothioamide and 4,5-dihydropyrazole-1-isonicotinoyl derivatives starting from substituted vanillin chalcones. Acetoxysulfonamide pyrazole derivatives were prepared from the reaction of chalcones with p-sulfamylphenylhydrazine followed by treatment with acetic anhydride. At the same time 4,5-dihydropyrazole-1-carbothioamide and 4,5-dihydropyrazole-1-isonicotinoyl derivatives were prepared from the reaction of chalcones with either thiosemicarbazide or isonicotinic acid hydrazide, respectively. The synthesized compounds were structurally characterized on the basis of IR, 1H-NMR, 13C-NMR spectral data and microanalyses. All of the newly isolated compounds were tested for their antimicrobial activities. The antimicrobial screening using the agar well-diffusion method revealed that the chloro derivatives are the most active ones. Moreover, the antioxidant and anti-inflammatory activity of these chloro derivatives are also studied using the DPPH radical scavenging and NO radical scavenging methods, respectively.

  4. Fluorination Effects on NOS Inhibitory Activity of Pyrazoles Related to Curcumin.

    PubMed

    Nieto, Carla I; Cabildo, María Pilar; Cornago, María Pilar; Sanz, Dionisia; Claramunt, Rosa M; Torralba, María Carmen; Torres, María Rosario; Elguero, José; García, José A; López, Ana; Acuña-Castroviejo, Darío

    2015-08-28

    A series of new (E)-3(5)-[β-(aryl)-ethenyl]-5(3)-phenyl-1H-pyrazoles bearing fluorine atoms at different positions of the aryl group have been synthesized starting from the corresponding β-diketones. All compounds have been characterized by elemental analysis, DSC as well as NMR (¹H, (13)C, (19)F and (15)N) spectroscopy in solution and in solid state. Three structures have been solved by X-ray diffraction analysis, confirming the tautomeric forms detected by solid state NMR. The in vitro study of their inhibitory potency and selectivity on the activity of nNOS and eNOS (calcium-calmodulin dependent) as well as iNOS (calcium-calmodulin independent) isoenzymes is presented. A qualitative structure-activity analysis allowed the establishment of a correlation between the presence/ absence of different substituents with the inhibition data proving that fluorine groups enhance the biological activity. (E)-3(5)-[β-(3-Fluoro-4-hydroxyphenyl)-ethenyl]-5(3)-phenyl-1H-pyrazole (13), is the best inhibitor of iNOS, being also more selective towards the other two isoforms.

  5. Synthesis and bioactivity of pyrazole and triazole derivatives as potential PDE4 inhibitors.

    PubMed

    Li, Ya-Sheng; Tian, Hao; Zhao, Dong-Sheng; Hu, De-Kun; Liu, Xing-Yu; Jin, Hong-Wei; Song, Gao-Peng; Cui, Zi-Ning

    2016-08-01

    A series of pyrazole and triazole derivatives containing 5-phenyl-2-furan functionality were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. The bioassay results showed that title compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNFα release. Meanwhile, the activity of compounds containing 1,2,4-triazole (series II) was higher than that of pyrazole-attached derivatives (series I). The primary structure-activity relationship study and docking results showed that the 1,2,4-triazole moiety of compound IIk played a key role to form integral hydrogen bonds and π-π stacking interaction with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4. Compound IIk would be great promise as a hit compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.

  6. Pyrazole derived ultra-short antimicrobial peptidomimetics with potent anti-biofilm activity.

    PubMed

    Ahn, Mija; Gunasekaran, Pethaiah; Rajasekaran, Ganesan; Kim, Eun Young; Lee, Soo-Jae; Bang, Geul; Cho, Kun; Hyun, Jae-Kyung; Lee, Hyun-Ju; Jeon, Young Ho; Kim, Nam-Hyung; Ryu, Eun Kyoung; Shin, Song Yub; Bang, Jeong Kyu

    2017-01-05

    In this study, we report on the first chemical synthesis of ultra-short pyrazole-arginine based antimicrobial peptidomimetics derived from the newly synthesized N-alkyl/aryl pyrazole amino acids. Through the systematic tuning of hydrophobicity, charge, and peptide length, we identified the shortest peptide Py11 with the most potent antimicrobial activity. Py11 displayed greater antimicrobial activity against antibiotic-resistant bacteria, including MRSA, MDRPA, and VREF, which was approximately 2-4 times higher than that of melittin. Besides its higher selectivity (therapeutic index) toward bacterial cells than LL-37, Py11 showed highly increased proteolytic stability against trypsin digestion and maintained its antimicrobial activity in the presence of physiological salts. Interestingly, Py11 exhibited higher anti-biofilm activity against MDRPA compared to LL-37. The results from fluorescence spectroscopy and transmission electron microscopy (TEM) suggested that Py11 kills bacterial cells possibly by integrity disruption damaging the cell membrane, leading to the cytosol leakage and eventual cell lysis. Furthermore, Py11 displayed significant anti-inflammatory (endotoxin-neutralizing) activity by inhibiting LPS-induced production of nitric oxide (NO) and TNF-α. Collectively, our results suggest that Py11 may serve as a model compound for the design of antimicrobial and antisepsis agents.

  7. Solution conformation of a tetradecapeptide stabilized by two di-n-propyl glycine residues.

    PubMed

    Sarojini, Vijayalekshmi; Balaji Rao, R; Ragothama, S; Balaram, Padmanabhan

    2010-08-01

    The solution conformation of a designed tetradecapeptide Boc-Val-Ala-Leu-Dpg-Val-Ala-Leu-Val-Ala-Leu-Dpg-Val-Ala-Leu-OMe (Dpg-14) containing two di-n-propyl glycine (Dpg) residues has been investigated by (1)H NMR and circular dichroism in organic solvents. The peptide aggregates formed at a concentration of 3 mM in the apolar solvent CDCl(3) were broken by the addition of 12% v/v of the more polar solvent DMSO-d(6). Successive N(i)H <--> N(i+1)H NOEs observed over the entire length of the sequence in this solvent mixture together with the observation of several characteristic medium-range NOEs support a major population of continuous helical conformations for Dpg-14. Majority of the observed coupling constants (3)JNHC(alpha)H) also support phi values in the helical conformation. Circular dichroism spectra recorded in methanol and propan-2-ol give further support in favor of helical conformation for Dpg-14 and the stability of the helix at higher temperature.

  8. Intricate internal rotation surface and fundamental infrared transitions of the n-propyl radical.

    PubMed

    Li, Chenyang; Agarwal, Jay; Wu, Chia-Hua; Allen, Wesley D; Schaefer, Henry F

    2015-01-22

    The potential energy surface for methylene hindered internal rotation is examined for the n-propyl radical, a molecule fundamental to combustion chemistry. Six stationary points are identified, and four of them are unique: 1, 2, TS1, and TS2. The remaining two structures 1' and TS1' are mirror images with respect to 1 and TS1. Focal point analysis, converged to the complete basis set limit of coupled-cluster theory with single, double, triple, and perturbative quadruple excitations [CCSDT(Q)], is employed to obtain the relative energies of these structures. A one-dimensional potential energy surface (PES) is constructed by explicitly mapping out a distinguished reaction path via constrained geometry optimizations. A "double-well" feature is observed on the electronic PES, but under the adiabatic approximation, the enthalpic (0 K) PES becomes a regular single-well potential with the expected 180° periodicity. The corresponding one-dimensional vibrational Schrödinger equation is solved using the Cooley-Numerov approach to obtain vibrational states of the methylene torsional motion. The predicted barrier for internal rotation is 105.5 and 137.2 cm(-1) for the electronic and enthalpic surfaces, respectively. Anharmonic (fundamental) vibrational frequencies are predicted for structure 1 using second-order vibrational perturbation theory, and the band origins for 11 modes are reported. Comparison with previous electron spin resonance and infrared spectroscopic work, in addition to other theoretical investigations, is made where possible.

  9. Growth of propyl-p-hydroxybenzoate single crystals and its characterizations

    NASA Astrophysics Data System (ADS)

    Karunagaran, N.; Ramasamy, P.

    2012-06-01

    Single crystals of Propyl-p-hydroxybenzoate (PHB) crystals have been grown by slow evaporation solution technique (SEST) using methanol as a solvent. The PHB single crystal of dimension up to 27×16×8 mm3 has been grown in a period of 18 days at room temperature. The optical transparency of the grown PHB crystal has been measured on (212) plane by UV-Vis-NIR spectrophotometer. The crystal has 60% of transparency in the entire visible region. The thermo gravimetric analysis (TG) and differential thermal analysis (DTA) studies reveal that the crystal is thermally stable up to 99°C. The mechanical strength of the grown PHB crystal is measured using Vickers microhardness tester. The chemical etching studies were carried out on (212) plane using methanol etchant. The laser damage threshold of PHB crystal is 1.3 GW/cm2. The dielectric properties have been investigated. The birefringence value is found to be 0.10148 at the wavelength of 504 nm. The refractive index of grown PHB single crystal is 1.6753.

  10. PPAR Agonists and Cardiovascular Disease in Diabetes

    PubMed Central

    Calkin, Anna C.; Thomas, Merlin C.

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARα agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARγ agonists, and more recently dual PPARα/γ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARγ receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease. PMID:18288280

  11. Long-term studies of dopamine agonists.

    PubMed

    Hubble, Jean P

    2002-02-26

    Dopamine agonists have long been used as adjunctive therapy for the treatment of Parkinson's disease (PD). In more recent years these drugs have also been proved safe and effective as initial therapy in lieu of levodopa in the treatment of PD. Long-term levodopa therapy is associated with motor complications, including fluctuating response patterns and dyskinesia. By initially introducing a dopamine agonist as symptomatic drug therapy, it may be possible to postpone the use of levodopa and delay or prevent the development of motor complications. Recently, four clinical trials have explored this hypothesis by comparing the long-term response and side effects of levodopa with dopamine agonist therapy. The drugs studied have included ropinirole, pramipexole, cabergoline, and pergolide. In each of these projects, the occurrence of motor complications, such as wearing off and dyskinesia, was significantly less in the subjects assigned to initiation of therapy with a dopamine agonist. The addition of levodopa could be postponed by many months or even several years. Therefore, these long-term studies of dopamine agonists support the initiation of a dopamine agonist instead of levodopa in an effort to postpone levodopa-related motor complications. This therapeutic approach may be particularly appropriate in PD patients with a long treatment horizon on the basis of age and general good health. The extension phase of the long-term study comparing pramipexole with levodopa is ongoing, and follow-up information may help to establish the value of this treatment strategy.

  12. Use of S-[2,3-bispalmitoyiloxy-(2R)-propyl]-R-cysteinyl-amido-monomethoxy polyethylene glycol as an adjuvant improved protective immunity associated with a DNA vaccine encoding Cu,Zn superoxide dismutase of Brucella abortus in mice.

    PubMed

    Retamal-Díaz, Angello; Riquelme-Neira, Roberto; Sáez, Darwin; Rivera, Alejandra; Fernández, Pablo; Cabrera, Alex; Guzmán, Carlos A; Oñate, Angel

    2014-11-01

    This study was conducted to evaluate the immunogenicity and protective efficacy of a DNA vaccine encoding Brucella abortus Cu,Zn superoxide dismutase (SOD) using the Toll-like receptor 2/6 agonist S-[2,3-bispalmitoyiloxy-(2R)-propyl]-R-cysteinyl-amido-monomethoxy polyethylene glycol (BPPcysMPEG) as an adjuvant. Intranasal coadministration of BPPcysMPEG with a plasmid carrying the SOD-encoding gene (pcDNA-SOD) into BALB/c mice elicited antigen-specific humoral and cellular immune responses. Humoral responses were characterized by the stimulation of IgG2a and IgG1 and by the presence of SOD-specific secretory IgA in nasal and bronchoalveolar lavage fluids. Furthermore, T-cell proliferative responses and increased production of gamma interferon were also observed upon splenocyte restimulation with recombinant SOD. Cytotoxic responses were also stimulated, as demonstrated by the lysis of RB51-SOD-infected J774.A1 macrophages by cells recovered from immunized mice. The pcDNA-SOD/BPPcysMPEG formulation induced improved protection against challenge with the virulent strain B. abortus 2308 in BALB/c mice over that provided by pcDNA-SOD, suggesting the potential of this vaccination strategy against Brucella infection.

  13. Structure of Pyrazole Derivatives Impact their Affinity, Stoichiometry, and Cooperative Interactions for CYP2E1 Complexes

    PubMed Central

    Hartman, Jessica H.; Bradley, Amber M.; Laddusaw, Ryan M; Perry, Martin D.; Miller, Grover P.

    2013-01-01

    CYP2E1 plays a critical role in detoxication and carcinogenic activation of drugs, pollutants, and dietary compounds; however, these metabolic processes can involve poorly characterized cooperative interactions that compromise the ability to understand and predict CYP2E1 metabolism. Herein, we employed an array of ten azoles with an emphasis on pyrazoles to establish the selectivity of catalytic and cooperative CYP2E1 sites through binding and catalytic studies. Spectral binding studies for monocyclic azoles suggested two binding events, while bicyclic azoles suggested one. Pyrazole had moderate affinity toward the CYP2E1 catalytic site that improved when a methyl group was introduced at either position 3 or 4. The presence of methyl groups simultaneously at positions 3 and 5 blocked binding, and a phenyl group at position 3 did not improve binding affinity. In contrast, pyrazole fusion to a benzene or cyclohexane ring greatly increased affinity. The consequences of these binding events on CYP2E1 catalysis were studied through inhibition studies with 4-nitrophenol, a substrate known to bind both sites. Most pyrazoles shared a common mixed cooperative inhibition mechanism in which pyrazole binding rescued CYP2E1 from substrate inhibition. Overall, inhibitor affinities toward the CYP2E1 catalytic site were similar to those reported in binding studies, and the same trend was observed for binding at the cooperative site. Taken together, these studies identified key structural determinants in the affinity and stoichiometry of azole interactions with CYP2E1 and consequences on catalysis that further advance an understanding of the relationship between structure and function for this enzyme. PMID:23811196

  14. Synthesis, characterization and cytotoxic activity of gallium(III) complexes anchored by tridentate pyrazole-based ligands.

    PubMed

    Silva, Francisco; Marques, Fernanda; Santos, I C; Paulo, António; Rodrigues, António Sebastião; Rueff, José; Santos, Isabel

    2010-05-01

    Reactions of GaCl(3) with pyrazole-containing ligands of the pyrazole-imine-phenol (HL(1)-HL(3)) or pyrazole-amine-phenol (HL(4)-HL(6)) types led to the synthesis of well-defined [GaL(2)](+) homoleptic complexes (1-6). Complexes 1-6 were characterized by elemental analysis, ESI-MS (electrospray ionization-mass spectrometry), IR and NMR spectroscopies, and in the case of Complex 1 also by X-ray diffraction analysis. In complexes 1-3, the pyrazole-imine-phenolate ligands act as monoanionic chelators that coordinate to the metal in a meridional fashion, while 4-6 contain monoanionic and facially coordinated pyrazole-amine-phenolate ligands. Complexes 1-3 have a greater stability in solution compared to 4-6, which have shown a more pronounced tendency to release the respective ancillary ligands. The cytotoxicity of 1-6 and of the respective ligands (HL(1)-HL(6)) was evaluated against human prostate cancer cells PC-3 and human breast cancer cells MCF-7. The substituents of the phenolate rings strongly influenced the cytotoxicity of the compounds. Complexes 3 and 6 that contain chloride substituents at the phenolate rings have shown the highest cytotoxicity, including in the cisplatin-resistant PC-3 cell line. The cytotoxic profile of 3 and 6 is very similar to the one displayed by the respective anchor ligands, respectively HL(1) and HL(6). The cytotoxic activity of 3 and 6 is slightly increased by the presence of transferrin, and both complexes provoke cell death mainly by induction of apoptotic pathways.

  15. 7-Chloro-2-[1-(4-methoxy-phen-yl)pyrazol-4-yl]-3,3-dimethyl-3H-indole.

    PubMed

    Helliwell, Madeleine; Afghan, Arash; Keshvari, Foroogh; Baradarani, Mehdi M; Joule, John A

    2009-12-12

    In the title compound, C(20)H(18)ClN(3)O, the dihedral angle between the pyrazole and the 3H-indole components is only 13.28 (6)°, indicating that there is conjugation between the two heterocyclic subunits. The N-methoxy-phenyl unit makes a dihedral angle of 25.10 (7)° with the pyrazole ring.

  16. The structural basis for agonist and partial agonist action on a β(1)-adrenergic receptor.

    PubMed

    Warne, Tony; Moukhametzianov, Rouslan; Baker, Jillian G; Nehmé, Rony; Edwards, Patricia C; Leslie, Andrew G W; Schertler, Gebhard F X; Tate, Christopher G

    2011-01-13

    β-adrenergic receptors (βARs) are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins upon binding catecholamine agonist ligands such as adrenaline and noradrenaline. Synthetic ligands have been developed that either activate or inhibit βARs for the treatment of asthma, hypertension or cardiac dysfunction. These ligands are classified as either full agonists, partial agonists or antagonists, depending on whether the cellular response is similar to that of the native ligand, reduced or inhibited, respectively. However, the structural basis for these different ligand efficacies is unknown. Here we present four crystal structures of the thermostabilized turkey (Meleagris gallopavo) β(1)-adrenergic receptor (β(1)AR-m23) bound to the full agonists carmoterol and isoprenaline and the partial agonists salbutamol and dobutamine. In each case, agonist binding induces a 1 Å contraction of the catecholamine-binding pocket relative to the antagonist bound receptor. Full agonists can form hydrogen bonds with two conserved serine residues in transmembrane helix 5 (Ser(5.42) and Ser(5.46)), but partial agonists only interact with Ser(5.42) (superscripts refer to Ballesteros-Weinstein numbering). The structures provide an understanding of the pharmacological differences between different ligand classes, illuminating how GPCRs function and providing a solid foundation for the structure-based design of novel ligands with predictable efficacies.

  17. Rhenium-mediated coupling of acetonitrile and pyrazoles. New molecular clefts for anion binding.

    PubMed

    Arroyo, Marta; Miguel, Daniel; Villafañe, Fernando; Nieto, Sonia; Pérez, Julio; Riera, Lucía

    2006-08-21

    The reaction of fac-[ReBr(CO)3(NCMe)2] (1) with either pyrazole (Hpz) or 3,5-dimethylpyrazole (Hdmpz) in a 1:2 Re/pyrazole ratio affords the known complexes fac-[ReBr(CO)3(Hpz)2] (2) and [ReBr(CO)3(Hdmpz)2] (3). Using a 1:1 ratio, MeCN as solvent, and longer reaction times led to a mixture in which the major components are the pyrazolylamidino complexes fac-[ReBr(CO)3(HN=C(CH3)pz-kappa2N,N)] (4) and fac-[ReBr(CO)3(HN=C(CH3)dmpz-kappa2N,N)] (5). The complexes fac-[ReBr(CO)3(Hpz)(NCMe)] (6) and fac-[ReBr(CO)3(Hdmpz)(NCMe)] (7) (along with 2 and 3) were found to be minor components of these reactions. Analogous reactions of fac-[Re(OClO3)(CO)3(NCMe)2] yielded fac-[Re(NCCH3)(CO)3(HN=C(CH3)pz-kappa2N,N)]ClO4 (8), fac-[Re(NCCH3)(CO)3(HN=C(CH3)dmpz-kappa2N,N)]ClO4 (9), fac-[Re(Hpz)(CO)3(HN=C(CH3)pz-kappa2N,N)]ClO4 (10), and fac-[Re(Hdmpz)(CO)3(HN=C(CH3)dmpz-kappa2N,N)]ClO4 (11). The X-ray structure of 11 showed the perchlorate anion to be hydrogen-bonded by the N-H groups of the pyrazole and pyrazolylamidino ligands. The behavior of the compound fac-[Re(Hdmpz)(CO)3(HN=C(CH3)dmpz-kappa2N,N)]BAr'4 (13) (synthesized by reaction of [ReBr(CO)3(Hdmpz)2] (3) with (i) AgOTf and (ii) NaBAr'(4)/MeCN) as an anion receptor has been studied in CD3CN solution. In addition, the structure of the supramolecular adduct fac-[Re(CO)3(Hdmpz)(HN=C(CH3)dmpz-kappa2N,N)].Cl (14), featuring chloride binding by the two N-H groups, was determined by X-ray diffraction.

  18. Pharmacological characterization of 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), a potent and selective hypoxia-inducible factor prolyl hydroxylase inhibitor.

    PubMed

    Barrett, Terrance D; Palomino, Heather L; Brondstetter, Theresa I; Kanelakis, Kimon C; Wu, Xiaodong; Haug, Peter V; Yan, Wen; Young, Andrew; Hua, Hong; Hart, Juliet C; Tran, Da-Thao; Venkatesan, Hariharan; Rosen, Mark D; Peltier, Hillary M; Sepassi, Kia; Rizzolio, Michele C; Bembenek, Scott D; Mirzadegan, Tara; Rabinowitz, Michael H; Shankley, Nigel P

    2011-06-01

    The hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) enzymes represent novel targets for the treatment of anemia, ulcerative colitis, and ischemic and metabolic disease inter alia. We have identified a novel small-molecule inhibitor of PHD, 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), through structure-based drug design methods. The pharmacology of JNJ-42041935 was investigated in enzyme, cellular, and whole-animal systems and was compared with other compounds described in the literature as PHD inhibitors. JNJ-42041935, was a potent (pK(I) = 7.3-7.9), 2-oxoglutarate competitive, reversible, and selective inhibitor of PHD enzymes. In addition, JNJ-42041935 was used to compare the effect of selective inhibition of PHD to intermittent, high doses (50 μg/kg i.p.) of an exogenous erythropoietin receptor agonist in an inflammation-induced anemia model in rats. JNJ-42041935 (100 μmol/kg, once a day for 14 days) was effective in reversing inflammation-induced anemia, whereas erythropoietin had no effect. The results demonstrate that JNJ-42041935 is a new pharmacological tool, which can be used to investigate PHD inhibition and demonstrate that PHD inhibitors offer great promise for the treatment of inflammation-induced anemia.

  19. 40 CFR 721.10346 - 3H-Indolium, 2-[2-[2-chloro-3-[2-(1,3-dihydro-3,3-dimethyl-1-propyl-2H-indol-2-ylidene)ethylidene...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...]ethenyl]-3,3-dimethyl-1-propyl-, iodide (1:1). 721.10346 Section 721.10346 Protection of Environment...-yl]ethenyl]-3,3-dimethyl-1-propyl-, iodide (1:1). (a) Chemical substance and significant new uses...]-3,3-dimethyl-1-propyl-, iodide (1:1) (PMN P-05-599; CAS No. 207399-07-3) is subject to...

  20. 40 CFR 721.10346 - 3H-Indolium, 2-[2-[2-chloro-3-[2-(1,3-dihydro-3,3-dimethyl-1-propyl-2H-indol-2-ylidene)ethylidene...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...]ethenyl]-3,3-dimethyl-1-propyl-, iodide (1:1). 721.10346 Section 721.10346 Protection of Environment...-yl]ethenyl]-3,3-dimethyl-1-propyl-, iodide (1:1). (a) Chemical substance and significant new uses...]-3,3-dimethyl-1-propyl-, iodide (1:1) (PMN P-05-599; CAS No. 207399-07-3) is subject to...

  1. 40 CFR 721.10346 - 3H-Indolium, 2-[2-[2-chloro-3-[2-(1,3-dihydro-3,3-dimethyl-1-propyl-2H-indol-2-ylidene)ethylidene...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...]ethenyl]-3,3-dimethyl-1-propyl-, iodide (1:1). 721.10346 Section 721.10346 Protection of Environment...-yl]ethenyl]-3,3-dimethyl-1-propyl-, iodide (1:1). (a) Chemical substance and significant new uses...]-3,3-dimethyl-1-propyl-, iodide (1:1) (PMN P-05-599; CAS No. 207399-07-3) is subject to...

  2. Developmental toxic potential of di-n-propyl phthalate administered orally to rats.

    PubMed

    Saillenfait, Anne-Marie; Roudot, Alain-Claude; Gallissot, Frédéric; Sabaté, Jean-Philippe; Chagnon, Marie-Christine

    2011-01-01

    The objective of this study was to evaluate the developmental toxic potential of di-n-propyl phthalate (DnPP) in rats. Pregnant Sprague-Dawley rats were given DnPP at doses of 0 (olive oil), 0.5, 1 and 1.5 g kg⁻¹ per day, by gavage, on gestation days 6-20. Benchmark doses were calculated for the effects of DnPP on fetal weight and anogenital distance of the male fetuses. Maternal body weight gain was significantly reduced at 1.5 g kg⁻¹ per day, over gestation days 6-9. DnPP-treated dams also showed a statistically significant increase in liver weight and a mild but statistically significant peroxisomal enzyme induction at 1 or 1.5 g kg⁻¹ per day. Male and female fetal body weights were significantly reduced at 1.5 g kg⁻¹ per day. There was a statistically significant decrease in the anogenital distance of the male fetuses at 1 and 1.5 g kg⁻¹ per day, and three males (of 75) showed malpositioned testis at the high dose. The mean percentage of fetuses per litter with cervical and thoracic rudimentary ribs was significantly increased at 1 and 1.5 g kg⁻¹ per day. Delayed ossification was seen at 1 g kg⁻¹ per day (phalanges) and 1.5 g kg⁻¹ per day (hyoid, sternebrae, and phalanges). No treatment-related effects on prenatal viability or on fetal external or visceral malformations or variations were observed at any dose. Thus, there was no evidence of teratogenicity up to the high dose of 1.5 g kg⁻¹ per day. The no-observed-adverse-effect level (NOAEL) for developmental toxicity was 0.5 g kg⁻¹ per day.

  3. Sensitization of visible and NIR emitting lanthanide(III) ions in noncentrosymmetric complexes of hexafluoroacetylacetone and unsubstituted monodentate pyrazole.

    PubMed

    Ahmed, Zubair; Iftikhar, K

    2013-11-07

    A series of highly volatile eight-coordinate air and moisture stable lanthanide complexes of the type [Ln(hfaa)3(L)2] (Ln = Pr (1), Nd (2), Eu (3), Gd (4), Tb (5), Dy (6), Ho (7), Er (8), Tm (9), and Yb (10); hfaa = anion of hexafluoroacetylacetone and L = pyrazole) have been synthesized and characterized by elemental analysis, IR, ESI-MS(+), and NMR studies. Single-crystal X-ray structures have been determined for the Eu(III) and Dy(III) complexes. These complexes crystallize in the monoclinic space group P2(1)/c. The lanthanide ion in each of these complexes is eight-coordinate with six oxygen atoms from three hfaa and two N-atoms from two pyrazole units, forming a coordination polyhedron best describable as a distorted square antiprism. The NMR spectra reveal that both the pyrazole units remain attached to the metal in solution and the β-diketonate and pyrazole protons are shifted in opposite directions in the case of paramagnetic complexes. The lanthanide-induced chemical shifts are dipolar in nature. The hypersensitive transitions of Nd(III), Ho(III), and Er(III) are sensitive to the environment (solvent), which is reflected by the oscillator strength and band shape of these transitions. The band shape due to the hypersensitive transition of Nd(III) in noncoordinating chloroform and dichloromethane is similar to those of the typical eight-coordinate Nd(III) β-diketonate complexes. The quantum yield and lifetime of Pr(III), Eu(III), Tb(III), Dy(III), and Tm(III) in visible and Pr(III), Nd(III), Dy(III), Ho(III), Er(III) Tm(III), and Yb(III) in the NIR region are sizable. The environment around these metal ions is asymmetric, which leads to increased radiative rates and luminescence efficiencies. The quantum yield of the complexes reveal that ligand-to-metal energy transfer follows the order Eu(III) > Tb(III) ≫ Pr(III) > Dy(III) > Tm(III). Both ligands (hfaa and pyrazole) are good sensitizers for all the visible and NIR emitters effectively, except for Tb

  4. Design and synthesis of pyrazole-oxindole conjugates targeting tubulin polymerization as new anticancer agents.

    PubMed

    Kamal, Ahmed; Shaik, Anver Basha; Jain, Nishant; Kishor, Chandan; Nagabhushana, Ananthamurthy; Supriya, Bhukya; Bharath Kumar, G; Chourasiya, Sumit S; Suresh, Yerramsetty; Mishra, Rakesh K; Addlagatta, Anthony

    2015-03-06

    A series of twenty one compounds with pyrazole and oxindole conjugates were synthesized by Knoevenagel condensation and investigated for their antiproliferative activity on different human cancer cell lines. The conjugates are comprised of a four ring scaffold; the structural isomers 12b and 12c possess chloro-substitution in the D ring. Among the congeners 12b, 12c, and 12d manifested significant cytotoxicity and inhibited tubulin assembly. Treatments with 12b, 12c and 12d resulted in accumulation of cells in G2/M phase, disruption of microtubule network, and increase in cyclin B1 protein. Zebrafish screening revealed that 12b, and 12d caused developmental defects. Docking analysis demonstrated that the congeners occupy the colchicine binding pocket of tubulin.

  5. Pyrazole prevention of CC14-induced ultrastructural changes in rat liver.

    PubMed Central

    Bernacchi, A. S.; de Castro, C. R.; de Toranzo, E. G.; Marzi, A.; de Ferreyra, E. C.; de Fenos, O. M.; Castro, J. A.

    1980-01-01

    Carbon tetrachloride (CC14) administration to rats leads to an early dilatation, vesiculation and disorganization of the liver endoplasmic reticulum (ER). This hepatotoxin also causes detachment of ribosomes from ER membranes, dilatation of the Golgi cisternae and occasionally dilatation of the perinuclear membrane. Prior treatment of the rats with pyrazole completely prevents CC14- induced ultrastructural alterations observed in liver at 3 h. This drug is known to decrease the intensity of the irreversible binding of CC14 reactive metabolites to cellular constituents without modifying the intensity of the CC14- induced lipid peroxidation, either in vitro or in vivo, as measured by the diene conjugation procedure or by decreases inthe arachidonic acid content of microsomal phospholipids. Results suggest that interaction of reactive metabolites rather than lipid peroxidation mediates deleterious effects of CCl4 on the liver ER. Images Fig. 1 Fig. 2 Fig. 3 PMID:7448119

  6. 7-(Pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-based derivatives for kinase inhibition: Co-crystallisation studies with Aurora-A reveal distinct differences in the orientation of the pyrazole N1-substituent.

    PubMed

    Bavetsias, Vassilios; Pérez-Fuertes, Yolanda; McIntyre, Patrick J; Atrash, Butrus; Kosmopoulou, Magda; O'Fee, Lisa; Burke, Rosemary; Sun, Chongbo; Faisal, Amir; Bush, Katherine; Avery, Sian; Henley, Alan; Raynaud, Florence I; Linardopoulos, Spiros; Bayliss, Richard; Blagg, Julian

    2015-10-01

    Introduction of a 1-benzyl-1H-pyrazol-4-yl moiety at C7 of the imidazo[4,5-b]pyridine scaffold provided 7a which inhibited a range of kinases including Aurora-A. Modification of the benzyl group in 7a, and subsequent co-crystallisation of the resulting analogues with Aurora-A indicated distinct differences in binding mode dependent upon the pyrazole N-substituent. Compounds 7a and 14d interact with the P-loop whereas 14a and 14b engage with Thr217 in the post-hinge region. These crystallographic insights provide options for the design of compounds interacting with the DFG motif or with Thr217.

  7. Selective, Tunable O2 Binding in Cobalt(II)-Triazolate/Pyrazolate Metal-Organic Frameworks.

    PubMed

    Xiao, Dianne J; Gonzalez, Miguel I; Darago, Lucy E; Vogiatzis, Konstantinos D; Haldoupis, Emmanuel; Gagliardi, Laura; Long, Jeffrey R

    2016-06-08

    The air-free reaction of CoCl2 with 1,3,5-tri(1H-1,2,3-triazol-5-yl)benzene (H3BTTri) in N,N-dimethylformamide (DMF) and methanol leads to the formation of Co-BTTri (Co3[(Co4Cl)3(BTTri)8]2·DMF), a sodalite-type metal-organic framework. Desolvation of this material generates coordinatively unsaturated low-spin cobalt(II) centers that exhibit a strong preference for binding O2 over N2, with isosteric heats of adsorption (Qst) of -34(1) and -12(1) kJ/mol, respectively. The low-spin (S = 1/2) electronic configuration of the metal centers in the desolvated framework is supported by structural, magnetic susceptibility, and computational studies. A single-crystal X-ray structure determination reveals that O2 binds end-on to each framework cobalt center in a 1:1 ratio with a Co-O2 bond distance of 1.973(6) Å. Replacement of one of the triazolate linkers with a more electron-donating pyrazolate group leads to the isostructural framework Co-BDTriP (Co3[(Co4Cl)3(BDTriP)8]2·DMF; H3BDTriP = 5,5'-(5-(1H-pyrazol-4-yl)-1,3-phenylene)bis(1H-1,2,3-triazole)), which demonstrates markedly higher yet still fully reversible O2 affinities (Qst = -47(1) kJ/mol at low loadings). Electronic structure calculations suggest that the O2 adducts in Co-BTTri are best described as cobalt(II)-dioxygen species with partial electron transfer, while the stronger binding sites in Co-BDTriP form cobalt(III)-superoxo moieties. The stability, selectivity, and high O2 adsorption capacity of these materials render them promising new adsorbents for air separation processes.

  8. Muscimol as an ionotropic GABA receptor agonist.

    PubMed

    Johnston, Graham A R

    2014-10-01

    Muscimol, a psychoactive isoxazole from Amanita muscaria and related mushrooms, has proved to be a remarkably selective agonist at ionotropic receptors for the inhibitory neurotransmitter GABA. This historic overview highlights the discovery and development of muscimol and related compounds as a GABA agonist by Danish and Australian neurochemists. Muscimol is widely used as a ligand to probe GABA receptors and was the lead compound in the development of a range of GABAergic agents including nipecotic acid, tiagabine, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, (Gaboxadol(®)) and 4-PIOL.

  9. Propyl gallate synthesis using acidophilic tannase and simultaneous production of tannase and gallic acid by marine Aspergillus awamori BTMFW032.

    PubMed

    Beena, P S; Basheer, Soorej M; Bhat, Sarita G; Bahkali, Ali H; Chandrasekaran, M

    2011-07-01

    Marine Aspergillus awamori BTMFW032, recently reported by us, produce acidophilic tannase as extracellular enzyme. Here, we report the application of this enzyme for synthesis of propyl gallate by direct transesterification of tannic acid and in tea cream solubilisation besides the simultaneous production of gallic acid along with tannase under submerged fermentation by this fungus. This acidophilic tannase enabled synthesis of propyl gallate by direct transesterification of tannic acid using propanol as organic reaction media under low water conditions. The identity of the product was confirmed with thin layer chromatography and Fourier transform infrared spectroscopy. It was noted that 699 U/ml of enzyme could give 60% solubilisation of tea cream within 1 h. Enzyme production medium was optimized adopting Box-Behnken design for simultaneous synthesis of tannase and gallic acid. Process variables including tannic acid, sodium chloride, ferrous sulphate, dipotassium hydrogen phosphate, incubation period and agitation were recognized as the critical factors that influenced tannase and gallic acid production. The model obtained predicted 4,824.61 U/ml of tannase and 136.206 μg/ml gallic acid after 48 h of incubation, whereas optimized medium supported 5,085 U/ml tannase and 372.6 μg/ml of gallic acid production after 36 and 84 h of incubation, respectively, with a 15-fold increase in both enzyme and gallic acid production. Results indicated scope for utilization of this acidophilic tannase for transesterification of tannic acid into propyl gallate, tea cream solubilisation and simultaneous production of gallic acid along with tannase.

  10. ARTICLES: Vapor-Liquid Equilibrium Data of Carbon Dioxide+Methyl Propionate and Carbon Dioxide+Propyl Propionate Systems

    NASA Astrophysics Data System (ADS)

    Xu, Wei; Xie, Chuan-xin; Li, Hong-ling; Tian, Yi-ling

    2010-06-01

    High-pressure vapor-liquid equilibrium data for the binary systems of methyl propionate+carbon dioxide and propyl propionate+carbon dioxide were measured at pressure from 1.00 MPa to 12.00 MPa and temperature in the range from 313 K to 373 K. Experimental results were correlated with the Peng-Robinson equation of state with the two-parameter van der Waals mixing rule. At the same time, the Henry's coefficient, partial molar enthalpy change and partial molar entropy change of CO2 during dissolution at different temperature were also calculated.

  11. Dibromido[N-propyl-N'-(2-pyridylmethyl-idene)ethane-1,2-diamine]zinc(II).

    PubMed

    Zhu, Xue-Wen; Yang, Xu-Zhao

    2008-07-31

    The title complex, [ZnBr(2)(C(11)H(17)N(3))], is a mononuclear zinc(II) compound derived from the Schiff base N-propyl-N'-(1-pyridin-2-ylmethyl-idene)ethane-1,2-diamine. The Zn(II) atom is five-coordinate, binding to the imine N, pyridine N, and amine N atoms of the Schiff base ligand and to two bromide anions in a distorted trigonal-bipyramidal coordination geometry. Adjacent mol-ecules are linked through inter-molecular N-H⋯Br hydrogen bonds, forming dimers.

  12. Quasielastic neutron scattering investigation of motion of water molecules in n-propyl alcohol-water mixture.

    PubMed

    Nakada, Masaru; Maruyama, Kenji; Yamamuro, Osamu; Misawa, Masakatsu

    2009-02-21

    The dynamics of water molecules in the n-propyl alcohol-water mixtures is investigated by using quasielastic neutron scattering measurements. The dynamic structure factor S(Q,E) obtained from incoherent scattering of hydrogen atoms of water is fitted with jump diffusion and relaxing cage models. The diffusion constant obtained from the relaxing cage model, which gives better fitting with S(Q,E), shows better agreement to the experimental value than that of jump diffusion model. The dependence of translational relaxation time tau(T)(Q) and stretched exponent beta(T)(Q) on the fraction of hydrophobic hydrating water molecules in the solution is discussed.

  13. Quasielastic neutron scattering investigation of motion of water molecules in n-propyl alcohol-water mixture

    NASA Astrophysics Data System (ADS)

    Nakada, Masaru; Maruyama, Kenji; Yamamuro, Osamu; Misawa, Masakatsu

    2009-02-01

    The dynamics of water molecules in the n-propyl alcohol-water mixtures is investigated by using quasielastic neutron scattering measurements. The dynamic structure factor S(Q,E) obtained from incoherent scattering of hydrogen atoms of water is fitted with jump diffusion and relaxing cage models. The diffusion constant obtained from the relaxing cage model, which gives better fitting with S(Q,E), shows better agreement to the experimental value than that of jump diffusion model. The dependence of translational relaxation time τT(Q) and stretched exponent βT(Q) on the fraction of hydrophobic hydrating water molecules in the solution is discussed.

  14. Synthesis and biological evaluation of novel formyl-pyrazoles bearing coumarin moiety as potent antimicrobial and antioxidant agents.

    PubMed

    Nagamallu, Renuka; Kariyappa, Ajay Kumar

    2013-12-01

    A series of coumarin appended formyl-pyrazoles 14-18 were synthesized by a simple and accessible approach. The reaction of 8-acetyl-4-methyl-7-hydroxy coumarin 3 and phenyl hydrazine hydrochlorides 4-8 produces the intermediate compounds 8-acetyl-4-methyl-7-hydroxy coumarin hydrazones 9-13. The reaction of compounds 9-13 and DMF in the presence of POCl3 yielded formyl-pyrazoles bearing coumarin moiety 14-18 in good yield. The synthesized new compounds 14-18 and the intermediates 8-acetyl-4-methyl-7-hydroxy coumarin hydrazones 9-13 prepared were screened in vitro for their antibacterial, antifungal antioxidant activities. The compounds 12 and 17 having chloro substitution exhibited promising antifungal and antibacterial activity against the different organisms tested. The compound 17 showed remarkable DPPH radical scavenging ability.

  15. Pyrazole bridged dinuclear Cu(II) and Zn(II) complexes as phosphatase models: Synthesis and activity

    NASA Astrophysics Data System (ADS)

    Naik, Krishna; Nevrekar, Anupama; Kokare, Dhoolesh Gangaram; Kotian, Avinash; Kamat, Vinayak; Revankar, Vidyanand K.

    2016-12-01

    Present work describes synthesis of dibridged dinuclear [Cu2L2(μ2-NN pyr)(NO3)2(H2O)2] and [Zn2L(μ-OH)(μ-NNpyr)(H2O)2] complexes derived from a pyrazole based ligand bis(2-hydroxy-3-methoxybenzylidene)-1H-pyrazole-3,5-dicarbohydrazide. The ligand shows dimeric chelate behaviour towards copper against monomeric for zinc counterpart. Spectroscopic evidences affirm octahedral environment around the metal ions in solution state and non-electrolytic nature of the complexes. Both the complexes are active catalysts towards phosphomonoester hydrolysis with first order kcat values in the range of 2 × 10-3s-1. Zinc complex exhibited promising catalytic efficiency for the hydrolysis. The dinuclear complexes hydrolyse via Lewis acid activation, whereby the phosphate esters are preferentially bound in a bidentate bridging fashion and subsequent nucleophilic attack to release phosphate group.

  16. Design, synthesis, characterization and in vitro and in vivo anti-inflammatory evaluation of novel pyrazole-based chalcones.

    PubMed

    Chavan, Hemant V; Adsul, Laxman K; Kotmale, Amol S; Dhakane, Valmik D; Thakare, Vishnu N; Bandgar, Babasaheb P

    2015-02-01

    Abstract A series of novel pyrazole-based chalcones have been designed, synthesized from 1-methyl-5-(2,4,6-trimethoxyphenyl)-1H-pyrazole (6). The structures of regioisomers 6 and 7 were determined by 2D (1)H-(1)H COSY, (1)H-(13)C HSQC and (1)H-(13)C HMBC experiments. The newly synthesized compounds were tested for their inhibitory activity against COX-1 and COX-2 using an in vitro cyclooxygenase (COX) inhibition assay. Moreover, they were investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw edema model for acute inflammation and cotton pellet-induced granuloma model for chronic inflammation. All the synthesized compounds showed potential to demonstrate anti-inflammatory activities, of particular interest compounds 10i, 10e, 10f, and 10h were found to be potent anti-inflammatory agents.

  17. Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain L-2-hydroxy acid oxidase.

    PubMed

    Barawkar, Dinesh A; Bandyopadhyay, Anish; Deshpande, Anil; Koul, Summon; Kandalkar, Sachin; Patil, Pradeep; Khose, Goraksha; Vyas, Samir; Mone, Mahesh; Bhosale, Shubhangi; Singh, Umesh; De, Siddhartha; Meru, Ashwin; Gundu, Jayasagar; Chugh, Anita; Palle, Venkata P; Mookhtiar, Kasim A; Vacca, Joseph P; Chakravarty, Prasun K; Nargund, Ravi P; Wright, Samuel D; Roy, Sophie; Graziano, Michael P; Cully, Doris; Cai, Tian-Quan; Singh, Sheo B

    2012-07-01

    Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.

  18. Ultrasonic irradiation assisted efficient regioselective synthesis of CF3-containing pyrazoles catalyzed by Cu(OTf)2/Et3N

    PubMed Central

    2013-01-01

    Background Most of the known approaches to the synthesis of CF3-containing organic compounds suffer from serious drawbacks. For example the starting materials required for these methods are rather difficult to obtain, or they are fairly toxic and inconvenient to work with and methods for direct fluorination and trifluoromethylation do not always allow the introduction of the CF3-group at the required position of a molecule. Results An efficient and attractive regioselective synthesis of a series of novel pyrazoles containing the trifluromethyl moiety was achieved using Cu(OTf)2/Et3N as an efficient catalytic system under ultrasonic irradiation. Conclusions Cu(OTf)2/Et3N catalyst showed a great advantage over all the investigated catalysts, and the ultrasonic irradiation method offered high yields of pyrazoles in short reaction time compared with classical conditions. gHMBC spectra of the product were used to rationalize the observed regioselectivity. PMID:23764261

  19. Microwave assisted efficient synthesis of diphenyl substituted pyrazoles using PEG-600 as solvent - A green approach.

    PubMed

    Ganapathi, M; Jayaseelan, D; Guhanathan, S

    2015-11-01

    A conventional and microwave assisted efficient synthesis of diphenyl substituted pyrazole using PEG 600 as green solvent has been described. A relatively shorter reaction time with excellent yield of the piperidine mediated protocol has been attracted economically attractive and eco-friendly. All newly synthesized compounds were characterized by standard spectroscopic techniques viz., UV-visible, FT-IR, (1)H-NMR and Mass spectra. The anti-microbial activities of compounds have also been tested using Minimum Inhibitory Concentration (MIC) method with two different microorganisms Staphylococcus aureus (MTCC3381) and Escherichia coli (MTCC739). The results of the antimicrobial activity revealed that the diphenyl substituted pyrazole derivatives have nice inhibiting nature against both types of bacteria of present investigation than corresponding chalcones. Since, the work has been focused on green chemical approach towards the synthesis, this protocol may be recommended for eco-friendly applications.

  20. A novel pyrazole biscoumarin based chemosensors for the selective detection of Cu(2+) and Zn(2+) ions.

    PubMed

    Kandasamy, Karthikeyan; Ganesabaskaran, Sivaprasad; Pachamuthu, Muthusamy Poomalai; Ramanathan, Anand

    2015-09-05

    A novel chemosensor based on pyrazole biscoumarin molecule "4-hydroxy-3-((4-hydroxy-2-oxo-2H-chromen-3-yl)(1,3-diphenyl-1H-pyrazol-4-yl)methyl)-2H-chromen-2-one" (PBC) was synthesized by a simple method. The chemosensing properties of PBC towards transition metal ions like Cu(2+) and Zn(2+) by naked eye, UV-Visible and fluorescence spectroscopic methods were described. The PBC solution with Cu(2+) and Zn(2+) ion showed brown and blue colour respectively. The UV-Visible spectra of PBC with Cu(2+) and Zn(2+) ions exposed their corresponding absorption maxima. Further, the Job's plot method confirmed the 1:1 and 2:1 stoichiometry of the complex formation between the PBC with Cu(2+) and Zn(2+) ions respectively. The fluorescence enhancement of PBC on binding with Cu(2+) and Zn(2+) is due to the inhibition of photo induced electron transfer mechanism.

  1. Synthesis, crystal structures, fluorescence and xanthine oxidase inhibitory activity of pyrazole-based 1,3,4-oxadiazole derivatives

    NASA Astrophysics Data System (ADS)

    Qi, De-Qiang; Yu, Chuan-Ming; You, Jin-Zong; Yang, Guang-Hui; Wang, Xue-Jie; Zhang, Yi-Ping

    2015-11-01

    A series of pyrazole-based 1,3,4-oxadiazole derivatives were rationally designed and synthesized in good yields by following a convenient route. All the newly synthesized molecules were fully characterized by IR, 1H NMR and elemental analysis. Eight compounds were structurally determined by single crystal X-ray diffraction analysis. The fluorescence properties of all the compounds were investigated in dimethyl sulfoxide media. In addition, these newly synthesized compounds were evaluated for in vitro inhibitory activity against commercial enzyme xanthine oxidase (XO) by measuring the formation of uric acid from xanthine. Among the compounds synthesized and tested, 3d and 3e were found to be moderate inhibitory activity against commercial XO with IC50 = 72.4 μM and 75.6 μM. The studies gave a new insight in further optimization of pyrazole-based 1,3,4-oxadiazole derivatives with excellent fluorescence properties and XO inhibitory activity.

  2. A novel pyrazole biscoumarin based chemosensors for the selective detection of Cu2+ and Zn2+ ions

    NASA Astrophysics Data System (ADS)

    Kandasamy, Karthikeyan; Ganesabaskaran, Sivaprasad; Pachamuthu, Muthusamy Poomalai; Ramanathan, Anand

    2015-09-01

    A novel chemosensor based on pyrazole biscoumarin molecule "4-hydroxy-3-((4-hydroxy-2-oxo-2H-chromen-3-yl)(1,3-diphenyl-1H-pyrazol-4-yl)methyl)-2H-chromen-2-one" (PBC) was synthesized by a simple method. The chemosensing properties of PBC towards transition metal ions like Cu2+ and Zn2+ by naked eye, UV-Visible and fluorescence spectroscopic methods were described. The PBC solution with Cu2+ and Zn2+ ion showed brown and blue colour respectively. The UV-Visible spectra of PBC with Cu2+ and Zn2+ ions exposed their corresponding absorption maxima. Further, the Job's plot method confirmed the 1:1 and 2:1 stoichiometry of the complex formation between the PBC with Cu2+ and Zn2+ ions respectively. The fluorescence enhancement of PBC on binding with Cu2+ and Zn2+ is due to the inhibition of photo induced electron transfer mechanism.

  3. Synthesis, structure and biological activity of 3(5)-trifluoromethyl-1H-pyrazoles derived from hemicurcuminoids

    NASA Astrophysics Data System (ADS)

    Nieto, Carla I.; Cabildo, M. Pilar; Cornago, M. Pilar; Sanz, Dionisia; Claramunt, Rosa M.; Alkorta, Ibon; Elguero, José; García, José A.; López, Ana; Acuña-Castroviejo, Darío

    2015-11-01

    Six new 3(5)-trifluoromethyl-5(3)-substituted-styryl-1H-pyrazoles have been synthesized and their tautomerism studied in solution and in the solid state. The determination of their structures has been based on multinuclear NMR spectroscopy together with GIAO/B3LYP/6-311++G(d,p) theoretical calculations of eight structures for each pyrazole (two tautomers and four conformations). Five out of the six compounds present inhibition percentages of the iNOS isoform higher than 50%. With regard to the nNOS inhibitory activity, only two of the studied compounds show an inhibition of about 50%. Finally, concerning the eNOS, there is a compound presenting a low percentage of inhibition (40.2%) attaining in the other cases 50%.

  4. Unexpected formation and crystal structure of tetra-kis-(1H-pyrazole-κN (2))-palladium(II) dichloride.

    PubMed

    Wagner, Thomas; Christiansen, Nena; Hrib, Cristian G; Kaufmann, Dieter E; Edelmann, Frank T

    2014-12-01

    The title salt, [Pd(C3H4N2)4]Cl2, was obtained unexpectedly by the reaction of palladium(II) dichloride with equimolar amounts of 1-chloro-1-nitro-2,2,2-tris-(pyrazol-yl)ethane in methanol solution. The Pd(2+) cation is located on an inversion centre and has a square-planar coordination sphere defined by four N atoms of four neutral pyrazole ligands. The average Pd-N distance is 2.000 (2) Å. The two chloride anions are not coordinating to Pd(2+). They are connected to the complex cations through N-H⋯Cl hydrogen bonds. In addition, C-H⋯Cl hydrogen bonds are observed, leading to a three-dimensional linkage of cations and anions.

  5. Tandem synthesis of highly functionalized pyrazole derivatives from terminal alkynes, sulfonyl azides, diethyl azadicarboxylate, and sodium arylsulfinates.

    PubMed

    Yavari, Issa; Nematpour, Manijeh

    2012-11-01

    The reaction between ketenimine intermediates [generated from terminal alkynes and sulfonyl azides], diethyl azadicarboxylate, and sodium arylsulfinates in N, N-dimethylformamide at room temperature, affords ethyl 2,3-dihydro-3-oxo-4-phenyl-2-tosyl-5-(tosylamino)pyrazole-1-carboxylates in moderate-to-good yields. When diisopropyl azadicarboxylate was used as the ester component, diisopropyl 1-arylsulfonyl-2-{[aryl(alkyl)sulfonyl]-2-phenylethanimidoyl}-1,2-hydrazinedicarboxylates were obtained.

  6. Crystal structure of 1-acetyl-3-(4-methylphenyl)-5-phenyl-4,5-dihydro-1 H-pyrazole

    NASA Astrophysics Data System (ADS)

    Bülbül, H.; Tinmaz, F.; Dege, N.; Özer İlhan, İ.; Sarıpınar, E.

    2014-12-01

    In the title compound, C18H18N2O, the whole molecule is not planar but the phenyl ring systems are planar individually. The central pyrazole ring system is twisted with puckering parameters Q = 0.1610(18) Å and φ = 82.2(6)°. The crystallographic structure is stabilized by C-H⋯N type intramolecular hydrogen bond, generating ring motif R(5).

  7. A systematic investigation of cooperativity between two types of hydrogen bonding in the nonlinear clusters of an aromatic molecule: Pyrazole

    NASA Astrophysics Data System (ADS)

    Amini, Saeed K.

    2014-06-01

    Crystalline pyrazole consists of nonlinear chains of an aromatic molecule. It includes two independent molecules which in turn causes two different types of hydrogen bonds (HBs). These two types of HBs with slight differences in their Nsbnd H⋯N geometries can be considered as interesting ones in the recent studies of cooperativity between different HBs. These HBs are investigated in several pyrazole clusters by electronic structure calculations. Parameters such as structure, binding energy, charge transfer, chemical shielding and electric field gradient (EFG) parameters calculated at the second order Moller-Plesset perturbation (MP2) and density functional (DF) levels of theory. Both the basis set superposition error (BSSE) and zero point vibrational energy (ZPVE) corrections on the cooperativity enhancement were considered. Changes of different properties of clusters against crystal size were investigated by proposed diagrams fitted to a logarithmic function which renders their extrema in the crystal limit. In each cluster, pyrazole molecules for which their parameters are more affected by cooperativity enhancement were explored employing these fitted diagrams. Most calculated energetic and spectroscopic parameters were in good linear correlations with both the structural parameters and charge transfer along HB (q). These correlations in the cases of nuclear magnetic resonance (NMR) and nuclear quadrupolar resonance (NQR) parameters, were explained in the terms of natural charges of bonding (σ(N1sbnd H1)) and antibonding (σ*(N1sbnd H1)) orbitals. Organizing calculated data for mental clusters with similar molecules and HB types produced better regression values in all linear correlations. According to the experimental CQ of N(2) in solid state and zero charge transfer in the gas phase, the value of charge transfer in the crystalline pyrazole and gas phase value of CQ of N(2) were assessed, respectively. Diagrams of the structural parameters against either

  8. Photolysis of n-Propyl Formate in the Presence of O2 and NO2: Peroxy Formyl Propyl Nitrate CH3CH2CH2OC(O)OONO2 Synthesis and Characterization.

    PubMed

    Vila, Jesús A; Argüello, Gustavo A; Malanca, Fabio E

    2016-01-21

    The photo-oxidation of n-propyl formate (initiated by chlorine atoms) was studied in the presence of NO2, and the products were identified. The Cl atom attack to the molecule occurs in four sites, leading to the formation of formic acid, carbon dioxide, dicarbonylic products, nitrates, peroxy propionyl nitrate (CH3CH2C(O)OONO2, PPN), and a new peroxynitrate, peroxy formyl propyl nitrate (CH3CH2CH2OC(O)OONO2, PFPN). To characterize bulk quantities of the PFPN, its synthesis was carried out by the photolysis of mixtures of CH3CH2CH2OC(O)H, NO2, Cl2, and O2. After purification, its infrared spectrum and thermal stability were determined. The main infrared absorption bands and their corresponding cross sections are 796, 1219, 1302, 1741, and 1831 cm(-1) (1.16, 3.11, 0.88, 2.42, and 1.34 × 10(-18) cm(2) molec(-1), respectively). Thermal decomposition was studied as a function of pressure from 6.0 to 1000 mbar at 298 K, and the activation energy was determined between 293 and 304 K at total pressures of 9.0 and 1000 mbar (Ea = 98 ± 3 and 110 ± 2 kJ/mol, respectively). The atmospheric thermal lifetimes were obtained from kinetic parameters.

  9. Corepressors of agonist-bound nuclear receptors

    SciTech Connect

    Gurevich, Igor; Aneskievich, Brian J.

    2007-09-15

    Nuclear receptors (NRs) rely on coregulator proteins to modulate transcription of target genes. NR coregulators can be broadly subdivided into coactivators which potentiate transcription and corepressors which silence gene expression. The prevailing view of coregulator action holds that in the absence of agonist the receptor interacts with a corepressor via the corepressor nuclear receptor (CoRNR, 'corner') box motifs within the corepressor. Upon agonist binding, a conformational change in the receptor causes the shedding of corepressor and the binding of a coactivator which interacts with the receptor via NR boxes within the coregulator. This view was challenged with the discovery of RIP140 which acts as a NR corepressor in the presence of agonist and utilizes NR boxes. Since then a number of other corepressors of agonist-bound NRs have been discovered. Among them are LCoR, PRAME, REA, MTA1, NSD1, and COPR1 Although they exhibit a great diversity of structure, mechanism of repression and pathophysiological function, these corepressors frequently have one or more NR boxes and often recruit histone deacetylases to exert their repressive effects. This review highlights these more recently discovered corepressors and addresses their potential functions in transcription regulation, disease pharmacologic responses and xenobiotic metabolism.

  10. Multiple tyrosine metabolites are GPR35 agonists

    PubMed Central

    Deng, Huayun; Hu, Haibei; Fang, Ye

    2012-01-01

    Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including β-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3′,5′-triiodothyronine, 3,3′,5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism. PMID:22523636

  11. Simultaneous determination of five pyrazole fungicides in cereals, vegetables and fruits using liquid chromatography/tandem mass spectrometry.

    PubMed

    Dong, Fengshou; Chen, Xiu; Liu, Xingang; Xu, Jun; Li, Yuanbo; Shan, Weili; Zheng, Yongquan

    2012-11-02

    The sensitive analytical method using quick, easy, cheap, effective, rugged, and safe (QuEChERS) procedure for simultaneous determination of five novel pyrazole fungicides residues in cereals (rice and wheat), vegetables (cucumber, tomato, and lettuce), and fruits (apple and grape) was developed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The five pyrazole fungicides (bixafen, fluxapyroxad, furametpyr, pyraclostrobin, and rabenzazole) were extracted from seven matrices using acetonitrile and subsequently cleaned up by octadecylsilane (C(18)) or graphitized carbon black (GCB) prior to LC-MS/MS analysis. The determination of the target compounds was achieved in less than 3.0min using an electrospray ionization source in positive mode (ESI+) for furametpyr, pyraclostrobin, and rabenzazole, while negative mode (ESI-) for bixafen and fluxapyroxad. The method showed excellent linearity (at least R(2)≥ 0.990) for all studied analytes. The limits of detection were below 3.0 μg kg(-1), and the limits of quantification did not exceed 9 μg kg(-1) in all matrices. The overall average recoveries in rice, wheat, cucumber, tomato, lettuce, apple, and grape at three levels (10, 100 and 1,000 μg kg(-1)) were ranged from 70.0% to 108% with all RSDs values less than 20.9% for all analytes. The method is demonstrated to be convenient and reliable for the routine monitoring of pyrazole fungicides in cereals, vegetables and fruits.

  12. Regioselective synthesis and biological studies of novel 1-aryl-3, 5-bis (het) aryl pyrazole derivatives as potential antiproliferative agents.

    PubMed

    Ananda, Hanumappa; Sharath Kumar, Kothanahally S; Nishana, Mayilaadumveettil; Hegde, Mahesh; Srivastava, Mrinal; Byregowda, Raghava; Choudhary, Bibha; Raghavan, Sathees C; Rangappa, Kanchugarakoppal S

    2017-02-01

    Pyrazole moiety represents an important category of heterocyclic compound in pharmaceutical and medicinal chemistry. The novel 1-aryl-3, 5-bis (het) aryl pyrazole derivatives were synthesized with complementary regioselectivity. The chemical structures were confirmed by IR, (1)H NMR, (13)C NMR, and mass spectral analysis. The chemical entities were screened in various cancer cell lines to assess their cell viability activity. Results showed that the compound 3-(1-(4-bromophenyl)-5-phenyl-1H-pyrazol-3-yl) pyridine (5d) possessed maximum cytotoxic effect against breast cancer and leukemic cells. The cytotoxicity was confirmed by live-dead cell assay and cell cycle analysis. Mitochondrial membrane potential, Annexin V-FITC staining, DNA fragmentation, Hoechst staining, and western blot assays revealed the ability of compound 5d to induce cell death by activating apoptosis in cancer cells. Thus, the present study demonstrates that compound 5d could be an attractive chemical entity for the development of small molecule inhibitors for treatment of leukemia and breast cancer.

  13. Serotonergic agonists behave as partial agonists at the dopamine D2 receptor.

    PubMed

    Rinken, A; Ferré, S; Terasmaa, A; Owman, C; Fuxe, K

    1999-02-25

    RAT dopamine D2short receptors expressed in CHO cells were characterized by activation of [35S]GTPgammaS binding. There were no significant differences between the maximal effects seen in activation of [35S]GTPgammaS binding caused by dopaminergic agonists, but the effects of 5-HT, 8OH-DPAT and 5-methoxytryptamine amounted to 47 +/- 7%, 43 +/- 5% and 70 +/- 7% of the dopamine effect, respectively. The dopaminergic antagonist (+)butaclamol inhibited activations of both types of ligands with equal potency (pA2 = 8.9 +/- 0.1), indicating that only one type of receptor is involved. In competition with [3H]raclopride binding, dopaminergic agonists showed 53 +/- 2% of the binding sites in the GTP-dependent high-affinity state, whereas 5-HT showed only 20 +/- 3%. Taken together, the results indicate that serotonergic agonists behave as typical partial agonists for D2 receptors with potential antiparkinsonian activity.

  14. Evaluation of H2CHXdedpa, H2dedpa- and H2CHXdedpa-N,N'-propyl-2-NI ligands for (64)Cu(ii) radiopharmaceuticals.

    PubMed

    Ramogida, Caterina F; Boros, Eszter; Patrick, Brian O; Zeisler, Stefan K; Kumlin, Joel; Adam, Michael J; Schaffer, Paul; Orvig, Chris

    2016-08-16

    The chiral acyclic "pa" ligand (pa = picolinic acid) H2CHXdedpa (N4O2) and two NI-containing dedpa analogues (H2CHXdedpa-N,N'-propyl-2-NI, H2dedpa-N,N'-propyl-2-NI, NI = nitroimidazole) were studied as chelators for copper radiopharmaceuticals (CHX = cyclohexyl, H2dedpa = 1,2-[[carboxypyridin-2-yl]methylamino]ethane). The hexadentate ligand H2CHXdedpa was previously established as a superb system for (67/68)Ga radiochemistry. The solid state X-ray crystal structures of [Cu(CHXdedpa-N,N'-propyl-2-NI)] and [Cu(dedpa-N,N'-propyl-2-NI)] reveal the predicted hexadentate, distorted octahedral binding of the copper(ii) ion. Cyclic voltammetry of [Cu(dedpa-N,N'-propyl-2-NI)] shows that there is one reversible couple associated with the NI redox, and one irreversible but reproducible couple attributed to the Cu(ii)/Cu(i) redox cycle. Quantitative radiolabeling (>99%) of CHXdedpa(2-) and (dedpa-N,N'-propyl-2-NI)(2-) with (64)Cu was achieved under fast and efficient labeling conditions (10 min, RT, 0.5 M sodium acetate buffer, pH 5.5) at ligand concentrations as low as 10(-6) M. In vitro kinetic inertness studies of the (64)Cu labelled complexes were studied in human serum at 37 °C over 24 hours; [(64)Cu(CHXdedpa)] was found to be 98% stable compared to previously investigated [(64)Cu(dedpa)] which was only 72% intact after 24 hours.

  15. Design, synthesis, antibacterial evaluation and docking study of novel 2-hydroxy-3-(nitroimidazolyl)-propyl-derived quinolone.

    PubMed

    Li, Qing; Xing, Junhao; Cheng, Haibo; Wang, Hui; Wang, Jing; Wang, Shuai; Zhou, Jinpei; Zhang, Huibin

    2015-01-01

    A novel series of 2-hydroxy-3-(nitroimidazolyl)-propyl-derived quinolones 6a-o were synthesized and evaluated for their in vitro antibacterial activity. Most of the target compounds exhibited potent activity against Gram-positive strains. Among them, moxifloxacin analog 6n displayed the most potent activity against Gram-positive strains including S. epidermidis (MIC = 0.06 μg/mL), MSSE (MIC = 0.125 μg/mL), MRSE (MIC = 0.03 μg/mL), S. aureus (MIC = 0.125 μg/mL), MSSA (MIC = 0.125 μg/mL), (MIC = 2 μg/mL). Its activity against MRSA was eightfold more potent than reference drug gatifloxacin. Finally, docking study of the target compound 6n revealed that the binding model of quinolone nucleus was similar to that of gatifloxacin and the 2-hydroxy-3-(nitroimidazolyl)-propyl group formed two additional hydrogen bonds.

  16. 1,3-Bis(3-ammonium-propyl)tetramethyldisiloxane-sulfate: Structural characterization and evaluation of some properties

    NASA Astrophysics Data System (ADS)

    Nistor, Alexandra; Soroceanu, Alina; Shova, Sergiu; Cazacu, Maria

    2012-08-01

    1,3-Bis(3-ammonium-propyl)tetramethyldisiloxane sulfate resulted from the reaction between 1,3-bis(3-aminopropyl)tetramethyldisiloxane with a proper transition metal (iron(III) or vanadium(IV) oxide) salt as anion generator and a carbonylic compound (4-imidazole carboxaldehyde or 2-hydroxybenzaldehyde) as a metal collector, in methanol, was thoroughly characterized. The compound's structure was proved by single-crystal X-ray diffraction and spectral (FT-IR, 1H NMR) analysis, while the thermal behavior was evaluated by thermogravimetry. Water vapor sorption capacity on the crystalline compound was measured in dynamic regime. The co-existence of hydrophobic bis(propyl)tetramethyldisiloxane moiety and telechelic hydrophilic groups constitutes a premise for surface activity, as confirmed by tensiometry. Formation of micelles and aggregates in solution was emphasized by dynamic light scattering and confirmed by AFM images taken on the spin coated films, both revealing closed values for size of the micelles (100-200 nm).

  17. Partially Hydrolyzed Poly(n-propyl-2-oxazoline): Synthesis, Aqueous Solution Properties, and Preparation of Gene Delivery Systems.

    PubMed

    Mees, Maarten; Haladjova, Emi; Momekova, Denitsa; Momekov, Georgi; Shestakova, Pavletta S; Tsvetanov, Christo B; Hoogenboom, Richard; Rangelov, Stanislav

    2016-11-14

    Random copolymers of n-propyl-2-oxazoline and ethylenimine (PPrOx-PEI) were prepared by partial acidic hydrolysis of poly(n-propyl-2-oxazoline) (PPrOx). Dynamic and electrophoretic light scattering and diffusion-ordered NMR spectroscopy were utilized to investigate aqueous solution properties of the copolymers. Above a specific cloud point temperature, well-defined nanoparticles were formed. The latter consisted of a core composed predominantly of PPrOx and a thin positively charged shell from PEI moieties that mediated formation of polyplexes with DNA. The polyplexes were prepared at 65 °C at varying N/P (amine-to-phosphate groups) ratios. They underwent structural changes upon temperature variations 65-25-37 °C depending on N/P. At N/P < 2, the polyplex particles underwent minor changes because of formation of a surface layer of DNA that acted as a barrier and prevented swelling and disintegration of the initial particles. Dramatic rearrangements at N/P ≥ 2 resulting in large swollen microgel particles were overcome by coating of the polyplex particles with a cross-linked polymeric shell. The shell retained the colloidal stability and preserved the physicochemical parameters of the initial polyplex particles while it reduced the high surface potential values. Progressive loss of cytotoxicity upon complexation with DNA and coating of polyplex particles was displayed.

  18. Three-dimensional model evaluation of the Ozone Depletion Potentials for n-propyl bromide, trichloroethylene and perchloroethylene

    NASA Astrophysics Data System (ADS)

    Wuebbles, D. J.; Patten, K. O.; Wang, D.; Youn, D.; Martínez-Avilés, M.; Francisco, J. S.

    2011-03-01

    The existing solvents trichloroethylene (TCE) and perchloroethylene (PCE) and proposed solvent n-propyl bromide (nPB) have atmospheric lifetimes from days to a few months, but contain chlorine or bromine that could affect stratospheric ozone. Several previous studies estimated the Ozone Depletion Potentials (ODPs) for various assumptions of nPB emissions location, but these studies used simplified modeling treatments. The primary purpose of this study is to reevaluate the ODP for n-propyl bromide (nPB) using a current-generation chemistry-transport model of the troposphere and stratosphere. For the first time, ODPs for TCE and PCE are also evaluated in a three-dimensional, global atmospheric chemistry-transport model. Emissions representing industrial use of each compound are incorporated on land surfaces from 30° N to 60° N. The atmospheric chemical lifetime obtained for nPB is 24.7 days, similar to past literature, but the ODP is 0.0049, lower than in our past study of nPB. The derived atmospheric lifetime for TCE is 13.0 days and for PCE is 111 days. The corresponding ODPs are 0.00037 and 0.0050, respectively.

  19. Conformations and Barriers to Methyl Group Internal Rotation in Two Asymmetric Ethers: Propyl Methyl Ether and Butyl Methyl Ether

    NASA Astrophysics Data System (ADS)

    Long, B. E.; Dechirico, F.; Cooke, S. A.

    2012-06-01

    The conformational preferences of the O-C-C-C unit are important in many biological systems with the unit generally preferring a gauche configuration compared to an anti configuration. Butyl methyl ether and propyl methyl ether provide very simple systems for this phenomenom to manifest. Pure rotational spectra of the title molecules have been recorded using chirped pulse Fourier transform microwave spectroscopy (CP-FTMW). In the case of butyl methyl ether, only one conformer has been observed. This conformer has torsional angles of COCC = 180°, OCCC = 62° and CCCC = 180° (anti-gauche-anti) and rotational constants of A = 10259.4591(33) MHz, B = 1445.6470(13) MHz, and C = 1356.2944(14) MHz. The rotational spectrum was doubled and has been analyzed to produce an effective barrier to methyl group internal rotation of 780(35) cm-1. A prior rotational spectroscopic study on propyl methyl ether had focused only on the high energy anti-anti conformer. We have analyzed spectra from the lowest energy anti-gauche conformer and the spectroscopic constants will be presented. A summary of the differences in conformational energies and methyl group internal rotation barriers for the class of aliphatic asymmetric ethers will be presented. K. N. Houk, J. E. Eksterowicz, Y.-D. Wu, C. D. Fuglesang, D. B. Mitchell. J. Am. Chem. Soc. 115 (4170), 1993. Hiroshi Kato, Jun Nakagawa, Michiro Hayashi. J. Mol. Spectrosc. 80 (272), 1980.

  20. Post-transcriptional regulation of coumarin 7-hydroxylase (P450coh) induction by xenobiotics in mouse liver: mRNA stabilization by pyrazole

    SciTech Connect

    Aida, K.; Negishi, M. )

    1991-03-15

    The induction mechanism by pyrazole or phenobarbital of coumarin 7-hydroxylase was investigated in DBA/2J male mice. The P450coh mRNA in the pyrazole-induced mice was increased gradually to a 20-fold higher level within 48 hr, yet transcription of the P450coh gene was not affected. The half-life of P450coh mRNA, on the other hand, was at least 4-fold longer in the pyrazole-induced DBA2J than in control DBA/2J male mice. The stabilization of P450coh mRNA, therefore, is the primary mechanism for the induction by pyrazole of coumarin 7-hydroxylase. Phenobarbital, on the other hand, regulates the induction translationally or post-translationally. This drug affected neither the P450coh mRNA nor the P450coh gene's transcription levels in the DBA/2J male mice, although Western blots showed a 2- to 3-fold increase of the P450coh protein in the liver microsomes of the drug-treated mice. The results indicate, therefore, that both phenobarbital and pyrazole regulate the P450coh induction post-transcriptional efficiency of P450coh mRNA or alters the degradation rate of P450coh protein, while the latter stabilizes P450coh mRNA.

  1. Synthesis, Structure and Electrochemistry of Tetranuclear Oxygen-Centered Copper(II) Clusters with Acetylacetone and Benz-pyrazole Hydrolyzed Derivatives as Ligand.

    PubMed

    Vafazadeh, Rasoul; Willis, Anthony C

    2016-01-01

    Two copper(II) clusters Cu(4)OCl(6)(pyrazole)4, 1, and Cu(4)OBr(6)(Br-pyrazole)4, 2, have been synthesized by reacting acetylacetone and benzohydrazide (1:1 ratio) with CuX(2) (X = Cl for 1 and X= Br for 2) in methanol solutions. The structures of both clusters have been established by X-ray crystallography. The clusters contain four Cu, one O, six μ(2)-X atoms, and four pyrazole ligands. The pyrazoles was prepared in situ by the reaction of acetylacetone with benzohydrazide in methanol under reflux. In 2, the methine hydrogens of the pyrazole ligands have been replaced by bromine atoms. The four copper atoms encapsulate the central O atom in a tetrahedral arrangement. All copper atoms are five-coordinate and have similar coordination environments with slightly distorted trigonal bipyramidal geometry. The cyclic voltammogram of the clusters 1 and 2 show a one-electron quasi-reversible reduction wave in the region 0.485 to 0.731 V, and a one-electron quasi-reversible oxidation wave in the region 0.767 to 0.898 V. In 1, one irreversible oxidative response is observed on the positive of side of the voltammogram at 1.512 V and this can be assigned to Cu(II) to Cu(III) oxidation.

  2. Synthesis and monoamine oxidase inhibitory activities of some 3-(4-fluorophenyl)-5-aryl-n-substituted-4,5-dihydro-(1H)-pyrazole-1-carbothioamide derivatives.

    PubMed

    Koç, G Ş; Tan, O U; Uçar, G; Yildirim, E; Erol, K; Palaska, E

    2014-11-01

    28 new 3-(4-fluorophenyl)-5-aryl-N-substituted-4,5-dihydro-1H-pyrazole-1-carbothioamide derivatives were synthesized and evaluated in vitro for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity. The derivatives substituted by halogen on the fifth position of pyrazole ring, inhibited MAO-A enzyme with a high selectivity index. On the other hand, compounds substituted with 2-naphthyl inhibited MAO-B enzyme with a moderate selectivity index. Docking studies were done to highlight the interactions of the most active derivative with the active site of MAO-A. In addition, in vivo antidepressant and anxiolytic activities of the compounds having selective MAO-A inhibitory effects, were investigated by using Porsolt forced swimming and elevated plus-maze tests respectively. 3-(4-Fluorophenyl)-5-(4-chloro-phenyl)-N-allyl-4,5-dihydro-1H-pyrazole-1-carbothio-amide has antidepressant, 3-(4-fluorophenyl)-5-(4-chlorophenyl)-N-methyl-4,5-dihydro-1H-pyrazole-1-carbothioamide and 3-(4-fluoro-phenyl)-5-(4-bromophenyl)-N-ethyl-4,5-dihydro-1H-pyrazole-1-carbothioamide have anxiolytic activity.

  3. Selective, Tunable O2 Binding in Cobalt(II)–Triazolate/Pyrazolate Metal–Organic Frameworks

    PubMed Central

    2016-01-01

    The air-free reaction of CoCl2 with 1,3,5-tri(1H-1,2,3-triazol-5-yl)benzene (H3BTTri) in N,N-dimethylformamide (DMF) and methanol leads to the formation of Co-BTTri (Co3[(Co4Cl)3(BTTri)8]2·DMF), a sodalite-type metal–organic framework. Desolvation of this material generates coordinatively unsaturated low-spin cobalt(II) centers that exhibit a strong preference for binding O2 over N2, with isosteric heats of adsorption (Qst) of −34(1) and −12(1) kJ/mol, respectively. The low-spin (S = 1/2) electronic configuration of the metal centers in the desolvated framework is supported by structural, magnetic susceptibility, and computational studies. A single-crystal X-ray structure determination reveals that O2 binds end-on to each framework cobalt center in a 1:1 ratio with a Co–O2 bond distance of 1.973(6) Å. Replacement of one of the triazolate linkers with a more electron-donating pyrazolate group leads to the isostructural framework Co-BDTriP (Co3[(Co4Cl)3(BDTriP)8]2·DMF; H3BDTriP = 5,5′-(5-(1H-pyrazol-4-yl)-1,3-phenylene)bis(1H-1,2,3-triazole)), which demonstrates markedly higher yet still fully reversible O2 affinities (Qst = −47(1) kJ/mol at low loadings). Electronic structure calculations suggest that the O2 adducts in Co-BTTri are best described as cobalt(II)–dioxygen species with partial electron transfer, while the stronger binding sites in Co-BDTriP form cobalt(III)–superoxo moieties. The stability, selectivity, and high O2 adsorption capacity of these materials render them promising new adsorbents for air separation processes. PMID:27180991

  4. Agonistic and reproductive interactions in Betta splendens.

    PubMed

    Bronstein, P M

    1984-12-01

    Reproductive and agonistic behaviors in Siamese fighting fish were investigated in eight experiments, and some consequences and determinants of these sequences were isolated. First, fights and the formation of dominance-subordinancy relations were studied. Second, it was determined that large body size as well as males' prior residency in a tank produced an agonistic advantage; the magnitude of this advantage was positively related to the duration of residency. Third, the prior-residency effect in Bettas was determined by males' familiarity with visual and/or tactile cues in their home tanks. Fourth, dominant males had greater access to living space and were more likely to display at a mirror, build nests, and approach females than were subordinates. Finally, it was discovered that chemical cues associated with presumedly inert plastic tank dividers influence Bettas' social behavior.

  5. Agonists block currents through acetylcholine receptor channels.

    PubMed Central

    Sine, S M; Steinbach, J H

    1984-01-01

    We have examined the effects of high concentrations of cholinergic agonists on currents through single acetylcholine receptor (AChR) channels on clonal BC3H1 cells. We find that raised concentrations of acetylcholine (ACh; above 300 microM) or carbamylcholine (Carb; above 1,000 microM) produce a voltage- and concentration-dependent reduction in the mean single-channel current. Raised concentrations of suberyldicholine (Sub; above 3 microM) produce a voltage- and concentration-dependent increase in the number of brief duration low-conductance interruptions of open-channel currents. These observations can be quantitatively described by a model in which agonist molecules enter and transiently occlude the ion-channel of the AChR. PMID:6478036

  6. Ropinirole, a non-ergoline dopamine agonist.

    PubMed

    Jost, Wolfgang H; Angersbach, Dieter

    2005-01-01

    Dopamine agonists have become indispensable in the treatment of Parkinson's disease. In every-day practice, however, the decision to select the best compound for an individual patient is rendered difficult because of the large number of substances available on the market. This review article provides a closer look at the experimental and clinical studies with ropinirole published so far. Ropinirole is a non-ergoline dopamine agonist which has been proven to be effective in both, monotherapy and combination therapy of idiopathic Parkinson's disease. In addition to ameliorating bradykinesia, rigor, and tremor, ropinirole facilitates the daily life and improves depressive moods of patients with Parkinson's disease. The long-term complications of levodopa are avoided, and problems commonly associated with levodopa treatment are reduced. Ropinirole appears to have a neuroprotective effect. In addition to Parkinson's disease, ropinirole has also been used successfully in the treatment of restless legs syndrome.

  7. The identification of orally bioavailable thrombopoietin agonists.

    PubMed

    Munchhof, Michael J; Antipas, Amy S; Blumberg, Laura C; Brissette, William H; Brown, Matthew F; Casavant, Jeffrey M; Doty, Jonathan L; Driscoll, James; Harris, Thomas M; Wolf-Gouveia, Lilli A; Jones, Christopher S; Li, Qifang; Linde, Robert G; Lira, Paul D; Marfat, Anthony; McElroy, Eric; Mitton-Fry, Mark; McCurdy, Sandra P; Reiter, Lawrence A; Ripp, Sharon L; Shavnya, Andrei; Thomasco, Lisa M; Trevena, Kristen A

    2009-03-01

    Recently, we disclosed a series of potent pyrimidine benzamide-based thrombopoietin receptor agonists. Unfortunately, the structural features required for the desired activity conferred physicochemical properties that were not favorable for the development of an oral agent. The physical properties of the series were improved by replacing the aminopyrimidinyl group with a piperidine-4-carboxylic acid moiety. The resulting compounds possessed favorable in vivo pharmacokinetic properties, including good bioavailability.

  8. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-08

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits.

  9. Neurotoxicological and thyroid evaluations of rats developmentally exposed to tris(1,3-dichloro-2-propyl)phosphate (TDICPP) and tris(2-chloro-2-ethyl)phosphate(TCEP)

    EPA Science Inventory

    ABSTRACT: Tris(1,3-dichloro-2-propyl)phosphate (TDICPP) and tris(2-chloro-2-ethyl)phosphate (TCEP) are organophosphorous flame retardants with widespread usage and human exposures through food, inhalation, and dust ingestion. They have been detected in human tissues including ur...

  10. 40 CFR 721.9516 - Siloxanes and silicones, 3-[(2-aminoethyl) amino]propyl Me, di-Me, reaction products with...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., di-Me, reaction products with polyethylene-polypropylene glycol Bu glycidal ether. 721.9516 Section... Substances § 721.9516 Siloxanes and silicones, 3- propyl Me, di-Me, reaction products with polyethylene..., reaction products with polyethylene-polypropylene glycol Bu glycidyl ether (PMN P-97-740; CAS No....

  11. 40 CFR 721.9516 - Siloxanes and silicones, 3-[(2-aminoethyl) amino]propyl Me, di-Me, reaction products with...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., di-Me, reaction products with polyethylene-polypropylene glycol Bu glycidal ether. 721.9516 Section... Substances § 721.9516 Siloxanes and silicones, 3- propyl Me, di-Me, reaction products with polyethylene..., reaction products with polyethylene-polypropylene glycol Bu glycidyl ether (PMN P-97-740; CAS No....

  12. 40 CFR 721.9516 - Siloxanes and silicones, 3-[(2-aminoethyl) amino]propyl Me, di-Me, reaction products with...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., di-Me, reaction products with polyethylene-polypropylene glycol Bu glycidal ether. 721.9516 Section... Substances § 721.9516 Siloxanes and silicones, 3- propyl Me, di-Me, reaction products with polyethylene..., reaction products with polyethylene-polypropylene glycol Bu glycidyl ether (PMN P-97-740; CAS No....

  13. 40 CFR 721.9516 - Siloxanes and silicones, 3-[(2-aminoethyl) amino]propyl Me, di-Me, reaction products with...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., di-Me, reaction products with polyethylene-polypropylene glycol Bu glycidal ether. 721.9516 Section... Substances § 721.9516 Siloxanes and silicones, 3- propyl Me, di-Me, reaction products with polyethylene..., reaction products with polyethylene-polypropylene glycol Bu glycidyl ether (PMN P-97-740; CAS No....

  14. 40 CFR 721.9516 - Siloxanes and silicones, 3-[(2-aminoethyl) amino]propyl Me, di-Me, reaction products with...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., di-Me, reaction products with polyethylene-polypropylene glycol Bu glycidal ether. 721.9516 Section... Substances § 721.9516 Siloxanes and silicones, 3- propyl Me, di-Me, reaction products with polyethylene..., reaction products with polyethylene-polypropylene glycol Bu glycidyl ether (PMN P-97-740; CAS No....

  15. New positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2): identification and synthesis of N-propyl-8-chloro-6-substituted isoquinolones.

    PubMed

    Trabanco, Andrés A; Duvey, Guillaume; Cid, José María; Macdonald, Gregor J; Cluzeau, Philippe; Nhem, Vanthea; Furnari, Rocco; Behaj, Nadia; Poulain, Géraldine; Finn, Terry; Lavreysen, Hilde; Poli, Sonia; Raux, Alexandre; Thollon, Yves; Poirier, Nicolas; D'Addona, David; Andrés, José Ignacio; Lutjens, Robert; Le Poul, Emmanuel; Imogai, Hassan; Rocher, Jean-Philippe

    2011-02-01

    A series of N-propyl-8-chloro-6-substituted isoquinolones was identified as positive allosteric modulators of metabotropic glutamate receptor 2 (mGluR2 PAM) via high throughput screening (HTS). The subsequent synthesis and initial SAR exploration that led to the identification of compound 28 is described.

  16. Anti-inflammatory activity of n-propyl gallate through down-regulation of NF-κB and JNK pathways.

    PubMed

    Jung, Hyun-Joo; Kim, Su-Jung; Jeon, Woo-Kwang; Kim, Byung-Chul; Ahn, Kisup; Kim, Kyunghoon; Kim, Young-Myeong; Park, Eun-Hee; Lim, Chang-Jin

    2011-10-01

    The present study aimed to assess anti-inflammatory activity and underlying mechanism of n-propyl gallate, the n-propyl ester of gallic acid. n-Propyl gallate was shown to contain anti-inflammatory activity using two experimental animal models, acetic acid-induced permeability model in mice, and air pouch model in rats. It suppressed production of nitric oxide and induction of inducible nitric oxide synthase and cyclooxygenase-2 in the lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. It was able to diminish reactive oxygen species level elevated in the LPS-stimulated RAW264.7 macrophage cells. It also suppressed gelatinolytic activity of matrix metalloproteinase-9 enhanced in the LPS-stimulated RAW264.7 macrophage cells. It inhibited inhibitory κB-α degradation and enhanced NF-κB promoter activity in the stimulated macrophage cells. It was able to suppress phosphorylation of c-Jun NH(2)-terminal kinase 1/2 (JNK1/2) and activation of c-Jun promoter activity in the stimulated macrophage cells. In brief, n-propyl gallate possesses anti-inflammatory activity via down-regulation of NF-κB and JNK pathways.

  17. Spectrophotometric Determination of 6-Propyl-2-Thiouracil in Pharmaceutical Formulations Based on Prussian Blue Complex Formation: An Undergraduate Instrumental Analysis Laboratory Experiment

    ERIC Educational Resources Information Center

    Zakrzewski, Robert; Skowron, Monika; Ciesielski, Witold; Rembisz, Zaneta

    2016-01-01

    The laboratory experiment challenges students to determine 6-propyl-2-thiouracil (PTU) based on Prussian blue complex formation. Prussian blue is formed by ferricyanide and Fe(II) ions which are generated in situ from Fe(III) ions reduced by PTU. The absorbance of this product was measured at a wavelength of 840 nm, after a reaction time of 30…

  18. Structural characterization of selenium and selenium-diiodine analogues of the antithyroid drug 6-n-propyl-2-thiouracil and its alkyl derivatives.

    PubMed

    Antoniadis, Constantinos D; Blake, Alexander J; Hadjikakou, Sotiris K; Hadjiliadis, Nick; Hubberstey, Peter; Schröder, Martin; Wilson, Claire

    2006-08-01

    The structures of four selenium analogues of the antithyroid drug 6-n-propyl-2-thiouracil [systematic name: 2,3-dihydro-6-n-propyl-2-thioxopyrimidin-4(1H)-one], namely 6-methyl-2-selenouracil, C(5)H(6)N(2)OSe (1), 6-ethyl-2-selenouracil, C(6)H(8)N(2)OSe (2), 6-n-propyl-2-selenouracil, C(7)H(10)N(2)OSe (3), and 6-isopropyl-2-selenouracil, C(7)H(10)N(2)OSe (4), are described, along with that of the dichloromethane monosolvate of 6-isopropyl-2-selenouracil, C(7)H(10)N(2)OSe.CH(2)Cl(2) (4.CH(2)Cl(2)). The extended structure of (1) is a two-dimensional sheet of topology 6(3) with a brick-wall architecture. The extended structures of (2) and (4) are analogous, being based on a chain of eight-membered R(8)(6)(32) hydrogen-bonded rings. In (3) and (4.CH(2)Cl(2)), R(2)(2)(8) hydrogen bonding links molecules into chains. 6-n-Propyl-2-selenouracil.I(2), C(7)H(10)N(2)OSe.I(2) (7), is a charge-transfer complex with a ;spoke' structure, the extended structure of which is based on a linear chain formed principally by intermolecular N-H...O hydrogen bonds. Re-crystallization of 6-ethyl-2-selenouracil or (7) from acetone gave crystals of the diselenides [N-(6'-ethyl-4'-pyrimidone)(6-ethyl-2-selenouracil)(2)(Se-Se)].2H(2)O (9.2H(2)O) or [N-(6'-n-propyl-4'-pyrimidone)(6-n-propyl-2-selenouracil)(2)(Se-Se)] (10), respectively: these have similar extended chain structures formed via N-H...O and C-H...O hydrogen bonds, stacked to give two-dimensional sheets. Re-crystallization of (7) from methanol/acetonitrile led via deselenation to the formation of crystals of 6-n-propyl-2-uracil (11), in which six symmetry-related molecules combine to form a six-membered R(6)(6)(24) hydrogen-bonded ring, with each pair of molecules linked by an R(2)(2)(8) motif.

  19. A combined experimental and DFT investigation of disazo dye having pyrazole skeleton

    NASA Astrophysics Data System (ADS)

    Şener, Nesrin; Bayrakdar, Alpaslan; Kart, Hasan Hüseyin; Şener, İzzet

    2017-02-01

    Disazo dye containing pyrazole skeleton has been synthesized. The structure of the dye has been confirmed by using FT-IR, 1H NMR, 13C NMR, HRMS spectral technique and elemental analysis. The molecular geometry and infrared spectrum are also calculated by the Density Functional Theory (DFT) employing B3LYP level with 6-311G (d,p) basis set. The chemical shifts calculation for 1H NMR of the title molecule is done by using by Gauge-Invariant Atomic Orbital (GIAO) method by utilizing the same basis sets. The total density of state, the partial density of state and the overlap population density of state diagram analysis are done via Gauss Sum 3.0 program. Frontier molecular orbitals such as highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and molecular electrostatic potential surface on the title molecule are predicted for various intramolecular interactions that are responsible for the stabilization of the molecule. The experimental results and theoretical values have been compared.

  20. Magnetocaloric effect in Mn2-pyrazole-[Nb(CN)8] molecular magnet by relaxation calorimetry

    NASA Astrophysics Data System (ADS)

    Pełka, R.; Gajewski, M.; Miyazaki, Y.; Yamashita, S.; Nakazawa, Y.; Fitta, M.; Pinkowicz, D.; Sieklucka, B.

    2016-12-01

    Magnetocaloric effect in {[Mn(pyrazole)4]2[Nb(CN)8]·4 H2O}n molecular magnet is reported. It crystallizes in tetragonal I41/a space group. The compound exhibits a phase transition to a long range magnetically ordered state at TN ≈ 22.8 K. Temperature dependences of the magnetic entropy change ΔSM as well as the adiabatic temperature change ΔTad due to applied field change μ0 ΔH in the range of 0.1-9 T have been inferred from the relaxation calorimetry measurements. A systematic approximate approach has been used to determine the lattice contribution to the heat capacity. The maximum value of ΔSM for μ0 ΔH = 5 T is 6.83 J mol-1 K-1 (6.65 J kg-1 K-1) at 24.3 K. The corresponding maximum value of ΔTad is 1.4 K at 23.8 K. The temperature dependence of the exponent n characterizing the field dependence of ΔSM has been estimated. It attains the value of 0.64 at the transition temperature, which is consistent with the 3D Heisenberg universality class. A hitherto unobserved two-peak structure has been revealed in the temperature dependence of ΔTad.

  1. A novel pyrazole derivative protects from ovariectomy-induced osteoporosis through the inhibition of NADPH oxidase

    PubMed Central

    Joo, Jung Hee; Huh, Jeong-Eun; Lee, Jee Hyun; Park, Doo Ri; Lee, Yoonji; Lee, Seul Gee; Choi, Sun; Lee, Hwa Jeong; Song, Seong-Won; Jeong, Yongmi; Goo, Ja-Il; Choi, Yongseok; Baek, Hye Kyung; Yi, Sun Shin; Park, Soo Jin; Lee, Ji Eun; Ku, Sae Kwang; Lee, Won Jae; Lee, Kee-In; Lee, Soo Young; Bae, Yun Soo

    2016-01-01

    Osteoclast cells (OCs) are differentiated from bone marrow-derived macrophages (BMMs) by activation of receptor activator of nuclear factor κB (NF-κB) ligand (RANKL). Activation of NADPH oxidase (Nox) isozymes is involved in RANKL-dependent OC differentiation, implicating Nox isozymes as therapeutic targets for treatment of osteoporosis. Here, we show that a novel pyrazole derivative, Ewha-18278 has high inhibitory potency on Nox isozymes. Blocking the activity of Nox with Ewha-18278 inhibited the responses of BMMs to RANKL, including reactive oxygen species (ROS) generation, activation of mitogen-activated protein (MAP) kinases and NF-κB, and OC differentiation. To evaluate the anti-osteoporotic function of Ewha-18278, the derivative was applied to estrogen-deficient ovariectomized (OVX) ddY mice. Oral administration of Ewha-18278 (10 mg/kg/daily, 4 weeks) into the mice recovered bone mineral density, trabecular bone volume, trabecular bone length, number and thickness, compared to control OVX ddY mice. Moreover, treatment of OVX ddY mice with Ewha-18278 increased bone strength by increasing cortical bone thickness. We provide that Ewha-18278 displayed Nox inhibition and blocked the RANKL-dependent cell signaling cascade leading to reduced differentiation of OCs. Our results implicate Ewha-18278 as a novel therapeutic agent for the treatment of osteoporosis. PMID:26975635

  2. Dihydropyrano [2,3-c] pyrazole: Novel in vitro inhibitors of yeast α-glucosidase.

    PubMed

    Kashtoh, Hamdy; Muhammad, Munira Taj; Khan, Jalaluddin J A; Rasheed, Saima; Khan, Ajmal; Perveen, Shahnaz; Javaid, Kulsoom; Atia-Tul-Wahab; Khan, Khalid Mohammed; Choudhary, M Iqbal

    2016-04-01

    Inhibition of α-glucosidase enzyme activity is a reliable approach towards controlling post-prandial hyperglycemia associated risk factors. During the current study, a series of dihydropyrano[2,3-c] pyrazoles (1-35) were synthesized and evaluated for their α-glucosidase inhibitory activity. Compounds 1, 4, 22, 30, and 33 were found to be the potent inhibitors of the yeast α-glucosidase enzyme. Mechanistic studies on most potent compounds reveled that 1, 4, and 30 were non-competitive inhibitors (Ki=9.75±0.07, 46±0.0001, and 69.16±0.01μM, respectively), compound 22 is a competitive inhibitor (Ki=190±0.016μM), while 33 was an uncompetitive inhibitor (Ki=45±0.0014μM) of the enzyme. Finally, the cytotoxicity of potent compounds (i.e. compounds 1, 4, 22, 30, and 33) was also evaluated against mouse fibroblast 3T3 cell line assay, and no toxicity was observed. This study identifies non-cytotoxic novel inhibitors of α-glucosidase enzyme for further investigation as anti-diabetic agents.

  3. Isatin-pyrazole benzenesulfonamide hybrids potently inhibit tumor-associated carbonic anhydrase isoforms IX and XII.

    PubMed

    Ibrahim, Hany S; Abou-Seri, Sahar M; Tanc, Muhammet; Elaasser, Mahmoud M; Abdel-Aziz, Hatem A; Supuran, Claudiu T

    2015-10-20

    New series of benzenesulfonamide derivatives incorporating pyrazole and isatin moieties were prepared using celecoxib as lead molecule. Biological evaluation of the target compounds was performed against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more precisely against the human isoforms hCA I, II (cytosolic), IX and XII (transmembrane, tumor-associated enzymes). Most of the tested compounds efficiently inhibited hCA I, II and IX, with KIs of 2.5-102 nM, being more effective than the reference drug acetazolamide. Compounds 11e, 11f, 16e and 16f were found to inhibit hCA XII with Ki of 3.7, 6.5, 5.4 and 7.2 nM, respectively. Compounds 11e and 16e, with 5-NO2 substitution on the isatin ring, were found to be selective inhibitors of hCA IX and hCA XII. Docking studies revealed that the NO2 group of both compounds participate in interactions with Asp132 within the hCA IX active site, and with residues Lys67 and Asp130 in hCA XII, respectively.

  4. The GABA(B) antagonist CGP 52432 attenuates the stimulatory effect of the GABA(B) agonist SKF 97541 on luteinizing hormone secretion in the male sheep.

    PubMed

    Jackson, Gary L; Kuehl, David

    2002-05-01

    The objectives of this study were to determine if the gamma-aminobutyric acid (GABA)(B) agonist, 3-aminopropyl (methyl) phosphinic acid (SKF97541), would increase luteinizing hormone (LH) secretion when infused by microdialysis into the medial basal hypothalamus (MBH) of the castrated ram, and to determine if the action of SKF97541 would be attenuated by co-infusion of the GABA(B) antagonist CGP52432. Initial experiments established that infusion of SKF alone, at concentrations as low as 5 microM, increased mean LH, LH pulse amplitude, and in some cases, pulse interval. In the last experiment, animals were treated with artificial cerebrospinal fluid (CSF) alone, SKF alone (30 microM), 3-[[(3, 4-dichlorophenol) methyl] amino] propyl] diethoxymethyl) phosphinic acid (CGP) alone (500 microM), or SKF plus CGP. SKF increased both mean LH and LH pulse amplitude as compared with CSF. CGP alone had no significant effect on LH, but it attenuated the effect of SKF on mean LH. These observations indicate that the stimulatory effects of GABA(B) agonists on LH pulse patterns are mediated through GABA(B) receptors and provide further evidence that GABA(B) receptors located in the MBH can regulate pulsatile GnRH-LH release.

  5. Inhibition of o(2) consumption resistant to cyanide and its development by N-propyl gallate and salicylhydroxamic Acid.

    PubMed

    Janes, H W; Wiest, S C

    1982-09-01

    Kinetics of inhibition of cyanide-insensitive O(2) uptake by n-propyl gallate (PG) and salicylhydroxamic acid (SHAM) were determined in fresh slices from ethylene-treated tubers of Solanum tuberosum ;Norchip' and with mitochondria and lipoxygenase (EC 1.13.11.12) isolated from these tubers. PG and SHAM appeared to be inhibiting at identical sites in mitochondria but at disparate sites in slices. The apparent K(I) for SHAM was similar in mitochondria and slices. However, the apparent K(I) for PG in mitochondria was about 40-fold lower than the K(I) for PG inhibition of lipoxygenase activity. The amount of lipoxygenase associated with mitochondria increased when tubers were treated with ethylene. PG, but not SHAM, inhibited aging-induced development of cyanide-insensitive respiration. The latter two phenomena are in accord with the hypothesis that lipid metabolism is required for the development of the alternative pathway.

  6. Bis[2,4-dibromo-6-(n-propyl-imino-methyl)phenolato-κN,O]cobalt(II).

    PubMed

    Li, Chunyan; Li, Rui; Zhang, Shufang

    2010-08-18

    In the title complex, [Co(C(10)H(10)Br(2)NO)(2)], the Co(II) atom lies on a twofold rotation axis, the N(2)O(2) units having distorted tetra-hedral coordination environments comprising two bidentate chelate 2,4-dibromo-6-(n-propyl-imino-meth-yl)phenolate Schiff base ligands [Co-N = 1.989 (3) Å, Co-O = 1.924 (2) Å and O/N-Co-O/N = 94.53 (10)-125.40 (15)°]. In the crystal structure, the mol-ecules are linked via weak inter-molecular C-H⋯O hydrogen bonds [3.334 (5) Å] and there are also short inversion-related intermolecular Br⋯Br contacts [3.4263 (6) Å].

  7. Silica-bonded N-propyl sulfamic acid used as a heterogeneous catalyst for transesterification of soybean oil with methanol.

    PubMed

    Xie, Wenlei; Yang, Dong

    2011-10-01

    The transesterification of soybean oil with methanol was carried out, to produce biodiesel, over silica-bonded N-propyl sulfamic acid in a heterogeneous manner. Results showed that a maximum conversion of 90.5% was achieved using a 1:20 M ratio of soybean oil to methanol and a catalyst amount of 7.5 wt.% at 423 K for 60 h. It was found that the free fatty acid (FFA) and water present in the feedstock had no significant influence on the catalytic activity to the transesterification reaction. Besides, the catalyst also showed activities towards the esterification reaction of FFAs, in terms of the FFA conversion of 95.6% at 423 K for 30 h. Furthermore, the catalyst could be recovered with a better reusability.

  8. Anharmonic modeling of the conformation-specific IR spectra of ethyl, n-propyl, and n-butylbenzene.

    PubMed

    Tabor, Daniel P; Hewett, Daniel M; Bocklitz, Sebastian; Korn, Joseph A; Tomaine, Anthony J; Ghosh, Arun K; Zwier, Timothy S; Sibert, Edwin L

    2016-06-14

    Conformation-specific UV-IR double resonance spectra are presented for ethyl, n-propyl, and n-butylbenzene. With the aid of a local mode Hamiltonian that includes the effects of stretch-scissor Fermi resonance, the spectra can be accurately modeled for specific conformers. These molecules allow for further development of a first principles method for calculating alkyl stretch spectra. Across all chain lengths, certain dihedral patterns impart particular spectral motifs at the quadratic level. However, the anharmonic contributions are consistent from molecule to molecule and conformer to conformer. This transferability of anharmonicities allows for the Hamiltonian to be constructed from only a harmonic frequency calculation, reducing the cost of the model. The phenyl ring alters the frequencies of the CH2 stretches by about 15 cm(-1) compared to their n-alkane counterparts in trans configurations. Conformational changes in the chain can lead to shifts in frequency of up to 30 cm(-1).

  9. Anharmonic modeling of the conformation-specific IR spectra of ethyl, n-propyl, and n-butylbenzene

    NASA Astrophysics Data System (ADS)

    Tabor, Daniel P.; Hewett, Daniel M.; Bocklitz, Sebastian; Korn, Joseph A.; Tomaine, Anthony J.; Ghosh, Arun K.; Zwier, Timothy S.; Sibert, Edwin L.

    2016-06-01

    Conformation-specific UV-IR double resonance spectra are presented for ethyl, n-propyl, and n-butylbenzene. With the aid of a local mode Hamiltonian that includes the effects of stretch-scissor Fermi resonance, the spectra can be accurately modeled for specific conformers. These molecules allow for further development of a first principles method for calculating alkyl stretch spectra. Across all chain lengths, certain dihedral patterns impart particular spectral motifs at the quadratic level. However, the anharmonic contributions are consistent from molecule to molecule and conformer to conformer. This transferability of anharmonicities allows for the Hamiltonian to be constructed from only a harmonic frequency calculation, reducing the cost of the model. The phenyl ring alters the frequencies of the CH2 stretches by about 15 cm-1 compared to their n-alkane counterparts in trans configurations. Conformational changes in the chain can lead to shifts in frequency of up to 30 cm-1.

  10. Characterization of a tannase from Emericella nidulans immobilized on ionic and covalent supports for propyl gallate synthesis.

    PubMed

    Gonçalves, Heloísa Bressan; Jorge, João Atílio; Pessela, Benevides Costa; Lorente, Glória Fernandez; Guisán, José Manuel; Guimarães, Luis Henrique Souza

    2013-04-01

    The extracellular tannase from Emericela nidulans was immobilized on different ionic and covalent supports. The derivatives obtained using DEAE-Sepharose and Q-Sepharose were thermally stable from 60 to 75 °C, with a half life (t50) >24 h at 80 °C at pH 5.0. The glyoxyl-agarose and amino-glyoxyl derivatives showed a thermal stability which was lower than that observed for ionic supports. However, when the stability to pH was considered, the derivatives obtained from covalent supports were more stable than those obtained from ionic supports. DEAE-Sepharose and Q-Sepharose derivatives as well as the free enzyme were stable in 30 and 50 % (v/v) 1-propanol. The CNBr-agarose derivative catalyzed complete tannic acid hydrolysis, whereas the Q-Sepharose derivative catalyzed the transesterification reaction to produce propyl gallate (88 % recovery), which is an important antioxidant.

  11. Corrosion mitigation of N-(2-hydroxy-3-trimethyl ammonium)propyl chitosan chloride as inhibitor on mild steel.

    PubMed

    Sangeetha, Y; Meenakshi, S; SairamSundaram, C

    2015-01-01

    The biopolymer N-(2-hydroxy-3-trimethyl ammonium)propyl chitosan chloride (HTACC) was synthesised and its influence as a novel corrosion inhibitor on mild steel in 1M HCl was studied using gravimetric and electrochemical experiments. The compound obtained was characterised using FTIR and NMR studies. The inhibition efficiency increased with the increase in concentration and reached a maximum of 98.9% at 500 ppm concentration. Polarisation studies revealed that HTACC acts both as anodic and cathodic inhibitor. Electrochemical impedance studies confirmed that the inhibition is through adsorption on the metal surface. The extent of inhibition exhibits a negative trend with increase in temperature. Langmuir isotherm provides the best description on the adsorption nature of the inhibitor. SEM analysis indicated the presence of protective film formed by the inhibitor on the metal surface.

  12. (E)-N′-Hy­droxy-1,3-diphenyl-4,5-di­hydro-1H-pyrazole-5-carboximidamide

    PubMed Central

    Chandra; Srikantamurthy, N.; Umesha, K. B.; Jeyaseelan, S.; Mahendra, M.

    2012-01-01

    In the mol­ecule of the title compound, C16H16N4O, the pyrazole ring makes dihedral angles of 8.52 (13) and 9.26 (12)° with the phenyl rings. The dihedral angle between the benzene rings is 1.86 (13)°. In the crystal, mol­ecules are linked into centrosymmetric dimers via pairs of O—H⋯N hydrogen bonds. Weak N—H⋯N inter­actions connect the dimers into a chain along the [100] direction. The pyrazole ring adopts a highly flattened envelope conformation. PMID:22719457

  13. A 1H, 13C and 15N NMR study in solution and in the solid state of six N-substituted pyrazoles and indazoles.

    PubMed

    Claramunt, Rosa M; Santa María, M Dolores; Sanz, Dionisia; Alkorta, Ibon; Elguero, José

    2006-05-01

    Three N-substituted pyrazoles and three N-substituted indazoles [1-(4-nitrophenyl)-3,5-dimethylpyrazole (1), 1-(2,4-dinitrophenyl)-3,5-dimethylpyrazole (2), 1-tosyl-pyrazole (3), 1-p-chlorobenzoylindazole (4), 1-tosylinda-zole (5) and 2-(2-hydroxy-2-phenylethyl)-indazole (6)] have been studied by NMR spectroscopy in solution (1H, 13C, 15N) and in the solid state (13C, 15N). The chemical shifts have been compared with GIAO/DFT calculated absolute shieldings. Some discrepancies have been analyzed.

  14. Synthesis, antioxidant and analgesic activities of Schiff bases of 4-amino-1,2,4-triazole derivatives containing a pyrazole moiety.

    PubMed

    Karrouchi, K; Chemlal, L; Taoufik, J; Cherrah, Y; Radi, S; El Abbes Faouzi, M; Ansar, M

    2016-11-01

    A series of Schiff bases of 4-amino-1,2,4-triazole derivatives containing pyrazole (5a-h) were synthesized from condensation of 4-amino-5-(5-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazole-3-thiol (3) derivative with various aromatic aldehydes (4a-h). The structures of the synthesized compounds were elucidated by IR, (1)H NMR, (13)C NMR, and mass spectrometry. All the synthesized compounds (5a-h) were screened for their in vivo analgesic and in vitro antioxidant activities revealing significant analgesic and antioxidant properties.

  15. Microwave-assisted synthesis of N-pyrazole ureas and the p38alpha inhibitor BIRB 796 for study into accelerated cell ageing.

    PubMed

    Bagley, Mark C; Davis, Terence; Dix, Matthew C; Widdowson, Caroline S; Kipling, David

    2006-11-21

    Microwave irradiation of substituted hydrazines and beta-ketoesters gives 5-aminopyrazoles in excellent yield, which can be transformed to the corresponding N-carbonyl derivatives by treatment with an isocyanate or chloroformate. Derivatization of 4-nitronaphth-1-ol using predominantly microwave heating methods and reaction with an N-pyrazole carbamate provides a rapid route to the N-pyrazole urea BIRB 796 in high purity, as a potent and selective inhibitor of p38alpha mitogen-activated protein kinase for the study of accelerated ageing in Werner syndrome cells.

  16. ABT-431: the diacetyl prodrug of A-86929, a potent and selective dopamine D1 receptor agonist: in vitro characterization and effects in animal models of Parkinson's disease.

    PubMed

    Shiosaki, K; Jenner, P; Asin, K E; Britton, D R; Lin, C W; Michaelides, M; Smith, L; Bianchi, B; Didomenico, S; Hodges, L; Hong, Y; Mahan, L; Mikusa, J; Miller, T; Nikkel, A; Stashko, M; Witte, D; Williams, M

    1996-01-01

    (-)-Trans 9,10-hydroxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5- azacyclopent-1-ena[c]phenanthrene hydrochloride (A-86929) is a potent and selective full agonist at the dopamine (DA) D1-like receptor. Judging by its binding affinities to the D1 and D2 classes of receptors, the compound is approximately 20-fold D1 receptor-selective, whereas relative potencies based on functional in vitro assays indicate that A-86929 is greater than 400-fold D1-selective. A-86929 has moderate to weak (Ki > 1 microM) affinity at other monoaminergic and peptidergic receptors, at ion channels and at monoamine uptake sites. The catechol of A-86929 was bis-acetylated to produce the prodrug, (-)-trans 9,10-acetoxy-2-propyl-4,5,5a,6,7,11-b-hexahydro-3-thia- 5-azacyclopent-1-ena[c]phenanthrene hydrochloride (ABT-431), which is more chemically stable yet is rapidly converted to the parent compound with a half-life of less than 1 min in plasma. Both A-86929 and ABT-431 produced contralateral rotation in rats bearing unilateral 6-hydroxydopamine lesions, with ED50 values of 0.24 mumol/kg s.c. and 0.54 mumol/kg s.c., respectively. A-86929 and ABT-431 improved behavioral disability scores and increased locomotor activity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmoset model of Parkinson's disease in a dose-dependent manner (the minimum effective dose was 0.10 mumol/kg s.c.). When administered three times daily for 30 consecutive days to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmosets, A-86929 significantly improved disability scores throughout the duration of the study. Current Parkinson's disease therapy includes L-dopa, which stimulates both classes of DA receptors by virtue of its conversion to DA in vivo, and direct-acting D2-selective agonists. Stimulation of the D2 receptor, which is associated with all current DA agonist-based therapies, may contribute to their dose-limiting side effects. An agent such as A-86929 (or its prodrug ABT-431), which

  17. Flash pyrolysis of ethyl, n-propyl, and isopropyl iodides as monitored by supersonic expansion vacuum ultraviolet photoionization time-of-flight mass spectrometry.

    PubMed

    Weber, Kevin H; Lemieux, Jessy M; Zhang, Jingsong

    2009-01-22

    The thermal decomposition of ethyl and propyl iodides, along with select isotopomers, up to 1300 K was performed by flash pyrolysis with a 20-100 mus time scale. The pyrolysis was followed by supersonic expansion to isolate the reactive intermediates and initial products, and detection was accomplished by vacuum ultraviolet single photon ionization time-of-flight mass spectrometry (VUV-SPI-TOFMS). The products monitored, such as CH(3), CH(3)I, C(2)H(5), C(2)H(4), HI, I, C(3)H(7), C(3)H(6), and I(2), provide for the simultaneous and direct observation of molecular elimination and bond fission pathways in ethyl and propyl iodides. In the pyrolysis of ethyl iodide, both C-I bond fission and HI molecular elimination pathways are competitive at the elevated temperatures, with C-I bond fission being preferred; at temperatures >or=1000 K, the ethyl radical products further dissociate to ethene + H atoms. In the pyrolysis of isopropyl iodide, both HI molecular elimination and C-I bond fission are observed and the molecular elimination channel is more important at all the elevated temperatures; the isopropyl radicals produced in the C-I fission channel undergo further decomposition to propene + H at temperatures >or=850 K. In contrast, bond fission is found to dominate the n-propyl iodide pyrolysis; at temperatures >or=950 K the n-propyl radicals produced decompose into methyl radical + ethene and propene + H atom. Isotopomer experiments characterize the extent of surface reactions and verify that the HI molecular eliminations in ethyl and propyl iodides proceed by a C1, C2 elimination mechanism (the 1,2 intramolecular elimination).

  18. Design, synthesis and biological evaluation of novel benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives as antitumour agents.

    PubMed

    Wu, Lin-tao; Jiang, Zhi; Shen, Jia-jia; Yi, Hong; Zhan, Yue-chen; Sha, Ming-quan; Wang, Zhen; Xue, Si-tu; Li, Zhuo-rong

    2016-05-23

    A series of novel benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives were designed and synthesized. The biological activities of these derivatives were then evaluated as potential antitumour agents. These compounds were assayed for growth-inhibitory activity against HCT116, MCF-7 and HepG2 cell lines in vitro. The IC50 values of compounds A1 and A7 against the cancer cells were 0.06-3.64 μM and 0.04-9.80 μM, respectively. Their antiproliferative activities were significantly better than that of 5-Fluorouracil (IC50: 56.96-174.50 μM) and were close to that of Paclitaxel (IC50: 0.026-1.53 μM). The activity of these derivatives was over 100 times more effective than other reported structures of chalcone analogues (licochalcone A). A preliminary mechanistic study suggested that these compounds inhibit p53-MDM2 binding. Compounds A1, A7 and A9 effectively inhibited tumour growth in BALB/c mice with colon carcinoma HCT116 cells. The group administered 200 mg/kg of compound A7 showed a 74.6% tumour growth inhibition with no signs of toxicity at high doses that was similar to the inhibition achieved with the 12.5 mg/kg irinotecan positive control (70.2%). Therefore, this class of benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives represents a promising lead structure for the development of possible p53-MDM2 inhibitors as new antitumour agents.

  19. Predictors of Tris(1,3-dichloro-2-propyl) phosphate Metabolite in the Urine of Office Workers

    PubMed Central

    Carignan, Courtney C.; McClean, Michael D.; Cooper, Ellen M.; Watkins, Deborah J.; Fraser, Alicia J.; Heiger-Bernays, Wendy; Stapleton, Heather M.; Webster, Thomas F.

    2013-01-01

    Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a flame retardant widely used in furniture containing polyurethane foam. It is a carcinogen, endocrine disruptor, and potentially neurotoxic. Our objectives were to characterize exposure of adult office workers (n=29) to TDCPP by measuring its primary metabolite, bis(1,3-dichloro-2-propyl) phosphate (BDCPP), in their urine; measuring TDCPP in dust from their homes; offices and vehicles; and assessing possible predictors of exposure. We identified TDCPP in 99% of dust (GM=4.43 µg/g) and BDCPP in 100% of urine samples (GM=408 pg/mL). Concentrations of TDCPP in dust were significantly higher in vehicles (GM=12.5 µg/g) and offices (GM=6.06 µg/g) than in dust from the main living area (GM=4.21 µg/g) or bedrooms (GM=1.40 µg/g) of worker homes. Urinary BDCPP concentrations among participants who worked in a new office building were 26% of those who worked in older buildings (p=0.01). We found some evidence of a positive trend between urinary BDCPP and TDCPP in office dust that was not observed in the other microenvironments and may be related to the timing of urine sample collection during the afternoon of a workday. Overall our findings suggest that exposure to TDCPP in the work environment is one of the contributors to the personal exposure for office workers. Further research is needed to confirm specific exposure sources (e.g., polyurethane foam), determine the importance of exposure in other microenvironments such as homes and vehicles, and address the inhalation and dermal exposure pathways. PMID:23523854

  20. Synthesis and evaluation of novel [alpha]-heteroaryl-phenylpropanoic acid derivatives as PPAR[alpha/gamma] dual agonists

    SciTech Connect

    Casimiro-Garcia, Agustin; Bigge, Christopher F.; Davis, Jo Ann; Padalino, Teresa; Pulaski, James; Ohren, Jeffrey F.; McConnell, Patrick; Kane, Christopher D.; Royer, Lori J.; Stevens, Kimberly A.; Auerbach, Bruce; Collard, Wendy; McGregor, Christine; Song, Kun; Pfizer

    2010-09-27

    The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the {alpha}-position and their evaluation for binding and activation of PPAR{alpha} and PPAR{gamma} are presented in this report. Among the new compounds, (S)-3-{l_brace}4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl{r_brace}-2-1,2,3-triazol-2-yl-propionic acid (17j), was identified as a potent human PPAR{alpha}/{gamma} dual agonist (EC{sub 50} = 0.013 and 0.061 {micro}M, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies.

  1. Resorcinol derivatives: a novel template for the development of cannabinoid CB(1)/CB(2) and CB(2)-selective agonists.

    PubMed

    Wiley, Jenny L; Beletskaya, Irina D; Ng, Edward W; Dai, Zongmin; Crocker, Peter J; Mahadevan, Anu; Razdan, Raj K; Martin, Billy R

    2002-05-01

    The role of the oxygen of the benzopyran substituent of Delta(9)-tetrahydrocannabinol in defining affinity for brain cannabinoid (CB(1)) receptors is not well understood; however, it is known that opening the pyran ring can result in either increased potency and affinity, as in CP 55,940 [(-)-cis-3-[2-hydroxy-4(1,1- dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol], or in an inactive cannabinoid, as in cannabidiol. In the present study, a series of bicyclic resorcinols that resemble cannabidiol were synthesized and tested in vitro and in vivo. Analysis of the structure-activity relationships of these analogs revealed several structural features that were important for maintaining CB(1) receptor recognition and in vivo activity, including the presence of a branched lipophilic side chain and free phenols as well as substitution of a cyclohexane as the second ring of these bicyclic cannabinoids. Many of these analogs exhibited CB(2) selectivity, particularly the dimethoxyresorcinol analogs, and this selectivity was enhanced by longer side chain lengths. Hence, unlike cannabidiol, these resorcinol derivatives had good affinity for CB(1) and/or CB(2) receptors as well as potent in vivo activity. These results suggest that the resorcinol series represent a novel template for the development of CB(2)-selective cannabinoid agonists that have the potential to offer insights into similarities and differences between structural requirements for receptor recognition at CB(1) and CB(2) receptors.

  2. n-Propyl gallate suppresses lipopolysaccharide-induced inducible nitric oxide synthase activation through protein kinase Cδ-mediated up-regulation of heme oxygenase-1 in RAW264.7 macrophages.

    PubMed

    Jeon, Wookwang; Park, Seong Ji; Kim, Byung-Chul

    2017-04-15

    n-Propyl gallate is a synthetic phenolic antioxidant with potential anti-inflammatory effects. However, the underlying mechanism remains largely unknown. In the present study, we showed that n-propyl gallate increases the expression and activity of the heme oxygenase-1 (HO-1), a stress-inducible protein with potent anti-inflammatory activity, in RAW264.7 macrophages. The inhibition of the HO-1 activity by treatment with zinc (II) protoporphyrin IX (ZnPP) or by knockdown of the HO-1 expression with small interference RNA significantly reversed the inhibitory effect of n-Propyl gallate on activations of nuclear factor-κB (NF-κB) and inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide (LPS). An additional mechanism study using inhibitors of signaling kinases revealed the involvement of protein kinase Cδ (PKCδ) in the expression of HO-1 induced by n-Propyl gallate. Consistent with these results, n-Propyl gallate increased the intracellular levels of phosphorylated PKCδ in concentration- and time-dependent manners. The inhibitory effects of n-Propyl gallate on LPS-induced iNOS expression and nitric oxide production were also significantly attenuated by pretreatment with the PKCδ inhibitor, rottlerin, or by transfection with PKCδ (K376R), a kinase-inactive form of PKCδ. Taken together, these findings provide the first evidence that n-Propyl gallate exerts its anti-inflammatory effect through PKCδ-mediated up-regulation of HO-1 in macrophages.

  3. Inhibition of 3(17)beta-hydroxysteroid dehydrogenase from Pseudomonas testosteroni by steroidal A ring fused pyrazoles.

    PubMed

    Levy, M A; Holt, D A; Brandt, M; Metcalf, B W

    1987-04-21

    Several 2,3- and 3,4-steroidal fused pyrazoles have been investigated as potential inhibitors of NAD(P)H-dependent steroid oxidoreductases. These compounds are proven to be potent, specific inhibitors for 3(17) beta-hydroxysteroid dehydrogenase from Pseudomonas testosteroni with Ki values of 6-100 nM. In contrast, the activities of 3 alpha,20 beta-hydroxysteroid dehydrogenase from Streptomyces hydrogenans, steroid 5 alpha-reductase from rat prostate, and 3 alpha-hydroxysteroid dehydrogenase from rat liver were unaffected by micromolar concentrations of these compounds. Product and dead-end inhibition studies indicate an ordered association to the beta-dehydrogenase with the cofactor binding prior to substrate or inhibitor. From the results of double inhibition experiments, it is proposed that inhibition occurs through formation of an enzyme-NAD+-inhibitor ternate. On the basis of pH profiles of Vm/Km, Vm, and 1/Ki and of absorbance difference spectra, a hypothetical mechanism of inhibition by the steroidal pyrazoles, drawn by analogy from the inhibition of liver alcohol dehydrogenase by alkylpyrazoles [Theorell, H., & Yonetani, T. (1963) Biochem. Z. 338, 537-553; Andersson, P., Kvassman, J. K., Lindström, A., Oldén, B., & Pettersson, G. (1981) Eur. J. Biochem. 113, 549-554], is reconsidered. The pH studies and enzyme modification experiments by diethyl pyrocarbonate suggest the involvement of histidine in binding of the inhibitor. A modified proposal for the structure of the enzyme-NAD+-steroidal pyrazole complex is proposed.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. 3-tert-Butyl-1-(3-nitro­phen­yl)-1H-pyrazol-5-amine

    PubMed Central

    Hernández-Ortega, Simón; Cuenú-Cabezas, Fernando; Abonia-González, Rodrigo; Cabrera-Ortiz, Armando

    2012-01-01

    In the title compound, C13H16N4O2, the pyrazole ring forms a dihedral angle of 50.61 (6)° with the 3-nitro-phenyl ring. The plane of the nitro group is twisted by 6.8 (7)° out of the plane of the phenyl ring. In the crystal, the mol­ecules are linked by N—H⋯N and N—H⋯O hydrogen bonds, forming sheets in the bc plane. In addition, a weak C—H⋯N inter­action is observed. PMID:23284484

  5. Dehydrozingerone based 1-acetyl-5-aryl-4,5-dihydro-1H-pyrazoles: Synthesis, characterization and anticancer activity

    NASA Astrophysics Data System (ADS)

    Ratković, Zoran; Muškinja, Jovana; Burmudžija, Adrijana; Ranković, Branislav; Kosanić, Marijana; Bogdanović, Goran A.; Marković, Bojana Simović; Nikolić, Aleksandar; Arsenijević, Nebojša; Đorđevic, Snežana; Vukićević, Rastko D.

    2016-04-01

    A small series of 1-acetyl-5-aryl-4,5-dihydro-1H-pyrazoles (aryl = 4-hydroxy-3-methoxyphenyl and 4-alkoxy-3-methoxyphenyl) was prepared, starting from 4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one, dehydrozingerone, and its alkyl derivatives. Their in vitro cytotoxic activity against some cancer cell lines was tested, showing significant anticancer activity. All the new compounds were well characterized by IR, 1H, 13C NMR and ESI-MS spectroscopy and physical data, whereas structures of two of them were determined by single crystal X-ray analysis.

  6. Dichloridobis(3,5-dimethyl-1H-pyrazol-4-amine-κN 2)cobalt(II)

    PubMed Central

    Cai, Xing-Wei; Zhao, Yu-Yuan; Han, Guang-Fan

    2008-01-01

    In the title compound, [CoCl2(C5H9N3)2], the CoII atom adopts a slightly distorted tetra­hedral coordination geometry provided by two chloride anions and two N atoms from the organic ligands. The dihedral angle between the pyrazole rings is 85.91 (10)°. In the crystal structure, mol­ecules are linked into a three-dimensional network by inter­molecular N—H⋯N and N—H⋯Cl hydrogen-bonding inter­actions. PMID:21203006

  7. Identification of novel series of pyrazole and indole-urea based DFG-out PYK2 inhibitors.

    PubMed

    Bhattacharya, Samit K; Aspnes, Gary E; Bagley, Scott W; Boehm, Markus; Brosius, Arthur D; Buckbinder, Leonard; Chang, Jeanne S; Dibrino, Joseph; Eng, Heather; Frederick, Kosea S; Griffith, David A; Griffor, Matthew C; Guimarães, Cristiano R W; Guzman-Perez, Angel; Han, Seungil; Kalgutkar, Amit S; Klug-McLeod, Jacquelyn; Garcia-Irizarry, Carmen; Li, Jianke; Lippa, Blaise; Price, David A; Southers, James A; Walker, Daniel P; Wei, Liuqing; Xiao, Jun; Zawistoski, Michael P; Zhao, Xumiao

    2012-12-15

    Previous drug discovery efforts identified classical PYK2 kinase inhibitors such as 2 and 3 that possess selectivity for PYK2 over its intra-family isoform FAK. Efforts to identify more kinome-selective chemical matter that stabilize a DFG-out conformation of the enzyme are described herein. Two sub-series of PYK2 inhibitors, an indole carboxamide-urea and a pyrazole-urea have been identified and found to have different binding interactions with the hinge region of PYK2. These leads proved to be more selective than the original classical inhibitors.

  8. Synthesis and Properties of a New Explosive, 4-Amino-3,5-Dinitro-lH-Pyrazole (LLM-116)

    SciTech Connect

    Schmidt, R D; Lee, G S; Pagoria, P F; Mitchell, A R; Gilardi, R

    2001-05-22

    A novel synthesis of the title compound was achieved by direct amination using Vicarious Nucleophilic Substitution (VNS) methodology. Reaction of 1,1,1-trimethylhydrazinium iodide with 3,5-dinitropyrazole in DMSO produces 4-amino-3,s-dinitro-1H-pyrazole as a 1:1 crystal solvate with DMSO. Recrystallization from water yields the monohydrated crystal. Recrystallization of the monohydrate from butyl acetate yields the compound in pure form. Crystallographic data and results of small-scale safety tests are reported. These data indicate that LLM-116 is a promising candidate as an insensitive high explosive.

  9. Synthesis and crystal structure studies of ethyl 5-methyl-1, 3-diphenyl-1H-pyrazole-4-carboxylate

    NASA Astrophysics Data System (ADS)

    Chandra, Srikantamurthy, N.; Babu, E. A. Jithesh; Umesha, K. B.; Mahendra, M.

    2014-04-01

    The title compound, C19H18N2O2, was investigated by single crystal X-ray diffraction method. It crystallizes in monoclinic class under the space group P21/c with cell parameters a= 8.4593(4) Å, b=15.6284(6) Å, c=12.4579(5) Å, α=90°, β=98.241(3)°, γ=90° and Z=2. The ethoxycarbonyl group is slightly twisted from the pyrazole ring, and adopts syn-periplanar conformation. The crystal structure is stabilized by intermolecular C-H….O hydrogen bonds, which help in stabilizing the crystal structure.

  10. Discovery of G Protein-Biased EP2 Receptor Agonists

    PubMed Central

    2016-01-01

    To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors. PMID:26985320

  11. Sports doping: emerging designer and therapeutic β2-agonists.

    PubMed

    Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F

    2013-10-21

    Beta2-adrenergic agonists, or β2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel β2-agonists molecules either by modifying the molecule of known β2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future.

  12. Agonist-receptor-arrestin, an alternative ternary complex with high agonist affinity.

    PubMed

    Gurevich, V V; Pals-Rylaarsdam, R; Benovic, J L; Hosey, M M; Onorato, J J

    1997-11-14

    The rapid decrease of a response to a persistent stimulus, often termed desensitization, is a widespread biological phenomenon. Signal transduction by numerous G protein-coupled receptors appears to be terminated by a strikingly uniform two-step mechanism, most extensively characterized for the beta2-adrenergic receptor (beta2AR), m2 muscarinic cholinergic receptor (m2 mAChR), and rhodopsin. The model predicts that activated receptor is initially phosphorylated and then tightly binds an arrestin protein that effectively blocks further G protein interaction. Here we report that complexes of beta2AR-arrestin and m2 mAChR-arrestin have a higher affinity for agonists (but not antagonists) than do receptors not complexed with arrestin. The percentage of phosphorylated beta2AR in this high affinity state in the presence of full agonists varied with different arrestins and was enhanced by selective mutations in arrestins. The percentage of high affinity sites also was proportional to the intrinsic activity of an agonist, and the coefficient of proportionality varies for different arrestin proteins. Certain mutant arrestins can form these high affinity complexes with unphosphorylated receptors. Mutations that enhance formation of the agonist-receptor-arrestin complexes should provide useful tools for manipulating both the efficiency of signaling and rate and specificity of receptor internalization.

  13. Evidence of Polymorphism on the Antitrypanosomal Naphthoquinone (4E)-2-(1H-Pyrazol-3-ylamino)-4-(1H-pyrazol-3-ylimino)naphthalen-1(4H)-one

    PubMed Central

    Sperandeo, Norma R.; Faudone, Sonia N.

    2013-01-01

    The aim of this study was to characterize the solid state properties of (4E)-2-(1H-pyrazol-3-ylamino)-4-(1H-pyrazol-3-ylimino)naphthalen-1(4H)-one (BiPNQ), a compound with a significant inhibitory activity against Trypanosoma cruzi, the etiological agent of Chagas disease (American trypanosomiasis). Methods used included Differential Scanning Calorimetry (DSC), Thermogravimetry (TG), Fourier Transform Infrared Spectroscopy (FTIR), Powder X-Ray Diffraction (PXRD), Hot Stage, and Confocal Microscopy. Two BiPNQ samples were obtained by crystallization from absolute methanol and 2-propanol-water that exhibited different thermal behaviours, PXRD patterns, and FTIR spectra, indicating the existence of an anhydrous form (BiPNQ-I) and a solvate (BIPNQ-s), which on heating desolvated leading to the anhydrous modification BiPNQ-I. It was determined that FTIR, DSC, and PXRD are useful techniques for the characterization and identification of the crystalline modifications of BiPNQ. PMID:24106678

  14. Agonistic behavior in food animals: review of research and techniques.

    PubMed

    McGlone, J J

    1986-04-01

    One type of social behavior--agonistic behavior--is commonly observed among food animals. Agonistic behaviors are those behaviors which cause, threaten to cause or seek to reduce physical damage. Agonistic behavior is comprised of threats, aggression and submission. While any one of these divisions of agonistic behavior may be observed alone, they usually are found, in sequence, from the start to the end of an interaction. Food animals may show interspecific or intraspecific agonistic behaviors. Interspecific agonistic behavior has not been extensively studied but it is agriculturally important because farm workers may become injured or killed by aggressive food animals. Types of intraspecific agonistic behavior are: when animals are brought together, intermale fighting, resource defense, inter-gender fighting and aberrant aggression. Common pitfalls in research on agonistic behavior among food animals include too few replicates to detect a biological difference, the assumptions of the analysis are not met, only aggression and not submission or other agonistic behavior components are measured, incomplete description of the behaviors are reported and a complete, quantitive ethogram did not form the basis for selecting behavioral measures.

  15. Computational modeling toward understanding agonist binding on dopamine 3.

    PubMed

    Zhao, Yaxue; Lu, Xuefeng; Yang, Chao-Yie; Huang, Zhimin; Fu, Wei; Hou, Tingjun; Zhang, Jian

    2010-09-27

    The dopamine 3 (D3) receptor is a promising therapeutic target for the treatment of nervous system disorders, such as Parkinson's disease, and current research interests primarily focus on the discovery/design of potent D3 agonists. Herein, a well-designed computational protocol, which combines pharmacophore identification, homology modeling, molecular docking, and molecular dynamics (MD) simulations, was employed to understand the agonist binding on D3 aiming to provide insights into the development of novel potent D3 agonists. We (1) identified the chemical features required in effective D3 agonists by pharmacophore modeling based upon 18 known diverse D3 agonists; (2) constructed the three-dimensional (3D) structure of D3 based on homology modeling and the pharmacophore hypothesis; (3) identified the binding modes of the agonists to D3 by the correlation between the predicted binding free energies and the experimental values; and (4) investigated the induced fit of D3 upon agonist binding through MD simulations. The pharmacophore models of the D3 agonists and the 3D structure of D3 can be used for either ligand- or receptor-based drug design. Furthermore, the MD simulations further give the insight that the long and flexible EL2 acts as a "door" for agonist binding, and the "ionic lock" at the bottom of TM3 and TM6 is essential to transduce the activation signal.

  16. Induction profiles of P450 in rat liver microsomes by pyrazole or methylpyrazole

    SciTech Connect

    Krikun, G.; Cederbaum, A.I.

    1986-05-01

    Rats were injected for 2-3 days with pyrazole (P) or 4-methylpyrazole (MP) potent inhibitors of alcohol dehydrogenase. While P treatment induced a P450 isozyme with MW 52,000 as seen on SDS gels, MP induced 2 or 3 P450s. One of the P450s induced by MP appeared to be similar to the one increased by P treatment. The increase of 2-3 bands by MP correlated with a two fold increased in total P450 content. Microsomes from the P treated rats displayed increased activity (per mg protein or per nmole P450) with aniline, p-nitroanisole, dimethylnitrosamine (low Km DMN) and ethanol as substrates, but not with aminopyrine, ethoxycoumarin or DMN (high Km). A stereochemical preference for + 2-butanol over the -isomer was also observed. Kinetic experiments indicated that P treatment increased the Vmax for ethanol, aniline and + 2-butanol. These properties are similar to those found after chronic ethanol treatment. MP treatment resulted in an increased in the oxidation of all the drugs and alcohols tested, primarily due to the increase in content of P450. In analogy to results with P, MP treatment also resulted in stereochemical preference for + vs -2-butanol, and increased turnover numbers with aniline and p-nitroanisole. However in contrast to P, no increase in turnover number with ethanol, + 2-butanol or DMN (low Km) was found after MP treatment. It is probable that these divergent effects are due to the induction of several isozymes, one of which has properties similar to that induced by P. Thus, P induces a P450 similar to that induced by ethanol whereas MP induces that isozyme in addition to others.

  17. Free radical reactions of isoxazole and pyrazole derivatives of hispolon: kinetics correlated with molecular descriptors.

    PubMed

    Shaikh, Shaukat Ali M; Barik, Atanu; Singh, Beena G; Modukuri, Ramani V; Balaji, Neduri V; Subbaraju, Gottumukkala V; Naik, Devidas B; Priyadarsini, K Indira

    2016-12-01

    Hispolon (HS), a natural polyphenol found in medicinal mushrooms, and its isoxazole (HI) and pyrazole (HP) derivatives have been examined for free radical reactions and in vitro antioxidant activity. Reaction of these compounds with one-electron oxidant, azide radicals ([Formula: see text]) and trichloromethyl peroxyl radicals ([Formula: see text]), model peroxyl radicals, studied by nanosecond pulse radiolysis technique, indicated formation of phenoxyl radicals absorbing at 420 nm with half life of few hundred microseconds (μs). The formation of phenoxyl radicals confirmed that the phenolic OH is the active centre for free radical reactions. Rate constant for the reaction of these radicals with these compounds were in the order kHI ≅ kHP > kHS. Further the compounds were examined for their ability to inhibit lipid peroxidation in model membranes and also for the scavenging of 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical and superoxide ([Formula: see text]) radicals. The results suggested that HP and HI are less efficient than HS towards these radical reactions. Quantum chemical calculations were performed on these compounds to understand the mechanism of reaction with different radicals. Lower values of adiabatic ionization potential (AIP) and elevated highest occupied molecular orbital (HOMO) for HI and HP compared with HS controlled their activity towards [Formula: see text] and [Formula: see text] radicals, whereas the contribution of overall anion concentration was responsible for higher activity of HS for DPPH, [Formula: see text], and lipid peroxyl radical. The results confirm the role of different structural moieties on the antioxidant activity of hispolon derivatives.

  18. Silver-pyrazole complexes as hybrid multifunctional materials with metallomesogenic and photoluminescent behaviour.

    PubMed

    Ovejero, Paloma; Asensio, Eduardo; Heras, José Vicente; Campo, José Antonio; Cano, Mercedes; Torres, M Rosario; Núñez, Cristina; Lodeiro, Carlos

    2013-02-14

    New pyridine-functionalised pyrazole compounds [Hpz(R(n)py)] (R(n) = C(6)H(4)OC(n)H(2n+1); n = 12, 14, 16, 18; 1-4) and their corresponding silver complexes [Ag(Hpz(R(n)py))(2)][A] ([A] = NO(3)(-), BF(4)(-); ) have been synthesised and characterised. All of them, with the exception of 1, are liquid crystal materials exhibiting monotropic or enantiotropic SmA mesophases, in contrast to the non-mesomorphic related R(n)-monosubstituted compounds. Because the molecular shape is a factor determinant in the organisation of molecules in the liquid crystal phase, we were interested in solving the crystal structure of representative examples of the mentioned compounds, such as 1 and 6. So, the X-ray crystal structure of [Hpz(R(12)py)] 1 shows the presence of dimeric units through N-H···N hydrogen bonds, which conform to an elongated molecular shape containing a double chain length. On the other hand, the structure of [Ag(Hpz(R(14)py))(2)][NO(3)] 6 also evidenced Ag-Ag bonded dimers from 'U'-shaped cationic entities. These dimers exhibit four chains, two by two alternated, so giving rise to a longer molecular length. Of particular interest was to observe that in both structures, the dimers are layer-like packed, their lamellar structures being related to that of the mesophases found in both kinds of compounds. Furthermore, the analysis of the optical data of the compounds 2 and 4 and the silver compounds 5, 6, 9 and 10 as representative examples pointed out their luminescent behaviour as well as their good ability to act as fluorescent probes for Zn(2+), Cu(2+) and Ag(+). An increase in the fluorescence quantum yields is observed in the final complexes produced in the titrations, this fact being specially notable when 9 was used as the starting compound.

  19. Pulse radiolysis studies of 3,5-dimethyl pyrazole derivatives of selenoethers.

    PubMed

    Barik, Atanu; Singh, Beena G; Sharma, Asmita; Jain, Vimal K; Priyadarsini, K Indira

    2014-11-06

    One electron redox reaction of two asymmetric 3,5-dimethyl pyrazole derivatives of selenoethers attached to ethanoic acid (DPSeEA) and propionic acid (DPSePA) were studied by pulse radiolysis technique using transient absorption detection. The reaction of the hydroxyl ((•)OH) radical with DPSeEA or DPSePA at pH 7 produced transients absorbing at 500 nm and at 300 nm, respectively. The absorbance at 500 nm increased with increasing parent concentration indicating formation of dimer radical cations. From the absorbance changes, the equilibrium constants for the formation of dimer radical cation of DPSeEA and DPSePA were estimated as 2020 and 1608 M(-1), respectively. The rate constants at pH 7 for the reaction of the (•)OH radical with DPSeEA and DPSePA were determined to be 9.6 × 10(9) and 1.4 × 10(10) M(-1) s(-1), respectively. The dimer radical cation of DPSeEA and DPSePA decayed by first order kinetics with a rate constant of 2.8 × 10(4) and 5.5 × 10(3) s(-1), respectively. The yield of radical cations of DPSeEA and DPSePA were estimated from the secondary electron transfer reaction, which corresponds to 38% and 48% of (•)OH radical yield, respectively. Some fraction of monomer radical cation undergoes decarboxylation reaction, and the yield of decarboxylation was 25% and 20% for DPSeEA and DPSePA, respectively. These results have implication in understanding their antioxidant activity. The reaction of trichloromethyl peroxyl radical, glutathione, and ascorbic acid further support their antioxidant behavior.

  20. Nanoscaled Zinc Pyrazolate Metal-Organic Frameworks as Drug-Delivery Systems.

    PubMed

    Rojas, Sara; Carmona, Francisco J; Maldonado, Carmen R; Horcajada, Patricia; Hidalgo, Tania; Serre, Christian; Navarro, Jorge A R; Barea, Elisa

    2016-03-07

    This work describes synthesis at the nanoscale of the isoreticular metal-organic framework (MOF) series ZnBDP_X, based on the assembly of Zn(II) metal ions and the functionalized organic spacers 1,4-bis(1H-pyrazol-4-yl)-2-X-benzene (H2BDP_X; X = H, NO2, NH2, OH). The colloidal stability of these systems was evaluated under different relevant intravenous and oral-simulated physiological conditions, showing that ZnBDP_OH nanoparticles exhibit good structural and colloidal stability probably because of the formation of a protein corona on their surface that prevents their aggregation. Furthermore, two antitumor drugs (mitroxantrone and [Ru(p-cymene)Cl2(pta)] (RAPTA-C) where pta = 1,3,5-triaza-7-phospaadamantane) were encapsulated within the pores of the ZnBDP_X series in order to investigate the effect of the framework functionalization on the incorporation/delivery of bioactive molecules. Thus, the loading capacity of both drugs within the ZnBDP_X series seems to directly depend on the surface area of the solids. Moreover, ligand functionalization significantly affects both the delivery kinetics and the total amount of released drug. In particular, ZnBDP_OH and ZnBDP_NH2 matrixes show a slower rate of delivery and higher percentage of release than ZnBDP_NO2 and ZnBDP_H systems. Additionally, RAPTA-C delivery from ZnBDP_OH is accompanied by a concomitant and progressive matrix degradation due to the higher polarity of the BPD_OH ligand, highlighting the impact of functionalization of the MOF cavities over the kinetics of delivery.

  1. The 5-hydroxytryptamine4 receptor agonists prucalopride and PRX-03140 increase acetylcholine and histamine levels in the rat prefrontal cortex and the power of stimulated hippocampal θ oscillations.

    PubMed

    Johnson, David E; Drummond, Elena; Grimwood, Sarah; Sawant-Basak, Aarti; Miller, Emily; Tseng, Elaine; McDowell, Laura L; Vanase-Frawley, Michelle A; Fisher, Katherine E; Rubitski, David M; Stutzman-Engwall, Kim J; Nelson, Robin T; Horner, Weldon E; Gorczyca, Roxanne R; Hajos, Mihaly; Siok, Chester J

    2012-06-01

    5-Hydroxytryptamine (5-HT)(4) receptor agonists reportedly stimulate brain acetylcholine (ACh) release, a property that might provide a new pharmacological approach for treating cognitive deficits associated with Alzheimer's disease. The purpose of this study was to compare the binding affinities, functional activities, and effects on neuropharmacological responses associated with cognition of two highly selective 5-HT(4) receptor agonists, prucalopride and 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-[3-(piperidin-1-yl)propyl]thieno[2,3-b]pyridine-5-carboxamide (PRX-03140). In vitro, prucalopride and PRX-03140 bound to native rat brain 5-HT(4) receptors with K(i) values of 30 nM and 110 nM, respectively, and increased cAMP production in human embryonic kidney-293 cells expressing recombinant rat 5-HT(4) receptors. In vivo receptor occupancy studies established that prucalopride and PRX-03140 were able to penetrate the brain and bound to 5-HT(4) receptors in rat brain, achieving 50% receptor occupancy at free brain exposures of 330 nM and 130 nM, respectively. Rat microdialysis studies revealed that prucalopride maximally increased ACh and histamine levels in the prefrontal cortex at 5 and 10 mg/kg, whereas PRX-03140 significantly increased cortical histamine levels at 50 mg/kg, failing to affect ACh release at doses lower than 150 mg/kg. In combination studies, donepezil-induced increases in cortical ACh levels were potentiated by prucalopride and PRX-03140. Electrophysiological studies in rats demonstrated that both compounds increased the power of brainstem-stimulated hippocampal θ oscillations at 5.6 mg/kg. These findings show for the first time that the 5-HT(4) receptor agonists prucalopride and PRX-03140 can increase cortical ACh and histamine levels, augment donepezil-induced ACh increases, and increase stimulated-hippocampal θ power, all neuropharmacological parameters consistent with potential positive effects on cognitive processes.

  2. D-Cycloserine: Agonist turned antagonist.

    PubMed

    Lanthorn, T H

    1994-10-01

    D-Cycloserine can enhance activation of the NMDA receptor complex and could enhance the induction of long-term potentiation (LTP). In animals and humans, D-cycloserine can enhance performance in learning and memory tasks. This enhancing effect can disappear during repeated administration. The enhancing effects are also lost when higher doses are used, and replaced by behavioral and biochemical effects like those produced by NMDA antagonists. It has been reported that NMDA agonists, applied before or after tetanic stimulation, can block the induction of LTP. This may be the result of feedback inhibition of second messenger pathways stimulated by receptor activation. This may explain the antagonist-like effects of glycine partial agonists like D-cycloserine. In clinical trials of D-cycloserine in age-associated memory impairment (AAMI) and Alzheimer's disease, chronic treatment provided few positive effects on learning and memory. This may be due to inhibition of second messenger pathways following chronic stimulation of the receptor complex.

  3. Inverse agonist properties of atypical antipsychotic drugs.

    PubMed

    Akam, Elizabeth; Strange, Philip G

    2004-06-01

    Mechanisms of action of several atypical antipsychotic drugs have been examined at the D(2) dopamine receptor expressed in CHO cells. The drugs tested were found to exhibit inverse agonist activity at the D(2) dopamine receptor based on their effects to potentiate forskolin-stimulated cyclic AMP (cAMP) accumulation. Each of the antipsychotic drugs tested (clozapine, olanzapine, quetiapine and risperidone) increased cAMP accumulation to the same extent. The increase in cAMP was also similar to that seen with typical antipsychotic drugs. Inverse agonism at the D(2) dopamine receptor seems, therefore, to be a property common to all classes of antipsychotic drugs. The effect of sodium ions on the binding of the drugs to the receptor was also assessed. Each of the atypical antipsychotic drugs tested here bound with higher affinity in the absence of sodium ions. Previous studies have shown that some antipsychotic drugs are insensitive to sodium ions and some bind with higher affinity in the presence of sodium ions. Given that all of these antipsychotic drugs are inverse agonists, it may be concluded that this sodium ion sensitivity is unrelated to mechanisms of inverse agonism.

  4. MICROWAVE-ASSISTED CYCLOCONDENSATION OF HYDRAZINE DERIVATIVES WITH ALKYL DIHALIDES OR DITOSYLATES IN AQUEOUS MEDIA: SYNTHESES OF PYRAZOLE, PYRAZOLIDINE AND PHTHALAZINE DERIVATIVES

    EPA Science Inventory

    Direct synthesis of 4,5-dihydro-pyrazole, pyrazolidine, and 1,2-dihydro-phthalazine derivatives via double alkylation of hydrazines by alkyl dihalides or ditosylates were accomplished in aqueous media under microwave irradiation conditions; the environmentally friendlier chemical...

  5. 21 CFR 73.3122 - 4-[(2,4-dimethylphenyl)azo]-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false 4- -2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one. 73.3122 Section 73.3122 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... exceed the minimum reasonably required to accomplish the intended coloring effect. (2) Authorization...

  6. 21 CFR 73.3122 - 4-[(2,4-dimethylphenyl)azo]-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false 4- -2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one. 73.3122 Section 73.3122 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... exceed the minimum reasonably required to accomplish the intended coloring effect. (2) Authorization...

  7. Biaryl ethers as potent allosteric inhibitors of reverse transcriptase and its key mutant viruses: aryl substituted pyrazole as a surrogate for the pyrazolopyridine motif.

    PubMed

    Su, Dai-Shi; Lim, John J; Tinney, Elizabeth; Tucker, Thomas J; Saggar, Sandeep; Sisko, John T; Wan, Bang-Lin; Young, Mary Beth; Anderson, Kenneth D; Rudd, Deanne; Munshi, Vandna; Bahnck, Carolyn; Felock, Peter J; Lu, Meiquing; Lai, Ming-Tain; Touch, Sinoeun; Moyer, Gregory; Distefano, Daniel J; Flynn, Jessica A; Liang, Yuexia; Sanchez, Rosa; Perlow-Poehnelt, Rebecca; Miller, Mike; Vacca, Joe P; Williams, Theresa M; Anthony, Neville J

    2010-08-01

    Biaryl ethers were recently reported as potent NNRTIs. Herein, we disclose a detailed effort to modify the previously reported compound 1. We have designed and synthesized a series of novel pyrazole derivatives as a surrogate for pyrazolopyridine motif that were potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells.

  8. Mononuclear thiocyanate containing nickel(II) and binuclear azido bridged nickel(II) complexes of N4-coordinate pyrazole based ligand: Syntheses, structures and magnetic properties

    NASA Astrophysics Data System (ADS)

    Solanki, Ankita; Monfort, Montserrat; Kumar, Sujit Baran

    2013-10-01

    Two mononuclear nickel(II) complexes [NiL1(NCS)2] (1) and [NiL2(NCS)2] (2) and two azido bridged binuclear nickel(II) complexes [Ni(()2()2] (3) and [Ni(()2()2] (4), where L1, L2, L1‧ and L2‧ are N,N-diethyl-N‧,N‧-bis((3,5-dimethyl-1H-pyrazol-1-yl)methyl)ethane-1,2-diamine (L1), N,N-bis((1H-pyrazol-1-yl)methyl)-N‧,N‧-diethylethane-1,2-diamine (L2), N,N-diethyl-N‧-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)ethane-1,2-diamine (L1‧) and N-((1H-pyrazol-1-yl)methyl)-N‧,N‧-diethylethane-1,2-diamine (L2‧) have been synthesized and characterized by microanalyses and physico-chemical methods. Single crystal X-ray diffraction analyses revealed that complexes 1 and 2 are mononuclear NCS- containing Ni(II) complex with octahedral geometry and complexes 3 and 4 are end-on (μ-1,1) azido bridged binuclear Ni(II) complexes with distorted octahedral geometry. Variable temperature magnetic studies of the complexes 3 and 4 display ferromagnetic interaction with J values 19 and 32 cm-1, respectively.

  9. Elucidating the mechanism of cytochrome P450-mediated pyrimidine ring conversion to pyrazole metabolites with the BACE1 inhibitor GNE-892 in rats.

    PubMed

    Takahashi, Ryan; Ma, Shuguang; Deese, Alan; Yue, Qin; Kim-Kang, Heasook; Yi, Yijun; Siu, Michael; Hunt, Kevin W; Kallan, Nicholas C; Hop, Cornelis E C A; Liu, Xingrong; Khojasteh, S Cyrus

    2014-05-01

    We investigated an uncommon biotransformation of pyrimidine during the metabolism of GNE-892 ((R)-2-amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro[imidazole-4,1'-naphthalen]-5(1H)-one), a β-secretase 1 inhibitor. Three novel metabolites, formed by conversion of pyrimidine to pyrazole, were observed in the (14)C-radiolabeled mass balance study in rats. Their structures were characterized by high-resolution mass spectrometry and nuclear magnetic resonance. Although these metabolites accounted for <5% of the administered dose, their unique nature prompted us to conduct further investigations. The pyrazole-containing metabolites were formed in vitro with rat hepatocytes and liver microsomes, which supported that they were formed during hepatic metabolism. Further, their generation was inhibited by 1-aminobenzotriazole, indicating involvement of cytochrome P450s. Studies with rat recombinant enzymes identified that CYP2D2 generated the N-hydroxypyrazole metabolite from GNE-892. This biotransformation proceeded through multiple steps from the likely precursor, pyrimidine N-oxide. On the basis of these data, we propose a mechanism in which the pyrimidine is activated via N-oxidation, followed by a second oxidative process that opens the pyrimidine ring to form a formamide intermediate. After hydrolysis of the formamide, a carbon is lost as formic acid, together with ring closure to form the pyrazole ring. This article highlights a mechanistic approach for determining the biotransformation of the pyrimidine to a pyrazole for GNE-892.

  10. Luminescent dinuclear copper(I) complexes bearing 1,4-bis(diphenylphosphino)butane and functionalized 3-(2'-pyridyl)pyrazole mixed ligands.

    PubMed

    Chen, Jing-Lin; Guo, Zong-Hao; Yu, Hua-Guang; He, Li-Hua; Liu, Sui-Jun; Wen, He-Rui; Wang, Jin-Yun

    2016-01-14

    A family of new dinuclear Cu(i) complexes with 1,4-bis(diphenylphosphino)butane (dppb) and functionalized 3-(2'-pyridyl)pyrazole mixed ligands has been synthesized and characterized. It is revealed that all these Cu(i) complexes include a [Cu2(dppb)2](2+) framework with the two Cu(i) atoms doubly bridged by a pair of dppb to generate a fourteen-membered Cu2P4C8 ring, and functionalized 3-(2'-pyridyl)pyrazole adopts a neutral chelating coordination mode without the N-H bond cleavage of the pyrazolyl ring. All these dinuclear Cu(i) complexes display a relatively weak low-energy absorption in CH2Cl2 solution, which is closely related to the variation of the Cu-N and Cu-P bonds caused by the substituent on the pyrazolyl ring. These dinuclear Cu(i) complexes are all emissive in solution and solid states at ambient temperature, which can be well modulated through structural modification of 3-(2'-pyridyl)pyrazole. It is shown that introduction of the trifluoromethyl group into the pyrazolyl ring is helpful for enhancing the luminescence properties of Cu(i) pyrazole phosphine complexes.

  11. A general and efficient approach to 2H-indazoles and 1H-pyrazoles through copper-catalyzed intramolecular N-N bond formation under mild conditions.

    PubMed

    Hu, Jiantao; Cheng, Yongfeng; Yang, Yiqing; Rao, Yu

    2011-09-28

    A new efficient copper-catalyzed intramolecular amination reaction has been developed to readily synthesise a wide variety of multi-substituted 2H-indazole and 1H-pyrazole derivatives from easily accessible starting materials under mild conditions. A highly selective ligand for estrogen receptor β was prepared in three steps by employing this method.

  12. Simple dialkyl pyrazole-3,5-dicarboxylates show in vitro and in vivo activity against disease-causing trypanosomatids.

    PubMed

    Reviriego, Felipe; Olmo, Francisco; Navarro, Pilar; Marín, Clotilde; Ramírez-Macías, Inmaculada; García-España, Enrique; Albelda, María Teresa; Gutiérrez-Sánchez, Ramón; Sánchez-Moreno, Manuel; Arán, Vicente J

    2017-04-03

    The synthesis and antiprotozoal activity of some simple dialkyl pyrazole-3,5-dicarboxylates (compounds 2-6) and their sodium salts (pyrazolates) (compounds 7-9) against Trypanosoma cruzi, Leishmania infantum and Leishmania braziliensis are reported. In most cases the studied compounds showed, especially against the clinically significant amastigote forms, in vitro activities higher than those of the reference drugs (benznidazole for T. cruzi and glucantime for Leishmania spp.); furthermore, the low non-specific cytotoxicities against Vero cells and macrophages shown by these compounds led to good selectivity indexes, which are 8-72 times higher for T. cruzi amastigotes and 15-113 times higher for Leishmania spp. amastigotes than those of the respective reference drugs. The high efficiency of diethyl ester 3 and its sodium salt 8 against the mentioned protozoa was confirmed by further in vitro assays on infection rates and by an additional in vivo study in a murine model of acute and chronic Chagas disease. The inhibitory capacity of compounds 3 and 8 on the essential iron superoxide dismutase of the aforementioned parasites may be related to the observed anti-trypanosomatid activity. The low acute toxicity of compounds 3 and 8 in mice is also reported in this article.

  13. Fates of endocytosed somatostatin sst2 receptors and associated agonists.

    PubMed Central

    Koenig, J A; Kaur, R; Dodgeon, I; Edwardson, J M; Humphrey, P P

    1998-01-01

    Somatostatin agonists are rapidly and efficiently internalized with the somatostatin sst2 receptor. The fate of internalized agonists and receptors is of critical importance because the rate of ligand recycling back to the cell surface can limit the amount of radioligand accumulated inside the cells, whereas receptor recycling might be of vital importance in providing the cell surface with dephosphorylated, resensitized receptors. Furthermore the accumulation of radioisotope-conjugated somatostatin agonists inside cancer cells resulting from receptor-mediated internalization has been used as a treatment for cancers that overexpress somatostatin receptors. In the present study, radio-iodinated agonists at the sst2 somatostatin receptor were employed to allow quantitative analysis of the fate of endocytosed agonist. After endocytosis, recycling back to the cell surface was the main pathway for both 125I-labelled somatostatin-14 (SRIF-14) and the more stable agonist 125I-labelled cyclo(N-Me-Ala-Tyr-d-Trp-Lys-Abu-Phe) (BIM-23027; Abu stands for aminobutyric acid), accounting for 75-85% of internalized ligand when re-endocytosis of radioligand was prevented. We have shown that there is a dynamic cycling of both somatostatin agonist ligands and receptors between the cell surface and internal compartments both during agonist treatment and after surface-bound agonist has been removed, unless steps are taken to prevent the re-activation of receptors by recycled agonist. Internalization leads to increased degradation of 125I-labelled SRIF-14 but not 125I-labelled BIM-23027. The concentration of recycled agonist accumulating in the extracellular medium was sufficient to re-activate the receptor, as measured both by the inhibition of forskolin-stimulated adenylate cyclase and the recovery of surface receptor number after internalization. PMID:9820803

  14. Activity of n-propyl pyrazinoate against pyrazinamide-resistant Mycobacterium tuberculosis: investigations into mechanism of action of and mechanism of resistance to pyrazinamide.

    PubMed

    Speirs, R J; Welch, J T; Cynamon, M H

    1995-06-01

    The mechanism of action of pyrazinamide (PZA) is not known. One hypothesis is that PZA functions as a prodrug of pyrazinoic acid. Susceptibility to PZA correlates with amidase activity of the Mycobacterium tuberculosis isolate in question. PZA-resistant isolates retain susceptibility in vitro to pyrazinoic acid and n-propyl pyrazinoate. Esters of pyrazinoic acid appear to circumvent the requirement for activation by mycobacterial amidase. The MICs of n-propyl pyrazinoate for M. tuberculosis isolates are lower than those of pyrazinoic acid. Further studies to assess the effects of modifications of the alcohol and pyrazine moieties of pyrazinoate esters on in vitro and in vivo antituberculosis activity are under way. This may lead to a candidate compound with enhanced activity against both PZA-susceptible and PZA-resistant M. tuberculosis isolates suitable for clinical development.

  15. In vitro and in vivo trypanocidal activity of the ethyl esters of N-allyl and N-propyl oxamates using different Trypanosoma cruzi strains.

    PubMed

    Aguirre-Alvarado, Charmina; Zaragoza-Martínez, Fabiola; Rodríguez-Páez, Lorena; Nogueda, Benjamín; Baeza, Isabel; Wong, Carlos

    2007-04-01

    The trypanocidal activity of N-allyl (NAOx) and N-propyl (NPOx) oxamates and that of the ethyl esters ofN-allyl (Et-NAOx) and N-propyl (Et-NPOx) oxamates were tested on cultured epimastigotes (in vitro) and murine trypanosomiasis (in vivo) using five different T. cruzi strains. NAOx and NPOx did not penetrate intact epimastigotes and therefore we were not able to detect any trypanocidal effect with these oxamates. Whereas the ethyl esters (Et-NAOx and Et-NPOx), acting as prodrugs, exhibited in vitro and in vivo trypanocidal activity on the five tested T. cruzi strains. On the contrary, when Nifurtimox and Benznidazole used as reference drugs were tested, we found that only three of the five tested T cruzi strains were affected, whereas the other two strains, Miguz and Compostela, were resistant to the in vitro and in vivo trypanocidal activity of these compounds.

  16. Crystal structure of [2-(tri-ethyl-ammonio)-eth-yl][(2,4,6-triiso-propyl-phen-yl)sulfon-yl]amide tetra-hydrate.

    PubMed

    Golz, C; Strohmann, C

    2015-05-01

    The zwitterionic title compound, C23H42N2O2S·4H2O, crystallized as a tetrahydrate from a solution of N-[(2,4,6-triiso-propyl-phen-yl)sulfon-yl]aziridine in tri-ethyl-amine, diethyl ether and pentane in the presence of moist air. It is formed by a nucleophillic ring-opening that is assumed to be reversible. The mol-ecular structure shows a major disorder of the triiso-propyl-phenyl group over two equally occupied locations. An inter-esting feature is the uncommon hydrate structure, exhibiting a tape-like motif which can be classified as a transition of the one-dimensional T4(2)6(2) motif into the two-dimensional L4(6)5(7)6(8) motif.

  17. Assignment of Milk Fat Fatty Acid Propyl Esters by GC-FID Analysis with the Aid of Ag-ion Solid-phase Extraction.

    PubMed

    Sasaki, Ryo; Umezawa, Masatoshi; Tsukahara, Satoru; Ishiguro, Takashi; Sato, Shinichi; Watanabe, Yomi

    2015-01-01

    The recovery of short-chain fatty acids (FAs) in milk fat (MF) is improved when the analysis of the FA composition of MF by gas chromatography (GC) is conducted with the propyl or butyl ester derivatives, instead of the methyl esters. However, this approach complicates the detection of minor FAs, such as the minor positional isomers of 16:1, which represent <0.2% of the total content. In addition, the standards of these minor esters are not commercially available. In this study, with the aim to identify minor FAs, the fatty acid propyl esters (FAPEs) of MF were fractionated by Ag-ion solid phase extraction (Ag(+)-SPE) and analyzed by GC using a DB-23 capillary column. FAPEs were successfully fractionated mainly according to the degree of unsaturation by adjusting the elution conditions of the Ag(+)-SPE, and the minor FAPEs were easily determined without the aid of standard compounds. For example, by comparison of the GC profile of the saturated Ag(+)-SPE fraction with that of the original MF, minor FAs, such as iso-, anteiso-, and saturated FAs of 15:0 and 17:0, were expected to be eluted in this order. In addition, 16:1 propyl ester was co-eluted with iso 17:0 propyl ester under the GC conditions used in this study, as confirmed by the detection of the corresponding molecular ions (296 and 312, respectively) by GC-MS. Moreover, 9c,11t-conjugated linoleic acid was found to elute between 18:3 and 20:0. To the best of our knowledge, this is the first report suggesting that the peak observed before that of cis-12:1 corresponds to trans-12:1. In conclusion, Ag(+)-SPE fractionation of FAPEs contributed to the identification of minor FAs in MF without the use of standard compounds.

  18. Estrogen receptor agonists for attenuation of neuroinflammation and neurodegeneration

    PubMed Central

    Chakrabarti, Mrinmay; Haque, Azizul; Banik, Naren L.; Nagarkatti, Prakash; Nagarkatti, Mitzi; Ray, Swapan K.

    2014-01-01

    Recent results from laboratory investigations and clinical trials indicate important roles for estrogen receptor (ER) agonists in protecting the central nervous system (CNS) from noxious consequences of neuroinflammation and neurodegeneration. Neurodegenerative processes in several CNS disorders including spinal cord injury (SCI), multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD) are associated with activation of microglia and astrocytes, which drive the resident neuroinflammatory response. During neurodegenerative processes, activated microglia and astrocytes cause deleterious effects on surrounding neurons. The inhibitory activity of ER agonists on microglia activation might be a beneficial therapeutic option for delaying the onset or progression of neurodegenerative injuries and diseases. Recent studies suggest that ER agonists can provide neuroprotection by modulation of cell survival mechanisms, synaptic reorganization, regenerative responses to axonal injury, and neurogenesis process. The anti-inflammatory and neuroprotective actions of ER agonists are mediated mainly via two ERs known as ERα and ERβ. Although some studies have suggested that ER agonists may be deleterious to some neuronal populations, the potential clinical benefits of ER agonists for augmenting cognitive function may triumph over the associated side effects. Also, understanding the modulatory activities of ER agonists on inflammatory pathways will possibly lead to the development of selective anti-inflammatory molecules with neuroprotective roles in different CNS disorders such as SCI, MS, PD, and AD in humans. Future studies should be concentrated on finding the most plausible molecular pathways for enhancing protective functions of ER agonists in treating neuroinflammatory and neurodegenerative injuries and diseases in the CNS. PMID:25245209

  19. TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

    EPA Science Inventory

    Fish early life stages are exceptionally sensitive to the lethal toxicity of chemicals that act as arylhydrocarbon receptor (AhR) agonists. Toxicity characterizations based on 2,3,7,8-tetrachlorodibenzo-p-dioxin, generally the most potent AhR agonist, support the toxicity equiva...

  20. Physical Chemistry to the Rescue: Differentiating Nicotinic and Cholinergic Agonists

    ERIC Educational Resources Information Center

    King, Angela G.

    2005-01-01

    Researches suggest that two agonists can bind to the same binding site of an important transmembrane protein and elicit a biological response through strikingly different binding interactions. Evidence is provided which suggests two possible types of nicotinic acetylcholine receptor agonist binding like acetlycholine (cholinergic) or like nicotine…

  1. Crystal structure of 6-amino-4-(3-bromo-4-meth-oxy-phen-yl)-3-methyl-2,4-di-hydro-pyrano[2,3-c]pyrazole-5-carbo-nitrile dimethyl sulfoxide monosolvate.

    PubMed

    Yousuf, Sammer; Bano, Huma; Muhammad, Munira Taj; Khan, Khalid Mohammed

    2015-07-01

    In the pyrazole mol-ecule of the title solvate, C15H13BrN4O2·C2H6OS, the dihedral angle between the benzene ring and the mean plane of the di-hydro-pyrano[2,3-c]pyrazole ring system [r.m.s deviation = 0.031 (2) Å] is 86.71 (14)°. In the crystal, the pyrazole mol-ecules are linked by N-H⋯N hydrogen bonds, forming a layer parallel to (10-1). The pyrazole and dimethyl sulfoxide mol-ecules are connected by an N-H⋯O hydrogen bond.

  2. 2-(1-(Arylimino)propyl)quinolin-8-olate half-titanocene dichlorides: synthesis, characterization and ethylene (co-)polymerization behaviour.

    PubMed

    Huang, Wei; Sun, Wen-Hua; Redshaw, Carl

    2011-07-07

    A series of 2-(1-(arylimino)propyl)quinolin-8-olate half-titanocene dichlorides, Cp'TiCl(2)L (Cp' = η(5)-C(5)H(5) or η(5)-C(5)Me(5), L = 2-(1-(2,6-R(1)-4-R(2)-phenylimino)propyl)quinolin-8-olate), was synthesized via the stoichiometric reaction of Cp'TiCl(3) with the corresponding potassium 2-(1-(2,6-R(1)-4-R(2)-phenylimino)propyl)quinolin-8-olate salt. All titanium compounds were characterized by elemental analysis, (1)H NMR and (13)C NMR spectroscopy; the molecular structures of two representative compounds were determined by single crystal X-ray diffraction. On activation with methylaluminoxane (MAO), all half-titanocene compounds showed high activity in ethylene polymerization, and furthermore, performed with good to high activities in the co-polymerization of ethylene with either 1-hexene or 1-octene affording polyethylenes with high co-monomer incorporation. Less bulky ortho-substituents (R(1)) on the phenylimino groups were found to enhance the catalytic activities of their titanium compounds. In general, the titanium pro-catalysts containing η(5)-C(5)Me(5) (C7-C12) exhibited higher activities than did their analogues bearing η(5)-C(5)H(5) (C1-C6). Some of the resultant polyolefins were ultrahigh molecular weight polyethylene.

  3. Trypanosoma cruzi: inhibition of alpha-hydroxyacid dehydrogenase isozyme II by N-allyl and N-propyl oxamates and their effects on intact epimastigotes.

    PubMed

    Chena, Miguel A; Elizondo-Jiménez, Silvia; Rodríguez-Páez, Lorena; Nogueda-Torres, Benjamín; Baeza-Ramírez, Isabel; Wong-Ramírez, Carlos

    2004-12-01

    N-allyl (NAOx) and N-propyl (NPOx) oxamates were designed as inhibitors of alpha-hydroxyacid dehydrogenase (HADH) isozyme II from Trypanosoma cruzi. The kinetic studies showed that NAOx and NPOx were competitive inhibitors of HADH-isozyme II (Ki = 72 microM, IC50 = 0.33 mM and 70 microM, IC50 = 0.32 mM, respectively). The attachment of the allylic and propylic chains to nitrogen of the competitive inhibitor oxamate (Ki = 0.91 mM, IC50 = 4.25 mM), increased 12.6 and 13-folds respectively, the affinity for T. cruzi HADH-isozyme II. NAOx and NPOx were selective inhibitors of HADH-isozyme II, because other T. cruzi dehydrogenases were not inhibited by these substances. Since HADH-isozyme II participates in the energy metabolism of T. cruzi, a trypanocidal effect can be expected with these inhibitors. However, we were not able to detect any trypanocidal activity with these oxamates. When the corresponding ethyl esters of N-allyl (Et-NAOx) and N-propyl (Et-NPOx) oxamates were tested as a possible trypanocidal prodrugs, in comparison with nifurtimox and benznidazole, the expected trypanocidal effects were obtained.

  4. The quest for complex molecules in space. Searches for cyanides related to n-propyl cyanide in Sgr B2(N)

    NASA Astrophysics Data System (ADS)

    Muller, H. S. P.; Belloche, A.; Menten, K. M.; Coutens, A.; Walters, A.; Grabow, J. U.; Schlemmer, S.

    2011-05-01

    A molecular line survey was carried out with the IRAM 30 m telecope toward the prolific hot core Sgr B2(N) in order to explore its molecular complexity. The entire 3 mm range as well as selected regions at 2 and 1.3 mm were covered. Notable results include the detections of aminoacetonitrile, ethyl formate, n-propyl cyanide, and the singly substituted 13C isotopologs of vinyl cyanide. There exists a branched isomer of n-propyl cyanide: iso-propyl cyanide. A search for this isomer in our line survey required a laboratory spectroscopic investigation beforehand. Even though promising emission features have been found for this as well as other, related molecules, there are rather few uncontaminated lines. Overlap by other emission or some absorption features occurs frequently, and uncertainties about the position of the baseline also contribute to considering detections to be inconclusive. Nevertheless, the determination of upper limits or abundances among isomers and related molecules will help to contrain astrochemical pathways. We will present our results and discuss promising strategies to search for complex molecules in space.

  5. Neuroprotection by Alpha 2-Adrenergic Agonists in Cerebral Ischemia

    PubMed Central

    Zhang, Yonghua; Kimelberg, Harold K.

    2005-01-01

    Ischemic brain injury is implicated in the pathophysiology of stroke and brain trauma, which are among the top killers worldwide, and intensive studies have been performed to reduce neural cell death after cerebral ischemia. Alpha 2-adrenergic agonists have been shown to improve the histomorphological and neurological outcome after cerebral ischemic injury when administered during ischemia, and recent studies have provided considerable evidence that alpha 2-adrenergic agonists can protect the brain from ischemia/reperfusion injury. Thus, alpha 2-adrenergic agonists are promising potential drugs in preventing cerebral ischemic injury, but the mechanisms by which alpha 2-adrenergic agonists exert their neuroprotective effect are unclear. Activation of both the alpha 2-adrenergic receptor and imidazoline receptor may be involved. This mini review examines the recent progress in alpha 2-adrenergic agonists - induced neuroprotection and its proposed mechanisms in cerebral ischemic injury. PMID:18369397

  6. Effects of Tris(1,3-dichloro-2-propyl) Phosphate (TDCPP) in Tetrahymena Thermophila: Targeting the Ribosome

    NASA Astrophysics Data System (ADS)

    Li, Jing; Giesy, John P.; Yu, Liqin; Li, Guangyu; Liu, Chunsheng

    2015-05-01

    Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) has been frequently detected in the environment, and exposure to TDCPP appears widespread. It has been implicated to cause toxicity in vertebrates, but its potential to affect lower-trophic-level species remains unknown. In the present study, the ciliated protozoan, Tetrahymena thermophila, was used as a model to evaluate toxic effects of TDCPP and explore molecular mechanisms by integrating phenotypic observation, RNA-Seq and transmission electron microscopy (TEM) Imaging technologies. Exposure to 0.01, 0.1 or 1 μM TDCPP for 5 days significantly decreased the relative biomass by reducing number of cells, size of cells and quantity of cilia in a dose-dependent manner. RNA-Seq analysis demonstrated that expression of twenty-one ribosome protein genes was down-regulated and these genes were enriched in “ribosome” term in KEGG pathway analysis. Furthermore, down-regulation of genes expressing ribosome proteins was accompanied by decreased ribosome quantity in rough endoplasmic reticulum and cytoplasm and enlarged ribosome size. Therefore, taken together, the data from the present study suggest that exposure to TDCPP affects growth and reproduction of Tetrahymena thermophila by targeting the ribosome. This information might provide insights into critical mechanisms of toxic action in other species and lead to useful bioindicators of exposure to TDCPP.

  7. Modeling of boldine alkaloid adsorption onto pure and propyl-sulfonic acid-modified mesoporous silicas. A comparative study.

    PubMed

    Geszke-Moritz, Małgorzata; Moritz, Michał

    2016-12-01

    The present study deals with the adsorption of boldine onto pure and propyl-sulfonic acid-functionalized SBA-15, SBA-16 and mesocellular foam (MCF) materials. Siliceous adsorbents were characterized by nitrogen sorption analysis, transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier-transform infrared (FT-IR) spectroscopy and thermogravimetric analysis. The equilibrium adsorption data were analyzed using the Langmuir, Freundlich, Redlich-Peterson, and Temkin isotherms. Moreover, the Dubinin-Radushkevich and Dubinin-Astakhov isotherm models based on the Polanyi adsorption potential were employed. The latter was calculated using two alternative formulas including solubility-normalized (S-model) and empirical C-model. In order to find the best-fit isotherm, both linear regression and nonlinear fitting analysis were carried out. The Dubinin-Astakhov (S-model) isotherm revealed the best fit to the experimental points for adsorption of boldine onto pure mesoporous materials using both linear and nonlinear fitting analysis. Meanwhile, the process of boldine sorption onto modified silicas was described the best by the Langmuir and Temkin isotherms using linear regression and nonlinear fitting analysis, respectively. The values of adsorption energy (below 8kJ/mol) indicate the physical nature of boldine adsorption onto unmodified silicas whereas the ionic interactions seem to be the main force of alkaloid adsorption onto functionalized sorbents (energy of adsorption above 8kJ/mol).

  8. A case study on quantitative in vitro to in vivo extrapolation for environmental esters: Methyl-, propyl- and butylparaben.

    PubMed

    Campbell, Jerry L; Yoon, Miyoung; Clewell, Harvey J

    2015-06-05

    Parabens have been reported as potential endocrine disrupters and are widely used in consumer projects including cosmetics, foods and pharmaceuticals. We report on the development of a PBPK model for methyl-, propyl-, and butylparaben. The model was parameterized through a combination of QSAR for tissue solubility and quantitative in vitro to in vivo extrapolation (IVIVE) for hydrolysis in portals of entry including intestine and skin as well as in the primary site of metabolism, the liver. Overall, the model provided very good agreement with published time-course data in blood and urine from controlled dosing studies in rat and human, and demonstrates the potential value of quantitative IVIVE in expanding the use of human biomonitoring data in safety assessment. An in vitro based cumulative margin of safety (MOS) was calculated by comparing the effective concentrations from an in vitro assay of estrogenicity to the free paraben concentrations predicted by the model to be associated with the 95th percentile urine concentrations reported in NHANES (2009-2010 collection period). The calculated MOS for adult females was 108, whereas the MOS for males was 444.

  9. Fabrication of calcium phosphate-calcium sulfate injectable bone substitute using hydroxy-propyl-methyl-cellulose and citric acid.

    PubMed

    Thai, Van Viet; Lee, Byong-Taek

    2010-06-01

    In this study, an injectable bone substitute (IBS) consisting of citric acid, chitosan, and hydroxyl propyl methyl cellulose (HPMC) as the liquid phase and tetra calcium phosphate (TTCP), dicalcium phosphate dihydrate (DCPD) and calcium sulfate dehydrate (CSD, CaSO4 x 2H2O) powders as the solid phase, were fabricated. Two groups were classified based on the percent of citric acid in the liquid phase (20, 40 wt%). In each groups, the HPMC percentage was 0, 2, and 4 wt%. An increase in compressive strength due to changes in morphology was confirmed by scanning electron microscopy images. A good conversion rate of HAp at 20% citric acid was observed in the XRD profiles. In addition, HPMC was not obviously affected by apatite formation. However, both HPMC and citric acid increased the compressive strength of IBS. The maximum compressive strength for IBS was with 40% citric acid and 4% HPMC after 14 days of incubation in 100% humidity at 37 degrees C.

  10. Genotoxicity assessment of propyl thiosulfinate oxide, an organosulfur compound from Allium extract, intended to food active packaging.

    PubMed

    Mellado-García, P; Maisanaba, S; Puerto, M; Llana-Ruiz-Cabello, M; Prieto, A I; Marcos, R; Pichardo, S; Cameán, A M

    2015-12-01

    Essential oils from onion (Allium cepa L.), garlic (Allium sativum L.), and their main components, such as propyl thiosulfinate oxide (PTSO) are being intended for active packaging with the purpose of maintaining and extending food product quality and shelf life. The present work aims to assess for the first time the potential mutagenicity/genotoxicity of PTSO (0-50 µM) using the following battery of genotoxicity tests: (1) the bacterial reverse-mutation assay in Salmonella typhimurium (Ames test, OECD 471); (2) the micronucleus test (OECD 487) (MN) and (3) the mouse lymphoma thymidine-kinase assay (OECD 476) (MLA) on L5178YTk(+/-), cells; and (4) the comet assay (with and without Endo III and FPG enzymes) on Caco-2 cells. The results revealed that PTSO was not mutagenic in the Ames test, however it was mutagenic in the MLA assay after 24 h of treatment (2.5-20 µM). The parent compound did not induce MN on mammalian cells; however, its metabolites (in the presence S9) produced positive results (from 15 µM). Data from the comet assay indicated that PTSO did not induce DNA breaks or oxidative DNA damage. Further in vivo genotoxicity tests are needed to confirm its safety before it is used as active additive in food packaging.

  11. No synergism between bis(propyl)-cognitin and rasagiline on protecting dopaminergic neurons in Parkinson's disease mice

    PubMed Central

    Zheng, Cheng-you; Guo, Bao-jian; Cai, Wei; Cui, Wei; Mak, Shing-hung; Wang, Yu-qiang; Lee, Simon Ming-yuen; Han, Yi-fan; Zhang, Zai-jun

    2016-01-01

    Rasagiline, a monoamine oxidase-B inhibitor, and bis(propyl)-cognitin (B3C), a novel dimer are reported to be neuroprotective. Herein, the synergistical neuroprotection produced by rasagiline and B3C was investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice of Parkinsonism. By using neurobehavioural tests, high-performance liquid chromatography and western blot assay, we showed that B3C at 0.3 mg/kg, rasagiline at 0.02 mg/kg, as well as co-treatment with B3C and rasagiline prevented MPTP-induced behavioural abnormities, increased the concentrations of dopamine and its metabolites in the striatum, and up-regulated the expression of tyrosine hydroxylase in the substantia nigra. However, the neuroprotective effects of co-treatment were not significantly improved when compared with those of B3C or rasagiline alone. Collectively, we have demonstrated that B3C at 0.3 mg/kg and rasagline at 0.02 mg/kg could not produce synergistic neuroprotective effects. PMID:27651784

  12. Effects of Tris(1,3-dichloro-2-propyl) Phosphate (TDCPP) in Tetrahymena Thermophila: Targeting the Ribosome

    PubMed Central

    Li, Jing; Giesy, John P.; Yu, Liqin; Li, Guangyu; Liu, Chunsheng

    2015-01-01

    Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) has been frequently detected in the environment, and exposure to TDCPP appears widespread. It has been implicated to cause toxicity in vertebrates, but its potential to affect lower-trophic-level species remains unknown. In the present study, the ciliated protozoan, Tetrahymena thermophila, was used as a model to evaluate toxic effects of TDCPP and explore molecular mechanisms by integrating phenotypic observation, RNA-Seq and transmission electron microscopy (TEM) Imaging technologies. Exposure to 0.01, 0.1 or 1 μM TDCPP for 5 days significantly decreased the relative biomass by reducing number of cells, size of cells and quantity of cilia in a dose-dependent manner. RNA-Seq analysis demonstrated that expression of twenty-one ribosome protein genes was down-regulated and these genes were enriched in “ribosome” term in KEGG pathway analysis. Furthermore, down-regulation of genes expressing ribosome proteins was accompanied by decreased ribosome quantity in rough endoplasmic reticulum and cytoplasm and enlarged ribosome size. Therefore, taken together, the data from the present study suggest that exposure to TDCPP affects growth and reproduction of Tetrahymena thermophila by targeting the ribosome. This information might provide insights into critical mechanisms of toxic action in other species and lead to useful bioindicators of exposure to TDCPP. PMID:25994279

  13. Over-expression of GAPDH in human colorectal carcinoma as a preferred target of 3-bromopyruvate propyl ester.

    PubMed

    Tang, Zhenjie; Yuan, Shuqiang; Hu, Yumin; Zhang, Hui; Wu, Wenjing; Zeng, Zhaolei; Yang, Jing; Yun, Jingping; Xu, Ruihua; Huang, Peng

    2012-02-01

    It has long been observed that many cancer cells exhibit increased aerobic glycolysis and rely more on this pathway to generate ATP and metabolic intermediates for cell proliferation. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme in glycolysis and has been known as a housekeeping molecule. In the present study, we found that GAPDH expression was significantly up-regulated in human colorectal carcinoma tissues compared to the adjacent normal tissues, and also increased in colon cancer cell lines compared to the non-tumor colon mucosa cells in culture. The expression of GAPDH was further elevated in the liver metastatic tissues compared to the original colon cancer tissue of the same patients, suggesting that high expression of GAPDH might play an important role in colon cancer development and metastasis. Importantly, we found that 3-bromopyruvate propyl ester (3-BrOP) preferentially inhibited GAPDH and exhibited potent activity in inducing colon cancer cell death by causing severe depletion of ATP. 3-BrOP at low concentrations (1-10 μM) inhibited GAPDH and a much higher concentration (300 μM) was required to inhibit hexokinase-2. The cytotoxic effect of 3-BrOP was associated with its inhibition of GAPDH, and colon cancer cells with loss of p53 were more sensitive to this compound. Our study suggests that GAPDH may be a potential target for colon cancer therapy.

  14. Expression of DNA damage-inducible genes of Escherichia coli upon treatment with methylating, ethylating and propylating agents.

    PubMed

    Volkert, M R; Gately, F H; Hajec, L I

    1989-03-01

    Several alkylation-inducible genes have been identified by construction of Mu-d1 (Apr lac) fusions to genes whose expression is increased in response to alkylation treatment, but not UV treatment. We have examined the induction of 4 different alkylation-inducible genes by treatment with a variety of methylating and ethylating agents, and a propylating agent. We have compared the induction of the alkylation-inducible genes with the induction of the sulA gene, which is a component of the SOS response to DNA damage. We find that the Ada-regulated adaptive response genes (ada-alkB, alkA and aidB) are induced primarily in response to methylation treatment. The ada-independent aidC gene is induced upon treatment with agents that alkylate predominantly by SN1 nucleophilic attack. aidC induction occurs only when cells are not aerated during treatment. The SOS response, as indicated by sulA induction, is strongly induced by all types of alkylating agents used.

  15. The physical stability of thermally-stressed phospholipid-based emulsions containing methyl, propyl and heptyl parabens as model drugs.

    PubMed

    Zhang, Xiaoguang; Kirsch, Lee E

    2003-10-20

    The objectives of the studies presented herein was to investigate the mechanisms of emulsion instability under thermal stress (121 degrees C) by evaluating the effects of a lipophilic drug dissolved in the internal phase of an oil-in-water (o/w) emulsion on growth rate suppression and the apparent microviscosity. Model drugs used were methyl, propyl and heptyl paraben. The o/w emulsions were prepared using medium chain triglycerides as an internal phase in aqueous glycerol solutions emulsified with phospholipids. Concentrations of paraben in the internal phase varied from 0.2-0.8 M. Microfluidization was used to reduce the droplet size to the submicron range. Microviscosity was calculated from the measured anisotropy of a fluorophore probe (1,6-phenyl-1,3,5-hexatriene) using a modified Perrin's equation. Emulsion aliquots were subjected to thermal stressed at 121 degrees C the droplet growth rate was determined from periodic measurements of the mean droplet diameter using photon correlation spectroscopy. The growth rate decreased in the presence of parabens. Maximal growth suppression occurred at paraben concentrations of 0.4 M. However in deference to theoretical predictions of the effects of increasing co-solute concentrations based on Ostwalt ripening, the droplet growth rates increased at concentrations greater than 0.4M. The logarithm of the growth rate was linearly correlated to the interfacial rigidity (inverse microviscosity) of the emulsion which suggests that coalescence rather than molecular diffusion was primarily responsible for emulsion instability under the conditions studied.

  16. Separation and solvent extraction of vanadium and uranium with n-propyl 2,3,4-trihydroxybenzoate.

    PubMed

    Jasim, F

    1969-06-01

    A spectrophotometric method is described for the separation and determination of trace quantities of vanadium(IV) and (V) from uranium(VI). Vanadium is selectively separated from uranium by extraction at pH 6.5 into n-propyl 2,3,4-trihydroxybenzoate (PTB) dissolved in t-pentanol. Up to 120 microg of vanadium can be determined by measuring the absorbance of the blue complex in the organic phase at 585 nm. Uranium(VI) remains in the aqueous layer and can be determined spectrophotometrically by its reaction with PTB in aqueous acetone to produce a brown-red colour at pH 7.6-8.8. Solutions containing 25-275 microg of uranium absorb at 370-380 nm according to Beer's law. By modification, this procedure can be used for the determination of the two metals in native phosphate rocks. The effects of diverse ions on the determination of vanadium and uranium have also been examined.

  17. A dry powder combination of pyrazinoic acid and its n-propyl ester for aerosol administration to animals.

    PubMed

    Durham, P G; Young, E F; Braunstein, M S; Welch, J T; Hickey, A J

    2016-12-05

    Combining the advantage of higher efficacy due to local pulmonary administration of pyrazinoic acid (POA) and potent effect of pyrazinoic acid ester (PAE) delivered as an aerosol would aid in tuberculosis therapy. A combination spray dried dry powder, composed of POA, PAE (n-propyl POA), maltodextrin and leucine, was prepared for aerosol delivery to animals. Solid-state characteristics of morphology (scanning electron microscopy) crystallinity (X-ray powder diffraction), thermal properties (thermogravimetric analysis and differential scanning calorimetry) and moisture content (Karl Fisher) were evaluated. Particle size distributions, by volume (laser diffraction) for the dispersed powder and by mass (inertial impaction) were determined. Efficient delivery of the powder to a nose only animal exposure chamber employed a novel rotating brush/micro-fan apparatus. Spherical, crystalline particles were prepared. The volume median diameter, ∼1.5μm, was smaller than the mass median aerodynamic diameter, ∼3.0μm, indicating modest aggregation. Drug content variations were observed across the particle size distribution and may be explained by PAE evaporative losses. Delivery to the nose-only exposure chamber indicated that boluses could be administered at approximately 3min intervals to avoid aerosol accumulation and effect uniform dose delivery with successive doses suitable for future pharmacokinetic and pharmacodynamic studies.

  18. Three-dimensional model evaluation of the Ozone Depletion Potentials for n-propyl bromide, trichloroethylene and perchloroethylene

    NASA Astrophysics Data System (ADS)

    Wuebbles, D. J.; Patten, K. O.; Wang, D.; Youn, D.; Martínez-Avilés, M.; Francisco, J. S.

    2010-07-01

    The existing solvents trichloroethylene (TCE) and perchloroethylene (PCE) and proposed solvent n-propyl bromide (nPB) have atmospheric lifetimes from days to a few months, but contain chlorine or bromine that could affect stratospheric ozone. Several previous studies estimated the Ozone Depletion Potentials (ODPs) for various assumptions for location of nPB emissions, but these studies used simplified modeling treatments. The primary purpose of this study is to reevaluate the ODP for nPB using a current-generation chemistry-transport model of the troposphere and stratosphere. For the first time, ODPs for TCE and PCE are also evaluated. Emissions representing industrial use of each compound are incorporated on land surfaces from 30° N to 60° N. The atmospheric chemical lifetime obtained for nPB is 24.7 days, similar to past literature, but the ODP is 0.0049, lower than in past studies. The derived atmospheric lifetime for TCE is 13.0 days and for PCE is 111 days. The corresponding ODPs are 0.00035 and 0.0060, respectively.

  19. Synthesis, adsorption and selectivity studies of N-propyl quaternized magnetic poly(4-vinylpyridine) for hexavalent chromium.

    PubMed

    Tavengwa, Nikita Tawanda; Cukrowska, Ewa; Chimuka, Luke

    2013-11-15

    The ability of solid N-propyl quaternized magnetic poly(4-vinylpyridine) for the extraction of chromium(VI) in aqueous solutions was investigated. For the synthesized Cr(VI) magnetic polymers, the optimum pH obtained was 4 for both the magnetic ion imprinted polymer (IIP) and the corresponding non-ion imprinted polymer NIP. The amount of the adsorbent which gave the maximum adsorption was determined to be 20 and 65 mg for the magnetic IIP and NIP, respectively. A Cr(VI) concentration which was adsorbed maximally was 5 mg L(-1) which was therefore taken as the optimum. The maximum adsorption capacities for the magnetic polymers were 6.20 and 1.87 mg g(-1) for the magnetic IIP and NIP, respectively. The optimum time for the adsorption of the Cr(VI) analyte was determined as 40 min. The prepared magnetic ion imprinted polymer showed good selectivity towards Cr(VI). The order of selectivity of the investigated anions followed the sequence: Cr2O7(2-)>SO4(2-)>F(-)>NO3(-).

  20. n-Propyl gallate activates hypoxia-inducible factor 1 by modulating intracellular oxygen-sensing systems.

    PubMed

    Kimura, Motohide; Takabuchi, Satoshi; Tanaka, Tomoharu; Murata, Miyahiko; Nishi, Kenichiro; Oda, Seiko; Oda, Tomoyuki; Kanai, Michiyuki; Fukuda, Kazuhiko; Kizaka-Kondoh, Shinae; Adachi, Takehiko; Takabayashi, Arimichi; Semenza, Gregg L; Hirota, Kiichi

    2008-04-01

    HIF-1 (hypoxia-inducible factor 1) is a master regulator of cellular adaptive responses to hypoxia. The expression and transcriptional activity of the HIF-1alpha subunit is stringently controlled by intracellular oxygen tension through the action of prolyl and asparaginyl hydroxylases. In the present study we demonstrate that PG (n-propyl gallate) activates HIF-1 and expression of its downstream target genes under normoxic conditions in cultured cells and in mice. The stability and transcriptional activity of HIF-1alpha are increased by PG. PG treatment inhibits the interaction between HIF-1alpha and VHL (von Hippel-Lindau protein) and promotes the interaction between HIF-1alpha and p300, indicating that PG inhibits the activity of both prolyl and asparaginyl HIF-1alpha hydroxylases. We conclude that PG activates HIF-1 and enhances the resultant gene expression by directly affecting the intracellular oxygen sensing system in vitro and in vivo and that PG represents a lead compound for the development of a non-toxic activator of HIF-1.

  1. Physicochemical properties of N-propyl-N-methylpyrrolidinium bis(fluorosulfonyl)imide for sodium metal battery applications.

    PubMed

    Yoon, Hyungook; Zhu, Haijin; Hervault, Aziliz; Armand, Michel; MacFarlane, Douglas R; Forsyth, Maria

    2014-06-28

    The physicochemical properties of a range of NaNTf2 (or NaTFSI) salt concentrations in N-propyl-N-methylpyrrolidinium bis(fluorosulfonyl)imide (or C3mpyrFSI) ionic liquid were investigated by DSC, conductivity, cyclic voltammetry and diffusivity studies. Cyclic voltammetry indicated a stable sodium plating behavior with a current of 5 mA cm(-2) at 25 °C to 20 mA cm(-2) at 100 °C, along with high reversibility identifying this electrolyte as a possible candidate for sodium-ion or sodium metal battery applications. (23)Na NMR chemical shifts and spectral linewidths (FWHM) indicate a complex coordination of the Na(+) ion which is dependent on both temperature and salt concentration with an apparently stronger coordination to the NTf2 anion upon increasing the NaNTf2 concentration. Temperature dependent PFG-NMR diffusion measurements show that both FSI and NTf2 have a comparable behaviour although the smaller FSI anion is more diffusive.

  2. Tris(1,3-dichloro-2-propyl)phosphate Induces Genome-Wide Hypomethylation within Early Zebrafish Embryos

    PubMed Central

    2016-01-01

    Tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) is a high-production volume organophosphate-based plasticizer and flame retardant widely used within the United States. Using zebrafish as a model, the objectives of this study were to determine whether (1) TDCIPP inhibits DNA methyltransferase (DNMT) within embryonic nuclear extracts; (2) uptake of TDCIPP from 0.75 h postfertilization (hpf, 2-cell) to 2 hpf (64-cell) or 6 hpf (shield stage) leads to impacts on the early embryonic DNA methylome; and (3) TDCIPP-induced impacts on cytosine methylation are localized to CpG islands within intergenic regions. Within this study, 5-azacytidine (5-azaC, a DNMT inhibitor) was used as a positive control. Although 5-azaC significantly inhibited zebrafish DNMT, TDCIPP did not affect DNMT activity in vitro at concentrations as high as 500 μM. However, rapid embryonic uptake of 5-azaC and TDCIPP from 0.75 to 2 hpf resulted in chemical- and chromosome-specific alterations in cytosine methylation at 2 hpf. Moreover, TDCIPP exposure predominantly resulted in hypomethylation of positions outside of CpG islands and within intragenic (exon) regions of the zebrafish genome. Overall, these findings provide the foundation for monitoring DNA methylation dynamics within zebrafish as well as identifying potential associations among TDCIPP exposure, adverse health outcomes, and DNA methylation status within human populations. PMID:27574916

  3. Propyl Gallate Inhibits Adipogenesis by Stimulating Extracellular Signal-Related Kinases in Human Adipose Tissue-Derived Mesenchymal Stem Cells

    PubMed Central

    Lee, Jeung-Eun; Kim, Jung-Min; Jang, Hyun-Jun; Lim, Se-young; Choi, Seon-Jeong; Lee, Nan-Hee; Suh, Pann-Ghill; Choi, Ung-Kyu

    2015-01-01

    Propyl gallate (PG) used as an additive in various foods has antioxidant and anti-inflammatory effects. Although the functional roles of PG in various cell types are well characterized, it is unknown whether PG has effect on stem cell differentiation. In this study, we demonstrated that PG could inhibit adipogenic differentiation in human adipose tissue-derived mesenchymal stem cells (hAMSCs) by decreasing the accumulation of intracellular lipid droplets. In addition, PG significantly reduced the expression of adipocyte-specific markers including peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT enhancer binding protein-α (C/EBP-α), lipoprotein lipase (LPL), and adipocyte fatty acid-binding protein 2 (aP2). PG inhibited adipogenesis in hAMSCs through extracellular regulated kinase (ERK) pathway. Decreased adipogenesis following PG treatment was recovered in response to ERK blocking. Taken together, these results suggest a novel effect of PG on adipocyte differentiation in hAMSCs, supporting a negative role of ERK1/2 pathway in adipogenic differentiation. PMID:25813451

  4. Enhanced cellular delivery of idarubicin by surface modification of propyl starch nanoparticles employing pteroic acid conjugated polyvinyl alcohol.

    PubMed

    Jain, Ratnesh; Dandekar, Prajakta; Loretz, Brigitta; Melero, Ana; Stauner, Thomas; Wenz, Gerhard; Koch, Marcus; Lehr, Claus-Michael

    2011-11-25

    Enhanced intracellular internalization of the anti-cancer active idarubicin (IDA) was achieved through appropriate surface modification of IDA loaded propyl starch nanoparticles. This was conducted by synthesizing pteroic acid modified polyvinyl alcohol (ptPVA) and employing this stabilizer for formulating the said nanoparticles. Pteroic acid attached at the nanoparticles improved the surface protein adsorption of the nanoparticle, a condition which the nanoparticles would largely experience in vitro and in vivo and hence improve their cellular internalization. Spherical, homogenous IDA nanoparticles (214 ± 5 nm) with surface modified by ptPVA were formulated using the solvent emulsification-diffusion technique. The encapsulation efficiency and drug loading amounted around 85%. In vitro release studies indicated a controlled release of IDA. Safety and efficacy of the nanoparticles was confirmed by suitable cellular cytotoxicity assays. Protein binding studies indicated a higher adsorption of the model protein on nanoparticles formulated with ptPVA as compared to PVA. Cellular uptake studies by confocal laser scanning microscopy revealed a higher cellular uptake of ptPVA stabilized nanoparticles thus confirming the proposed hypothesis of higher protein adsorption being responsible for higher cellular internalization.

  5. Effects of selenium treatment on 6-n-propyl-2-thiouracil-induced impairment of long-term potentiation.

    PubMed

    Bitiktaş, Soner; Tan, Burak; Batakçı, Melek; Kavraal, Şehrazat; Dursun, Nurcan; Süer, Cem

    2016-08-01

    The goal of this study was to evaluate whether sodium selenite could afford protection against the effects of hypothyroidism on long-term potentiation (LTP), which is thought to be the cellular basis for learning and memory. Hypothyroidism was induced in young-adult rats by the administration of 6-n-propyl-2-thiouracil (PTU) in tap water for 21 days. Half of these hypothyroid and euthroid rats were given 10ppM selenium with their drinking water. Field potentials were recorded from the dentate gyrus in response to stimulation of the medial perforant pathway in vivo. PTU treatment resulted in a significant reduction in both free T3 and free T4 levels, whereas selenium administration to PTU-treated rats restored only the levels of free T3 to their control values. Thyroid hormone levels were not affected by selenium in euthyroid rats. PTU-treated rats exhibited an attenuation of population spike (PS) - LTP, but a comparable potentiation of excitatory postsynaptic potential (EPSP) was found among these rats. The administration of selenium to PTU-treated rats was partially able to attenuate impairment of LTP, but not of potentiation during the LTP induction protocol in hypothyroid rats. Interestingly, the hypothyroid rats that were supplemented with selenium had a lower EPSP potentiation during induction protocol than the control rats. The present study suggests a possible importance of T3 in Se-induced rescue of impaired PS-LTP in hypothyroidism.

  6. Imprinted propyl gallate electrochemical sensor based on graphene/single walled carbon nanotubes/sol-gel film.

    PubMed

    Xu, Guilin; Chi, Yu; Li, Lu; Liu, Shouhua; Kan, Xianwen

    2015-06-15

    A novel imprinted sol-gel electrochemical sensor for the determination of propyl gallate (PG) was developed based on a composite of graphene and single walled carbon nanotubes (GR-SWCNTs). It was fabricated by stepwise modifying GR-SWCNTs and molecularly imprinted polymers and stored in 0.10 mol L(-1) phosphate buffer solution pH 6.0, which endowed the sensor good sensitivity and selective recognition towards template molecules. The morphology and specific adsorption capacity of the sensor was characterized by scanning electron microscope and electrochemical methods, respectively. Under the optimized conditions, a linear range of the sensor to PG was 8.0 × 10(-8)-2.6 × 10(-3)mo lL(-1) with a limit of detection of 5.0 × 10(-8)mol L(-1) (S/N=3). The sensor exhibited specificity and selectivity towards template molecules as well as excellent reproducibility, regeneration and stability. Furthermore, the sensor could be applied to determine PG in edible oils, instant noodles and cookies with satisfactory results.

  7. Molecularly imprinted electrochemical sensor for propyl gallate based on PtAu bimetallic nanoparticles modified graphene-carbon nanotube composites.

    PubMed

    Cui, Min; Huang, Jiadong; Wang, Yu; Wu, Yumin; Luo, Xiliang

    2015-06-15

    A novel molecularly imprinted electrochemical sensor for propyl gallate (PG) determination was developed via electropolymerization of an o-phenylenediamine membrane in the presence of template molecules on glassy carbon electrode surface modified by PtAu bimetallic nanoparticles-capped graphene-carbon nanotubes composites (PtAu-GrCNTs). The modified electrodes were characterized by cyclic voltammetry, scanning electron microscope, x-ray diffraction and chronoamperometry. Moreover, experimental parameters such as scan cycles, incubation time, molar ratios of template molecules to functional monomers and extraction time were optimized. It was found that the PtAu-GrCNTs composite could effectively enhance the electron transfer efficiency and remarkably improve the sensitivity of the sensor. The results revealed the sensor displayed superb resistance to no-specific binding, very attractive detection limit as low as 2.51×10(-8) mol/L, and a wide linear range from 7×10(-8) mol/L to 1×10(-5) mol/L towards PG. Furthermore, the MIPs sensor was also successfully used for the detection of PG in food samples. Therefore, the MIPs-based electrochemical sensing strategy might provide a sensitive, rapid, and cost-effective method for PG determination and related food safety analysis.

  8. Agonist-Biased Signaling via Proteinase Activated Receptor-2: Differential Activation of Calcium and Mitogen-Activated Protein Kinase Pathways

    PubMed Central

    Ramachandran, Rithwik; Mihara, Koichiro; Mathur, Maneesh; Rochdi, Moulay Driss; Bouvier, Michel; DeFea, Kathryn

    2009-01-01

    We evaluated the ability of different trypsin-revealed tethered ligand (TL) sequences of rat proteinase-activated receptor 2 (rPAR2) and the corresponding soluble TL-derived agonist peptides to trigger agonist-biased signaling. To do so, we mutated the proteolytically revealed TL sequence of rPAR2 and examined the impact on stimulating intracellular calcium transients and mitogen-activated protein (MAP) kinase. The TL receptor mutants, rPAR2-Leu37Ser38, rPAR2-Ala37–38, and rPAR2-Ala39–42 were compared with the trypsin-revealed wild-type rPAR2 TL sequence, S37LIGRL42—. Upon trypsin activation, all constructs stimulated MAP kinase signaling, but only the wt-rPAR2 and rPAR2-Ala39–42 triggered calcium signaling. Furthermore, the TL-derived synthetic peptide SLAAAA-NH2 failed to cause PAR2-mediated calcium signaling but did activate MAP kinase, whereas SLIGRL-NH2 triggered both calcium and MAP kinase signaling by all receptors. The peptides AAIGRL-NH2 and LSIGRL-NH2 triggered neither calcium nor MAP kinase signals. Neither rPAR2-Ala37–38 nor rPAR2-Leu37Ser38 constructs recruited β-arrestins-1 or -2 in response to trypsin stimulation, whereas both β-arrestins were recruited to these mutants by SLIGRL-NH2. The lack of trypsin-triggered β-arrestin interactions correlated with impaired trypsin-activated TL-mutant receptor internalization. Trypsin-stimulated MAP kinase activation by the TL-mutated receptors was not blocked by inhibitors of Gαi (pertussis toxin), Gαq [N-cyclohexyl-1-(2,4-dichlorophenyl)-1,4-dihydro-6-methylindeno[1,2-c]pyrazole-3-carboxamide (GP2A)], Src kinase [4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]-pyrimidine (PP1)], or the epidermal growth factor (EGF) receptor [4-(3′-chloroanilino)-6,7-dimethoxy-quinazoline (AG1478)], but was inhibited by the Rho-kinase inhibitor (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide, 2HCl (Y27362). The data indicate that the proteolytically revealed TL sequence(s) and the mode

  9. {2,6-Bis[(2,6-diisopropyl-phosphan-yl)-oxy]-4-fluoro-phenyl-κ(3)P,C(1),P'}(1H-pyrazole-κN(2))nickel(II) hexa-fluoro-phosphate.

    PubMed

    Kwan, Man-Lung; Conry, Sara J; Carfagna, Charles S; Press, Loren P; Ozerov, Oleg V; Hoffman, Norris W; Sykora, Richard E

    2012-10-01

    The title compound, [Ni(C(18)H(30)FO(2)P(2))(C(3)H(4)N(2))]PF(6), was prepared by halide abstraction with TlPF(6) in the presence of CH(3)CN in CDCl(3) from the respective neutral pincer chlorido analogue followed by addition of pyrazole. The PO-C-OP pincer ligand acts in typical trans-P(2) tridentate fashion to generate a distorted square-planar nickel structure. The Ni-N(pyrazole) distance is 1.925 (2) Å and the plane of the pyrazole ligand is rotated 56.2 (1)° relative to the approximate square plane surrounding the Ni(II) center in which the pyrazole is bound to the Ni(II) atom through its sp(2)-hybridized N atom. This Ni-N distance is similar to bond lengths in the other reported Ni(II) pincer-ligand square-planar pyrazole complex structures; however, its dihedral angle is significantly larger than any of those for the latter set of pyrazole complexes.

  10. Quantifying agonist activity at G protein-coupled receptors.

    PubMed

    Ehlert, Frederick J; Suga, Hinako; Griffin, Michael T

    2011-12-26

    When an agonist activates a population of G protein-coupled receptors (GPCRs), it elicits a signaling pathway that culminates in the response of the cell or tissue. This process can be analyzed at the level of a single receptor, a population of receptors, or a downstream response. Here we describe how to analyze the downstream response to obtain an estimate of the agonist affinity constant for the active state of single receptors. Receptors behave as quantal switches that alternate between active and inactive states (Figure 1). The active state interacts with specific G proteins or other signaling partners. In the absence of ligands, the inactive state predominates. The binding of agonist increases the probability that the receptor will switch into the active state because its affinity constant for the active state (K(b)) is much greater than that for the inactive state (K(a)). The summation of the random outputs of all of the receptors in the population yields a constant level of receptor activation in time. The reciprocal of the concentration of agonist eliciting half-maximal receptor activation is equivalent to the observed affinity constant (K(obs)), and the fraction of agonist-receptor complexes in the active state is defined as efficacy (ε) (Figure 2). Methods for analyzing the downstream responses of GPCRs have been developed that enable the estimation of the K(obs) and relative efficacy of an agonist. In this report, we show how to modify this analysis to estimate the agonist K(b) value relative to that of another agonist. For assays that exhibit constitutive activity, we show how to estimate K(b) in absolute units of M(-1). Our method of analyzing agonist concentration-response curves consists of global nonlinear regression using the operational model. We describe a procedure using the software application, Prism (GraphPad Software, Inc., San Diego, CA). The analysis yields an estimate of the product of K(obs) and a parameter proportional to efficacy (

  11. Agonistic behavior in males and females: effects of an estrogen receptor beta agonist in gonadectomized and gonadally intact mice

    PubMed Central

    Allen, Amy E. Clipperton; Cragg, Cheryl L.; Wood, Alexis J.; Pfaff, Donald W.; Choleris, Elena

    2010-01-01

    Summary Affiliative and agonistic social interactions are mediated by gonadal hormones. Research with estrogen receptor alpha (ERα) or beta (ERβ) knockout (KO) mice show that long-term inactivation of ERα decreases, while inactivation of ERβ increases, male aggression. Opposite effects were found in female αERKO and βERKO mice. The role of acute activation of ERα or ERβ in the agonistic responses of adult non-KO mice is unknown. We report here the effects of the ERβ selective agonist WAY-200070 on agonistic and social behavior in gonadally intact and gonadectomized (gonadex) male and female CD-1 mice towards a gonadex, same-sex intruder. All 15 min resident-intruder tests were videotaped for comprehensive behavioral analysis. Separate analyses assessed: 1) effects of WAY-200070 on each sex and gonadal condition; 2) differences between sexes, and between gonadally intact and gonadex mice, in untreated animals. Results show that in gonadally intact male and female mice WAY-200070 increased agonistic behaviors such as pushing down and aggressive grooming, while leaving attacks unaffected. In untreated mice, males attacked more than females, and gonadex animals showed less agonistic behavior than same-sex, gonadally intact mice. Overall, our detailed behavioral analysis suggested that in gonadally intact male and female mice, ERβ mediates patterns of agonistic behavior that are not directly involved in attacks. This suggests that specific aspects of aggressive behavior are acutely mediated by ERβ in adult mice. Our results also showed that, in resident-intruder tests, female mice spend as much time in intrasexual agonistic interactions as males, but use agonistic behaviors that involve extremely low levels of direct attacks. This non-attack aggression in females is increased by acute activation of ERβ. Thus, acute activation of ERβ similarly mediates agonistic behavior in adult male and female CD-1 mice. PMID:20129736

  12. The cardiovascular effects of peroxisome proliferator-activated receptor agonists.

    PubMed

    Friedland, Sayuri N; Leong, Aaron; Filion, Kristian B; Genest, Jacques; Lega, Iliana C; Mottillo, Salvatore; Poirier, Paul; Reoch, Jennifer; Eisenberg, Mark J

    2012-02-01

    Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation.

  13. Halogen-bonded network of trinuclear copper(II) 4-iodo­pyrazolate complexes formed by mutual breakdown of chloro­form and nanojars

    PubMed Central

    Surmann, Stuart A.; Mezei, Gellert

    2016-01-01

    Crystals of bis­(tetra­butyl­ammonium) di-μ3-chlorido-­tris­(μ2-4-iodo­pyrazolato-κ2 N:N′)tris­[chlorido­cuprate(II)] 1,4-dioxane hemisolvate, (C16H36N)2[Cu3(C3H2IN2)3Cl5]·0.5C4H8O or (Bu4N)2[CuII 3(μ 3-Cl)2(μ-4-I-pz)3Cl3]·0.5C4H8O, were obtained by evaporating a solution of (Bu4N)2[{CuII(μ-OH)(μ-4-I-pz)}nCO3] (n = 27–31) nanojars in chloro­form/1,4-dioxane. The decomposition of chloro­form in the presence of oxygen and moisture provides HCl, which leads to the breakdown of nanojars to the title trinuclear copper(II) pyrazolate complex, and possibly CuII ions and free 4-iodo­pyrazole. CuII ions, in turn, act as catalyst for the accelerated decomposition of chloro­form, ultimately leading to the complete breakdown of nanojars. The crystal structure presented here provides the first structural description of a trinuclear copper(II) pyrazolate complex with iodine-substituted pyrazoles. In contrast to related trinuclear complexes based on differently substituted 4-R-pyrazoles (R = H, Cl, Br, Me), the [Cu3(μ-4-I-pz)3Cl3] core in the title complex is nearly planar. This difference is likely a result of the presence of the iodine substituent, which provides a unique, novel feature in copper pyrazolate chemistry. Thus, the iodine atoms form halogen bonds with the terminal chlorido ligands of the surrounding complexes [mean length of I⋯Cl contacts = 3.48 (1) Å], leading to an extended two-dimensional, halogen-bonded network along (-110). The cavities within this framework are filled by centrosymmetric 1,4-dioxane solvent mol­ecules, which create further bridges via C—H⋯Cl hydrogen bonds with terminal chlorido ligands of the trinuclear complex not involved in halogen bonding. PMID:27840698

  14. Synthetic RORγ agonists regulate multiple pathways to enhance antitumor immunity

    PubMed Central

    Hu, Xiao; Liu, Xikui; Moisan, Jacques; Wang, Yahong; Lesch, Charles A.; Spooner, Chauncey; Morgan, Rodney W.; Zawidzka, Elizabeth M.; Mertz, David; Bousley, Dick; Majchrzak, Kinga; Kryczek, Ilona; Taylor, Clarke; Van Huis, Chad; Skalitzky, Don; Hurd, Alexander; Aicher, Thomas D.; Toogood, Peter L.; Glick, Gary D.; Paulos, Chrystal M.; Zou, Weiping; Carter, Laura L.

    2016-01-01

    ABSTRACT RORγt is the key transcription factor controlling the development and function of CD4+ Th17 and CD8+ Tc17 cells. Across a range of human tumors, about 15% of the CD4+ T cell fraction in tumor-infiltrating lymphocytes are RORγ+ cells. To evaluate the role of RORγ in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate RORγ to a greater extent than the endogenous agonist desmosterol. These RORγ agonists enhance effector function of Type 17 cells by increasing the production of cytokines/chemokines such as IL-17A and GM-CSF, augmenting expression of co-stimulatory receptors like CD137, CD226, and improving survival and cytotoxic activity. RORγ agonists also attenuate immunosuppressive mechanisms by curtailing Treg formation, diminishing CD39 and CD73 expression, and decreasing levels of co-inhibitory receptors including PD-1 and TIGIT on tumor-reactive lymphocytes. The effects of RORγ agonists were not observed in RORγ−/− T cells, underscoring the selective on-target activity of the compounds. In vitro treatment of tumor-specific T cells with RORγ agonists, followed by adoptive transfer to tumor-bearing mice is highly effective at controlling tumor growth while improving T cell survival and maintaining enhanced IL-17A and reduced PD-1 in vivo. The in vitro effects of RORγ agonists translate into single agent, immune system-dependent, antitumor efficacy when compounds are administered orally in syngeneic tumor models. RORγ agonists integrate multiple antitumor mechanisms into a single therapeutic that both increases immune activation and decreases immune suppression resulting in robust inhibition of tumor growth. Thus, RORγ agonists represent a novel immunotherapy approach for cancer. PMID:28123897

  15. Triplet excited state distortions in a pyrazolate bridged platinum dimer measured by X-ray transient absorption spectroscopy.

    PubMed

    Lockard, Jenny V; Rachford, Aaron A; Smolentsev, Grigory; Stickrath, Andrew B; Wang, Xianghuai; Zhang, Xiaoyi; Atenkoffer, Klaus; Jennings, Guy; Soldatov, Alexander; Rheingold, Arnold L; Castellano, Felix N; Chen, Lin X

    2010-12-09

    The excited-state structure of a dinuclear platinum(II) complex with tert-butyl substituted pyrazolate bridging units, [Pt(ppy)(μ-(t)Bu(2)pz)](2) (ppy = 2-phenylpyridine; (t)Bu(2)pz = 3,5-di-tert-butylpyrazolate) is studied by X-ray transient absorption (XTA) spectroscopy to reveal the transient electronic and nuclear geometry. DFT calculations predict that the lowest energy triplet excited state, assigned to a metal-metal-to-ligand charge transfer (MMLCT) transition, has a contraction in the Pt-Pt distance. The Pt-Pt bond length and other structural parameters extracted from fitting the experimental XTA difference spectra from full multiple scattering (FMS) and multidimensional interpolation calculations indicates a metal-metal distance decrease by approximately 0.2 Å in the triplet excited state. The advantages and challenges of this approach in resolving dynamic transient structures of nonbonding or weak-bonding dinuclear metal complexes in solution are discussed.

  16. Diaqua-(5-methyl-1H-pyrazole-3-carboxyl-ato)(4-nitro-benzoato)copper(II).

    PubMed

    Hu, Fei-Long; Yin, Xian-Hong; Feng, Yu; Mi, Yan; Zhang, Shan-Shan

    2009-01-23

    In the title complex, [Cu(C(7)H(4)NO(4))(C(5)H(5)N(2)O(2))(H(2)O)(2)], the Cu(II) ion is coordinated in a slightly distorted square-pyramidal enviroment. The basal plane is formed by an N atom and an O atom from a 5-methyl-1H-pyrazole-3-carboxyl-ate ligand and by two O atoms from two water ligands. The apical position is occupied by a carboxylate O atom from a 4-nitro-benzoate ligand. In the crystal structure, inter-molecular O-H⋯O and N-H⋯O hydrogen bonds link complex moleclues, forming extended chains parallel to the a axis.

  17. Synthesis, structure characterization and antimicrobial evaluation of 4-(substituted phenylazo)-3,5-diacetamido-1H-pyrazoles

    NASA Astrophysics Data System (ADS)

    Kinali-Demirci, Selin; Demirci, Serkan; Kurt, Mustafa

    2013-04-01

    The present article deals with the synthesis, spectral characterization and antimicrobial activity of phenylazo dyes. All of the synthesized phenylazo dyes were characterized using ATR-FTIR, FT-Raman, 1H NMR, 13C NMR, elemental analysis and mass spectroscopic techniques. Solvent effects on the UV-Vis absorption spectra of these phenylazo dyes were studied. Acid and base effects on the visible absorption maxima of the phenylazo dyes were also reported. The structural and spectroscopic analysis of the molecules were carried out using Density Functional Theory (DFT) employing the standard 6-31G(d) basis set, and the optimized geometries and calculated vibrational frequencies were evaluated via comparison with experimental values. The antimicrobial activity of 4-(substituted phenylazo)-3,5-diacetamido-1H-pyrazoles was reported against bacteria, including B. cereus (RSKK 863), S. aureus (ATCC 259231), M. luteus (NRRL B-4375), E. coli (ATCC 11230) and the yeast C. albicans (ATCC 10239).

  18. New structural forms in molecular metal phosphonates: novel tri- and hexanuclear zinc(II) cages containing phosphonate and pyrazole ligands.

    PubMed

    Chandrasekhar, Vadapalli; Kingsley, Savariraj; Rhatigan, Brian; Lam, Matthew K; Rheingold, Arnold L

    2002-03-11

    The reaction of ZnCl(2) with tert-butylphosphonic acid and 3,5-dimethylpyrazole in the presence of triethylamine as a hydrogen chloride scavenger affords a trinuclear molecular zinc phosphonate [Zn(3)Cl(2)(3,5-Me(2)Pz)(4)(t-BuPO(3))(2)]. The structure of this compound contains a planar trizinc assembly containing two bicapping mu(3) [t-BuPO(3)](2-) ligands and terminal pyrazole and chloride ligands. In contrast an analogous reaction of ZnCl(2) with phenylphosphonic acid and 3,5-dimethylpyrazole affords a hexanuclear zinc phosphonate [Zn(6)Cl(4)(3,5-Me(2)PzH)(8)(PhPO(3))(4)]. The six zinc centers are arranged in a chairlike conformation. The four phosphonates in this complex also act as bridging tripodal mu(3) [RPO(3)](2-) ligands.

  19. Stereoselective formation and catalytic activity of hydrido(acylphosphane)(chlorido)(pyrazole)rhodium(III) complexes. Experimental and DFT studies.

    PubMed

    San Nacianceno, Virginia; Azpeitia, Susan; Ibarlucea, Lourdes; Mendicute-Fierro, Claudio; Rodríguez-Diéguez, Antonio; Seco, José M; San Sebastian, Eider; Garralda, María A

    2015-08-07

    The reaction of [{RhCl(COD)}2] (COD = 1,5-cyclooctadiene) with L = pyrazole (Hpz), 3(5)-methylpyrazole (Hmpz) or 3,5-dimethylpyrazole (Hdmpz) and PPh2(o-C6H4CHO) (Rh : L : P = 1 : 2 : 1) gives hydridoacyl complexes [RhHCl{PPh2(o-C6H4CO)}(L)2] (). Stereoselective formation of and with pyrazoles trans to hydrido and phosphorus and hydrogen bond formation with O-acyl and chlorido occur. is a mixture of two linkage isomers in a 9 : 1 ratio, with two 5-methylpyrazole ligands or with one 3- and one 5-methylpyrazole ligand, respectively. Fluxional undergoes metallotropic tautomerization and is a mixture of equal amounts of and , with hydrido trans to pyrazole or chlorido, respectively. Complexes readily exchange hydrido by chlorido to afford [RhCl2{PPh2(o-C6H4CO)}(L)2] (, and ) as single isomers with cis chloridos and two N-HCl hydrogen bonds. The reaction of with PPh3 or PPh2OH affords static [RhHCl{PPh2(o-C6H4CO)}(PPh3)L] () or [RhHCl{PPh2(o-C6H4CO)}(PPh2OH)L] () respectively with trans P-atoms and pyrazoles forming N-HCl hydrogen bonds. and contain single species with hydrido cis to chlorido, while is a mixture of equal amounts of and . Complexes , with an additional O-HO hydrogen bond, selectively contain only the cis-H,Cl species with all the three ligands. The reaction of [{RhCl(COD)}2] with L and PPh2(o-C6H4CHO) (Rh : L : P = 1 : 1 : 2) led to complexes with trans P-atoms, [RhHCl{PPh2(o-C6H4CO)}{PPh2(o-C6H4CHO)-κP}L] (, and ), at room temperature, and to [RhCl{PPh2(o-C6H4CO)}{PPh2(o-C6H4CHOH)}(Hmpz)] () or [RhCl{PPh2(o-C6H4CO)}2L] () with hydrogen evolution in refluxing benzene. DFT calculations were used to predict the correct isomers, their ratios and the particular intramolecular hydrogen bonds in these complexes. Single crystal X-ray diffraction analysis was performed on , and . Complexes are efficient homogeneous catalysts (0.5 mol% loading) in the hydrolysis of amine- or ammonia-borane (AB) to generate up to 3 equivalents

  20. Synthesis and crystal structure studies of ethyl 5-methyl-1, 3-diphenyl-1H-pyrazole-4-carboxylate

    SciTech Connect

    Chandra,; Babu, E. A. Jithesh; Mahendra, M.; Srikantamurthy, N.; Umesha, K. B.

    2014-04-24

    The title compound, C{sub 19}H{sub 18}N{sub 2}O{sub 2}, was investigated by single crystal X-ray diffraction method. It crystallizes in monoclinic class under the space group P2{sub 1}/c with cell parameters a= 8.4593(4) Å, b=15.6284(6) Å, c=12.4579(5) Å, α=90°, β=98.241(3)°, γ=90° and Z=2. The ethoxycarbonyl group is slightly twisted from the pyrazole ring, and adopts syn-periplanar conformation. The crystal structure is stabilized by intermolecular C-H….O hydrogen bonds, which help in stabilizing the crystal structure.

  1. Novel pyrazole and indazole derivatives: synthesis and evaluation of their anti-proliferative and anti-angiogenic activities.

    PubMed

    Tzanetou, Evangelia; Liekens, Sandra; Kasiotis, Konstantinos M; Fokialakis, Nikolas; Haroutounian, Serkos A

    2012-10-01

    The synthesis of several new pyrazole and indazole derivatives from acetophenone and tetralone substrates is reported. The bioactivities of the new compounds were evaluated through in vitro assays for endothelial cell proliferation and tube formation. Results herein indicate that the easily prepared compounds containing the indazole structural framework exhibit potent cytostatic properties against all cell lines tested, with compounds 13 and 14 being the most active displaying IC(50) values of 1.5 ± 0.4 µM and 5.6 ± 2.5 µM, respectively, against MCF-7 cells. In addition, the indazole derivative 16 was assessed as a competent inhibitor of endothelial tube formation at 30 µM.

  2. Organically modified silica with pyrazole-3-carbaldehyde as a new sorbent for solid-liquid extraction of heavy metals.

    PubMed

    Radi, Smaail; Tighadouini, Said; Bacquet, Maryse; Degoutin, Stéphanie; Cazier, Francine; Zaghrioui, Mustapha; Mabkhot, Yahia N

    2013-12-24

    A new chelating matrix, SiNP, has been prepared by immobilizing 1.5-dimethyl-1H-pyrazole-3-carbaldehyde on silica gel modified with 3-aminopropyl-trimethoxysilane. This new chelating material was well characterized by elemental analysis, FT-IR spectroscopy, cross polarization magic angle spinning solid state 13C-NMR, nitrogen adsorption-desorption isotherm, BET surface area, BJH pore size, and scanning electron microscopy (SEM). The new product exhibits good chemical and thermal stability as determined by thermogravimetry curves (TGA). The new prepared material was used as an adsorbent for the solid-phase extraction (SPE) of Pb(II), Cd(II), Cu(II) and Zn(II) from aqueous solutions using a batch method, prior to their determination by flame atomic adsorption spectrometry. The adsorption capacity was investigated using kinetics and pH effects. Common coexisting ions did not interfere with separation and determination.

  3. [Histrelin acetate--the first once yearly LHRH agonist].

    PubMed

    Altarac, Silvio

    2011-01-01

    Long-acting synthetic luteinising hormone-releasing hormone agonists have become the mainstay for androgen-deprivation therapy, because they avoid the physical and psychological discomfort associated with orchidectomy and lack the potential cardiotoxicity associated with estrogens such as diethylstilbestrol. Currently available luteinising hormone-releasing hormone agonist analogues include leuprolide, goserelin, triptorelin, degarelix and buserelin were administered as either intramuscular or subcutaneous depot injections on a 1, 2, 3 or 6 months basis. Histrelin acetate is the first long-acting luteinising hormone-releasing hormone agonist available as a once-yearly subcutaneous implant.

  4. Toll-like receptor agonists in cancer therapy

    PubMed Central

    Adams, Sylvia

    2010-01-01

    Toll-like receptors (TLRs) are pattern-recognition receptors related to the Drosophila Toll protein. TLR activation alerts the immune system to microbial products and initiates innate and adaptive immune responses. The naturally powerful immunostimulatory property of TLR agonists can be exploited for active immunotherapy against cancer. Antitumor activity has been demonstrated in several cancers, and TLR agonists are now undergoing extensive clinical investigation. This review discusses recent advances in the field and highlights potential opportunities for the clinical development of TLR agonists as single agent immunomodulators, vaccine adjuvants and in combination with conventional cancer therapies. PMID:20563267

  5. Effect of glucosamine conjugation to zinc(II) complexes of a bis-pyrazole ligand: syntheses, characterization and anticancer activity.

    PubMed

    Bhattacharyya, Sudipta; Sarkar, Amrita; Dey, Suman Kr; Mukherjee, Arindam

    2014-11-01

    The bis(3,5-dimethyl-1H- pyrazol-1yl)acetic acid (bdmpza) ligand was conjugated with tert-butyl-N-(2-aminoethyl) carbonate, methyl-2-amino-4-(methylthio)butanoate and 1,3,4,6-tetra-O-acetyl-β-d-glucosamine hydrochloride via amide coupling method to form three ligands L1-L3 which were then reacted with Zn(II) salts to form four zinc complexes (1-4). The complexes were characterized by (1)H NMR, (13)C NMR, electrospray ionization mass spectrometry (ESI-MS), FT-IR, CHN analyses. Complexes 1, 2 and 4 were also characterized by single crystal X-ray diffraction. It was found that Zn(II) salts could selectively remove the acetyl group from anomeric position leaving everything else intact. The cytotoxicity studies of the ligand and the complexes showed that the conjugation to acetylated glucosamine enhances cytotoxic ability although the complexes become more hydrophilic. Cytotoxicity studies in human breast adenocarcinoma (MCF-7), human cervical cancer (HeLa WT) and human lung adenocarcinoma (A549) showed that the acetylated glucosamine conjugation to the bis-pyrazole ligated Zn(II) complex led to 2-4 fold increase in cytotoxicity (IC50 values ca. 57-80μM) against HeLa WT and MCF-7 cell lines. The Zn(II) complex bearing the acetylated glucosamine inhibits the cell cycle in the G2/M phase of MCF-7 cell line. ICP-MS data shows more accumulation of Zn(II) inside the cell upon use of complex 4 as compared to Zn(II) salts or the other presented complexes. Further studies suggest that the mitochondrial transmembrane potential changes in the presence of complex 4 and caspase-7 is activated by Zn(II) salts but the activation is much more by complex 4 and hence there is apoptosis and dose dependent chromatin condensation/nuclear fragmentation as observed by microscopy.

  6. Pharmacological and toxicological evaluations of the new pyrazole compound (LQFM-021) as potential analgesic and anti-inflammatory agents.

    PubMed

    Florentino, Iziara F; da Silva, Daiany P B; Martins, José Luís R; da Silva, Taciane S; Santos, Fernanda C A; Tonussi, Carlos R; Vasconcelos, Géssica A; Vaz, Boniek G; Lião, Luciano M; Menegatti, Ricardo; Costa, Elson A

    2016-10-01

    Chronic inflammation is a world health problem. There is a need to develop new anti-inflammatory and analgesic drugs with improved activity and reduced side effects. In this context, the aim of this study was to evaluate the antinociceptive and anti-inflammatory effects of the pyrazole compound LQFM-021 after acute and sub-chronic administration in rats submitted to a CFA-induced chronic arthritis model, as well as compare the toxicity of this compound to that of dipyrone, given throughout 7 days. Firstly, we observed that acute oral administration of the higher dose (130 µmol/kg) of LQFM-021 reduced paw lifting time (PET) and edema formation. These effects disappeared on the following day, requiring another dose to maintain the effects. This dose also promoted reduction of the polymorphonuclear recruitment in the synovial fluid. In another experiment, both treatments with LQFM-021, 65 µmol/kg twice a day and 130 µmol/kg once a day, produced a progressive and permanent reduction of the PET and edema, also reducing polymorphonuclear recruitment. However, the single treatment with 130 µmol/kg was more effective than the double treatment with 65 µmol/kg. LQFM-021 did not produce toxicity signs. However, dipyrone (130 µmol/kg once a day) promoted erosion of the epithelial cells and decreased mucus in the gastric mucosa. These data indicate that LQFM-021 produced antinociceptive and anti-inflammatory effects in CFA-induced arthritis in rats. These effects occurred in the absence of apparent toxic effects, indicating that the pyrazole compound LQFM-021 may be considered a good prototype for development of new analgesic/anti-inflammatory drug.

  7. Modulating structural dimensionality of cadmium(II) coordination polymers by means of pyrazole, tetrazole and pyrimidine derivative ligands

    NASA Astrophysics Data System (ADS)

    Seco, Jose Manuel; Calahorro, Antonio; Cepeda, Javier; Rodríguez-Diéguez, Antonio

    2015-06-01

    Six new compounds with functionalized pyrazole, tetrazole, and pyrimidine ligands, namely [Cd(μ-4-Hampz)(μ-Cl)2]n(1), [Cd(μ3-pzdc)(μ-H2O)(H2O)]n(2), [Cd(μ-5-amtz)2(eda)]n(3), {[Cd9(μ4-5-amtz)8(μ-Cl)10(H2O)2]ṡxH2O}n(4), {[Cd2(μ-dm2-pmc)2Cl2(H2O)2]ṡH2O}n(5), and [Cd2(μ-Br2-pmc)(μ-Cl)3(H2O)2]n(6) (where 4-Hampz = 4-aminopyrazole, pzdc = 3,5-pyrazoledicarboxylate, 5-amtz = 5-aminotetrazolate, eda = ethylenediamine, dm2-pmc = 4,6-dimethoxy-2-pyrimidinecarboxylate, Br2-pmc = 5-bromopyrimidine-2-carboxylate) have been synthesized under hydrothermal conditions and structurally characterized by single crystal X-ray diffraction. Compounds 1 and 2 share the structural feature of being constructed from dinuclear building units that are further connected through the pyrazole based ligands, rendering a compact and a potentially open 3D frameworks, respectively. On the other hand, 5-amtz ligand exhibits two different coordination modes in compounds 3 and 4 as a result of the presence or absence of an additional blocking ligand. In this way, the μ-κ4N,N‧,N″,N‴ mode in 4 affords robust clusters that are joined in a topologically novel 3D open architecture containing two types of channels, whereas a simple bidentate bridging mode is limited for 5-amtz in 3 due to the presence of the chelating eda ligand. 1D and 3D structures are obtained with pyrimidine ligands in compounds 5 and 6 according to the steric hindrance of the substituents.

  8. Antidepressant Potential of 5-HT3 Receptor Antagonist, N-n- propyl-3-ethoxyquinoxaline-2-carboxamide (6n).

    PubMed

    Mahesh, R; Bhatt, S; Devadoss, T; Jindal, Ak; Gautam, Bk; Pandey, Dk

    2012-10-01

    The present study was designed to evaluate the antidepressant potential of 5-HT3 receptor antagonist N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n). The compound '6n' with optimum log P and pA 2 value identified from a series of compounds synthesized in our laboratory was subjected to forced Swim Test (FST) (1, 2, and 4 mg/kg, i.p) and Tail Suspension Test (TST) (1, 2, and 4 mg/kg, i.p.). The compound '6n' significantly reduced the duration of immobility in mice without affecting the baseline locomotion. Moreover, '6n' (2 mg/kg, i.p.) potentiated the 5-hydroxytryptophan (5-HTP)-induced head twitch responses in mice and '6n' at tested dose (1 and 2 mg/kg, i.p.) reversed the reserpine-induced hypothermia in rats. In interaction studies of '6n' with various standard drugs/ligands using FST, '6n' (1 mg/kg, i.p.) potentiated the antidepressant effect of venlafaxine (4 and 8 mg/kg, i.p.) and fluoxetine (10 and 20 mg/kg, i.p.). Additionally, '6n' (1 and 2 mg/kg, i.p.) influenced the effect of harmane (5 mg/ kg, i.p.) as well as reversed the effect of parthenolide (1 mg/kg, i.p.) by reducing the duration of immobility in FST. Furthermore, '6n' (1 mg/kg, i.p.) potentiated the effect of bupropion (10 and 20 mg/kg, i.p.) in TST. Chronic '6n' (1 and 2 mg/kg, i.p.) treatment attenuated the behavioral abnormalities in olfactory bulbectomized rats. In conclusion, these various findings reiterated the antidepressant-like effects of '6n' in behavioral models of depression.

  9. Tris (1,3-dichloro-2-propyl) phosphate induces toxicity by stimulating CaMK2 in PC12 cells.

    PubMed

    Li, Chaonan; Li, Li; Lin, Bencheng; Fang, Yanjun; Yang, Honglian; Liu, Huanliang; Xi, Zhuge

    2017-02-09

    Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is one of the widely used organophosphorus flame retardants (OPFRs), which are regarded as suitable substitutes for brominated flame retardants (BFRs). Previously, we have validated the toxicity of TDCIPP in PC12 cells owing to the induced alterations in GAP43, NF-H, CaMK2a/2b, and tubulin α/β proteins; however, limited information is currently available on the toxicity and mechanism of TDCIPP. In the present study, cytotoxicity effects were evaluated by exposing PC12 cells to different concentrations of TDCIPP (0-50 μM) for 4 days. To explore the possible mechanisms through which cytotoxicity is induced, changes in intracellular [Ca(2+) ]i levels and the activation of calmodulin dependent protein kinase 2 (CaMK2), c-Jun N-terminal kinase (JNK), extracellular regulated protein kinases (ERK1/2), and p38 mitogen-activated protein kinases (MAPK) pathways were evaluated. Furthermore, PC12 cells were pretreated with CaMK2 inhibitor KN93 to investigate the relationship between TDCIPP-induced phosphorylation of CaMK2 and activation of JNK, ERK1/2, and p38 MAPK pathways. Our results indicate that TDCIPP-induced toxicity might be associated with the overload of [Ca(2+) ]i levels, increased phosphorylation of CaMK2, and activation of the JNK, ERK1/2, and p38 MAPK pathways, the lattermost of which was further demonstrated to be partially elicited by the CaMK2 phosphorylation.

  10. Instrumental Dependent Dissociations of n-Propyl/Isopropyl Phosphonate Isomers: Evaluation of Resonant and Non-Resonant Vibrational Activations

    NASA Astrophysics Data System (ADS)

    Bennaceur, Chafia; Afonso, Carlos; Alves, Sandra; Bossée, Anne; Tabet, Jean-Claude

    2013-08-01

    Structural elucidation and distinction of isomeric neurotoxic agents remain a challenge. Tandem mass spectrometry can be used for this purpose in particular if a "diagnostic" product ion is observed. Different vibrational activation methods were investigated to enhance formation of diagnostic ions through consecutive processes from O,O-dialkyl alkylphosphonates. Resonant and non-resonant collisional activation and infrared multiphoton dissociation (IRMPD) were used with different mass spectrometers: a hybrid quadrupole Fourier transform ion cyclotron resonance (Qh-FTICR) and a hybrid linear ion trap-Orbitrap (LTQ/Orbitrap). Double resonance (DR) experiments, in ion cyclotron resonance (ICR) cell, were used for unambiguous determination of direct intermediate yielding diagnostic ions. From protonated n-propyl and isopropyl O-O-dialkyl-phosphonates, a diagnostic m/ z 83 ion characterizes the isopropyl isomer. This ion is produced through consecutive dissociation processes. Conditions to favor its formation and observation using different activation methods were investigated. It was shown that with the LTQ, consecutive experimental steps of isolation/activation with modified trapping conditions limiting the low mass cut off (LMCO) effect were required, whereas with FT-ICR by CID and IRMPD the diagnostic ion detection was provided only by one activation step. Among the different investigated activation methods it was shown that by using low-pressure conditions or using non-resonant methods, efficient and fast differentiation of isomeric neurotoxic agents was obtained. This work constitutes a unique comparison of different activation modes for distinction of isomers showing the instrumental dependence characteristic of the consecutive processes. New insights in the dissociation pathways were obtained based on double-resonance IRMPD experiments using a FT-ICR instrument with limitation at low mass values.

  11. Instrumental dependent dissociations of n-propyl/isopropyl phosphonate isomers: evaluation of resonant and non-resonant vibrational activations.

    PubMed

    Bennaceur, Chafia; Afonso, Carlos; Alves, Sandra; Bossée, Anne; Tabet, Jean-Claude

    2013-08-01

    Structural elucidation and distinction of isomeric neurotoxic agents remain a challenge. Tandem mass spectrometry can be used for this purpose in particular if a "diagnostic" product ion is observed. Different vibrational activation methods were investigated to enhance formation of diagnostic ions through consecutive processes from O,O-dialkyl alkylphosphonates. Resonant and non-resonant collisional activation and infrared multiphoton dissociation (IRMPD) were used with different mass spectrometers: a hybrid quadrupole Fourier transform ion cyclotron resonance (Qh-FTICR) and a hybrid linear ion trap-Orbitrap (LTQ/Orbitrap). Double resonance (DR) experiments, in ion cyclotron resonance (ICR) cell, were used for unambiguous determination of direct intermediate yielding diagnostic ions. From protonated n-propyl and isopropyl O-O-dialkyl-phosphonates, a diagnostic m/z 83 ion characterizes the isopropyl isomer. This ion is produced through consecutive dissociation processes. Conditions to favor its formation and observation using different activation methods were investigated. It was shown that with the LTQ, consecutive experimental steps of isolation/activation with modified trapping conditions limiting the low mass cut off (LMCO) effect were required, whereas with FT-ICR by CID and IRMPD the diagnostic ion detection was provided only by one activation step. Among the different investigated activation methods it was shown that by using low-pressure conditions or using non-resonant methods, efficient and fast differentiation of isomeric neurotoxic agents was obtained. This work constitutes a unique comparison of different activation modes for distinction of isomers showing the instrumental dependence characteristic of the consecutive processes. New insights in the dissociation pathways were obtained based on double-resonance IRMPD experiments using a FT-ICR instrument with limitation at low mass values.

  12. The ozone productivity of n-propyl bromide: Part 2--An exception to the Maximum Incremental Reactivity Scale.

    PubMed

    Whitten, Gary Z; Yarwood, Greg

    2008-07-01

    In an earlier paper the ozone-forming potential of n-propyl bromide (NPB) was studied with a new methodology designed to address issues associated with a marginal smog-forming compound. However, the U.S. Environmental Protection Agency (EPA) subsequently revised its policy and now recommends using the Maximum Incremental Reactivity (MIR) scale to rank the ozone-forming potential of all volatile organic compounds (VOCs), including those of marginal ozone productivity. Nevertheless, EPA contemplated exceptions to the box-model-derived MIR scale by allowing use of photochemical grid-model simulations for case specific reactivity assessments. The California Air Resources Board (CARB) also uses the MIR scale and CARB has a Reactivity Scientific Advisory Committee that can consider exceptions to the MIR scale. In this study, grid-model simulations that were recommended by EPA are used to evaluate the incremental ozone impacts of NPB using an update to the chemical mechanism developed in an earlier paper. New methods of analysis of the grid-model output are further developed here to quantify the relative reactivities between NPB and ethane over a wide range of conditions. The new grid-model-based analyses show that NPB is significantly different and generally less in ozone-forming potential (i.e., reactivity) than predicted by the box-model-based MIR scale relative to ethane, EPA's "bright-line" test for non-VOC status. Although NPB has low reactivity compared to typical VOCs on any scale, the new grid-model analyses developed here show that NPB is far less reactive (and even has negative reactivity) compared to the reactivity predicted by the MIR scale.

  13. Antidepressant Potential of 5-HT3 Receptor Antagonist, N-n- propyl-3-ethoxyquinoxaline-2-carboxamide (6n)

    PubMed Central

    Mahesh, R; Bhatt, S; Devadoss, T; Jindal, AK; Gautam, BK; Pandey, DK

    2012-01-01

    The present study was designed to evaluate the antidepressant potential of 5-HT3 receptor antagonist N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n). The compound ‘6n’ with optimum log P and pA2 value identified from a series of compounds synthesized in our laboratory was subjected to forced Swim Test (FST) (1, 2, and 4 mg/kg, i.p) and Tail Suspension Test (TST) (1, 2, and 4 mg/kg, i.p.). The compound ‘6n’ significantly reduced the duration of immobility in mice without affecting the baseline locomotion. Moreover, ‘6n’ (2 mg/kg, i.p.) potentiated the 5-hydroxytryptophan (5-HTP)-induced head twitch responses in mice and ‘6n’ at tested dose (1 and 2 mg/kg, i.p.) reversed the reserpine-induced hypothermia in rats. In interaction studies of ‘6n’ with various standard drugs/ligands using FST, ‘6n’ (1 mg/kg, i.p.) potentiated the antidepressant effect of venlafaxine (4 and 8 mg/kg, i.p.) and fluoxetine (10 and 20 mg/kg, i.p.). Additionally, ‘6n’ (1 and 2 mg/kg, i.p.) influenced the effect of harmane (5 mg/ kg, i.p.) as well as reversed the effect of parthenolide (1 mg/kg, i.p.) by reducing the duration of immobility in FST. Furthermore, ‘6n’ (1 mg/kg, i.p.) potentiated the effect of bupropion (10 and 20 mg/kg, i.p.) in TST. Chronic ‘6n’ (1 and 2 mg/kg, i.p.) treatment attenuated the behavioral abnormalities in olfactory bulbectomized rats. In conclusion, these various findings reiterated the antidepressant-like effects of ‘6n’ in behavioral models of depression. PMID:23493308

  14. Application of poly[oxyethylene(dimethylimino)propyl-(dimethylimino)ethylene] as enzyme stabilizer for bilirubin oxidase immobilized electrode.

    PubMed

    Katano, Hajime; Uematsu, Kohei; Hibi, Takao; Ikeda, Tokuji; Tsukatani, Toshihide

    2009-09-01

    It has been shown that polyammonium cations comprising quaternary ammonium and hydrophilic groups such as amide and hydroxyl groups stabilize a redox enzyme bilirubin oxidase (BOD). The BOD catalyzes the reaction: 4[Fe(CN)6]4- + 4H+ + O2 --> 4[Fe(CN)6]3- + 2H2O, and has been a promising enzyme for use as a cathode catalyst in biofuel cells. In this study, the stabilizing effect of poly[oxyethylene(dimethylimino)propyl(dimethylimino)ethylene] (PA1) on BOD has been investigated. The sample solution containing BOD and the PA1 salt was kept at a given temperature, and the loss of the enzymatic activity was detected after given stored times. The activity decreased exponentially with stored time so that the first-order rate-constant of inactivation was determined. The inactivation rate-constant lowered with increasing the concentration of the PA1 salt, suggesting that BOD was stabilized by the association with the PA1 cation. The PA1 cation may act like a protective colloid or decrease the local disorder of BOD by its wrapping. A membrane-covered electrode containing BOD, PA1, and [Fe(CN)6](4-/3-) in the internal solution phase was examined in air-saturated aqueous solution. The electrode gave a well-defined current-potential curve with a steady state limiting current due to the PA1-[Fe(CN)6](4-/3-) polyion complex-mediated bioelectrocatalytic current for the reduction of O2. The decreasing of the steady state limiting current became slower in the presence of the PA1 salt, indicating again the stabilizing effect of PA1 cation on BOD.

  15. Preparation and evaluation of gastroretentive floating pellets of metronidazole using Na-alginate and hydroxyl propyl methyl cellulose polymers.

    PubMed

    Biswas, S K; Paul, S; Chowdhury, A; Das, J

    2012-03-15

    Gastroretentive floating pellets of metronidazole were formulated to prolong the gastric residence time in order to obtain controlled release characteristics of the drug. Nine formulations of metronidazole floating pellets such as AX, BX, CX, AY, BY, CY, AZ, BZ and CZ were prepared by extrusion method using different quantities of hydroxyl propyl methyl cellulose (HPMC) polymers such as methocel K4M premium and methocel K100LV premium in the ratio of 2:1, 1:2 and 1.5:1.5 while the amount of Na-alginate used in the formulations was 3.50, 5.25 and 7.0 g, respectively. The in vitro dissolution studies were carried out in 900 mL of phosphate buffer (pH 1.2) at 37 +/- 0.5 degrees C and 50 rpm for 6 h using USP XXIV paddle method and the content of drug release was done by UV spectrophotometer at 277 nm. It was found that the percent release of metronidazole from different formulations was different with passing of time. The drug release profile of the formulation (AX) having Na-alginate 3.50 g methocel K4M premium and methocel K100LV premium in the ratio of 2:1 showed best fit to Higuchi release kinetics with R2 value of 0.994. Finally, it might be concluded that the polymers had significant effect on drug release kinetics of metronidazole from floating pellets. The selection and use of suitable polymers in appropriate ratio might be very important in designing floating pellets and using the capabilities of these polymers, suitable floating pellets of metronidazole with desirable release rate could be formulated. Thus, in vivo research studies by the future researchers will confirm the appropriateness of these formulated metronidazole floating pellets.

  16. Characterization of a novel bivalent morphinan possessing kappa agonist and micro agonist/antagonist properties.

    PubMed

    Mathews, Jennifer L; Peng, Xuemei; Xiong, Wennan; Zhang, Ao; Negus, S Stevens; Neumeyer, John L; Bidlack, Jean M

    2005-11-01

    Previous research has shown that compounds with mixed kappa and mu activity may have utility for the treatment of cocaine abuse and dependence. The present study characterizes the pharmacological profile of a bivalent morphinan that was shown to be a kappa opioid receptor agonist and a mu opioid receptor agonist/antagonist. MCL-145 [bis(N-cyclobutylmethylmorphinan) fumarate] is related to the morphinan cyclorphan and its N-cyclobutylmethyl derivative MCL-101 [3-hydroxy-N-cyclobutylmethyl morphinan S-(+)-mandelate]. MCL-145 consists of two morphinans connected by a spacer at the 3-hydroxy position. This compound had K(i) values of 0.078 and 0.20 nM for the kappa and mu opioid receptors, respectively, using radioligand binding assays as shown by Neumeyer et al. in 2003. In the guanosine 5'-O -(3-[(35) S]thiotriphosphate) binding assay, MCL-145 produced an E(max) value of 80% for the kappa opioid receptor and 42% for the mu opioid receptor. The EC(50) values obtained for this compound were 4.3 and 3.1 nM for the kappa and mu opioid receptors, respectively. In vivo MCL-145 produced a full dose-response curve in the 55 degrees C warm water tail-flick test and was equipotent to morphine. The agonist properties of MCL-145 were antagonized by the mu-selective antagonist beta-funaltrexamine and the kappa-selective antagonist nor-binaltorphimine. MCL-145 also acted as a mu antagonist, as measured by the inhibition of morphine-induced antinociception.

  17. Octopaminergic agonists for the cockroach neuronal octopamine receptor.

    PubMed

    Hirashima, Akinori; Morimoto, Masako; Kuwano, Eiichi; Eto, Morifusa

    2003-01-01

    The compounds 1-(2,6-diethylphenyl)imidazolidine-2-thione and 2-(2,6-diethylphenyl)imidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor.

  18. (R)-(-)-10-methyl-11-hydroxyaporphine: a highly selective serotonergic agonist.

    PubMed

    Cannon, J G; Mohan, P; Bojarski, J; Long, J P; Bhatnagar, R K; Leonard, P A; Flynn, J R; Chatterjee, T K

    1988-02-01

    Prior work in these laboratories identified (+/-)-5-hydroxy-6-methyl-2- (di-n-propylamino)tetralin as a dopaminergic agonist prodrug. The ortho methyl hydroxy aromatic substitution pattern in this molecule has now been incorporated into the aporphine ring system to give a congener of the dopaminergic agonist apomorphine in which the position 10 OH group has been replaced by methyl. Preparation of the target compound involved acid-catalyzed rearrangement of the 3-(1-phenyltetrazolyl) ether of morphine and subsequent molecular modification of the product, the 10-(1-phenyltetrazolyl) ether of (R)-(-)-apomorphine. Surprisingly, the target compound elicited no responses in any assays for effects at dopamine receptors, but rather it displayed pharmacological properties consistent with its being a serotonergic agonist with a high degree of selectivity for 5-HT1A receptors similar to the serotonergic agonist 8-hydroxy-2-(di-n-propylamino)tetralin.

  19. Partial agonist therapy in schizophrenia: relevance to diminished criminal responsibility.

    PubMed

    Gavaudan, Gilles; Magalon, David; Cohen, Julien; Lançon, Christophe; Léonetti, Georges; Pélissier-Alicot, Anne-Laure

    2010-11-01

    Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility.

  20. Agonist Replacement for Stimulant Dependence: A Review of Clinical Research

    PubMed Central

    Stoops, William W.; Rush, Craig R.

    2013-01-01

    Stimulant use disorders are an unrelenting public health concern worldwide. Agonist replacement therapy is among the most effective strategies for managing substance use disorders including nicotine and opioid dependence. The present paper reviewed clinical data from human laboratory self-administration studies and clinical trials to determine whether agonist replacement therapy is a viable strategy for managing cocaine and/or amphetamine use disorders. The extant literature suggests that agonist replacement therapy may be effective for managing stimulant use disorders, however, the clinical selection of an agonist replacement medication likely needs to be based on the pharmacological mechanism of the medication and the stimulant abused by patients. Specifically, dopamine releasers appear most effective for reducing cocaine use whereas dopamine reuptake inhibitors appear most effective for reducing amphetamine use. PMID:23574440

  1. Selecting agonists from single cells infected with combinatorial antibody libraries.

    PubMed

    Zhang, Hongkai; Yea, Kyungmoo; Xie, Jia; Ruiz, Diana; Wilson, Ian A; Lerner, Richard A

    2013-05-23

    We describe a system for direct selection of antibodies that are receptor agonists. Combinatorial antibody libraries in lentiviruses are used to infect eukaryotic cells that contain a fluorescent reporter system coupled to the receptor for which receptor agonist antibodies are sought. In this embodiment of the method, very large numbers of candidate antibodies expressing lentivirus and eukaryotic reporter cells are packaged together in a format where each is capable of replication, thereby forging a direct link between genotype and phenotype. Following infection, cells that fluoresce are sorted and the integrated genes encoding the agonist antibodies recovered. We validated the system by illustrating its ability to generate rapidly potent antibody agonists that are complete thrombopoietin phenocopies. The system should be generalizable to any pathway where its activation can be linked to production of a selectable phenotype.

  2. (E)-1-(Naphthalen-1-yl)-3-(1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-one

    PubMed Central

    Asiri, Abdullah M.; Al-Youbi, Abdulrahman O.; Faidallah, Hassan M.; Alamry, Khalid A.; Ng, Seik Weng

    2011-01-01

    In the title mol­ecule, C22H16N2O, the phenyl ring is twisted slightly with respect to the plane of the central pyrazole ring [dihedral angle = 14.8 (2)°]; the central ring is connected to the naphthyl ring through a —CH=CH—C(=O)— fragment, whose C=C double bond has an E configuration. The pyrazole ring and naphthalene ring system are twisted by 46.3 (1)°. Weak inter­molecular C—H⋯O hydrogen bonds link the mol­ecules, forming supra­molecular chains running along the a axis. The crystal studied was a non-merohedral twin with a component ratio of 0.544 (2):0.456 (2). PMID:22064894

  3. Cobalt, nickel, copper and zinc complexes with 1,3-diphenyl-1H-pyrazole-4-carboxaldehyde Schiff bases: antimicrobial, spectroscopic, thermal and fluorescence studies.

    PubMed

    Singh, Kiran; Kumar, Yogender; Puri, Parvesh; Kumar, Mahender; Sharma, Chetan

    2012-06-01

    Two new Schiff bases of 1,3-diphenyl-1H-pyrazole-4-carboxaldehyde and 4-amino-5-mercapto-3-methyl/H-1,2,4-triazole [HL(1-2)] and their Cobalt, Nickel, Copper and Zinc complexes have been synthesized and characterized by elemental analyses, spectral (UV-vis, IR, (1)H NMR, Fluorescence) studies, thermal techniques and magnetic measurements. A square planar geometry for Cu(II) and octahedral geometry for Co(II), Ni(II) and Zn(II) complexes have been proposed. In order to evaluate the biological activity of Schiff bases and to assess the role of metal ion on biological activity, the pyrazole Schiff bases and their metal complexes have been studied in vitro antibacterial against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and antifungal against Aspergillus niger, and Aspergillus flavus. In most of the cases higher activity was exhibited upon coordination with metal ions.

  4. Synthesis and biological evaluation of imidazole derivatives as novel NOP/ORL1 receptor antagonists: exploration and optimization of alternative pyrazole structure.

    PubMed

    Sugimoto, Yuichi; Kobayashi, Kensuke; Asai, Masanori; Ohno, Akio; Yamada, Koji; Ozaki, Satoshi; Ohta, Hisashi; Okamoto, Osamu

    2009-08-15

    Nonpeptidic small-molecule NOP/ORL1 receptor antagonists with an imidazole scaffold were designed and synthesized to investigate alternatives to the pyrazole analog. Systematic modification of the original pyrazole lead [Kobayashi et al., Bioorg. Med. Chem. Lett.2009, 19, 3627; Kobayashi et al., Bioorg. Med. Chem. Lett., in press] to change the heterocyclic core, substituted side chain, and pendant functional group demonstrated that examining the structure-activity relationship for novel templates allowed the identification of potent, fully substituted 4-aminomethyl-1H-imidazole and 2-aminomethyl-1H-imidazole. These compounds exhibited excellent potency for ORL1 receptor with minimal P-gp efflux and/or reduced hERG affinity.

  5. Straightforward synthesis of a novel ring-fused pyrazole-lactam and in vitro cytotoxic activity on cancer cell lines.

    PubMed

    Bertuzzi, G; Locatelli, E; Colecchia, D; Calandro, P; Bonini, B F; Chandanshive, J Z; Mazzanti, A; Zani, P; Chiariello, M; Comes Franchini, M

    2016-07-19

    In this paper a straightforward synthesis of a novel pyrazole derivative is reported. Prominent feature of this synthetic process is a 1,3-Dipolar Cycloaddition of a suitable nitrile imine with an activated α,β-unsaturated lactam to afford directly and regioselectively the corresponding ring-fused pyrazole. Having obtained the central core of the synthetic target, a double stepwise functionalization with a "side chain" characterized by a terminal cyclic aliphatic amine was carried out. This molecular structure was designed to interact strongly with typical biological residues, and indeed it showed potent anticancer capability: in vitro cytotoxicity test on five different cancer cell lines showed interesting IC50 values in the range of 15-60 μM for exposure time of 24-72 h, thus resulting comparable with commercially available and nowadays therapeutically exploited anticancer compounds, such as 5-FU and NVP-BEZ235.

  6. Synthesis and Biological Evaluation of 3-Alkyl-1,5-Diaryl-1H-Pyrazoles as Rigid Analogues of Combretastatin A-4 with Potent Antiproliferative Activity

    PubMed Central

    Xu, Qile; Qi, Huan; Sun, Maolin; Zuo, Daiying; Jiang, Xuewei; Wen, Zhiyong; Wang, Zhiwei; Wu, Yingliang; Zhang, Weige

    2015-01-01

    A series of novel 3-alkyl-1,5-diaryl-1H-pyrazoles were synthesized as combretastatin A-4 (CA-4) analogues and evaluated for antiproliferative activity against three human cancer cell lines (SGC-7901, A549 and HT-1080). Most of the target compounds displayed moderate to potent antiproliferative activity, and 7k was found to be the most potent compound. Structure-activity relationships indicated that compounds with a trimethoxyphenyl A-ring at the N-1 position of the pyrazole skeleton were more potent than those with the A-ring at the C-5 position. Tubulin polymerization and immunostaining experiments revealed that 7k potently inhibited tubulin polymerization and disrupted tubulin microtubule dynamics in a manner similar to CA-4. Computational modelling demonstrated that the binding of 7k to the colchicine binding site on microtubules may involve a similar mode as CA-4. PMID:26061410

  7. Crystal structure of ethyl N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-di­hydro-1H-pyrazol-4-yl)carbamate

    PubMed Central

    Danish, Muhammad; Tahir, Muhammad Nawaz; Anwar, Uzma; Raza, Muhammad Asam

    2015-01-01

    In the title compound, C14H17N3O3, the dihedral angle between the benzene ring and the five-membered di­hydro­pyrazole ring is 52.26 (9)°. The ethyl ester group is approximately planar (r.m.s. deviation 0.0568 Å) and subtends an angle 67.73 (8)° to the pyrazole ring. In the crystal, molecules are linked by pairs of N—H⋯O hydrogen bonds, forming inversion dimers with an R 2 2(10) ring motif. Weaker C—H⋯O contacts link these dimers into a three-dimensional network of mol­ecules stacked along the a-axis direction. Offset π–π stacking inter­actions between the benzene rings [centroid-to-centroid distance = 3.8832 (12) Å] further stabilize the crystal packing. PMID:26029449

  8. Agonist pharmacology of two Drosophila GABA receptor splice variants.

    PubMed Central

    Hosie, A. M.; Sattelle, D. B.

    1996-01-01

    1. The Drosophila melanogaster gamma-aminobutyric acid (GABA) receptor subunits, RDLac and DRC 17-1-2, form functional homo-oligomeric receptors when heterologously expressed in Xenopus laevis oocytes. The subunits differ in only 17 amino acids, principally in regions of the N-terminal domain which determine agonist pharmacology in vertebrate ionotropic neurotransmitter receptors. A range of conformationally restricted GABA analogues were tested on the two homo-oligomers and their agonists pharmacology compared with that of insect and vertebrate iontropic GABA receptors. 2. The actions of GABA, isoguvacine and isonipecotic acid on RDLac and DRC 17-1-2 homo-oligomers were compared, by use of two-electrode voltage-clamp. All three compounds were full agonists of both receptors, but were 4-6 fold less potent agonists of DRC 17-1-2 homo-oligomers than of RDLac. However, the relative potencies of these agonists on each receptor were very similar. 3. A more complete agonist profile was established for RDLac homo-oligomers. The most potent agonists of these receptors were GABA, muscimol and trans-aminocrotonic acid (TACA), which were approximately equipotent. RDLac homo-oligomers were fully activated by a range of GABA analogues, with the order of potency: GABA > ZAPA ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid) > isoguvacine > imidazole-4-acetic acid > or = isonipecotic acid > or = cis-aminocrotonic acid (CACA) > beta-alanine. 3-Aminopropane sulphonic acid (3-APS), a partial agonist of RDLac homo-oligomers, was the weakest agonist tested and 100 fold less potent than GABA. 4. SR95531, an antagonist of vertebrate GABAA receptors, competitively inhibited the GABA responses of RDLac homo-oligomers, which have previously been found to insensitive to bicuculline. However, its potency (IC50 500 microM) was much reduced when compared to GABAA receptors. 5. The agonist pharmacology of Drosophila RDLac homo-oligomers exhibits aspects of the characteristic pharmacology of

  9. SA4503, a novel cognitive enhancer with sigma1 receptor agonist properties, facilitates NMDA receptor-dependent learning in mice.

    PubMed

    Maurice, T; Privat, A

    1997-06-05

    The selective sigma1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenyl propyl)piperazine dihydrochloride (SA4503) was reported to reverse the amnesia induced by the muscarinic receptor antagonist scopolamine at sub-mg/kg doses. We examined its effect on the learning impairment induced in mice by the non-competitive NMDA receptor antagonist dizocilpine. Learning capacities were evaluated using spontaneous alternation in the Y-maze for spatial working memory, and step-down type passive avoidance. SA4503 (0.03-1 mg/kg s.c.) attenuated the dizocilpine (0.15 mg/kg i.p.)-induced memory deficits following a bell-shaped curve in both tests. These effects of SA4503 were blocked by haloperidol (0.05 mg/kg i.p.), implicating sigma1 receptors. SA4503 also reversed the alternation deficit induced by N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 mg/kg i.p.) at the same dosage, indicating that it acted on working memory through the nitric oxide (NO)-mediated signalling pathway. Furthermore, progesterone (2 mg/kg s.c.) blocked the SA4503 effects in the dizocilpine- and L-NAME-amnesia models, in accordance with the purported neurosteroids/sigma1 receptors interaction. These results demonstrate a promising neurobehavioural profile of SA4503, a ligand equally efficient to reverse the deficit in the glutamatergic as well as in the cholinergic amnesia model. Pertinent informations on the potential mechanism of the anti-amnesic effects of sigma1 receptor ligands were also obtained.

  10. A dopamine receptor d2-type agonist attenuates the ability of stress to alter sleep in mice.

    PubMed

    Jefferson, F; Ehlen, J C; Williams, N S; Montemarano, J J; Paul, K N

    2014-11-01

    Although sleep disruptions that accompany stress reduce quality of life and deteriorate health, the mechanisms through which stress alters sleep remain obscure. Psychological stress can alter sleep in a variety of ways, but it has been shown to be particularly influential on rapid eye movement (REM) sleep. Prolactin (PRL), a sexually dimorphic, stress-sensitive hormone whose basal levels are higher in females, has somnogenic effects on REM sleep. In the current study, we examined the relationship between PRL secretion and REM sleep after restraint stress to determine whether: 1) the ability of stress to increase REM sleep is PRL-dependent, and 2) fluctuating PRL levels underlie sex differences in sleep responses to stress. Because dopamine D2 receptors in the pituitary gland are the primary regulator of PRL secretion, D2 receptor agonist, 1-[(6-allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino) propyl]-3-ethylurea (cabergoline), was used to attenuate PRL levels in mice before 1 hour of restraint stress. Mice were implanted with electroencephalographic/electromyographic recording electrodes and received an ip injection of either 0.3-mg/kg cabergoline or vehicle before a control procedure of 1 hour of sleep deprivation by gentle handling during the light phase. Six days after the control procedure, mice received cabergoline or vehicle 15 minutes before 1 hour of restraint stress. Cabergoline blocked the ability of restraint stress to increase REM sleep amount in males but did not alter REM sleep amount after stress in females even though it reduced basal REM sleep amount in female controls. These data provide evidence that the ability for restraint stress to increase REM sleep is dependent on PRL and that sex differences in REM sleep amount may be driven by PRL.

  11. Beta2-agonists and exercise-induced asthma.

    PubMed

    Anderson, Sandra D; Caillaud, Corinne; Brannan, John D

    2006-01-01

    Beta2-agonists taken immediately before exercise provide significant protection against exercise- induced asthma (EIA) in most patients. However, when they are taken daily, there are some negative aspects regarding severity, control, and recovery from EIA. First, there is a significant minority (15-20%) of asthmatics whose EIA is not prevented by beta2-agonists, even when inhaled corticosteroids are used concomitantly. Second, with daily use, there is a decline in duration of the protective effect of long-acting beta2-agonists. Third, if breakthrough EIA occurs, recovery of lung function is slower in response to a beta2-agonist, and additional doses are often required to achieve pre-exercise values. If a person who takes a beta2-agonist daily experiences problems with exercise, then the physician should consider changing the treatment regimen to achieve better control of EIA. These problems likely result from desensitization of the beta2-receptor on the mast cell, which enhances mediator release, and on the bronchial smooth muscle, which enhances the bronchoconstrictor response and delays recovery from EIA. These effects are reversed within 72 h after cessation of a beta2-agonists. The important clinical question is: Are we actually compromising the beneficial effects of beta2-agonists on the prevention and recovery from EIA by prescribing them daily? Patients with EIA need to ensure that their doses of inhaled corticosteroid or other anti-inflammatory therapy are optimized so that, if necessary, a beta2-agonist can be used intermittently as prophylactic medication with greater confidence in the outcome.

  12. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs.

  13. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs.

  14. Identification of M-CSF agonists and antagonists

    DOEpatents

    Pandit, Jayvardhan; Jancarik, Jarmila; Kim, Sung-Hou; Koths, Kirston; Halenbeck, Robert; Fear, Anna Lisa; Taylor, Eric; Yamamoto, Ralph; Bohm, Andrew

    2000-02-15

    The present invention is directed to methods for crystallizing macrophage colony stimulating factor. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

  15. Opioid receptor agonists reduce brain edema in stroke.

    PubMed

    Yang, Li; Wang, Hezhen; Shah, Kaushik; Karamyan, Vardan T; Abbruscato, Thomas J

    2011-04-06

    Cerebral edema is a leading cause of mortality in stroke patients. The purpose of this study was to assess a non-selective opioid receptor agonist, biphalin, in decreasing reducing brain edema formation using both in vitro and in vivo models of stroke. For the in situ model of ischemia, hippocampal slices were exposed to oxygen glucose deprivation (OGD) conditions and we observed that hippocampal water content was increased, compared to normoxia. Treatment with the mu agonist, Tyr-D-Ala', N-CH, -Phe4, Glyol-Enkephalin (DAMGO), delta opioid agonists, D-pen(2), D-phe(5) enkephalin (DPDPE), and kappa agonist, U50 488, all significantly decreased brain slice water gain. Interestingly, the non-selective agonist, biphalin, exhibited a statistically significant (P<0.01) greater effect in decreasing water content in OGD-exposed hippocampal slices, compared with mu, delta, and kappa selective opioid agonists. Moreover, biphalin exhibited anti-edematous effects in a dose responsive manner. The non-selective opioid antagonist, naloxone, returned the water content nearly back to original OGD values for all opioid agonist treatments, supporting that these effects were mediated by an opioid receptor pathway. Furthermore, biphalin significantly decreased edema (53%) and infarct (48%) ratios, and neuronal recovery from stroke, compared with the vehicle-treated groups in a 12h permanent middle cerebral artery occlusion (MCAO) model of focal ischemia. Biphalin also significantly decreased the cell volume increase in primary neuronal cells exposed to OGD condition. These data suggest that opioid receptor activation may provide neuroprotection during stroke and further investigations are needed in the development of novel opioid agonist as efficacious treatments for brain ischemia.

  16. Novel ferrocenyl pyrazoles inhibit breast cancer cell viability via induction of apoptosis and inhibition of PI3K/Akt and ERK1/2 signaling.

    PubMed

    Atmaca, Harika; Özkan, Ayşe Nur; Zora, Metin

    2017-02-01

    Despite the advances in early detection and targeted therapies, chemotherapy is still of vital importance in breast cancer treatment. However, development of drug resistance and serious side effects limits their usage. Thus, there is an urgent need for safer and more effective agents against breast cancer. We have previously described the synthesis of a number of pyrazole derivatives, and in the current study, we have investigated the effects of two different ferrocenyl pyrazole (FP) derivates, 5-ferrocenyl-1-phenyl-1H-pyrazole (FP-Ph) and 5-ferrocenyl-1H-pyrazole (FP-H), on breast cancer cells. First, we investigated the effects of both FPs on cell viability and induction of cell death in breast cancer cells and benign MCF-10A cells by XTT and DNA fragmentation assays, respectively. Morphological changes in human breast cancer cells after FPs treatment were detected by both phase contrast microscope and atomic force microscopy (AFM). Then, we tested whether FPs exert their cytotoxic effect through inhibiting PI3K/Akt and/or ERK1/2 signaling pathways by using specific inhibitors. Both FPs induced cytotoxicity in a time and concentration-dependent manner in breast cancer cells; however, MCF-10A benign breast epithelial cells were much less susceptible to the cytotoxic effect of both FPs. FPs inhibited both PI3K/Akt and ERK 1/2 signaling pathways in breast cancer cells. The ultra structure images of MCF-7 cells by AFM showed that the cell surface was smooth in untreated cells, but it was rough with protrusions in treated cells. Both FPs induced apoptotic cell death in MDA-MB-231 cells; however, necrotic cell death was induced in caspase-3 lack MCF-7 cells, which implies that the synthesized FPs may induce apoptosis through caspase-3 dependent mechanism. In summary, these results suggest that FPs might be promising agents for the breast cancer therapy.

  17. Design and synthesis of novel complexes containing N-phenyl-1H-pyrazole moiety: Ni complex as potential antifungal and antiproliferative compound

    NASA Astrophysics Data System (ADS)

    El-Gamel, Nadia E. A.; Farghaly, Thoraya A.

    2013-11-01

    Cu(II) (1), Ni(II) (2), Cr(III) (3) and Fe(III) (4) complexes with 3-acetyl-4-benzoyl-1-phenyl-1H-pyrazole (L1) were prepared and structurally characterized. Usual coordination of L1 was achieved through nitrogen of pyrazole moiety and carbonyl acetyl group. Electronic spectra of the complexes indicate that the geometry of the metal center was six coordinate octahedral. In vitro antimicrobial activity of the ligand and complex compounds was screened in terms of antibacterial effect on Staphylococcus aureus (Gram-positive), Escherichia coli (Gram-negative) and antifungal effect on the fungi Aspergillus flavus and candida albicans using the modified Kirby-Bauer disc diffusion and minimum inhibitory concentrations (MIC) methods. Ni(II) complex (2) exhibited remarkable antifungal inhibition against Candida albicans equal to the standard antifungal agent. To continue our study some structural modifications are formed by adding 4-fluoro-benzoyl moiety to L1 in different forms to produce different ligands, 3-acetyl-4-(4-flourobenzoyl)-1-phenyl-1H-pyrazole (L2) and 3-[(3-acetyl-1-phenyl-1H-4-pyrazolyl)carbonyl]-1-phenyl-4-(4-flourobenzoyl)-1H-pyrazole (L3), Ni complexes (5 and 6) are prepared and comparable in vitro antimicrobial study is evaluated. In vitro cytotoxicity of the Ni(II) complex (2) is studied using MTT assay. The analysis of the cell test showed that (2) displayed quite small cytotoxic response at the higher concentration level which indeed would further enable us for more opportunities in therapeutic and biomedical challenges. Both of the capability as a potent in vitro antifungal agent and the cell test analysis show Ni(II) complex (2) as a promising material in the translation of observed in vitro biological phenomenon into clinical therapies settings.

  18. Design and synthesis of novel complexes containing N-phenyl-1H-pyrazole moiety: Ni complex as potential antifungal and antiproliferative compound.

    PubMed

    El-Gamel, Nadia E A; Farghaly, Thoraya A

    2013-11-01

    Cu(II) (1), Ni(II) (2), Cr(III) (3) and Fe(III) (4) complexes with 3-acetyl-4-benzoyl-1-phenyl-1H-pyrazole (L1) were prepared and structurally characterized. Usual coordination of L1 was achieved through nitrogen of pyrazole moiety and carbonyl acetyl group. Electronic spectra of the complexes indicate that the geometry of the metal center was six coordinate octahedral. In vitro antimicrobial activity of the ligand and complex compounds was screened in terms of antibacterial effect on Staphylococcus aureus (Gram-positive), Escherichia coli (Gram-negative) and antifungal effect on the fungi Aspergillus flavus and candida albicans using the modified Kirby-Bauer disc diffusion and minimum inhibitory concentrations (MIC) methods. Ni(II) complex (2) exhibited remarkable antifungal inhibition against Candida albicans equal to the standard antifungal agent. To continue our study some structural modifications are formed by adding 4-fluoro-benzoyl moiety to L1 in different forms to produce different ligands, 3-acetyl-4-(4-flourobenzoyl)-1-phenyl-1H-pyrazole (L2) and 3-[(3-acetyl-1-phenyl-1H-4-pyrazolyl)carbonyl]-1-phenyl-4-(4-flourobenzoyl)-1H-pyrazole (L3), Ni complexes (5 and 6) are prepared and comparable in vitro antimicrobial study is evaluated. In vitro cytotoxicity of the Ni(II) complex (2) is studied using MTT assay. The analysis of the cell test showed that (2) displayed quite small cytotoxic response at the higher concentration level which indeed would further enable us for more opportunities in therapeutic and biomedical challenges. Both of the capability as a potent in vitro antifungal agent and the cell test analysis show Ni(II) complex (2) as a promising material in the translation of observed in vitro biological phenomenon into clinical therapies settings.

  19. Behavioural effects of selective tachykinin agonists in midbrain dopamine regions.

    PubMed

    Stoessl, A J; Szczutkowski, E; Glenn, B; Watson, I

    1991-11-29

    The effects of selective NK-1, NK-2 and NK-3 tachykinin agonists in midbrain dopamine cell containing regions were investigated in the rat. The NK-3 agonist senktide induced locomotion, rearing and sniffing following infusion into the substantia nigra pars compacta, and to a lesser extent in the ventral tegmental area. These behavioural responses were not seen following infusion of the selective NK-1 agonist [Sar9,Met (O2)11]SP or the NK-2 agonist [N1e10]NKA4-10. In contrast, grooming was induced only by the NK-1 agonist administered into the substantia nigra. Yawning, chewing mouth movements and wet dog shakes were all seen following infusion of senktide into the ventral tegmental area. These findings suggest that (i) dopamine-mediated behavioural responses seen following tachykinin administration into the midbrain are dependent upon stimulation of NK-3 tachykinin receptors, (ii) tachykinin-induced grooming is mediated by stimulation of NK-1 receptors and (iii) some of the previously described 5-HT mediated behaviours seen following administration of NK-3 tachykinin agonists are probably generated by stimulation of 5-HT cell bodies in the ventral tegmental area.

  20. Histamine H3-receptor inverse agonists as novel antipsychotics.

    PubMed

    Ito, Chihiro

    2009-06-01

    Schizophrenia (SZ) that is resistant to treatment with dopamine (DA) D2 antagonists may involve changes other than those in the dopaminergic system. Recently, histamine (HA), which regulates arousal and cognitive functions, has been suggested to act as a neurotransmitter in the central nervous system. Four HA receptors-H1, H2, H3, and H4-have been identified. Our recent basic and clinical studies revealed that brain HA improved the symptoms of SZ. The H3 receptor is primarily localized in the central nervous system, and it acts not only as a presynaptic autoreceptor that modulates the HA release but also as a presynaptic heteroreceptor that regulates the release of other neurotransmitters such as monoamines and amino acids. H3-receptor inverse agonists have been considered to improve cognitive functions. Many atypical antipsychotics are H3-receptor antagonists. Imidazole-containing H3-receptor inverse agonists inhibit not only cytochrome P450 but also hERG potassium channels (encoded by the human ether-a-go-go-related gene). Several imidazole H3-receptor inverse agonists also have high affinity for H4 receptors, which are expressed at high levels in mast cells and leukocytes. Clozapine is an H4-receptor agonist; this agonist activity may be related to the serious side effect of agranulocytosis caused by clozapine. Therefore, selective non-imidazole H3-receptor inverse agonists can be considered as novel antipsychotics that may improve refractory SZ.

  1. Vibrational spectroscopic investigations, molecular dynamic simulations and molecular docking studies of N‧-diphenylmethylidene-5-methyl-1H-pyrazole-3-carbohydrazide

    NASA Astrophysics Data System (ADS)

    Pillai, Renjith Raveendran; Menon, Vidya V.; Mary, Y. Shyma; Armaković, Stevan; Armaković, Sanja J.; Panicker, C. Yohannan

    2017-02-01

    FT-IR and FT-Raman spectra of N‧-diphenylmethylidene-5-methyl-1H-pyrazole-3-carbohydrazide were recorded and analyzed. Due to the industrial and biological importance of pyrazole derivatives, we have carried out an extensive quantum chemical study on N‧-diphenylmethylidene-5-methyl-1H-pyrazole-3-carbohydrazide. The theoretical ground state geometry and electronic structure of the title molecule were optimized by DFT/B3LYP/6-311G++(d,p) method and compared with those of the crystal data. The wave numbers obtained are assigned by potential energy distribution. The ring breathing modes of the benzene rings are assigned theoretically at 1009 cm-1 for the mono substituted phenyl rings. The first order hyperpolarizability is comparable with that of similar derivatives and 16 times that of the standard NLO material urea. Conformational analysis was conducted in order to locate all possible conformations of the title compound, followed by investigation of local reactivity properties by MEP and ALIE surfaces. Natural bond orbital analysis has been carried out to analyse the stability of the molecule arising from hyper-conjugative interactions and charge delocalization. Further, reactive properties via autoxidation and hydrolysis mechanisms have been assessed through calculations of bond dissociation energies and radial distribution functions. Docking results confirmed that the compound was a potential inhibitor of CDK2s and were in agreement with the previous reported studies.

  2. Structure-based design, synthesis and biological evaluation of N-pyrazole, N'-thiazole urea inhibitors of MAP kinase p38α.

    PubMed

    Getlik, Matthäus; Grütter, Christian; Simard, Jeffrey R; Nguyen, Hoang D; Robubi, Armin; Aust, Beate; van Otterlo, Willem A L; Rauh, Daniel

    2012-02-01

    In this paper, we present the structure-based design, synthesis and biological activity of N-pyrazole, N'-thiazole-ureas as potent inhibitors of p38α mitogen-activated protein kinase (p38α MAPK). Guided by complex crystal structures, we employed the initially identified N-aryl, N'-thiazole urea scaffold and introduced key structural elements that allowed the formation of novel hydrogen bonding interactions within the allosteric site of p38α, resulting in potent type III inhibitors. [4-(3-tert-Butyl-5-{[(1,3-thiazol-2-ylamino)carbonyl]amino}-1H-pyrazol-1-yl)-phenyl]acetic acid 18c was found to be the most potent compound within this series and inhibited p38α activity with an IC(50) of 135 ± 21 nM. Its closest analog, ethyl [4-(3-tert-butyl-5-{[(1,3-thiazol-2-ylamino)carbonyl]amino}-1H-pyrazol-1-yl)phenyl]acetate 18b, effectively inhibited p38α mediated phosphorylation of the mitogen activated protein kinase activated protein kinase 2 (MK2) in HeLa cells.

  3. Synthesis, characterization and potent superoxide dismutase like activity of novel bis(pyrazole) – 2,2′-bipyridyl mixed ligand copper(II) complexes

    PubMed Central

    Potapov, Andrei S.; Nudnova, Evgenia A.; Domina, Galina A.; Kirpotina, Liliya N.; Quinn, Mark T.; Khlebnikov, Andrei I.; Schepetkin, Igor A.

    2010-01-01

    Eleven new complexes of Cu(II) chloride and nitrate with bis(pyrazol-1-yl)propane and bis[2-(pyrazol-1-yl)ethyl]ether ligands were prepared and characterized by spectral and electrochemical methods. X-ray crystal structure determination of bis[2-(3,5-dimethylpyrazol-1-yl)ethyl]etherdinitratocopper revealed a hepta-coordinated structure with the bis(pyrazole) ligand coordinated in a tridentate NNO-fashion and both of the nitrate ions in a bidentate fashion. Reaction of Cu(II) nitrate complexes with 2,2′-bipyridyl led to the displacement of one of the nitrate ions into the outer sphere and the formation of mixed-ligand complexes. Mixed-ligand bipyridyl Cu(II) complexes demonstrated the highest superoxide dismutase (SOD)-like activity in a chemical superoxide anion-generating system, with IC50 values in the low micromolar range. Density functional theory calculations showed that introduction of a bipypidyl ligand into the complexes dramatically lowered the lowest unoccupied molecular orbital (LUMO) energy level, which explains the increased SOD-like activity of these complexes compared to non-bipy species. These bipy complexes were also effective scavengers of reactive oxygen species generated by phagocytes (human neutrophils and murine bone marrow leukocytes) ex vivo. Thus, these bipy mixed-ligand complexes represent a promising class of SOD mimetics for future development. PMID:19488447

  4. Experimental (XRD, IR and NMR) and theoretical investigations on 1-(2-nitrobenzoyl)3,5-bis(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole

    NASA Astrophysics Data System (ADS)

    Evecen, Meryem; Tanak, Hasan; Tinmaz, Feyza; Dege, Necmi; Özer İlhan, İlhan

    2016-12-01

    The pyrazole compound 1-(2-nitrobenzoyl)3,5-bis(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole (I) has been synthesized and characterized by IR, NMR and X-ray diffraction methods. The compound crystallizes in the monoclinic space group C2/c with a = 36.126(5) Ǻ, b = 8.1963(7) Ǻ, c = 14.3983(18) Ǻ, β = 100.825(10)° and Z = 8. The molecular geometry, vibrational frequencies and Gauge-Independent Atomic Orbital (GIAO) 1H and 13C NMR chemical shift values of 1-(2-nitrobenzoyl)3,5-bis(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole in the ground state have been calculated using the density functional method (B3LYP) with the 6-311++G(d,p) basis set. The optimized parameters are in agreement with X-ray data. The calculated vibrational frequencies and chemical shift values were compared with experimental IR and NMR values. In addition, frontier molecular orbitals, molecular electrostatic potential and NBO analysis of (I) were investigated by DFT calculations.

  5. Synthesis, photoluminescence properties and theoretical insights on 1,3-diphenyl-5-(9-anthryl)-2-pyrazoline and -1H-pyrazole.

    PubMed

    Dong, Baoli; Wang, Mingliang; Xu, Chunxiang

    2013-01-01

    1,3-Diphenyl-5-(9-anthryl)-2-pyrazoline and 1,3-diphenyl-5-(9-anthryl)-1H-pyrazole with an anthryl chromophore were synthesized and characterized using (1) H NMR, (13) C NMR, FT-IR, mass spectrometry and elemental analysis. Their optical properties were characterized by UV-vis absorption and fluorescence spectroscopy. It was observed that the absorption and fluorescence spectra of the two compounds showed a red shift with respect to that of anthracene. Pyrazole exhibited high fluorescent quantum yields (Φf  = 0.90 in toluene) while pyrazoline showed nearly no fluorescence in solution. The significant fluorescence divergence of the two similar compounds was investigated theoretically through density functional theory (DFT) calculations. The energetically lowest-lying state S1 in the pyrazoline exhibited both characteristics of locally excited and electron-transfer states that resulted in the fluorescence quenching of anthryl chromophore whereas the S1 state in the pyrazole corresponded to an optically allowed state that led to high fluorescence quantum yields in solutions.

  6. A convenient synthesis and molecular modeling study of novel pyrazolo[3,4-d]pyrimidine and pyrazole derivatives as anti-tumor agents.

    PubMed

    Nassar, Ibrahim F; Atta-Allah, Saad R; Elgazwy, Abdel-Sattar S Hamad

    2015-06-01

    An efficient method to obtain ethyl 5-amino-1-tosyl-1H-pyrazole-4-carboxylate (3) was outlined using condensation reactions of 4-methylbenzenesulfonylhydrazide with (E)-ethyl 2-cyano-3-ethoxyacrylate. The cyclocondensation reaction of this substrate and its hydrazide derivative with urea, thiourea, formamide, formic acid, d-glucose, o-phenylenediamine, 4-dimethylaminobenzaldehyde, anthracene-9-carbaldehyde, thioglycolic acid and carbon disulphide then with hydrazine hydrate analogues furnished a series of pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4-d]oxazin-4-one, pyrazole-4-glucoside, 4-benzo[d]imidazole, 1,3-thiazolidinone, 1,3,4-oxadiazol-2(3H)-thione and 1,2,4-triazol-5(4H)-thione derivatives respectively. The structure of the compound 3 was supported by X-Ray crystallographic data. Orally administrated, one of each of the series of pyrazoles showed significant effects in mouse tumor model cancer cell lines (EAC) and two human cancer cell lines of Colon cancer (HCT-29) and Breast cancer (MCF-7) with docking studies.

  7. Synthesis and anticonvulsant activity of 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues.

    PubMed

    Ahsan, Mohamed Jawed; Khalilullah, Habibullah; Stables, James P; Govindasamy, Jeyabalan

    2013-06-01

    A series of fourteen 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues were synthesized and evaluated for anticonvulsant activity according to the Antiepileptic Drug Development Programme (ADD) protocol. Some of the synthesized compounds showed significant activity in minimal clonic seizure model (6 Hz psychomotor seizure test). 3-(4-Fluorophenyl)-N-(4-bromophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4c) was found to be the most active compound of the series showing 75% (3/4, 0.25-2.0 h) and 50% (2/4, 4.0 h) protection against minimal clonic seizure at 100 mg/kg without any toxicity. 3-(Pyridin-4-yl)-N-(4-chlorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4f) showed protection in maximal electroshock (MES) seizure and subcutaneous metrazol (scMET) seizure at 300 mg/kg.

  8. Synthesis, structure-activity relationships, and in vitro antibacterial and antifungal activity evaluations of novel pyrazole carboxylic and dicarboxylic acid derivatives.

    PubMed

    Mert, Samet; Kasımoğulları, Rahmi; İça, Tuba; Çolak, Ferdağ; Altun, Ahmet; Ok, Salim

    2014-05-06

    A series of pyrazole-3-carboxylic acid and pyrazole-3,4-dicarboxylic acid derivatives were synthesized, the structures were confirmed by their NMR ((1)H and (13)C) and FT-IR spectra, and elemental analyses. The antibacterial and antifungal activities of the compounds against five bacterial and five fungal pathogens were screened using modified agar well diffusion assay. Most of the molecules have inhibitory effects on both standard and clinical Candida albicans strains. However, only the molecules 8, 10, 21, and 22 demonstrate some inhibitory effects on Candida parapsilosis, Candida tropicalis, and Candida glabrata strains. The structure-antifungal activity relationships of the compounds on the C. albicans strains were investigated by electron-conformational method. The pharmacophores and antipharmacophores responsible for the inhibition and non-inhibition of the C. albicans strains were obtained by electronic and geometrical characteristics of the reactive fragments of the molecules. These fragments along with the associated parameters can be used in designing the future more potent antifungal agents. It has been shown that both the positions of electronegative atoms like F and O in the pyrazole substituents and the amount of the associated charges on such atoms are crucial in regulating the strength of antifungal activity for the C. albicans strain.

  9. Crystal structure of 3-(thio-phen-2-yl)-5-p-tolyl-4,5-di-hydro-1H-pyrazole-1-carbo-thio-amide.

    PubMed

    Naveen, S; Pavithra, G; Abdoh, Muneer; Ajay Kumar, K; Warad, Ismail; Lokanath, N K

    2015-07-01

    In the title compound, C15H15N3S2, the central pyrazole ring adopts a twisted conformation on the -CH-CH2- bond. Its mean plane makes dihedral angles of 7.19 (12) and 71.13 (11)° with those of the thio-phene and toluene rings, respectively. The carbothi-amide group [C(=S)-N] is inclined to the pyrazole ring mean plane by 16.8 (2)°. In the crystal, mol-ecules are linked by N-H⋯S hydrogen bonds, forming chains propagating along [010]. Within the chains, there are N-H⋯π inter-actions present. Between the chains there are weak parallel slipped π-π inter-actions involving inversion-related thio-phene and pyrazole rings [inter-centroid distance = 3.7516 (14) Å; inter-planar distance = 3.5987 (10) Å; slippage = 1.06 Å].

  10. Infrared spectrum, structural and optical properties and molecular docking study of 3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carbaldehyde

    NASA Astrophysics Data System (ADS)

    Mary, Y. Sheena; Panicker, C. Yohannan; Sapnakumari, M.; Narayana, B.; Sarojini, B. K.; Al-Saadi, Abdulaziz A.; Van Alsenoy, C.; War, Javeed Ahmad; Fun, H. K.

    2015-03-01

    The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of 3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carbaldehyde have been investigated experimentally and theoretically. The title compound was optimized using at HF and DFT levels of calculations. The B3LYP/6-311++G(d,p) (5D,7F) results and in agreement with experimental infrared bands. The normal modes are assigned using potential energy distribution. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using natural bonding orbital analysis. The frontier molecular orbital analysis is used to determine the charge transfer within the molecule. From molecular electrostatic potential map, it is evident that the negative electrostatic potential regions are mainly localized over the carbonyl group and mono substituted phenyl ring and are possible sites for electrophilic attack and, positive regions are localized around all para substituted phenyl and pyrazole ring, indicating possible sites for nucleophilic attack. First hyperpolarizability is calculated in order to find its role in nonlinear optics. The geometrical parameters are in agreement with experimental data. From the molecular docking studies, it is evident that the fluorine atom attached to phenyl ring and the carbonyl group attached to pyrazole ring are crucial for binding and the results draw us to the conclusion that the compound might exhibit phosphodiesterase inhibitory activity.

  11. Antimicrobial screening and one-pot synthesis of 4-(substituted-anilinomethyl)-3-(2-naphthyl)-1-phenyl-1H-pyrazole derivatives

    PubMed Central

    Goel, Neelima; Drabu, Sushma; Afzal, Obaid; Bawa, Sandhya

    2014-01-01

    Aim: Synthesis of series of 4-(substituted-anilinomethyl-3-(2-naphthyl)-1-phenyl-1H-pyrazole derivatives (4a–4k) and their in vitro antifungal and antibacterial screening. Materials and Methods: A series of compounds (4a–4k) was synthesized through direct reductive amination of 3-(naphthalen-2-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde with various substituted aromatic amines using NaBH4 in the presence of I2 as reducing agent. The reaction was carried out in anhydrous methanol under neutral conditions at room temperature. The structures of synthesized compounds (4a–4k) were established on the basis of IR, 1H and 13C-NMR, and mass spectral data. Results: All 4-(substituted-anilinomethyl-3-(2-naphthyl)-1-phenyl-1H-pyrazole derivatives (4a–4k) were tested in vitro for antifungal and antibacterial activities against different fungal and bacterial strains. Most of the compounds exhibited considerable antifungal activity, but poor antibacterial activity against the test strains. Conclusion: In the series compound 4e, 4g, 4j, and 4k, showed excellent antifungal activity against the fungal strain Aspergillus niger (MTCC) 281 and Aspergillus flavus MTCC 277 (% inhibition in the range of 47.7–58.9). PMID:25400408

  12. The Quest for Complex Molecules in Space. Searches for Cyanides Related to n-PROPYL Cyanide in SGR B2(N)

    NASA Astrophysics Data System (ADS)

    Müller, Holger S. P.; Schlemmer, S.; Belloche, A.; Menten, K. M.; Coutens, A.; Walters, A.; Grabow, J.-U.

    2011-06-01

    A molecular line survey was carried out with the IRAM 30 m telescope toward the prolific hot core Sgr B2(N) in order to explore its molecular complexity. The entire 3 mm range as well as selected regions at 2 and 1.3 mm were covered. Notable results include the detections of aminoacetonitrile, ethyl formate, n-propyl cyanide,^b and the singly substituted 13C isotopologs of vinyl cyanide. There exists a branched isomer of n-propyl cyanide: iso-propyl cyanide. A search for this isomer in our line survey required a laboratory spectroscopic investigation beforehand. Even though promising emission features have been found for this as well as other, related molecules, there are rather few uncontaminated lines. Overlap by other emission or some absorption features occurs frequently, and uncertainties about the position of the baseline also contribute to considering detections to be inconclusive. Nevertheless, the determination of upper limits or abundances among isomers and related molecules will help to constrain astrochemical pathways. We will present our results and discuss promising strategies to search for complex molecules in space. A. Belloche, K. M. Menten, C. Comito, H. S. P. Müller, P. Schilke, J. Ott, S. Thorwirth, C. Hieret, Astron. Astrophys. 482 (2008) 179. A. Belloche, R. T. Garrod, H. S. P. Müller, K. M. Menten, C. Comito, P. Schilke, Astron. Astrophys. 499 (2009), 215. H. S. P. Müller, A. Belloche, K. M. Menten, C. Comito, P. Schilke, J. Mol. Spectrosc. 251 (2008) 319. H. S. P. Müller, A. Coutens, A. Walters, J.-U. Grabow, S. Schlemmer, submitted to J. Mol. Spectrosc.

  13. No-carrier-added carbon-11-labeled sn-1,2- and sn-1,3-diacylglycerols by (11C)propyl ketene method

    SciTech Connect

    Imahori, Y.; Fujii, R.; Ueda, S.; Ido, T.; Nishino, H.; Moriyama, Y.; Yamamoto, Y.L.; Nakahashi, H. )

    1991-08-01

    This article describes the preparation of sn-1,2-(11C)diacylglycerols and sn-1,3-(11C)diacylglycerols by a no-carrier-added reaction based on a labeling method using (1-11C)propyl ketene, which is one of the most potent acylating agents. (1-11C)Propyl ketene was produced by pyrolytic decomposition of (1-11C)butyric acid and was trapped in pyridine containing L-alpha-palmitoyl-lysophosphatidylcholine, producing L-alpha-palmitoyl-2-(1-11C)butyryl-sn-glycero-3-phosphorylcholine. The authors adopted an enzymatic reaction to remove the phosphorylcholine, in which L-alpha-palmitoyl-2-(1-11C)butyryl-sn-glycero-3-phosphorylcholine was incubated with phospholipase C, hydrolyzing to produce 1-palmitoyl-sn-2-(1-11C)butyrylglycerol. Total synthesis time was about 50 minutes and the specific activity was estimated at 93 GBq/mumol (2.5 Ci/mumol) at end of synthesis. Radiochemical yield was 3.8% based on the trapped 11CO2. sn-1,3-(11C)Diacylglycerol was also synthesized by (1-11C)propyl ketene reaction with 1-palmitoyl-sn-glycerol in a single procedure. The regional brain tissue radioactivities obtained in sn-1,2-(11C)diacylglycerol were higher than those of sn-1,3-(11C)diacylglycerol, and the regional values varied widely. In autoradiography of brain slices from conscious rats, sn-1,2-(11C)diacylglycerol incorporation sites were discretely localized, especially in the amygdala, cerebral cortex, and hippocampus, suggesting that intensive neuronal processing occurred in these areas on the basis of phosphatidylinositol turnover.

  14. Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y12

    PubMed Central

    Schmidt, Philipp; Ritscher, Lars; Dong, Elizabeth N.; Hermsdorf, Thomas; Cöster, Maxi; Wittkopf, Doreen; Meiler, Jens

    2013-01-01

    The ADP receptor P2Y12 belongs to the superfamily of G protein–coupled receptors (GPCRs), and its activation triggers platelet aggregation. Therefore, potent antagonists, such as clopidogrel, are of high clinical relevance in prophylaxis and treatment of thromboembolic events. P2Y12 displays an elevated basal activity in vitro, and as such, inverse agonists may be therapeutically beneficial compared with antagonists. Only a few inverse agonists of P2Y12 have been described. To expand this limited chemical space and improve understanding of structural determinants of inverse agonist-receptor interaction, this study screened a purine compound library for lead structures using wild-type (WT) human P2Y12 and 28 constitutively active mutants. Results showed that ATP and ATP derivatives are agonists at P2Y12. The potency at P2Y12 was 2-(methylthio)-ADP > 2-(methylthio)-ATP > ADP > ATP. Determinants required for agonistic ligand activity were identified. Molecular docking studies revealed a binding pocket for the ATP derivatives that is bordered by transmembrane helices 3, 5, 6, and 7 in human P2Y12, with Y105, E188, R256, Y259, and K280 playing a particularly important role in ligand interaction. N-Methyl-anthraniloyl modification at the 3′-OH of the 2′-deoxyribose leads to ligands (mant-deoxy-ATP [dATP], mant-deoxy-ADP) with inverse agonist activity. Inverse agonist activity of mant-dATP was found at the WT human P2Y12 and half of the constitutive active P2Y12 mutants. This study showed that, in addition to ADP and ATP, other ATP derivatives are not only ligands of P2Y12 but also agonists. Modification of the ribose within ATP can result in inverse activity of ATP-derived ligands. PMID:23093496

  15. Expanding the scope of sulfur-centered Arbuzov rearrangement in diethyl/di-n-propyl sulfite for the synthesis of mixed-ligand di-n-butyltin alkanesulfonates.

    PubMed

    Shankar, Ravi; Singh, Atul Pratap; Upreti, Shailesh

    2006-11-13

    A one-pot reaction between di-n-butyltin oxide and diethyl/di-n-propyl sulfite in the presence of an equimolar amount of alkyl iodide proceeds via sulfur-centered Arbuzov rearrangement to afford the corresponding di-n-butyltin (alkoxy)alkanesulfonates n-Bu2Sn(OR')OS(O)2R [R = R' = Et (1), n-Pr (2); R = Me, R' = Et (3), n-Pr (4)]. The compounds 1 and 3 react with methylphosphonic acid under mild conditions to give [n-Bu2Sn(OS(O)2R)OP(O)(OH)Me]n [R = Et (5), Me (6), respectively].

  16. Synthesis of a Nanostructured Composite: Octakis(1-propyl-1H-1,2,3-triazole-4-yl(methyl 2-chlorobenzoate))octasilsesquioxane via Click Reaction.

    PubMed

    Ghodsi, Mohammadi Ziarani; Shakiba Nahad, Monireh; Lashgari, Negar; Alireza, Badiei

    2015-01-01

    Octakis(1-propyl-1H-1,2,3-triazole-4-yl(methyl 2-chlorobenzoate))octasilsesquioxanes as functionalized silsesquioxanes were synthesized via click reaction (copper-catalyzed Huisgen 1,3-dipolar cycloaddition reaction) between azidemoiety functionalized silsesquioxane and prop-2-ynyl 2-chlorobenzoate. The latter one was synthesized via the condensation reaction of propargyl alcohol and 2-chlorobenzoyl chloride in the presence of SBA-Pr-NH(2) (Santa Barbara Amorphous type material) as a nano basic catalyst. This approach provides a simple and convenient route to efficiently functionalize a wide range of new structures on the surface of silsesquioxanes.

  17. Volumetric Properties of the Mixture 2-Chloroethanol C2H5ClO + C5H10O2 Propyl ethanoate (VMSD1511, LB4799_V)

    NASA Astrophysics Data System (ADS)

    Cibulka, I.; Fontaine, J.-C.; Sosnkowska-Kehiaian, K.; Kehiaian, H. V.

    This document is part of Subvolume C 'Binary Liquid Systems of Nonelectrolytes III' of Volume 26 'Heats of Mixing, Vapor-Liquid Equilibrium, and Volumetric Properties of Mixtures and Solutions' of Landolt-Börnstein Group IV 'Physical Chemistry'. It contains the Chapter 'Volumetric Properties of the Mixture 2-Chloroethanol C2H5ClO + C5H10O2 Propyl ethanoate (VMSD1511, LB4799_V)' providing data from direct measurement of low-pressure thermodynamic speed of sound at variable mole fraction and constant temperature, in the single-phase region(s).

  18. Origin of the gauche preference of n-propyl halides and related molecules investigated by ab initio MO calculations: Importance of the CH/ n hydrogen bond

    NASA Astrophysics Data System (ADS)

    Takahashi, Osamu; Yamasaki, Katsuyoshi; Kohno, Yuji; Ueda, Kazuyoshi; Suezawa, Hiroko; Nishio, Motohiro

    2007-05-01

    Ab initio MO calculations were carried out to investigate the conformational preference of n-propyl halides, isobutyl halides, sec-butyl halides, and n-butyl halides. It has been found in most cases that the conformer in which a methyl group is close to the halogen atom is favored. The distance between the halogen atom and one of the hydrogens in the interacting CH 3 group has been shown, in every case, to be shorter than the van der Waals distance. Natural bond orbital (NBO) charges have given results consistent with this finding. We suggest that the CH/ n hydrogen bond contributes in determining the conformation of these molecules.

  19. Preliminary study of propyl bromide exposure among New Jersey dry cleaners as a result of a pending ban on perchloroethylene.

    PubMed

    Blando, James D; Schill, Donald P; De La Cruz, Mary Pauline; Zhang, Lin; Zhang, Junfeng

    2010-09-01

    Many states are considering, and some states have actively pursued, banning the use of perchloroethylene (PERC) in dry cleaning establishments. Proposed legislation has led many dry cleaners to consider the use of products that contain greater than 90% n-propyl bromide (n-PB; also called 1-bromopropane or 1-BP). Very little information is known about toxicity and exposure to n-PB. Some n-PB-containing products are marketed as nonhazardous and "green" or "organic." This has resulted in some users perceiving the solvent as nontoxic and has resulted in at least one significant poisoning incident in New Jersey. In addition, many dry cleaning operators may not realize that the machine components and settings must be changed when converting from PERC to n-PB containing products. Not performing these modifications may result in overheating and significant leaks in the dry cleaning equipment. A preliminary investigation was conducted of the potential exposures to n-PB and isopropyl bromide (iso-PB; also called 2-bromopropane or 2-BP) among dry cleaners in New Jersey who have converted their machines from PERC to these new solvent products. Personal breathing zone and area samples were collected using the National Institute for Occupational Safety and Health Sampling and Analytical Method 1025, with a slight modification to gas chromatography conditions to facilitate better separation of n-PB from iso-PB. During the preliminary investigation, exposures to n-PB among some workers in two of three shops were measured that were greater than the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value (TLV) for n-PB. The highest exposure measured among a dry cleaning machine operator was 54 parts per million (ppm) as an 8-hr time-weighted average, which is more than 5 times the ACGIH TLV of 10 ppm. The preliminary investigation also found that the work tasks most likely to result in the highest short-term exposures included the introduction of

  20. New methodology for Ozone Depletion Potentials of short-lived compounds: n-Propyl bromide as an example

    NASA Astrophysics Data System (ADS)

    Wuebbles, Donald J.; Patten, Kenneth O.; Johnson, Matthew T.; Kotamarthi, Rao

    2001-07-01

    A number of the compounds proposed as replacements for substances controlled under the Montreal Protocol have extremely short atmospheric lifetimes, on the order of days to a few months. An important example is n-propyl bromide (also referred to as 1-bromopropane, CH2BrCH2CH3 or simplified as 1-C3H7Br or nPB). This compound, useful as a solvent, has an atmospheric lifetime of less than 20 days due to its reaction with hydroxyl. Because nPB contains bromine, any amount reaching the stratosphere has the potential to affect concentrations of stratospheric ozone. The definition of Ozone Depletion Potentials (ODP) needs to be modified for such short-lived compounds to account for the location and timing of emissions. It is not adequate to treat these chemicals as if they were uniformly emitted at all latitudes and longitudes as normally done for longer-lived gases. Thus, for short-lived compounds, policymakers will need a table of ODP values instead of the single value generally provided in past studies. This study uses the MOZART2 three-dimensional chemical-transport model in combination with studies with our less computationally expensive two-dimensional model to examine potential effects of nPB on stratospheric ozone. Multiple facets of this study examine key questions regarding the amount of bromine reaching the stratosphere following emission of nPB. Our most significant findings from this study for the purposes of short-lived replacement compound ozone effects are summarized as follows. The degradation of nPB produces a significant quantity of bromoacetone which increases the amount of bromine transported to the stratosphere due to nPB. However, much of that effect is not due to bromoacetone itself, but instead to inorganic bromine which is produced from tropospheric oxidation of nPB, bromoacetone, and other degradation products and is transported above the dry and wet deposition processes of the model. The MOZART2 nPB results indicate a minimal correction of the

  1. Dihydrocodeine/Agonists for Alcohol Dependents

    PubMed Central

    Ulmer, Albrecht; Müller, Markus; Frietsch, Bernhard

    2012-01-01

    Objective: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14 years, we have prescribed such substances with own addictive character for these patients. Methods: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC) to 102 heavily alcohol addicted patients, later, also Buprenorphine, Clomethiazole (>6 weeks), Baclofen, and in one case Amphetamine, each on individual indication. This paper focuses on the data with DHC, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. Results: The 102 patients with the DHC treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4 years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-steps scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2 years. The demand for medically assisted detoxifications in the 2 years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6 U/l at baseline to 66.8 U/l after 2 years. Experiences with the other substances are similar but different in details. Conclusion: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around 1/4 of the patients already. Many further

  2. Synthesis, X-ray crystal structure and optical properties of novel 5-(3-aryl-1 H-pyrazol-5-yl)-2-(6-methoxy-3-methylbenzofuran-2-yl)-1,3,4-oxadiazole

    NASA Astrophysics Data System (ADS)

    Jiang, Zhen-Ju; Liu, Jin-Ting; Lv, Hong-Shui; Zhao, Bao-Xiang

    2012-02-01

    A series of novel 5-(3-aryl-1 H-pyrazol-5-yl)-2-(6-methoxy-3-methylbenzofuran-2-yl)-1,3,4-oxadiazole derivatives has been synthesized from 6-methoxy-3-methylbenzofuran-2-carboxylic acid and ethyl 3-aryl-1 H-pyrazole-5-carboxylate. The structures of compounds obtained were determined by IR, 1H NMR and HRMS spectra. Typically, the spatial structure of compound 7e was determined by using X-ray diffraction analysis. UV-vis absorption and fluorescence spectral characteristics of the compounds in dichloromethane and acetonitrile were investigated. The results showed that the absorption maxima of the compounds vary from 321 to 339 nm depending on the substituents in N-1 position of pyrazole moiety and para position of benzene moiety. The maximum emission spectra of compounds in two different solvents were mainly dependent on groups in N-1 position of pyrazole moiety. The intensity of absorption and fluorescence was also correlated with substituents on the aryl ring bonded to pyrazole moiety. In addition, the absorption and emission spectra of these compounds change with increasing solvent polarity.

  3. Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist

    PubMed Central

    Taylor, A M W; Roberts, K W; Pradhan, A A; Akbari, H A; Walwyn, W; Lutfy, K; Carroll, F I; Cahill, C M; Evans, C J

    2015-01-01

    BACKGROUND AND PURPOSE The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the μ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. EXPERIMENTAL APPROACH We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. KEY RESULTS Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg−1), unmasked etorphine (3 mg·kg−1) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg−1) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg−1) and diazepam (1 mg·kg−1). CONCLUSIONS AND IMPLICATIONS Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles

  4. Ligand effects on the structure and magnetic properties of alternating copper(II) chains with 2,2'-bipyrimidine- and polymethyl-substituted pyrazolates as bridging ligands.

    PubMed

    Castro, Isabel; Calatayud, M Luisa; Barros, Wdeson P; Carranza, José; Julve, Miguel; Lloret, Francesc; Marino, Nadia; De Munno, Giovanni

    2014-06-02

    A novel series of heteroleptic copper(II) compounds of formulas {[Cu2(μ-H2O)(μ-pz)2(μ-bpm)(ClO4)(H2O)]ClO4·2H2O}n (1), {[Cu2(μ-H2O)(μ-3-Mepz)2(μ-bpm)](ClO4)2·2H2O}n (2), and {[Cu2(μ-OH)(μ-3,5-Me2pz)(μ-bpm)(H-3,5-Me2pz)2](ClO4)2}n (3) [bpm = 2,2'-bipyrimidine, Hpz = pyrazole, H-3-Mepz = 3-methylpyrazole, and H-3,5-Me2pz = 3,5-dimethylpyrazole] have been synthesized and structurally characterized by X-ray diffraction methods. The crystal structures of 1 and 2 consist of copper(II) chains with regular alternating bpm and bis(pyrazolate)(aqua) bridges, whereas that of 3 is made up of copper(II) chains with regular alternating bpm and (pyrazolate)(hydroxo) bridges. The copper centers are six- (1) or five-coordinate (2) in axially elongated, octahedral (1) or square-pyramidal (2) environments in 1 and 2, whereas they are five-coordinate in distorted trigonal-bipyramidal surroundings in 3. The values of the copper-copper separations across the bpm/pyrazolate bridges are 5.5442(7)/3.3131(6) (1), 5.538(1)/3.235(1) (2), and 5.7673(7)/3.3220(6) Å (3). The magnetic properties of 1-3 have been investigated in the temperature range of 25-300 K. The analysis of their magnetic susceptibility data through the isotropic Hamiltonian for an alternating antiferromagnetic copper(II) chain model [H = -J∑i=1-n/2 (S2i·S2i-1 + αS2i·S2i+1), with α = J'/J and Si = SCu = 1/2] reveals the presence of a strong to moderate antiferromagnetic coupling through the bis(pyrazolate)(aqua) [-J = 217 (1) and 215 cm(-1) (2)] and (pyrazolate)(hydroxo) bridges [-J = 153 cm(-1) (3)], respectively, whereas a strong to weak antiferromagnetic coupling occurs through the bis-bidentate bpm [-J' = 211 (1), 213 (2), and 44 cm(-1) (3)]. A simple orbital analysis of the magnetic exchange interaction within the bpm- and pyrazolate-bridged dicopper(II) fragments of 1-3 visualizes the σ-type pathways involving the (dx(2)-y(2)) (1 and 2) or d(z(2)) (3) magnetic orbitals on each metal ion, which account

  5. GABA receptor agonists: pharmacological spectrum and therapeutic actions.

    PubMed

    Bartholini, G

    1985-01-01

    From the data discussed in this review it appears that GABA receptor agonists exhibit a variety of actions in the central nervous system, some of which are therapeutically useful (Table V). GABA receptor agonists, by changing the firing rate of the corresponding neurons accelerate noradrenaline turnover without changes in postsynaptic receptor density and diminish serotonin liberation with an up-regulation of 5HT2 receptors. These effects differ from those of tricyclic antidepressants which primarily block monoamine re-uptake and cause down-regulation of beta-adrenergic and 5HT2 receptors. The GABA receptor agonist progabide has been shown to exert an antidepressant action which is indistinguishable from that of imipramine in patients with major affective disorders. The fact that: (a) GABA receptor agonists and tricyclic antidepressants affect noradrenergic and serotonergic transmission differently; and (b) tricyclic antidepressants alter GABA-related parameters challenges the classical monoamine hypothesis of depression and suggests that GABA-mediated mechanisms play a role in mood disorders. Decreases in cellular excitability produced by GABAergic stimulation leads to control of seizures in practically all animal models of epilepsy. GABA receptor agonists have a wide spectrum as they antagonize not only seizures which are dependent on decreased GABA synaptic activity but also convulsant states which are apparently independent of alterations in GABA-mediated events. These results in animals are confirmed in a wide range of human epileptic syndromes. GABA receptor agonists decrease dopamine turnover in the basal ganglia and antagonize neuroleptic-induced increase in dopamine release. On repeated treatment, progabide prevents or reverses the neuroleptic-induced up-regulation of dopamine receptors in the rat striatum and antagonizes the concomitant supersensitivity to dopaminomimetics. Behaviorally, GABA receptor agonists diminish the stereotypies induced by

  6. Preconcentration and determination of mercury(II) at a chemically modified electrode containing 3-(2-thioimidazolyl)propyl silica gel.

    PubMed

    Dias Filho, Newton L; do Carmo, Devaney R; Caetano, Laércio; Rosa, André H

    2005-11-01

    A mercury-sensitive chemically modified graphite paste electrode was constructed by incorporating modified silica gel into a conventional graphite paste electrode. The functional group attached to the (3-chloropropyl) silica gel surface was 2-mercaptoimidazole, giving a new product denoted by 3-(2-thioimidazolyl)propyl silica gel, which is able to complex mercury ions. Mercury was chemically adsorbed on the modified graphite paste electrode containing 3-(2-thioimidazolyl)propyl silica (TIPSG GPE) by immersion in a Hg(II) solution, and the resultant surface was characterized by cyclic and differential pulse anodic stripping voltammetry. One cathodic peak at 0.1 V and other anodic peak at 0.34 V were observed on scanning the potential from -0.1 to 0.8 V (0.01 M KNO3; v = 2.0 mV s(-1) vs. Ag/AgCl). The anodic peak at 0.34 V show an excellent sensitivity for Hg(II) ions in the presence of several foreign ions. A calibration graph covering the concentration range from 0.02 to 2 mg L(-1) was obtained. The detection limit was estimated to be 5 microg L(-1). The precision for six determinations of 0.05 and 0.26 mg L(-1) Hg(II) was 3.0 and 2.5% (relative standard deviation), respectively. The method can be used to determine the concentration of mercury(II) in natural waters contaminated by this metal.

  7. Novel copper(II) complex of N-propyl-norfloxacin and 1,10-phenanthroline with enhanced antileukemic and DNA nuclease activities.

    PubMed

    Katsarou, Maria E; Efthimiadou, Eleni K; Psomas, George; Karaliota, Alexandra; Vourloumis, Dionisios

    2008-02-14

    We have synthesized and characterized a novel copper(II) complex of the fluoroquinolone antibacterial drug N-propyl-norfloxacin (Hpr-norf) in the presence of 1,10-phenanthroline (Phen) and studied its biological properties as antitumor antibiotic and antimicrobial agent. Human acute myeloid leukemia cell line HL-60, MTT assay, and Trypan blue assay were used to test the antileukemic, the cell viability, and the structural integrity of the cell membrane and cell proliferation properties of (chloro)(Phen)( N-propyl-norfloxacinato)copper(II) (complex 1), respectively. We found that the proliferation rate and viability of HL-60 cells decreased after treatment with complex 1, leading to cell death through apoptosis in a time-dependent manner. The antimicrobial activity of complex 1 has been tested, revealing an increased potency in comparison to the free Hpr-norf. Complex 1 proved to be capable of acting as an independent nuclease by inducing nicking of supercoiled pUC19 plasmid. Our results suggest that 1 may provide a valuable tool in cancer chemotherapy.

  8. Silica chemically bonded N-propyl kriptofix 21 and 22 with immobilized palladium nanoparticles for solid phase extraction and preconcentration of some metal ions.

    PubMed

    Ghaedi, Mehrorang; Niknam, Khodabakhsh; Zamani, Saeed; Larki, Habib Abasi; Roosta, Mostafa; Soylak, Mustafa

    2013-08-01

    Silica gel chemically bonded N-propyl kriptofix 21 (SBNPK 21) and N-propyl kriptofix 22 (SBNPK 22) and subsequently immobilized with palladium nanoparticles (PNP-SBNPK 21 and PNP-SBNPK 22) to produce two new complexing lipophilic materials. Then these novel sorbents were applied for the enrichment of some metal ions and their subsequent determination by flame atomic absorption spectroscopy (FAAS). The influences of the variables including pH, amount of solid phase, sample flow rate, eluent conditions and sample volume on the metal ion recoveries were investigated. The detection limit of proposed method was in the interval 2.1-2.3 and 1.7-2.8 ng mL(-1) for PNP-SBNPK 21 and PNP-SBNPK 22 respectively, while the preconcentration factor was 80 for two sorbents. The relative standard deviations of recoveries were between 1.23-1.31 and 1.28-1.49 for PNP-SBNPK 21 and PNP-SBNPK 22 respectively. The method has high sorption-preconcentration efficiency even in the presence of various interfering ions. Due to the reasonable selectivity of proposed method, the relative standard deviation of recoveries of all understudied metal ions in some complicated matrices was less than 3.0%.

  9. Intracerebroventricular administration of kappa-agonists induces convulsions in mice.

    PubMed

    Bansinath, M; Ramabadran, K; Turndorf, H; Shukla, V K

    1991-07-01

    Intracerebroventricular (ICV) administration of kappa-agonists (PD 117302, U-50488H and U-69593) induced convulsions in a dose-related manner in mice. The dose at which 50% of animals convulsed (CD50) was in nmol ranges for all opioids. Among the opioids used, PD 117302 was the most potent convulsant. ICV administration of either vehicle alone or U-53445E, a non-kappa-opioid (+) enantiomer of U-50488H did not induce convulsions. The convulsive response of kappa-agonists was differentially susceptible for antagonism by naloxone and/or MR 2266. Collectively, these findings support the view that convulsions induced by kappa-agonists in mice involve stereospecific opioid receptor mechanisms. Furthermore, the convulsant effect of kappa-agonists could not be modified by pretreatment with MK-801, ketamine, muscimol or baclofen. It is concluded that kappa-opioid but not NMDA or GABA receptor mechanisms are involved in convulsions induced by kappa-agonists. These results are the first experimental evidence implicating stereospecific kappa-receptor mechanisms in opioid-induced convulsions in mice.

  10. Modification of opiate agonist binding by pertussis toxin

    SciTech Connect

    Abood, M.E.; Lee, N.M.; Loh, H.H.

    1986-03-05

    Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in /sup 3/(H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding.

  11. Coordination chemistry of platinum and palladium in the solid-state: synthesis of imidazole and pyrazole complexes.

    PubMed

    Adams, Christopher J; Haddow, Mairi F; Hughes, Robert J I; Kurawa, Mukhtar A; Orpen, A Guy

    2010-04-21

    Solid-state reactions of palladium(II) and platinum(II) chloride complexes with imidazole (Him) and pyrazole (Hpz) or their hydrochloride salts are shown to produce metal complex salts and coordination compounds. Thus, K(2)[MCl(4)] or MCl(2) can be ground with imidazolium chloride ([H(2)im]Cl) to produce the salts [H(2)im](2)[MCl(4)] (M = Pd, 1; Pt, 5), which can then be dehydrochlorinated in the solid state to produce the coordination compounds trans-[PdCl(2)(Him)(2)] 3 or cis-[PtCl(2)(Him)(2)] 6. The complex cis-[PdCl(2)(Him)(2)] 2 is produced when Pd(OAc)(2) is ground with [H(2)im]Cl. Reaction of platinum chloride reagents with imidazole (Him) also produces cis-[PtCl(2)(Him)(2)] 6, but reaction of imidazole with analogous palladium chloride reagents first produces [Pd(Him)(4)]Cl(2) 4 which then slowly converts to trans-[PdCl(2)(Him)(2)] 3. Grinding pyrazolium chloride with K(2)[MCl(4)] produces [H(2)pz](2)[MCl(4)] (M = Pd, 7; Pt, 10), which may also be dehydrochlorinated in the solid state to produce the coordination compounds trans-[PdCl(2)(Hpz)(2)] 8 or cis-[PtCl(2)(Hpz)(2)] 11. Grinding K(2)[PdCl(4)] or PdCl(2) with pyrazole gives [Pd(Hpz)(4)]Cl(2) 9, which is then slowly converted into trans-[PdCl(2)(Hpz)(2)] 8. Grinding PtCl(2) with Hpz generates [Pt(Hpz)(4)]Cl(2) 12, but using K(2)PtCl(4) as the metal source does not generate the same product. The single-crystal structures of 8, a new polymorph of 11 and [H(2)pz](2)[PtCl(6)].2H(2)O (isolated as a decomposition product) are reported for the first time, and the structures of 5 and 10 have been solved ab ibitio from XRPD data.

  12. Blue-emitting platinum(II) complexes bearing both pyridylpyrazolate chelate and bridging pyrazolate ligands: synthesis, structures, and photophysical properties.

    PubMed

    Chang, Sheng-Yuan; Chen, Jing-Lin; Chi, Yun; Cheng, Yi-Ming; Lee, Gene-Hsiang; Jiang, Chang-Ming; Chou, Pi-Tai

    2007-12-24

    A new Pt(II) dichloride complex [Pt(fppzH)Cl2] (1), in which fppzH = 3-(trifluoromethyl)-5-(2-pyridyl)pyrazole, was prepared by the treatment of a pyridylpyrazole chelate fppzH with K2PtCl4 in aqueous HCl solution. Complex 1 could further react with its parent pyrazole (pzH), 3,5-dimethylpyrazole (dmpzH), or 3,5-di-tert-butylpyrazole (dbpzH) to afford the monometallic [Pt(fppz)(pzH)Cl] (2), [Pt(fppz)(dmpzH)Cl] (3), [Pt(fppz)(dmpzH)2]Cl (4), or two structural isomers with formula [Pt(fppz)(dbpzH)Cl] (5a,b). Single-crystal X-ray diffraction studies of 2, 4, and 5a,b revealed a square planar Pt(II) framework, among which a strong interligand hydrogen bonding occurred between fppz and pzH ligands in 2. This interligand H-bonding is replaced by dual N-H...Cl interaction in 4 and both intermolecular N-H...O (with THF solvate) and N-H...Cl interaction in 5a,b, respectively; the latter are attributed to the bulky tert-butyl substituents that force the dbpzH ligand to adopt the perpendicular arrangement. Furthermore, complex 2 underwent rapid deprotonation in basic media to afford two isomeric complexes with formula [Pt(fppz)(mu-pz)]2 (6a,b), which are related to each other according to the spatial orientation of the fppz chelates, i.e., trans- and cis-isomerism. Similar reaction exerted on 3 afforded isomers 7a,b. Both 6a,b (7a,b) are essentially nonemissive in room-temperature fluid state but afford strong blue phosphorescence in solid state prepared via either vacuum-deposited thin film or 77 K CH2Cl2 matrix. As also supported by the computational approaches, the nature of emission has been assigned to be ligand-centered triplet pipi* mixed with certain metal-to-ligand charge-transfer character.

  13. Substituent directed selectivity in anion recognition by a new class of simple osmium-pyrazole derived receptors.

    PubMed

    Das, Ankita; Mondal, Prasenjit; Dasgupta, Moumita; Kishore, Nand; Lahiri, Goutam Kumar

    2016-02-14

    The present article deals with the structurally, spectroscopically and electrochemically characterised osmium-bipyridyl derived complexes [(bpy)2Os(II)(HL1)Cl]ClO4 [1]ClO4 and [(bpy)2Os(II)(HL2)Cl]ClO4 [2]ClO4 incorporating neutral and monodentate pyrazole derivatives (HL) with one free NH function (bpy = 2,2'-bipyridine, HL1 = pyrazole, HL2 = 3,5-dimethylpyrazole). The crystal structures of [1]ClO4 and [2]ClO4 reveal intramolecular hydrogen bonding interactions between the free NH proton of HL and the equatorially placed Cl(-) ligand (N-HCl) with donor-acceptor distances of 3.114(7) Å and 3.153(6) Å as well as intermolecular hydrogen bonding interactions between the NH proton and one of the oxygen atoms of ClO4(-) (N-HO) with donor-acceptor distances of 2.870(10) Å and 3.024(8) Å, respectively. The effect of hydrogen bonding interactions has translated into the less acidic nature of the NH proton of the coordinated HL with estimated pKa > 12. 1(+) and 2(+) exhibit reversible Os(II)/(III) and irreversible Os(III)/(IV) processes in CH3CN within ± 2.0 V versus SCE. The effect of 3,5-dimethyl substituted HL2 on 2(+) has been reflected in the appreciable lowering (40 mV) of the Os(II/III) potential, along with the further decrease in the acidity of the NH proton (pKa > 13.0) with regard to HL1 coordinated 1(+) (pKa: ∼ 12.3). The electronic spectral features of Os(ii) (1(+)/2(+)) and electrochemically generated Os(III) (1(2+)/2(2+)) derived complexes have been analysed by TD-DFT calculations. The efficacy of the 1(+) and 2(+) encompassing free NH proton towards the anion recognition process has been evaluated by different experimental investigations using a wide variety of anions. It however establishes that receptor 1(+) can recognise both F(-) and OAc(-) in acetonitrile solution, while 2(+) is exclusively selective for the F(-) ion.

  14. Increased complexity in interstellar chemistry: detection and chemical modeling of ethyl formate and n-propyl cyanide in Sagittarius B2(N)

    NASA Astrophysics Data System (ADS)

    Belloche, A.; Garrod, R. T.; Müller, H. S. P.; Menten, K. M.; Comito, C.; Schilke, P.

    2009-05-01

    Context: In recent years, organic molecules of increasing complexity have been found toward the prolific Galactic center source Sagittarius B2. Aims: We wish to explore the degree of complexity that the interstellar chemistry can reach in star-forming regions. Methods: We carried out a complete line survey of the hot cores Sgr B2(N) and (M) with the IRAM 30 m telescope in the 3 mm range, plus partial surveys at 2 and 1.3 mm. We analyzed this spectral survey in the local thermodynamical equilibrium approximation. We modeled the emission of all known molecules simultaneously, which allows us to search for less abundant, more complex molecules. We compared the derived column densities with the predictions of a coupled gas-phase and grain-surface chemical code. Results: We report the first detection in space of ethyl formate (C2H5OCHO) and n-propyl cyanide (C3H7CN) toward Sgr B2(N). The detection of n-propyl cyanide is based on refined spectroscopic parameters derived from combined analyses of available laboratory spectroscopic data. For each molecule, we identified spectral features at the predicted frequencies having intensities compatible with a unique rotation temperature. For an assumed source size of 3 arcsec, our modeling yields a column density of 5.4 × 1016 cm-2, a temperature of 100 K, and a linewidth of 7 km s-1 for ethyl formate. n-Propyl cyanide is detected with two velocity components having column densities of 1.5 × 1016 cm-2 and 6.6 × 1015 cm-2, respectively, for a source size of 3 arcsec, a temperature of 150 K, and a linewidth of 7 km s-1. The abundances of ethyl formate and n-propyl cyanide relative to H2 are estimated to be 3.6 × 10-9 and 1.0 × 10-9, respectively. We derived column density ratios of 0.8/15/1 for the related species t-HCOOH/CH3OCHO/C2H5OCHO and 108/80/1 for CH3CN/C2H5CN/C3H7CN. Our chemical modeling reproduces these ratios reasonably well. It suggests that the sequential, piecewise construction of ethyl and n-propyl cyanide from

  15. 4-Alkyloxyimino Derivatives of Uridine-5′-triphosphate: Distal Modification of Potent Agonists as a Strategy for Molecular Probes of P2Y2, P2Y4, and P2Y6 Receptors

    PubMed Central

    2015-01-01

    Extended N4-(3-arylpropyl)oxy derivatives of uridine-5′-triphosphate were synthesized and potently stimulated phospholipase C stimulation in astrocytoma cells expressing G protein-coupled human (h) P2Y receptors (P2YRs) activated by UTP (P2Y2/4R) or UDP (P2Y6R). The potent P2Y4R-selective N4-(3-phenylpropyl)oxy agonist was phenyl ring-substituted or replaced with terminal heterocyclic or naphthyl rings with retention of P2YR potency. This broad tolerance for steric bulk in a distal region was not observed for dinucleoside tetraphosphate agonists with both nucleobases substituted. The potent N4-(3-(4-methoxyphenyl)-propyl)oxy analogue 19 (EC50: P2Y2R, 47 nM; P2Y4R, 23 nM) was functionalized for chain extension using click tethering of fluorophores as prosthetic groups. The BODIPY 630/650 conjugate 28 (MRS4162) exhibited EC50 values of 70, 66, and 23 nM at the hP2Y2/4/6Rs, respectively, and specifically labeled cells expressing the P2Y6R. Thus, an extended N4-(3-arylpropyl)oxy group accessed a structurally permissive region on three Gq-coupled P2YRs, and potency and selectivity were modulated by distal structural changes. This freedom of substitution was utilized to design of a pan-agonist fluorescent probe of a subset of uracil nucleotide-activated hP2YRs. PMID:24712832

  16. Novel nonsecosteroidal VDR agonists with phenyl-pyrrolyl pentane skeleton.

    PubMed

    Shen, Wei; Xue, Jingwei; Zhao, Zekai; Zhang, Can

    2013-11-01

    In order to find the vitamin D receptor (VDR) ligand whose VDR agonistic activity is separated from the calcemic activity sufficiently, novel nonsecosteroidal analogs with phenyl-pyrrolyl pentane skeleton were synthesized and evaluated for the VDR binding affinity, antiproliferative activity in vitro and serum calcium raising ability in vivo (tacalcitol used as control). Among them, several compounds showed varying degrees of VDR agonistic and growth inhibition activities of the tested cell lines. The most effective compound 2g (EC₅₀: 1.06 nM) exhibited stronger VDR agonistic activity than tacalcitol (EC₅₀: 7.05 nM), inhibited the proliferations of HaCaT and MCF-7 cells with IC₅₀ of 2.06 μM and 0.307 μM (tacalcitol: 2.07 μM and 0.057 μM) and showed no significant effect on serum calcium.

  17. Compulsive eating and weight gain related to dopamine agonist use.

    PubMed

    Nirenberg, Melissa J; Waters, Cheryl

    2006-04-01

    Dopamine agonists have been implicated in causing compulsive behaviors in patients with Parkinson's disease (PD). These have included gambling, hypersexuality, hobbyism, and other repetitive, purposeless behaviors ("punding"). In this report, we describe 7 patients in whom compulsive eating developed in the context of pramipexole use. All of the affected patients had significant, undesired weight gain; 4 had other comorbid compulsive behaviors. In the 5 patients who lowered the dose of pramipexole or discontinued dopamine agonist treatment, the behavior remitted and no further weight gain occurred. Physicians should be aware that compulsive eating resulting in significant weight gain may occur in PD as a side-effect of dopamine agonist medications such as pramipexole. Given the known risks of the associated weight gain and obesity, further investigation is warranted.

  18. Captive female gorilla agonistic relationships with clumped defendable food resources.

    PubMed

    Scott, Jennifer; Lockard, Joan S

    2006-07-01

    Minimal feeding competition among female mountain gorillas (Gorilla gorilla beringei) has resulted in egalitarian social relationships with poorly defined agonistic dominance hierarchies. Thus, gorillas are generally viewed as non-competitive egalitarian folivores that have had little need to develop effective competitive strategies to access food resources. However, this generalization is inconsistent with more recent research indicating that most gorillas are frugivorous, feeding on patchily distributed food resources. The current study at Howletts Wild Animal Park, Kent, England, explores the effects of clumped and defendable foods on female gorilla agonistic relationships among three groups of western lowland gorillas (G. g. gorilla), conditions that are predicted to lead to well-differentiated agonistic dominance hierarchies among female primates. The Howletts gorillas foraged all day on low-energy/-nutrient, high-fiber foods widely distributed around their enclosure by the keepers. However, they also had periodic access to high-energy foods (e.g., nuts, raisins, strawberries, etc.) that the keepers would spread in a clumped and defendable patch. Frequencies of agonistic and submissive behaviors between females and proximity data were gathered. High-status females were found to monopolize the food patch and kept the low-status females at bay with cough-grunt threat vocalizations or by chasing them away. Agonistic interactions were initiated mostly by females of high status; these were directed towards females of low status and were generally not reciprocal. In addition, females of low status engaged in submissive behaviors the most often, which they directed primarily at females of high status, especially in response to aggression by the latter. Agonistic interactions between high- and low-status females had decided outcomes more often than not, with low-status females the losers. Competition over highly desirable foods distributed in defendable clumps at

  19. Switching cannabinoid response from CB(2) agonists to FAAH inhibitors.

    PubMed

    Tourteau, Aurélien; Leleu-Chavain, Natascha; Body-Malapel, Mathilde; Andrzejak, Virginie; Barczyk, Amélie; Djouina, Madjid; Rigo, Benoit; Desreumaux, Pierre; Chavatte, Philippe; Millet, Régis

    2014-03-01

    A series of 3-carboxamido-5-aryl-isoxazoles designed as CB2 agonists were evaluated as FAAH inhibitors. The pharmacological results led to identify structure-activity relationships enabling to switch cannabinoid response from CB2 agonists to FAAH inhibitors. Two compounds were selected for their FAAH and/or CB2 activity, and evaluated in a colitis model for their anti-inflammatory activity. Results showed that compounds 10 and 11 inhibit the development of DSS-induced acute colitis in mice and then, are interesting leads to explore new drug candidates for IBD.

  20. Partial agonistic action of endomorphins in the mouse spinal cord.

    PubMed

    Mizoguchi, H; Wu, H E; Narita, M

    2001-09-07

    The partial agonistic properties of endogenous mu-opioid peptides endomorphin-1 and endomorphin-2 for G-protein activation were determined in the mouse spinal cord, monitoring the increases in guanosine-5'-o-(3-[35S]thio)triphosphate binding. The G-protein activation induced by endogenous opioid peptide beta-endorphin in the spinal cord was significantly, but partially, attenuated by co-incubation with endomorphin-1 or endomorphin-2. The data indicates that endomorphin-1 and endomorphin-2 are endogenous partial agonists for mu-opioid receptor in the mouse spinal cord.