Alkylating Agent-Induced NRF2 Blocks Endoplasmic Reticulum Stress-Mediated Apoptosis via Control of Glutathione Pools and Protein Thiol Homeostasis.

PubMed

Zanotto-Filho, Alfeu; Masamsetti, V Pragathi; Loranc, Eva; Tonapi, Sonal S; Gorthi, Aparna; Bernard, Xavier; Gonçalves, Rosângela Mayer; Moreira, José C F; Chen, Yidong; Bishop, Alexander J R

2016-12-01

Alkylating agents are a commonly used cytotoxic class of anticancer drugs. Understanding the mechanisms whereby cells respond to these drugs is key to identify means to improve therapy while reducing toxicity. By integrating genome-wide gene expression profiling, protein analysis, and functional cell validation, we herein demonstrated a direct relationship between NRF2 and Endoplasmic Reticulum (ER) stress pathways in response to alkylating agents, which is coordinated by the availability of glutathione (GSH) pools. GSH is essential for both drug detoxification and protein thiol homeostasis within the ER, thus inhibiting ER stress induction and promoting survival, an effect independent of its antioxidant role. NRF2 accumulation induced by alkylating agents resulted in increased GSH synthesis via GCLC/GCLM enzyme, and interfering with this NRF2 response by either NRF2 knockdown or GCLC/GCLM inhibition with buthionine sulfoximine caused accumulation of damaged proteins within the ER, leading to PERK-dependent apoptosis. Conversely, upregulation of NRF2, through KEAP1 depletion or NRF2-myc overexpression, or increasing GSH levels with N-acetylcysteine or glutathione-ethyl-ester, decreased ER stress and abrogated alkylating agents-induced cell death. Based on these results, we identified a subset of lung and head-and-neck carcinomas with mutations in either KEAP1 or NRF2/NFE2L2 genes that correlate with NRF2 target overexpression and poor survival. In KEAP1-mutant cancer cells, NRF2 knockdown and GSH depletion increased cell sensitivity via ER stress induction in a mechanism specific to alkylating drugs. Overall, we show that the NRF2-GSH influence on ER homeostasis implicates defects in NRF2-GSH or ER stress machineries as affecting alkylating therapy toxicity. Mol Cancer Ther; 15(12); 3000-14. ©2016 AACR. ©2016 American Association for Cancer Research.

Direct Aldehyde C-H Arylation and Alkylation via the Combination of Nickel, Hydrogen Atom Transfer, and Photoredox Catalysis.

PubMed

Zhang, Xiaheng; MacMillan, David W C

2017-08-23

A mechanism that enables direct aldehyde C-H functionalization has been achieved via the synergistic merger of photoredox, nickel, and hydrogen atom transfer catalysis. This mild, operationally simple protocol transforms a wide variety of commercially available aldehydes, along with aryl or alkyl bromides, into the corresponding ketones in excellent yield. This C-H abstraction coupling technology has been successfully applied to the expedient synthesis of the medicinal agent haloperidol.

Distributed Drug Discovery, Part 2: Global Rehearsal of Alkylating Agents for the Synthesis of Resin-Bound Unnatural Amino Acids and Virtual D3 Catalog Construction

PubMed Central

2008-01-01

Distributed Drug Discovery (D3) proposes solving large drug discovery problems by breaking them into smaller units for processing at multiple sites. A key component of the synthetic and computational stages of D3 is the global rehearsal of prospective reagents and their subsequent use in the creation of virtual catalogs of molecules accessible by simple, inexpensive combinatorial chemistry. The first section of this article documents the feasibility of the synthetic component of Distributed Drug Discovery. Twenty-four alkylating agents were rehearsed in the United States, Poland, Russia, and Spain, for their utility in the synthesis of resin-bound unnatural amino acids 1, key intermediates in many combinatorial chemistry procedures. This global reagent rehearsal, coupled to virtual library generation, increases the likelihood that any member of that virtual library can be made. It facilitates the realistic integration of worldwide virtual D3 catalog computational analysis with synthesis. The second part of this article describes the creation of the first virtual D3 catalog. It reports the enumeration of 24 416 acylated unnatural amino acids 5, assembled from lists of either rehearsed or well-precedented alkylating and acylating reagents, and describes how the resulting catalog can be freely accessed, searched, and downloaded by the scientific community. PMID:19105725

Hybrid ligand-alkylating agents targeting telomeric G-quadruplex structures.

PubMed

Doria, Filippo; Nadai, Matteo; Folini, Marco; Di Antonio, Marco; Germani, Luca; Percivalle, Claudia; Sissi, Claudia; Zaffaroni, Nadia; Alcaro, Stefano; Artese, Anna; Richter, Sara N; Freccero, Mauro

2012-04-14

The synthesis, physico-chemical properties and biological effects of a new class of naphthalene diimides (NDIs) capable of reversibly binding telomeric DNA and alkylate it through an electrophilic quinone methide moiety (QM), are reported. FRET and circular dichroism assays showed a marked stabilization and selectivity towards telomeric G4 DNA folded in a hybrid topology. NDI-QMs' alkylating properties revealed a good reactivity on single nucleosides and selectivity towards telomeric G4. A selected NDI was able to significantly impair the growth of melanoma cells by causing telomere dysfunction and down-regulation of telomerase expression. These findings points to our hybrid ligand-alkylating NDIs as possible tools for the development of novel targeted anticancer therapies. This journal is © The Royal Society of Chemistry 2012

Α-aryl-N-alkyl nitrones, as potential agents for stroke treatment: synthesis, theoretical calculations, antioxidant, anti-inflammatory, neuroprotective, and brain-blood barrier permeability properties.

PubMed

Chioua, Mourad; Sucunza, David; Soriano, Elena; Hadjipavlou-Litina, Dimitra; Alcázar, Alberto; Ayuso, Irene; Oset-Gasque, María Jesús; González, María Pilar; Monjas, Leticia; Rodríguez-Franco, María Isabel; Marco-Contelles, José; Samadi, Abdelouahid

2012-01-12

We report the synthesis, theoretical calculations, the antioxidant, anti-inflammatory, and neuroprotective properties, and the ability to cross the blood-brain barrier (BBB) of (Z)-α-aryl and heteroaryl-N-alkyl nitrones as potential agents for stroke treatment. The majority of nitrones compete with DMSO for hydroxyl radicals, and most of them are potent lipoxygenase inhibitors. Cell viability-related (MTT assay) studies clearly showed that nitrones 1-3 and 10 give rise to significant neuroprotection. When compounds 1-11 were tested for necrotic cell death (LDH release test) nitrones 1-3, 6, 7, and 9 proved to be neuroprotective agents. In vitro evaluation of the BBB penetration of selected nitrones 1, 2, 10, and 11 using the PAMPA-BBB assay showed that all of them cross the BBB. Permeable quinoline nitrones 2 and 3 show potent combined antioxidant and neuroprotective properties and, therefore, can be considered as new lead compounds for further development in specific tests for potential stroke treatment.

Novel ascorbic acid based ionic liquids for the in situ synthesis of quasi-spherical and anisotropic gold nanostructures in aqueous medium.

PubMed

Dinda, Enakshi; Si, Satyabrata; Kotal, Atanu; Mandal, Tarun K

2008-01-01

A series of newly designed ascorbic acid based room temperature ionic liquids were successfully used to prepare quasi-spherical and anisotropic gold nanostructures in an aqueous medium at ambient temperature. The synthesis of these room temperature ionic liquids involves, first, the preparation of a 1-alkyl (such as methyl, ethyl, butyl, hexyl, octyl, and decyl) derivative of 3-methylimidazolium hydroxide followed by the neutralization of the derivatised product with ascorbic acid. These ionic liquids show significantly better thermal stability and their glass transition temperature (Tg) decreases with increasing alkyl chain length. The ascorbate counter anion of these ionic liquids acts as a reducing agent for HAuCl4 to produce metallic gold and the alkylated imidazolium counter cation acts as a capping/shape-directing agent. It has been found that the nature of the ionic liquids and the mole ratio of ionic liquid to HAuCl4 has a significant effect on the morphology of the formed gold nanostructures. If an equimolar mixture of ionic liquid and HAuCl4 is used, predominantly anisotropic gold nanostructures are formed and by varying the alkyl chain length attached to imidazolium cation of the ionic liquids, various particle morphologies can formed, such as quasispherical, raspberry-like, flakes or dendritic. A probable formation mechanism for such anisotropic gold nanostructures has been proposed, which is based on the results of some control experiments.

Synthesis and serotonin transporter activity of sulphur-substituted alpha-alkyl phenethylamines as a new class of anticancer agents.

PubMed

Cloonan, Suzanne M; Keating, John J; Butler, Stephen G; Knox, Andrew J S; Jørgensen, Anne M; Peters, Günther H; Rai, Dilip; Corrigan, Desmond; Lloyd, David G; Williams, D Clive; Meegan, Mary J

2009-12-01

The discovery that some serotonin reuptake transporter (SERT) ligands have the potential to act as pro-apoptotic agents in the treatment of cancer adds greatly to their diverse pharmacological application. 4-Methylthioamphetamine (MTA) is a selective ligand for SERT over other monoamine transporters. In this study, a novel library of structurally diverse 4-MTA analogues were synthesised with or without N-alkyl and/or C-alpha methyl or ethyl groups so that their potential SERT-dependent antiproliferative activity could be assessed. Many of the compounds displayed SERT-binding activity as well as cytotoxic activity. While there was no direct correlation between these two effects, a number of derivatives displayed anti-tumour effects in lymphoma, leukaemia and breast cancer cell lines, showing further potential to be developed as possible chemotherapeutic agents.

Involvement of Escherichia coli DNA Polymerase IV in Tolerance of Cytotoxic Alkylating DNA Lesions in Vivo

PubMed Central

Bjedov, Ivana; Dasgupta, Chitralekha Nag; Slade, Dea; Le Blastier, Sophie; Selva, Marjorie; Matic, Ivan

2007-01-01

Escherichia coli PolIV, a DNA polymerase capable of catalyzing synthesis past replication-blocking DNA lesions, belongs to the most ubiquitous branch of Y-family DNA polymerases. The goal of this study is to identify spontaneous DNA damage that is bypassed specifically and accurately by PolIV in vivo. We increased the amount of spontaneous DNA lesions using mutants deficient for different DNA repair pathways and measured mutation frequency in PolIV-proficient and -deficient backgrounds. We found that PolIV performs an error-free bypass of DNA damage that accumulates in the alkA tag genetic background. This result indicates that PolIV is involved in the error-free bypass of cytotoxic alkylating DNA lesions. When the amount of cytotoxic alkylating DNA lesions is increased by the treatment with chemical alkylating agents, PolIV is required for survival in an alkA tag-proficient genetic background as well. Our study, together with the reported involvement of the mammalian PolIV homolog, Polκ, in similar activity, indicates that Y-family DNA polymerases from the DinB branch can be added to the list of evolutionarily conserved molecular mechanisms that counteract cytotoxic effects of DNA alkylation. This activity is of major biological relevance because alkylating agents are continuously produced endogenously in all living cells and are also present in the environment. PMID:17483416

Synthesis of High-Load, Hybrid Silica-Immobilized Heterocyclic Benzyl Phosphate (Si–OHBP) and Triazolyl Phosphate (Si–OHTP) Alkylating Reagents

PubMed Central

2016-01-01

The development of new ROMP-derived silica-immobilized heterocyclic phosphate reagents and their application in purification-free protocols is reported. Grafting of norbornenyl norbornenyl-functionalized (Nb-tagged) silica particles with functionalized Nb-tagged heterocyclic phosphate monomers efficiently yield high-load, hybrid silica-immobilized oligomeric heterobenzyl phosphates (Si–OHBP) and heterotriazolyl phosphates (Si–OHTP) as efficient alkylation agents. Applications of these reagents for the diversification of N-, O-, and S-nucleophilic species, for efficient heterobenzylation and hetero(triazolyl)methylation have been validated. PMID:27300761

Direct reductive amination of aldehyde bisulfite adducts induced by 2-picoline borane: application to the synthesis of a DPP-IV inhibitor.

PubMed

Faul, Margaret; Larsen, Rob; Levinson, Adam; Tedrow, Jason; Vounatsos, Filisaty

2013-02-15

Aldehyde-bisulfite adducts dervied from unstable parent aldehydes were reductively alkylated in a direct fashion with a variety of amines. This approach features the use of 2-picoline borane as the reducing agent and a protic solvent for the reaction media and has been successfully applied to the synthesis of a DPP-IV inhibitor and a variety of other amines.

N-O chemistry for antibiotics: discovery of N-alkyl-N-(pyridin-2-yl)hydroxylamine scaffolds as selective antibacterial agents using nitroso Diels-Alder and ene chemistry.

PubMed

Wencewicz, Timothy A; Yang, Baiyuan; Rudloff, James R; Oliver, Allen G; Miller, Marvin J

2011-10-13

The discovery, syntheses, and structure-activity relationships (SAR) of a new family of heterocyclic antibacterial compounds based on N-alkyl-N-(pyridin-2-yl)hydroxylamine scaffolds are described. A structurally diverse library of ∼100 heterocyclic molecules generated from Lewis acid-mediated nucleophilic ring-opening reactions with nitroso Diels-Alder cycloadducts and nitroso ene reactions with substituted alkenes was evaluated in whole cell antibacterial assays. Compounds containing the N-alkyl-N-(pyridin-2-yl)hydroxylamine structure demonstrated selective and potent antibacterial activity against the Gram-positive bacterium Micrococcus luteus ATCC 10240 (MIC(90) = 2.0 μM or 0.41 μg/mL) and moderate activity against other Gram-positive strains including antibiotic resistant strains of Staphylococcus aureus (MRSA) and Enterococcus faecalis (VRE). A new synthetic route to the active core was developed using palladium-catalyzed Buchwald-Hartwig amination reactions of N-alkyl-O-(4-methoxybenzyl)hydroxylamines with 2-halo-pyridines that facilitated SAR studies and revealed the simplest active structural fragment. This work shows the value of using a combination of diversity-oriented synthesis (DOS) and parallel synthesis for identifying new antibacterial scaffolds.

N-O Chemistry for Antibiotics: Discovery of N-Alkyl-N-(pyridin-2-yl)hydroxylamine Scaffolds as Selective Antibacterial Agents Using Nitroso Diels-Alder and Ene Chemistry

PubMed Central

Wencewicz, Timothy A.; Yang, Baiyuan; Rudloff, James R.; Oliver, Allen G.; Miller, Marvin J.

2011-01-01

The discovery, syntheses, and structure-activity relationships (SAR) of a new family of heterocyclic antibacterial compounds based on N-alkyl-N-(pyridin-2-yl)hydroxylamine scaffolds are described. A structurally diverse library of ~100 heterocyclic molecules generated from Lewis acid-mediated nucleophilic ring opening reactions with nitroso Diels-Alder cycloadducts and nitroso ene reactions with substituted alkenes was evaluated in whole cell antibacterial assays. Compounds containing the N-alkyl-N-(pyridin-2-yl)hydroxylamine structure demonstrated selective and potent antibacterial activity against the Gram-positive bacterium Micrococcus luteus ATCC 10240 (MIC90 = 2.0 μM or 0.41 μg/mL) and moderate activity against other Gram-positive strains including antibiotic resistant strains of Staphylococcus aureus (MRSA) and Enterococcus faecalis (VRE). A new synthetic route to the active core was developed using palladium-catalyzed Buchwald-Hartwig amination reactions of N-alkyl-O-(4-methoxybenzyl)hydroxylamines with 2-halo-pyridines that facilitated SAR studies and revealed the simplest active structural fragment. This work shows the value of using a combination of diversity-oriented synthesis (DOS) and parallel synthesis for identifying new antibacterial scaffolds. PMID:21859126

Asymmetric intramolecular α-cyclopropanation of aldehydes using a donor/acceptor carbene mimetic

PubMed Central

Luo, Chaosheng; Wang, Zhen; Huang, Yong

2015-01-01

Enantioselective α-alkylation of carbonyl is considered as one of the most important processes for asymmetric synthesis. Common alkylation agents, that is, alkyl halides, are notorious substrates for both Lewis acids and organocatalysts. Recently, olefins emerged as a benign alkylating species via photo/radical mechanisms. However, examples of enantioselective alkylation of aldehydes/ketones are scarce and direct asymmetric dialkylation remains elusive. Here we report an intramolecular α-cyclopropanation reaction of olefinic aldehydes to form chiral cyclopropane aldehydes. We demonstrate that an α-iodo aldehyde can function as a donor/acceptor carbene equivalent, which engages in a formal [2+1] annulation with a tethered double bond. Privileged bicyclo[3.1.0]hexane-type scaffolds are prepared in good optical purity using a chiral amine. The synthetic utility of the products is demonstrated by versatile transformations of the bridgehead formyl functionality. We expect the concept of using α-iodo iminium as a donor/acceptor carbene surrogate will find wide applications in chemical reaction development. PMID:26644194

Recent Advances in Cyanamide Chemistry: Synthesis and Applications.

PubMed

Prabhath, M R Ranga; Williams, Luke; Bhat, Shreesha V; Sharma, Pallavi

2017-04-12

The application of alkyl and aryl substituted cyanamides in synthetic chemistry has diversified multi-fold in recent years. In this review, we discuss recent advances (since 2012) in the chemistry of cyanamides and detail their application in cycloaddition chemistry, aminocyanation reactions, as well as electrophilic cyanide-transfer agents and their unique radical and coordination chemistry.

Balancing repair and tolerance of DNA damage caused by alkylating agents.

PubMed

Fu, Dragony; Calvo, Jennifer A; Samson, Leona D

2012-01-12

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity.

SERIES: Genomic instability in cancer Balancing repair and tolerance of DNA damage caused by alkylating agents

PubMed Central

Fu, Dragony; Calvo, Jennifer A.; Samson, Leona D

2013-01-01

Alkylating agents comprise a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER), and mismatch repair (MMR) respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for an organism's favorable response to alkylating agents. Furthermore, an individual's response to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity. PMID:22237395

A Convenient Approach to Synthesizing Peptide C-Terminal N-Alkyl Amides

PubMed Central

Fang, Wei-Jie; Yakovleva, Tatyana; Aldrich, Jane V.

2014-01-01

Peptide C-terminal N-alkyl amides have gained more attention over the past decade due to their biological properties, including improved pharmacokinetic and pharmacodynamic profiles. However, the synthesis of this type of peptide on solid phase by current available methods can be challenging. Here we report a convenient method to synthesize peptide C-terminal N-alkyl amides using the well-known Fukuyama N-alkylation reaction on a standard resin commonly used for the synthesis of peptide C-terminal primary amides, the PAL-PEG-PS (Peptide Amide Linker-polyethylene glycol-polystyrene) resin. The alkylation and oNBS deprotection were conducted under basic conditions and were therefore compatible with this acid labile resin. The alkylation reaction was very efficient on this resin with a number of different alkyl iodides or bromides, and the synthesis of model enkephalin N-alkyl amide analogs using this method gave consistently high yields and purities, demonstrating the applicability of this methodology. The synthesis of N-alkyl amides was more difficult on a Rink amide resin, especially the coupling of the first amino acid to the N-alkyl amine, resulting in lower yields for loading the first amino acid onto the resin. This method can be widely applied in the synthesis of peptide N-alkyl amides. PMID:22252422

The Alkylating-HDAC Inhibition Fusion Principle: Taking Chemotherapy to the Next Level with the First in Class Molecule EDO-S101.

PubMed

Mehrling, Thomas; Chen, Yi

2016-01-01

Chemotherapy may still be an essential component to treat cancer in combination with new targeted therapies. But chemotherapy needs to get smarter in order to make those combination regimens more effective and also more tolerable, particularly for an aging population. We describe the first time the synthesis and pharmacological testing of a fusion molecule comprising of the alkylator bendamustine and the HDAC-inhibitor vorinostat. The drug was designed to allow for the exploitation of both mechanisms of action simultaneously with the goal to provide a molecule with superior efficacy over the single agents. The pharmacological testing confirms the full functional capacity of both moieties and encouraging pharmacological data raises the hope that the drug may turn out to be a great addition to the armentarium of anticancer agents.

Reaction of Orthoesters with Amine Hydrochlorides: An Introductory Organic Lab Experiment Combining Synthesis, Spectral Analysis, and Mechanistic Discovery

ERIC Educational Resources Information Center

Saba, Shahrokh; Ciaccio, James A.

2016-01-01

While orthoesters are often used by chemists as alkylating, acylating, and formylating agents, they are rarely encountered in introductory organic chemistry curricula. We describe a second-semester organic chemistry laboratory experiment in which students acetylate unknown amine hydrochloride salts with trimethyl orthoacetate (TMOA) in the absence…

3-bromopyruvate: a new targeted antiglycolytic agent and a promise for cancer therapy.

PubMed

Ganapathy-Kanniappan, S; Vali, M; Kunjithapatham, R; Buijs, M; Syed, L H; Rao, P P; Ota, S; Kwak, B K; Loffroy, R; Geschwind, J F

2010-08-01

The pyruvate analog, 3-bromopyruvate, is an alkylating agent and a potent inhibitor of glycolysis. This antiglycolytic property of 3-bromopyruvate has recently been exploited to target cancer cells, as most tumors depend on glycolysis for their energy requirements. The anticancer effect of 3-bromopyruvate is achieved by depleting intracellular energy (ATP) resulting in tumor cell death. In this review, we will discuss the principal mechanism of action and primary targets of 3-bromopyruvate, and report the impressive antitumor effects of 3-bromopyruvate in multiple animal tumor models. We describe that the primary mechanism of 3-bromopyruvate is via preferential alkylation of GAPDH and that 3-bromopyruvate mediated cell death is linked to generation of free radicals. Research in our laboratory also revealed that 3-bromopyruvate induces endoplasmic reticulum stress, inhibits global protein synthesis further contributing to cancer cell death. Therefore, these and other studies reveal the tremendous potential of 3-bromopyruvate as an anticancer agent.

Structure activity relationship of C-2 ether substituted 1,5-naphthyridine analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-5).

PubMed

Singh, Sheo B; Kaelin, David E; Meinke, Peter T; Wu, Jin; Miesel, Lynn; Tan, Christopher M; Olsen, David B; Lagrutta, Armando; Fukuda, Hideyuki; Kishii, Ryuta; Takei, Masaya; Takeuchi, Tomoko; Takano, Hisashi; Ohata, Kohei; Kurasaki, Haruaki; Nishimura, Akinori; Shibata, Takeshi; Fukuda, Yasumichi

2015-09-01

Oxabicyclooctane linked novel bacterial topoisomerase inhibitors (NBTIs) are new class of recently reported broad-spectrum antibacterial agents. They target bacterial DNA gyrase and topoisomerase IV and bind to a site different than quinolones. They show no cross-resistance to known antibiotics and provide opportunity to combat drug-resistant bacteria. A structure activity relationship of the C-2 substituted ether analogs of 1,5-naphthyridine oxabicyclooctane-linked NBTIs are described. Synthesis and antibacterial activities of a total of 63 analogs have been summarized representing alkyl, cyclo alkyl, fluoro alkyl, hydroxy alkyl, amino alkyl, and carboxyl alkyl ethers. All compounds were tested against three key strains each of Gram-positive and Gram-negative bacteria as well as for hERG binding activities. Many key compounds were also tested for the functional hERG activity. Six compounds were evaluated for efficacy in a murine bacteremia model of Staphylococcus aureus infection. Significant tolerance for the ether substitution (including polar groups such as amino and carboxyl) at C-2 was observed for S. aureus activity however the same was not true for Enterococcus faecium and Gram-negative strains. Reduced clogD generally showed reduced hERG activity and improved in vivo efficacy but was generally associated with decreased overall potency. One of the best compounds was hydroxy propyl ether (16), which mainly retained the potency, spectrum and in vivo efficacy of AM8085 associated with the decreased hERG activity and improved physical property. Copyright © 2015 Elsevier Ltd. All rights reserved.

Synthesis of Norbornane Bisether Antibiotics via Silver-mediated Alkylation

PubMed Central

Hickey, Shane M.; Ashton, Trent D.; White, Jonathan M.; Li, Jian; Nation, Roger L.; Yu, Heidi Y.; Elliott, Alysha G.; Butler, Mark S.; Huang, Johnny X.; Cooper, Matthew A.

2015-01-01

A small series of norbornane bisether diguanidines have been synthesized and evaluated as antibacterial agents. The key transformation—bisalkylation of norbornane diol 6—was not successful using Williamson methodology but has been accomplished using Ag2O mediated alkylation. Further functionalization to incorporate two guanidinium groups gave rise to a series of structurally rigid cationic amphiphiles; several of which (16d, 16g and 16h) exhibited antibiotic activity. For example, compound 16d was active against a broad range of bacteria including Pseudomonas aeruginosa (MIC = 8 µg/mL), Escherichia coli (MIC = 8 µg/mL) and methicillin-resistant Staphylococcus aureus (MIC = 8 µg/mL). PMID:26251697

Synthesis and Characterization of New Phosphazene Polymers.

DTIC Science & Technology

1988-01-21

reaction of a poly( alkyl /arylphosphazene). In this study, one-half of the methyl groups in [Ph(Me)PN]n (chosen for its solubility in THF as opposed to...polymerization reaction ; and (5) the derivative chemistry of the preformed poly( alkyl /arylphosphazenes)., Synthesis of Poly( alkyl /arylphosphazenes) SC A... vessels , these phosphoranimines quantitatively eliminate the silyl ether byproduct, Me3SiOCH2CF 3 , to form the poly( alkyl /arylphosphazenes). The synthesis

FY08 Chemical Synthesis for the Self-Decontaminating Coatings Project

DTIC Science & Technology

2013-08-01

These synthesized materials consist of Boltorn hyperbranched polymers that are functionalized with hydantoin, alkyl, and perfluorinated groups. 15...envisioned that completely prevents sorption of chemical agents, enables autonomous decontamination, reduces the volume of cleaning solution...modified with perfluorinated octanoic acid (PFOA), lauric acid, and a hydantoin moiety. HO OH CH3 HO O 3 Figure 2. Synthetic targets 1–3

[Alkylating agents].

PubMed

Pourquier, Philippe

2011-11-01

With the approval of mechlorethamine by the FDA in 1949 for the treatment of hematologic malignancies, alkylating agents are the oldest class of anticancer agents. Even though their clinical use is far beyond the use of new targeted therapies, they still occupy a major place in specific indications and sometimes represent the unique option for the treatment of refractory diseases. Here, we are reviewing the major classes of alkylating agents and their mechanism of action, with a particular emphasis for the new generations of alkylating agents. As for most of the chemotherapeutic agents used in the clinic, these compounds are derived from natural sources. With a complex but original mechanism of action, they represent new interesting alternatives for the clinicians, especially for tumors that are resistant to conventional DNA damaging agents. We also briefly describe the different strategies that have been or are currently developed to potentiate the use of classical alkylating agents, especially the inhibition of pathways that are involved in the repair of DNA lesions induced by these agents. In this line, the development of PARP inhibitors is a striking example of the recent regain of interest towards the "old" alkylating agents.

Synthesis and antibacterial activity of Schiff bases and amines derived from alkyl 2-(2-formyl-4-nitrophenoxy)alkanoates.

PubMed

Goszczyńska, Agata; Kwiecień, Halina; Fijałkowski, Karol

A series of novel Schiff bases and secondary amines were obtained in good yields, as a result of the reductive amination of alkyl 2-(2-formyl-4-nitrophenoxy)alkanoates with both aniline and 4-methoxyaniline under established mild reaction conditions. Sodium triacetoxyborohydride as well as hydrogen in the presence of palladium on carbon were used as efficient reducing agents of the Schiff bases, in both direct and stepwise reductive amination processes. The Schiff bases, amines, and amine hydrochlorides were designed as potential antibacterial agents, and structure-activity relationship could be established following in vitro assays against Gram-positive and Gram-negative bacteria. The minimal inhibitory concentration and zone of inhibition were also determined. In these tests, some of Schiff bases and secondary amine hydrochlorides showed moderate-to-good activity against Gram-positive bacteria, including S. aureus , M. luteus , and S. mutans .

Merging Photoredox and Nickel Catalysis: The Direct Synthesis of Ketones via the Decarboxylative Arylation of α-Oxo Acids**

PubMed Central

Chu, Lingling; Lipshultz, Jeffrey M.

2015-01-01

The direct decarboxylative arylation of α-oxo acids has been achieved via synergistic visible light-mediated photoredox and nickel catalyses. This method offers rapid entry to aryl and alkyl ketone architectures from simple α-oxo acid precursors via an acyl radical intermediate. Significant substrate scope is observed with respect to both the oxo acid and arene coupling partners. This mild decarboxylative arylation can also be utilized to efficiently access medicinal agents, as demonstrated by the rapid synthesis of fenofibrate. PMID:26014029

Thioimidazolium Ionic Liquids as Tunable Alkylating Agents.

PubMed

Guterman, Ryan; Miao, Han; Antonietti, Markus

2018-01-19

Alkylating ionic liquids based on the thioimidazolium structure combine the conventional properties of ionic liquids, including low melting point and nonvolatility, with the alkylating function. Alkyl transfer occurs exclusively from the S-alkyl position, thus allowing for easy derivatization of the structure without compromising specificity. We apply this feature to tune the electrophilicty of the cation to profoundly affect the reactivity of these alkylating ionic liquids, with a caffeine-derived compound possessing the highest reactivity. Anion choice was found to affect reaction rates, with iodide anions assisting in the alkylation reaction through a "shuttling" process. The ability to tune the properties of the alkylating agent using the toolbox of ionic liquid chemistry highlights the modular nature of these compounds as a platform for alkylating agent design and integration in to future systems.

Persistence of DNA adducts, hypermutation and acquisition of cellular resistance to alkylating agents in glioblastoma.

PubMed

Head, R J; Fay, M F; Cosgrove, L; Y C Fung, K; Rundle-Thiele, D; Martin, J H

2017-12-02

Glioblastoma is a lethal form of brain tumour usually treated by surgical resection followed by radiotherapy and an alkylating chemotherapeutic agent. Key to the success of this multimodal approach is maintaining apoptotic sensitivity of tumour cells to the alkylating agent. This initial treatment likely establishes conditions contributing to development of drug resistance as alkylating agents form the O 6 -methylguanine adduct. This activates the mismatch repair (MMR) process inducing apoptosis and mutagenesis. This review describes key juxtaposed drivers in the balance between alkylation induced mutagenesis and apoptosis. Mutations in MMR genes are the probable drivers for alkylation based drug resistance. Critical to this interaction are the dose-response and temporal interactions between adduct formation and MMR mutations. The precision in dose interval, dose-responses and temporal relationships dictate a role for alkylating agents in either promoting experimental tumour formation or inducing tumour cell death with chemotherapy. Importantly, this resultant loss of chemotherapeutic selective pressure provides opportunity to explore novel therapeutics and appropriate combinations to minimise alkylation based drug resistance and tumour relapse.

ATM regulates 3-methylpurine-DNA glycosylase and promotes therapeutic resistance to alkylating agents.

PubMed

Agnihotri, Sameer; Burrell, Kelly; Buczkowicz, Pawel; Remke, Marc; Golbourn, Brian; Chornenkyy, Yevgen; Gajadhar, Aaron; Fernandez, Nestor A; Clarke, Ian D; Barszczyk, Mark S; Pajovic, Sanja; Ternamian, Christian; Head, Renee; Sabha, Nesrin; Sobol, Robert W; Taylor, Michael D; Rutka, James T; Jones, Chris; Dirks, Peter B; Zadeh, Gelareh; Hawkins, Cynthia

2014-10-01

Alkylating agents are a first-line therapy for the treatment of several aggressive cancers, including pediatric glioblastoma, a lethal tumor in children. Unfortunately, many tumors are resistant to this therapy. We sought to identify ways of sensitizing tumor cells to alkylating agents while leaving normal cells unharmed, increasing therapeutic response while minimizing toxicity. Using an siRNA screen targeting over 240 DNA damage response genes, we identified novel sensitizers to alkylating agents. In particular, the base excision repair (BER) pathway, including 3-methylpurine-DNA glycosylase (MPG), as well as ataxia telangiectasia mutated (ATM), were identified in our screen. Interestingly, we identified MPG as a direct novel substrate of ATM. ATM-mediated phosphorylation of MPG was required for enhanced MPG function. Importantly, combined inhibition or loss of MPG and ATM resulted in increased alkylating agent-induced cytotoxicity in vitro and prolonged survival in vivo. The discovery of the ATM-MPG axis will lead to improved treatment of alkylating agent-resistant tumors. Inhibition of ATM and MPG-mediated BER cooperate to sensitize tumor cells to alkylating agents, impairing tumor growth in vitro and in vivo with no toxicity to normal cells, providing an ideal therapeutic window. ©2014 American Association for Cancer Research.

Molecular design of sequence specific DNA alkylating agents.

PubMed

Minoshima, Masafumi; Bando, Toshikazu; Shinohara, Ken-ichi; Sugiyama, Hiroshi

2009-01-01

Sequence-specific DNA alkylating agents have great interest for novel approach to cancer chemotherapy. We designed the conjugates between pyrrole (Py)-imidazole (Im) polyamides and DNA alkylating chlorambucil moiety possessing at different positions. The sequence-specific DNA alkylation by conjugates was investigated by using high-resolution denaturing polyacrylamide gel electrophoresis (PAGE). The results showed that polyamide chlorambucil conjugates alkylate DNA at flanking adenines in recognition sequences of Py-Im polyamides, however, the reactivities and alkylation sites were influenced by the positions of conjugation. In addition, we synthesized conjugate between Py-Im polyamide and another alkylating agent, 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI). DNA alkylation reactivies by both alkylating polyamides were almost comparable. In contrast, cytotoxicities against cell lines differed greatly. These comparative studies would promote development of appropriate sequence-specific DNA alkylating polyamides against specific cancer cells.

Mechanisms of chemoresistance to alkylating agents in malignant glioma.

PubMed

Sarkaria, Jann N; Kitange, Gaspar J; James, C David; Plummer, Ruth; Calvert, Hilary; Weller, Michael; Wick, Wolfgang

2008-05-15

Intrinsic or acquired chemoresistance to alkylating agents is a major cause of treatment failure in patients with malignant brain tumors. Alkylating agents, the mainstay of treatment for brain tumors, damage the DNA and induce apoptosis, but the cytotoxic activity of these agents is dependent on DNA repair pathways. For example, O6-methylguanine DNA adducts can cause double-strand breaks, but this is dependent on a functional mismatch repair pathway. Thus, tumor cell lines deficient in mismatch repair are resistant to alkylating agents. Perhaps the most important mechanism of resistance to alkylating agents is the DNA repair enzyme O6-methylguanine methyltransferase, which can eliminate the cytotoxic O6-methylguanine DNA adduct before it causes harm. Another mechanism of resistance to alkylating agents is the base excision repair (BER) pathway. Consequently, efforts are ongoing to develop effective inhibitors of BER. Poly(ADP-ribose)polymerase plays a pivotal role in BER and is an important therapeutic target. Developing effective strategies to overcome chemoresistance requires the identification of reliable preclinical models that recapitulate human disease and which can be used to facilitate drug development. This article describes the diverse mechanisms of chemoresistance operating in malignant glioma and efforts to develop reliable preclinical models and novel pharmacologic approaches to overcome resistance to alkylating agents.

ATM regulates 3-Methylpurine-DNA glycosylase and promotes therapeutic resistance to alkylating agents

PubMed Central

Agnihotri, Sameer; Burrell, Kelly; Buczkowicz, Pawel; Remke, Marc; Golbourn, Brian; Chornenkyy, Yevgen; Gajadhar, Aaron; Fernandez, Nestor A.; Clarke, Ian D.; Barszczyk, Mark S.; Pajovic, Sanja; Ternamian, Christian; Head, Renee; Sabha, Nesrin; Sobol, Robert W.; Taylor, Michael D; Rutka, James T.; Jones, Chris; Dirks, Peter B.; Zadeh, Gelareh; Hawkins, Cynthia

2014-01-01

Alkylating agents are a frontline therapy for the treatment of several aggressive cancers including pediatric glioblastoma, a lethal tumor in children. Unfortunately, many tumors are resistant to this therapy. We sought to identify ways of sensitizing tumor cells to alkylating agents while leaving normal cells unharmed; increasing therapeutic response while minimizing toxicity. Using a siRNA screen targeting over 240 DNA damage response genes, we identified novel sensitizers to alkylating agents. In particular the base excision repair (BER) pathway, including 3-methylpurine-DNA glycosylase (MPG), as well as ataxia telangiectasia mutated (ATM) were identified in our screen. Interestingly, we identified MPG as a direct novel substrate of ATM. ATM-mediated phosphorylation of MPG was required for enhanced MPG function. Importantly, combined inhibition or loss of MPG and ATM resulted in increased alkylating agent-induced cytotoxicity in vitro and prolonged survival in vivo. The discovery of the ATM-MPG axis will lead to improved treatment of alkylating agent-resistant tumors. PMID:25100205

Influence of some DNA-alkylating drugs on thermal stability, acid and osmotic resistance of the membrane of whole human erythrocytes and their ghosts.

PubMed

Ivanov, I T; Gadjeva, V

2000-09-01

Human erythrocytes and their resealed ghosts were alkylated under identical conditions using three groups of alkylating antitumor agents: mustards, triazenes and chloroethyl nitrosoureas. Osmotic fragility, acid resistance and thermal stability of membranes were changed only in alkylated ghosts in proportion to the concentration of the alkylating agent. All the alkylating agents decreased acid resistance in ghosts. The clinically used drugs sarcolysine, dacarbazine and lomustine all decreased osmotic fragility and thermal stability of ghost membranes depending on their lipophilicity. DM-COOH did not decrease osmotic fragility and thermal stability of ghost membranes, while NEM increased thermal stability of membranes. The preliminary but not subsequent treatment of ghosts with DM-COOH fully abolished the alkylation-induced thermal labilization of ghost membrane proteins while NEM had a partial effect only. The present study gives direct evidence that alkylating agents, having a high therapeutic activity against malignant growth, bind covalently to proteins of cellular membranes.

REVISITING CLASSICAL NUCLEOPHILIC SUBSTITUTIONS IN AQUEOUS MEDIUM: MICROWAVE-ASSISTED SYNTHESIS OF ALKYL AZIDES

EPA Science Inventory

An efficient and clean synthesis of alkyl azides using microwave (MW) radiation is described in aqueous medium by reacting alkyl halides or tosylates with alkali azides. This general and expeditious MW-enhanced approach to nucleophilic substitution reactions is applicable to the ...

Sage Gene Expression Profiles Characterizing Cure

DTIC Science & Technology

2005-10-01

achieved in haematological malignancies. In addition, tumour cell lines showed a log-linear dose re- sponse when exposed to alkylating agents [26,27...direct carcinogen, N-methyl nitrosourea (NMU) and an indirect carcinogen, 7,12- dimethylbenzanthracene each depend upon the estrous cycle phase at the...a single dose of N-methyl-N- nitrosourea . Cancer Res 45: 3042–3047, 1995 8. Nagasawa H, Yanai R, Taniguchi H: Importance of mammary gland DNA synthesis

Design, microwave-mediated synthesis and biological evaluation of novel 4-aryl(alkyl)amino-3-nitroquinoline and 2,4-diaryl(dialkyl)amino-3-nitroquinolines as anticancer agents.

PubMed

Chauhan, Monika; Rana, Anil; Alex, Jimi Marin; Negi, Arvind; Singh, Sandeep; Kumar, Raj

2015-02-01

Design, microwave-assisted synthesis of novel 4-aryl (alkyl)amino-3-nitroquinoline (1a-1l) and 2,4-diaryl (dialkyl)amino-3-nitroquinolines (2a-2k and 3a) via regioselective and complete nucleophilic substitution of 2,4-dichloro-3-nitroquinoline, respectively in water are presented. The newly synthesized compounds were evaluated for the first time for antiproliferative activity against EGFR overexpressing human lung (A-549 and H-460) and colon (HCT-116-wild type and HCT-116-p53 null) cancer cell lines. Some notions about structure-activity relationships (SAR) are presented. Compounds 2e, 2f, 2j and 3a overall exhibited excellent anticancer activity comparable to erlotinib which was used as a positive control. Molecular modeling studies disclosed the recognition pattern of the compounds and also supported the observed SAR. Copyright © 2014 Elsevier Inc. All rights reserved.

Functional copolymer/organo-MMT nanoarchitectures. VI. Synthesis and characterization of novel nanocomposites by interlamellar controlled/living radical copolymerization via preintercalated RAFT-agent/organoclay complexes.

PubMed

Rzayev, Zakir M O; Söylemez, A Ernur

2011-04-01

We have developed a new approach for the synthesis of polymer nanocomposites using a bifunctional reversible addition-fragmentation chain transfer (RAFT) agent, two types of organo-montmorillonites, such as a non-reactive dimethyldodecyl ammonium (DMDA)-MMT and a reactive octadecylamine (ODA)-MMT organoclays, and a radical initiator. The method includes the following stages: (1) synthesis of RAFT intercalated O-MMTs by a physical or chemical interaction of the RAFT agent having two pendant carboxylic groups [S,S-bis(alpha,alpha'-dimethyl-alpha"-acetic acid)trithiocarbonate] with surface alkyl amines of O-MMT containing tertiary ammonium cation or primary amine groups through strong H-bonding and complexing/amidization reactions, respectively, and (2) utilization of these well-dispersed and intercalated RAFT ... O-MMT complexes and their amide derivatives as new modified RAFT agents in radical-initiated interlamellar controlled/living copolymerization of itaconic acid (IA)-n-butylmethacrylate (BMA) monomer pair. The structure and compositions of the synthesized RAFT ... O-MMT complexes and functional copolymer/O-MMT hybrids were confirmed by FTIR, XRD, thermal (DSC-TGA), SEM and TEM morphology analyses. It was demonstrated that the degree of interaction/exfoliation, morphology and thermal behavior of nanocomposites significantly depended on the type of organoclay and in situ interaction, as well as on the content of flexible butyl-ester linkages as a internal plasticizer. The results of the comparative analysis of the nanocomposites structure-composition-property relations show that the functional copolymer-organoclay hybrids prepared with reactive RAFT ... ODA-MMT complex and containing a combination of partially intercalated and predominantly exfoliated nano-structures exhibit relatively higher thermal stability and fine dispersed morphology. These effects were explained by in situ interfacial chemical reactions through amidization of RAFT with surface alkyl amine of MMT clay in interlamellar copolymerization. This simple and versatile method can be applied to a wide range of functional monomer/comonomer systems and mono- and bifunctional RAFT compounds for preparation new generation of nanomaterials.

Rituximab, alkylating agents or combination therapy for gastric mucosa-associated lymphoid tissue lymphoma: a monocentric non-randomised observational study.

PubMed

Amiot, A; Lévy, M; Copie-Bergman, C; Dupuis, J; Szablewski, V; Le Baleur, Y; Baia, M; Belhadj, K; Sobhani, I; Leroy, K; Haioun, C; Delchier, J-C

2014-03-01

There is no consensus on the standard treatment of gastric mucosa-associated lymphoid tissue (MALT) lymphoma for Helicobacter pylori-negative patients and for patients with persistent disease despite H. pylori eradication. To evaluate the comparative efficacy and safety of alkylating agents and rituximab alone or in combination. In this monocentric retrospective study, which included 106 patients who had not been previously treated with anti-cancer agents, we evaluated the efficacy and safety of oral alkylating agents monotherapy (n = 48), rituximab monotherapy (n = 28) and the therapy combining both drugs (n = 30). Evaluations were performed at weeks 6 (W6), 25 (W25), and 52 (W52) and after 2 years (W104). After a median follow-up period of 4.9 years (range 0.4-17.2 years), complete remission and overall response were significantly higher in patients in the combination therapy group at W104 (92% and 100% respectively) compared with patients treated with alkylating agents alone (66% and 68%) and rituximab alone (64% and 73%). The 5-year progression-free survival probabilities were 68%, 70% and 89% in patients treated with alkylating agents alone, rituximab alone and combination therapy respectively. Haematological adverse events were reported in 32 (30%) patients (mostly grade 1) and were more frequent in the two groups receiving alkylating agents (P = 0.05 and P < 0.001). No toxicity-related death was reported. The use of anti-cancer systemic therapy is safe and efficient in gastric MALT lymphoma. In this retrospective study, the combination of rituximab plus chlorambucil seems more efficient than rituximab or alkylating agents alone. Rituximab has a better safety profile than regimens containing alkylating agents. © 2014 John Wiley & Sons Ltd.

The Scarlet Letter of Alkylation: A Mini Review of Selective Alkylating Agents

PubMed Central

Oronsky, Bryan T; Reid, Tony; Knox, Susan J; Scicinski, Jan J

2012-01-01

If there were a stigma scale for chemotherapy, alkylating agents would be ranked at the top of the list. The chemical term alkylation is associated with nonselective toxicity, an association that dates back to the use of nitrogen mustards during World War I as chemical warfare agents. That this stigma persists and extends to compounds that, through selectivity, attempt to “tame” the indiscriminate destructive potential of alkylation is the subject of this review. Selective alkylation, as it is referred to herein, constitutes an extremely nascent and dynamic field in oncology. The pharmacodynamic response to this selective strategy depends on a delicate kinetic balance between specificity and the rate and extent of binding. Three representative compounds are presented: RRx-001, 3-bromopyruvate, and TH-302. The main impetus for the development of these compounds has been the avoidance of the serious complications of traditional alkylating agents; therefore, it is the thesis of this review that they should not experience stigma by association. PMID:22937173

Phase selective synthesis of quantum cutting nanophosphors and the observation of a spontaneous room temperature phase transition.

PubMed

Ghosh, Pushpal; Mudring, Anja-Verena

2016-04-21

Oxygen-free Eu(3+)-doped NaGdF4 nanocrystals with high quantum cutting efficiency are accessible at low temperatures (room temperature to 80 °C) using task-specific ionic liquids (ILs) as structure directing agents and only water as solvent. Selective tuning of the shape, morphology and, most importantly, the crystal phase of the host lattice is achieved by changing the alkyl side length, the H-bonding capabilities and the concentration of 1-alkyl-3-methylimidazolium bromide ILs, [C(n)mim]Br. When using [C2mim]Br, hexagonal NaGdF4 nanoparticles are obtained. In the case of methylimidazolium bromides with longer pendant alkyl chains such as butyl (C4), octyl (C8) or decyl (C10), extremely small nanoparticles of the cubic polymorph form, which then convert even at room temperature (RT) to the thermodynamically favored hexagonal modification. To the best of our knowledge, this kind of spontaneous phase transition is not yet reported. The hexagonal nanomaterial shows a substantial quantum cutting efficiency (154%) whilst in the cubic material, the effect is negligible (107%). The easy yet highly phase selective green synthesis of the materials promises large scale industrial application in environmentally benign energy efficient lighting.

Nitric oxide donors attenuate clongenic potential in rat C6 glioma cells treated with alkylating chemotherapeutic agents.

PubMed

Yang, Jir-Jei; Yin, Jiu-Haw; Yang, Ding-I

2007-05-11

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) kills tumor cells via multiple actions including alkylation and carbamoylation. Previously, we have reported that formation of S-nitrosoglutathione (GSNO) in glioma cells overexpressing inducible nitric oxide synthase (iNOS) contributed to nitric oxide (NO)-dependent carbamoylating chemoresistance against BCNU. To further characterize the effects of NO on alkylating cytotoxicity, colony formation assay was applied to evaluate the effects of various NO donors on rat C6 glioma cells challenged with alkylating agents. We demonstrate that NO donors including GSNO, diethylamine NONOate (DEA/NO), and sodium nitroprusside (SNP) substantially reduced the extent of colony formation in glioma cells treated with alkylating agents, namely methyl methanesulfonate (MMS), N-methyl-N-nitrosourea (MNU), and N-ethyl-N-nitrosourea (ENU). Without alkylating agents these NO-releasing agents alone had no effects on clongenic potential of rat C6 glioma cells. Among these three NO donors used, the effectiveness in potentiating alkylating cytotoxicity is in the order of "GSNO>DEA/NO>SNP" when applied at the same dosages. GSNO also exerted similar synergistic actions reducing the extents of colony formation when co-administrated with 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-hydrazine (compound #1), another alkylating agent that mimics the chloroethylating action of BCNU. Together with our previous findings, we propose that NO donors may be used as adjunct chemotherapy with alkylating agents for such malignant brain tumors as glioblastoma multiforme (GBM). In contrast, production of NO as a result of iNOS induction, such as that occurring after surgical resection of brain tumors, may compromise the efficacy of carbamoylating chemotherapy.

Effects of Antiparasite Chemotherapeutic Agents on Immune Functions.

DTIC Science & Technology

1984-05-01

OF ALKYLATING AGENTS AGAINST CELLS PARTICIPATING IN SUPPRESSION OF ANTIBODY RESPONSES* RONALD D. PAUL, ABOUL GHAFFARt and M. MICHAEL SIGEL Department... alkylating agents on the induction and expression of specific suppressor cell activity induced by supraoptimal immunization (SO[) with (4x 109) SRBC was...including 1982b). different subsets of T cells (Cantor & Gershon, A number of alkylating agents which are used as 1979). It is therefore necessary to

Cytologic Effects of Air Force Chemicals

DTIC Science & Technology

1980-11-01

Studies of DNA replication and repair in cell cultures have shown that hydrazine, although highly toxic to cells, does not damage DNA and thus...interfere directly with DNA replication in Chinese hamster ovary cells grown in vitro, nor does it affect DNA repair synthesis in CCL-185 human lung cells...vitro with chemicals and monitoring their effect on DNA replication and repair. This method has been used to show that the alkylating agents MMS and 4

The clinical pharmacology of alkylating agents in high-dose chemotherapy.

PubMed

Huitema, A D; Smits, K D; Mathôt, R A; Schellens, J H; Rodenhuis, S; Beijnen, J H

2000-08-01

Alkylating agents are widely used in high-dose chemotherapy regimens in combination with hematological support. Knowledge about the pharmacokinetics and pharmacodynamics of these agents administered in high doses is critical for the safe and efficient use of these regimens. The aim of this review is to summarize the clinical pharmacology of the alkylating agents (including the platinum compounds) in high-dose chemotherapy. Differences between conventional and high doses will be discussed.

Protection Against the Acute and Delayed Toxicity of Mustards and Mustard-Like Compounds

DTIC Science & Technology

1987-02-01

environ- mental agents can be more important than modification at the major alkylation sites, an important inicial objective of this work was to identify...position of guanine in DNA. A mechanism has been discovered for certain antitumor agents which leads to DNA cross-linking following alkylation of the O...been discovered. Simple monofunctional alkylating agents , including methylating agents , appear to cause cross-link- ing through the reactions of the

Combination of Pim kinase inhibitor SGI-1776 and bendamustine in B-cell lymphoma.

PubMed

Yang, Qingshan; Chen, Lisa S; Neelapu, Sattva S; Gandhi, Varsha

2013-09-01

SGI-1776 is a small-molecule Pim kinase inhibitor that primarily targets c-MYC-driven transcription and cap-dependent translation in mantle cell lymphoma (MCL) cells. Bendamustine is an alkylating chemotherapeutic agent approved for use in B-cell lymphoma that is known to induce DNA damage and initiate response to repair. Our studies were conducted in MCL cell lines JeKo-1 and Mino, as well as primary B-cell lymphoma samples of MCL and splenic marginal zone lymphoma (SMZL), where we treated cells with SGI-1776 and bendamustine. We measured levels of cellular apoptosis, macromolecule synthesis inhibition, and DNA damage induced by drug treatments. Both SGI-1776 and bendamustine effectively induced apoptosis as single agents, and when used in combination, an additive effect in cell killing was observed in MCL cell lines JeKo-1 and Mino, as well as in MCL and SMZL primary cells. As expected, SGI-1776 was effective in inducing a decrease of global RNA and protein synthesis, and bendamustine significantly inhibited DNA synthesis and generated a DNA damage response. When used in combination, the effects were intensified in DNA, RNA, and protein synthesis inhibition compared with single-agent treatments. These data provide a foundation and suggest the feasibility of using Pim kinase inhibitors in combination with chemotherapeutic agents such as bendamustine in B-cell lymphoma. Copyright © 2013 Elsevier Inc. All rights reserved.

Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1

PubMed Central

Calvo, Jennifer A.; Moroski-Erkul, Catherine A.; Lake, Annabelle; Eichinger, Lindsey W.; Shah, Dharini; Jhun, Iny; Limsirichai, Prajit; Bronson, Roderick T.; Christiani, David C.; Meira, Lisiane B.; Samson, Leona D.

2013-01-01

Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER) is essential in repairing DNA alkylation damage, under certain conditions, initiation of BER can be detrimental. Here we illustrate that the alkyladenine DNA glycosylase (AAG) mediates alkylation-induced tissue damage and whole-animal lethality following exposure to alkylating agents. Aag-dependent tissue damage, as observed in cerebellar granule cells, splenocytes, thymocytes, bone marrow cells, pancreatic β-cells, and retinal photoreceptor cells, was detected in wild-type mice, exacerbated in Aag transgenic mice, and completely suppressed in Aag −/− mice. Additional genetic experiments dissected the effects of modulating both BER and Parp1 on alkylation sensitivity in mice and determined that Aag acts upstream of Parp1 in alkylation-induced tissue damage; in fact, cytotoxicity in WT and Aag transgenic mice was abrogated in the absence of Parp1. These results provide in vivo evidence that Aag-initiated BER may play a critical role in determining the side-effects of alkylating agent chemotherapies and that Parp1 plays a crucial role in Aag-mediated tissue damage. PMID:23593019

Reichardt's dye and its reactions with the alkylating agents 4-chloro-1-butanol, ethyl methanesulfonate, 1-bromobutane and Fast Red B - a potentially useful reagent for the detection of genotoxic impurities in pharmaceuticals.

PubMed

Corrigan, Damion K; Whitcombe, Michael J; McCrossen, Sean; Piletsky, Sergey

2009-04-01

Alkylating agents are potentially genotoxic impurities that may be present in drug products. These impurities occur in pharmaceuticals as by-products from the synthetic steps involved in drug production, as impurities in starting materials or from in-situ reactions that take place in the final drug product. Currently, analysis for genotoxic impurities is typically carried out using either HPLC/MS or GC/MS. These techniques require specialist expertise, have long analysis times and often use sample clean-up procedures. Reichardt's dye is well known for its solvatochromic properties. In this paper the dye's ability to undergo alkylation is reported. The reaction between Reichardt's dye and alkylating agents such as 4-chloro-1-butanol and ethyl methanesulfonate was monitored spectrophotometrically at 618 nm in acetonitrile and 624 nm in N,N-dimethylformamide. Changes in absorption were observed using low levels of alkylating agent (5-10 parts per million). Alkylation of the dye with 4-chloro-1-butanol and ethyl methanesulfonate was confirmed. Reichardt's dye, and its changing UV absorption, was examined in the presence of paracetamol (10 and 100 mg/ml). Whilst the alkylation-induced changes in UV absorption were not as pronounced as with standard solutions, detection of alkylation was still possible. Using standard solutions and in the presence of a drug matrix, Reichardt's dye shows promise as a reagent for detection of low levels of industrially important alkylating agents.

One-pot synthesis of MWW zeolite nanosheets using a rationally designed organic structure-directing agent

DOE PAGES

Luo, Helen Y.; Michaelis, Vladimir K.; Hodges, Sydney; ...

2015-07-22

A new material MIT-1 comprised of delaminated MWW zeolite nanosheets is synthesized in one-pot using a rationally designed organic structure-directing agent (OSDA). The OSDA is comprised of a hydrophilic head segment that resembles the OSDA used to synthesize the zeolite precursor MCM22(P), a hydrophobic tail segment that resembles the swelling agent used to swell MCM22(P), and a di-quaternary ammonium linker that connects both segments. MIT-1 features high crystallinity and surface areas exceeding 500 m 2g -1, and can be synthesized over a wide synthesis window that includes Si/Al ratios ranging from 13 to 67. Characterization data reveal high mesoporosity andmore » acid strength with no detectable amorphous silica phases. In conclusion, compared to MCM-22 and MCM-56, MIT-1 shows a three-fold increase in catalytic activity for the Friedel-Crafts alkylation of benzene with benzyl alcohol.« less

Sorbate-nitrite interactions: acetonitrile oxide as an alkylating agent.

PubMed

Pérez-Prior, M Teresa; Gómez-Bombarelli, Rafael; González-Pérez, Marina; Manso, José A; García-Santos, M Pilar; Calle, Emilio; Casado, Julio

2009-07-01

Because chemical species with DNA-damaging and mutagenic activity are formed in sorbate-nitrite mixtures and because sorbic acid sometimes coexists with nitrite occurring naturally or incorporated as a food additive, the study of sorbate-nitrite interactions is important. Here, the alkylating potential of the products resulting from such interactions was investigated. Drawn were the following conclusions: (i) Acetonitrile oxide (ACNO) is the compound responsible for the alkylating capacity of sorbate-nitrite mixtures; (ii) ACNO alkylates 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilic characteristics similar to those of DNA bases, forming an adduct (AD; epsilon = 1.4 x 10(4) M(-1) cm(-1); lambda = 519 nm); (iii) the NBP alkylation reaction complies with the rate equation, r = d[AD]/dt = k(alk)(ACNO)[ACNO][NBP]-k(hyd)(AD)[AD], k(alk)(ACNO) being the NBP alkylation rate constant for ACNO and k(hyd)(AD) the rate constant for the adduct hydrolysis reaction; (iv) the small fraction of ACNO forming the adduct with NBP, as well as the small magnitude of the quotient (k(alk) (ACNO)/k(hyd)(ACNO)) as compared with those reported for other alkylating agents, such as some lactones and N-alkyl-N-nitrosoureas, reveals the ACNO effective alkylating capacity to be less significant; (v) the low value of the NBP-ACNO adduct life (defined as the total amount of adduct present along the progression of the NBP alkylation per unit of alkylating agent concentration) points to the high instability of this adduct; and (vi) the obtained results are in accordance with the low carcinogenicity of ACNO.

When alcohol is the answer: trapping, identifying and quantifying simple alkylating species in aqueous environments

PubMed Central

Penketh, P. G.; Shyam, K.; Baumann, R. P; Zhu, Rui; Ishiguro, K.; Sartorelli, A. C.; Ratner, E. S.

2016-01-01

Alkylating agents are a significant class of environmental carcinogens as well as commonly used anticancer therapeutics. Traditional alkylating activity assays have utilized the colorimetric reagent 4-(4-nitrobenzyl)pyridine (4NBP). However, 4NBP based assays have a relatively low sensitivity towards harder, more oxophilic alkylating species and are not well suited for the identification of the trapped alkyl moiety due to adduct instability. Herein we describe a method using water as the trapping agent which permits the trapping of simple alkylating electrophiles with a comparatively wide range of softness/hardness and permits the identification of donated simple alkyl moieties. PMID:27188264

Comparative Biochemistry and Metabolism. Part 1. Carcinogenesis

DTIC Science & Technology

1981-10-01

qualitatively equivalent to administration of a strong alkylating agent ; this may add another consideration to Roberts’ hypothesis, but ultimately the effect...Removal, Arch. Pathol. 12:186-202. Karran, P., T. Lindahl and B. Griffin, (1979), Adaptive Responses to Alkylating Agents Involves Alterative In Situ of...the Adaptive Response to Alkylating Agents , Nature (Lond.) 280:74-76. Ruchirawat, M., (1974), Relationship Between Metabolism and Toxicity of

Combination of Pim kinase inhibitor, SGI-1776, with bendamustine in B-cell lymphoma

PubMed Central

Yang, Qingshan; Chen, Lisa S; Neelapu, Sattva S.; Gandhi, Varsha

2013-01-01

SGI-1776 is a small molecule Pim kinase inhibitor that primarily targets c-Myc-driven transcription and cap-dependent translation in mantle cell lymphoma (MCL) cells. Bendamustine is an alkylating chemotherapeutic agent approved for use in B-cell lymphoma that is known to induce DNA damage and to initiate response to repair. We hypothesized that while each drug leads to the effects as stated above, combination of these drugs will enhance SGI-1776-induced inhibition of global transcription and translation processes, while promoting bendamustine-triggered decrease of DNA synthesis and DNA damage response in B-cell lymphoma. Both SGI-1776 and bendamustine as single agents effectively induced apoptosis and when used in combination, additive effect in cell killing was observed in MCL cell lines, JeKo-1 and Mino, as well as MCL and splenic marginal zone lymphoma (a type of B-cell lymphoma) primary cells. As expected, SGI-1776 was effective in inducing decrease of global RNA and protein synthesis, while bendamustine significantly inhibited DNA synthesis and generated DNA damage response. When used in combination, effects were intensified in DNA, RNA and protein syntheses compared to single agent treatments. Together, these data provided foundation and suggested feasibility of using Pim kinase inhibitor in combination with chemotherapeutic agents such as bendamustine in B-cell lymphoma. PMID:24290221

When alcohol is the answer: Trapping, identifying and quantifying simple alkylating species in aqueous environments.

PubMed

Penketh, Philip G; Shyam, Krishnamurthy; Baumann, Raymond P; Zhu, Rui; Ishiguro, Kimiko; Sartorelli, Alan C; Ratner, Elena S

2016-09-01

Alkylating agents are a significant class of environmental carcinogens as well as commonly used anticancer therapeutics. Traditional alkylating activity assays have utilized the colorimetric reagent 4-(4-nitrobenzyl)pyridine (4NBP). However, 4NBP based assays have a relatively low sensitivity towards harder, more oxophilic alkylating species and are not well suited for the identification of the trapped alkyl moiety due to adduct instability. Herein we describe a method using water as the trapping agent which permits the trapping of simple alkylating electrophiles with a comparatively wide range of softness/hardness and permits the identification of donated simple alkyl moieties. Copyright © 2016 Elsevier Inc. All rights reserved.

Controllable synthesis of nitrogen-doped hollow mesoporous carbon spheres using ionic liquids as template for supercapacitors

NASA Astrophysics Data System (ADS)

Chen, Aibing; Li, Yunqian; Liu, Lei; Yu, Yifeng; Xia, Kechan; Wang, Yuying; Li, Shuhui

2017-01-01

We have demonstrated a facile and controllable synthesis of monodispersed nitrogen-doped hollow mesoporous carbon spheres (N-HMCSs) using resorcinol/formaldehyde resin as a carbon precursor, tetraethyl orthosilicate as a structure-assistant agent, ionic liquids (ILs) as soft template, partial carbon sources, and nitrogen sources. The sizes and the architectures including hollow and yolk-shell of resultant carbon spheres can be efficiently controlled through the adjustment of the content of ILs. Alkyl chain length of the ILs also has an important effect on the formation of N-HMCSs. With proper alkyl chain length and content of ILs, the resultant N-HMCSs show monodispersed hollow spheres with high surface areas (up to 1158 m2 g-1), large pore volumes (up to 1.70 cm3 g-1), and uniform mesopore size (5.0 nm). Combining the hollow mesoporous structure, high porosity, large surface area, and nitrogen functionality, the as-synthesized N-HMCSs have good supercapacitor performance with good capacitance (up to 159 F g-1) and favorable capacitance retention (88% capacitive retention after 5000 cycles).

Alkylsilyl Peroxides as Alkylating Agents in the Copper-Catalyzed Selective Mono-N-Alkylation of Primary Amides and Arylamines.

PubMed

Sakamoto, Ryu; Sakurai, Shunya; Maruoka, Keiji

2017-07-06

The copper-catalyzed selective mono-N-alkylation of primary amides or arylamines using alkylsilyl peroxides as alkylating agents is reported. The reaction proceeds under mild reaction conditions and exhibits a broad substrate scope with respect to the alkylsilyl peroxides, as well as to the primary amides and arylamines. Mechanistic studies suggest that the present reaction should proceed through a free-radical process that includes alkyl radicals generated from the alkylsilyl peroxides. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Development of Novel Bifunctional Compounds that Induce Apoptosis in Prostate Cancer Cells

DTIC Science & Technology

2006-02-01

were different from those of other alkylating agents used in chemotherapy. The apoptotic responses of prostate cancer cells suggested that the 11β... alkylating DNA Damaging Agent Tethered to an Androgen Receptor Ligand. Chemistry & Biology 12; 779-787. Personnel Supported Dr. Robert Croy...our work was the design of DNA-damag- ing agents that disrupt both DNA repair and signaling pathways in prostate tumor cells. A DNA alkylator (N,N

Cytologic Effects of Air Force Chemicals

DTIC Science & Technology

1979-08-01

mitomycin C (MMC, Sigma), a well known bifunctional DNA alkylating agent . Figure 3 shows typical metaphase spreads of a rat lymphocyte and a rat bone...monofunctional DNA alkylating agents and well known mutagens, are shown in Figures 7 and 8, respectively. Fig- ure 9 shows the induction of micronuclei by MMC...a bifunctional alkyl - ating agent . These three chemicals serve as positive controls for the in vitro exposures. In all three figures, the general

Activation of Poly(ADP-Ribose) Polymerase by Sulfur Mustard in Hela Cell Cultures

DTIC Science & Technology

1993-05-13

i O : DUTiC-TID INTRODUCTION Sulfur mustard ( 2,2’-dichlorodiethyl sulfide or HD) is a bifunctional alkylating agent which reacts with a wide variety...of biological molecules. It is a strong alkylating agent of purine bases in DNA (Kohn 1983). Early studies strongly implicate DNA as a principal...cells have previously demonstrated stimulation of PADPRP activity following exposure to a monofunctional alkylating agent , methylnitrosourea (MNU

From old alkylating agents to new minor groove binders.

PubMed

Puyo, Stéphane; Montaudon, Danièle; Pourquier, Philippe

2014-01-01

Alkylating agents represent the oldest class of anticancer agents with the approval of mechloretamine by the FDA in 1949. Even though their clinical use is far beyond the use of new targeted therapies, they still occupy a major place in the treatment of specific malignancies, sometimes representing the unique option for the treatment of refractory tumors. Here, we are reviewing the major classes of alkylating agents, with a particular focus on the latest generations of compounds that specifically target the minor groove of the DNA. These naturally occurring derivatives have a unique mechanism of action that explains the recent regain of interest in developing new classes of alkylating agents that could be used in combination with other anticancer drugs to enhance tumor response in the clinic. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Biocatalytic organic synthesis of optically pure (S)-scoulerine and berbine and benzylisoquinoline alkaloids.

PubMed

Schrittwieser, Joerg H; Resch, Verena; Wallner, Silvia; Lienhart, Wolf-Dieter; Sattler, Johann H; Resch, Jasmin; Macheroux, Peter; Kroutil, Wolfgang

2011-08-19

A chemoenzymatic approach for the asymmetric total synthesis of the title compounds is described that employs an enantioselective oxidative C-C bond formation catalyzed by berberine bridge enzyme (BBE) in the asymmetric key step. This unique reaction yielded enantiomerically pure (R)-benzylisoquinoline derivatives and (S)-berbines such as the natural product (S)-scoulerine, a sedative and muscle relaxing agent. The racemic substrates rac-1 required for the biotransformation were prepared in 4-8 linear steps using either a Bischler-Napieralski cyclization or a C1-Cα alkylation approach. The chemoenzymatic synthesis was applied to the preparation of fourteen enantiomerically pure alkaloids, including the natural products (S)-scoulerine and (R)-reticuline, and gave overall yields of up to 20% over 5-9 linear steps.

Potent antitumor bifunctional DNA alkylating agents, synthesis and biological activities of 3a-aza-cyclopenta[a]indenes.

PubMed

Kakadiya, Rajesh; Dong, Huajin; Lee, Pei-Chih; Kapuriya, Naval; Zhang, Xiuguo; Chou, Ting-Chao; Lee, Te-Chang; Kapuriya, Kalpana; Shah, Anamik; Su, Tsann-Long

2009-08-01

A series of bifunctional DNA interstrand cross-linking agents, bis(hydroxymethyl)- and bis(carbamates)-8H-3a-azacyclopenta[a]indene-1-yl derivatives were synthesized for antitumor evaluation. The preliminary antitumor studies revealed that these agents exhibited potent cytotoxicity in vitro and antitumor therapeutic efficacy against human tumor xenografts in vivo. Furthermore, these derivatives have little or no cross-resistance to either Taxol or Vinblastine. Remarkably, complete tumor remission in nude mice bearing human breast carcinoma MX-1 xenograft by 13a,b and 14g,h and significant suppression against prostate adenocarcinoma PC3 xenograft by 13b were achieved at the maximum tolerable dose with relatively low toxicity. In addition, these agents induce DNA interstrand cross-linking and substantial G2/M phase arrest in human non-small lung carcinoma H1299 cells. The current studies suggested that these agents are promising candidates for preclinical studies.

Novel fluconazole derivatives with promising antifungal activity.

PubMed

Thamban Chandrika, Nishad; Shrestha, Sanjib K; Ngo, Huy X; Howard, Kaitlind C; Garneau-Tsodikova, Sylvie

2018-02-01

The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action. Copyright © 2017 Elsevier Ltd. All rights reserved.

Soft antimicrobial agents: synthesis and activity of labile environmentally friendly long chain quaternary ammonium compounds.

PubMed

Thorsteinsson, Thorsteinn; Másson, Már; Kristinsson, Karl G; Hjálmarsdóttir, Martha A; Hilmarsson, Hilmar; Loftsson, Thorsteinn

2003-09-11

A series of soft quaternary ammonium antimicrobial agents, which are analogues to currently used quaternary ammonium preservatives such as cetyl pyridinium chloride and benzalkonium chloride, were synthesized. These soft analogues consist of long alkyl chain connected to a polar headgroup via chemically labile spacer group. They are characterized by facile nonenzymatic and enzymatic degradation to form their original nontoxic building blocks. However, their chemical stability has to be adequate in order for them to have antimicrobial effects. Stability studies and antibacterial and antiviral activity measurements revealed relationship between activity, lipophilicity, and stability. Their minimum inhibitory concentration (MIC) was as low as 1 microg/mL, and their viral reduction was in some cases greater than 6.7 log. The structure-activity studies demonstrate that the bioactive compounds (i.e., MIC for Gram-positive bacteria of <10 microg/mL) have an alkyl chain length between 12 and 18 carbon atoms, with a polar headgroup preferably of a small quaternary ammonium group, and their acquired inactivation half-life must be greater than 3 h at 60 degrees C.

Design, Synthesis and Biological Evaluation of Novel Pyrimido[4,5-d]pyrimidine CDK2 Inhibitors as Anti-Tumor Agents

PubMed Central

El-Moghazy, Samir M.; Ibrahim, Diaa A.; Abdelgawad, Nagwa M.; Farag, Nahla A. H.; El-Khouly, Ahmad S.

2011-01-01

A series of 2,5,7-trisubstituted pyrimido[4,5-d]pyrimidine cyclin-dependent kinase (CDK2) inhibitors is designed and synthesized. 6-Amino-2-thiouracil is reacted with an aldehyde and thiourea to prepare the pyrimido[4,5-d]-pyrimidines. Alkylation and amination of the latter ones give different amino derivatives. These compounds show potent and selective CDK inhibitory activities and inhibit in vitro cellular proliferation in cultured human tumor cells. PMID:21886895

DIRECT SYNTHESIS OF TERTIARY AMINES IN WATER USING MICROWAVES

EPA Science Inventory

A direct synthesis of tertiary amines is presented that proceeds expeditiously via N-alkylation of amines using alkyl halides in alkaline aqueous medium. This environmentally benign reaction is accelerated upon exposure to microwave irradiation resulting in shortened reaction tim...

L-β-N-methylamino-l-alanine (BMAA) nitrosation generates a cytotoxic DNA damaging alkylating agent: An unexplored mechanism for neurodegenerative disease.

PubMed

Potjewyd, G; Day, P J; Shangula, S; Margison, G P; Povey, A C

2017-03-01

L-β-N-methylamino-l-alanine (BMAA) is a non-proteinic amino acid, that is neurotoxic in vitro and in animals, and is implicated in the causation of amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS-PDC) on Guam. Given that natural amino acids can be N-nitrosated to form toxic alkylating agents and the structural similarity of BMAA to other amino acids, our hypothesis was that N-nitrosation of BMAA might result in a toxic alkylating agent, providing a novel mechanistic hypothesis for BMAA action. We have chemically nitrosated BMAA with sodium nitrite to produce nitrosated BMAA (N-BMAA) which was shown to react with the alkyl-trapping agent, 4-(p-nitrobenzyl)pyridine, cause DNA strand breaks in vitro and was toxic to the human neuroblastoma cell line SH-SY5Y under conditions in which BMAA itself was minimally toxic. Our results indicate that N-BMAA is an alkylating agent and toxin suggesting a plausible and previously unrecognised mechanism for the neurotoxic effects of BMAA. Copyright © 2017 Elsevier B.V. All rights reserved.

Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents.

PubMed

Wang, Pu; Wu, Jing; Ma, Shenghong; Zhang, Lei; Yao, Jun; Hoadley, Katherine A; Wilkerson, Matthew D; Perou, Charles M; Guan, Kun-Liang; Ye, Dan; Xiong, Yue

2015-12-22

Chemotherapy of a combination of DNA alkylating agents, procarbazine and lomustine (CCNU), and a microtubule poison, vincristine, offers a significant benefit to a subset of glioma patients. The benefit of this regimen, known as PCV, was recently linked to IDH mutation that occurs frequently in glioma and produces D-2-hydroxyglutarate (D-2-HG), a competitive inhibitor of α-ketoglutarate (α-KG). We report here that D-2-HG inhibits the α-KG-dependent alkB homolog (ALKBH) DNA repair enzymes. Cells expressing mutant IDH display reduced repair kinetics, accumulate more DNA damages, and are sensitized to alkylating agents. The observed sensitization to alkylating agents requires the catalytic activity of mutant IDH to produce D-2-HG and can be reversed by the deletion of mutant IDH allele or overexpression of ALKBH2 or AKLBH3. Our results suggest that impairment of DNA repair may contribute to tumorigenesis driven by IDH mutations and that alkylating agents may merit exploration for treating IDH-mutated cancer patients. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Synthesis and in vitro antiplasmodial evaluation of 7-chloroquinoline-chalcone and 7-chloroquinoline-ferrocenylchalcone conjugates.

PubMed

Raj, Raghu; Saini, Anu; Gut, Jiri; Rosenthal, Philip J; Kumar, Vipan

2015-05-05

The manuscript describes the synthesis of novel amide tethered 7-chloroquinoline-chalcone and 7-chloroquinoline-ferrocenylchalcone bifunctional hybrids and their evaluation as antimalarial agents against W2 resistant strain of Plasmodium falciparum. The antiplasmodial activity of 7-chloroquinoline-ferrocenylchalcones was found to be less than their corresponding simple chalcone conjugates. The presence of a methoxy substituent at para position of ring B on chalcones and longer alkyl chain length markedly improved the antiplasmodial profiles of the synthesized scaffolds with the most potent of the test compound exhibiting an IC50 value of 17.8 nM. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Lanthanide alkyl and silyl compounds: Synthesis, reactivity and catalysts for green

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pindwal, Aradhana

2016-01-01

The last few decades have witnessed enormous research in the field of organometallic lanthanide chemistry. Our research group has developed a few rare earth alkyl compounds containing tris(dimethylsilyl)methyl ligand and explored their reactivity. This thesis focusses on extending the study of lanthanide alkyl and silyl compounds to develop strategies for their synthesis and explore their reactivity and role as catalysts in processes such as hydrosilylation and cross-dehydrocoupling.

Chlorambucil

MedlinePlus

... Chlorambucil is in a class of medications called alkylating agents. It works by slowing or stopping the growth ... pharmacist if you are allergic to chlorambucil, other alkylating agents such as bendamustine (Treanda), busulfan (Myleran, Busulfex), carmustine ( ...

Sensitive Bioanalytical Methods for Mustard Gas Exposure Diagnosis

DTIC Science & Technology

2006-11-01

8217-dichlorodiethyl sulfide) is an alkylating vesicating agent . The injuries resulting from SM exposure are mainly characterized by epithelial damage of the...for SM and NM and was not seen for the other alkylating agents tested. We also found that 200 μM SM or NM degraded the integrin β4 unit of α6β4. An...similarly as nonspecific bifunctional alkylating agents , reacting with a host of compounds that are vital to living cells (Smith et al., 1998

Studies on the Mechanism of Action of Hydrazine-Induced Methylation of DNA Guanne

DTIC Science & Technology

1984-10-03

potent methylating agent , diazomethane (-CH -N+-N). Several in vivo studies were carried out to determine the role of aldehydes in the alkylation of DNA...methylating agent available to interact with DNA. If such a mechanism occurs, it may explain why disulfiram appears to inhibit the alkylation of DNA...a much slower/poorer alkylating agent for DNA. Effect of the 1-Carbon Pool on DNA Methylation in Hydrazine Toxicity: In Vitro In vitro studies were

mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy.

PubMed

Weiler, Markus; Blaes, Jonas; Pusch, Stefan; Sahm, Felix; Czabanka, Marcus; Luger, Sebastian; Bunse, Lukas; Solecki, Gergely; Eichwald, Viktoria; Jugold, Manfred; Hodecker, Sibylle; Osswald, Matthias; Meisner, Christoph; Hielscher, Thomas; Rübmann, Petra; Pfenning, Philipp-Niklas; Ronellenfitsch, Michael; Kempf, Tore; Schnölzer, Martina; Abdollahi, Amir; Lang, Florian; Bendszus, Martin; von Deimling, Andreas; Winkler, Frank; Weller, Michael; Vajkoczy, Peter; Platten, Michael; Wick, Wolfgang

2014-01-07

A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O(6)-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids.

mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy

PubMed Central

Weiler, Markus; Blaes, Jonas; Pusch, Stefan; Sahm, Felix; Czabanka, Marcus; Luger, Sebastian; Bunse, Lukas; Solecki, Gergely; Eichwald, Viktoria; Jugold, Manfred; Hodecker, Sibylle; Osswald, Matthias; Meisner, Christoph; Hielscher, Thomas; Rübmann, Petra; Pfenning, Philipp-Niklas; Ronellenfitsch, Michael; Kempf, Tore; Schnölzer, Martina; Abdollahi, Amir; Lang, Florian; Bendszus, Martin; von Deimling, Andreas; Winkler, Frank; Weller, Michael; Vajkoczy, Peter; Platten, Michael; Wick, Wolfgang

2014-01-01

A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O6-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids. PMID:24367102

Enhanced Synthesis of Alkyl Amino Acids in Miller's 1958 H2S Experiment

NASA Technical Reports Server (NTRS)

Parker, Eric T.; Cleaves, H. James; Callahan, Michael P.; Dworkin, James P.; Glavin, Daniel P.; Lazcano, Antonio; Bada, Jeffrey L.

2011-01-01

Stanley Miller's 1958 H2S-containing experiment, which included a simulated prebiotic atmosphere of methane (CH4), ammonia (NH3), carbon dioxide (CO2), and hydrogen sulfide (H2S) produced several alkyl amino acids, including the alpha-, beta-, and gamma-isomers of aminobutyric acid (ABA) in greater relative yields than had previously been reported from his spark discharge experiments. In the presence of H2S, aspariic and glutamic acids could yield alkyl amino acids via the formation of thioimide intermediates. Radical chemistry initiated by passing H2S through a spark discharge could have also enhanced alkyl amino acid synthesis by generating alkyl radicals that can help form the aldehyde and ketone precursors to these amino acids. We propose mechanisms that may have influenced the synthesis of certain amino acids in localized environments rich in H2S and lightning discharges, similar to conditions near volcanic systems on the early Earth, thus contributing to the prebiotic chemical inventory of the primordial Earth.

Parallel and automated library synthesis of 2-long alkyl chain benzoazoles and azole[4,5-b]pyridines under microwave irradiation.

PubMed

Martínez-Palou, Rafael; Zepeda, L Gerardo; Höpfl, Herbert; Montoya, Ascensión; Guzmán-Lucero, Diego J; Guzmán, Javier

2005-01-01

A versatile route to 40-membered library of 2-long alkyl chain substituted benzoazoles (1 and 2) and azole[4,5-b]pyridines (3 and 4) via microwave-assisted combinatorial synthesis was developed. The reactions were carried out in both monomode and multimode microwave oven. With the latter, all reactions were performed in high-throughput experimental settings consisting of an 8 x 5 combinatorial library designed to synthesize 40 compounds. Each step, from the addition of reagents to the recovery of final products, was automated. The microwave-assisted N-long chain alkylation reactions of 2-alkyl-1H-benzimidazole (1) and 2-alkyl-1H-benzimidazole[4,5-b] pyridines (3) were also studied.

Gallic acid-based alkyl esters synthesis in a water-free system by celite-bound lipase of Bacillus licheniformis SCD11501.

PubMed

Sharma, Shivika; Kanwar, Shamsher S; Dogra, Priyanka; Chauhan, Ghanshyam S

2015-01-01

Gallic acid (3, 4, 5- trihydroxybenzoic acid) is an important antioxidant, anti-inflammatory, and radical scavenging agent. In the present study, a purified thermo-tolerant extra-cellular lipase of Bacillus licheniformis SCD11501 was successfully immobilized by adsorption on Celite 545 gel matrix followed by treatment with a cross-linking agent, glutaraldehyde. The celite-bound lipase treated with glutaraldehyde showed 94.8% binding/retention of enzyme activity (36 U/g; specific activity 16.8 U/g matrix; relative increase in enzyme activity 64.7%) while untreated matrix resulted in 88.1% binding/retention (28.0 U/g matrix; specific activity 8.5 U/g matrix) of lipase. The celite-bound lipase was successfully used to synthesis methyl gallate (58.2%), ethyl gallate (66.9%), n-propyl gallate (72.1%), and n-butyl gallate (63.8%) at 55(o) C in 10 h under shaking (150 g) in a water-free system by sequentially optimizing various reaction parameters. The low conversion of more polar alcohols such as methanol and ethanol into their respective gallate esters might be due to the ability of these alcohols to severely remove water from the protein hydration shell, leading to enzyme inactivation. Molecular sieves added to the reaction mixture resulted in enhanced yield of the alkyl ester(s). The characterization of synthesised esters was done through fourier transform infrared (FTIR) spectroscopy and (1) H NMR spectrum analysis. © 2015 American Institute of Chemical Engineers.

Sensitization of human carcinoma cells to alkylating agents by small interfering RNA suppression of 3-alkyladenine-DNA glycosylase.

PubMed

Paik, Johanna; Duncan, Tod; Lindahl, Tomas; Sedgwick, Barbara

2005-11-15

One of the major cytotoxic lesions generated by alkylating agents is DNA 3-alkyladenine, which can be excised by 3-alkyladenine DNA glycosylase (AAG). Inhibition of AAG may therefore result in increased cellular sensitivity to chemotherapeutic alkylating agents. To investigate this possibility, we have examined the role of AAG in protecting human tumor cells against such agents. Plasmids that express small interfering RNAs targeted to two different regions of AAG mRNA were transfected into HeLa cervical carcinoma cells and A2780-SCA ovarian carcinoma cells. Stable derivatives of both cell types with low AAG protein levels were sensitized to alkylating agents. Two HeLa cell lines with AAG protein levels reduced by at least 80% to 90% displayed a 5- to 10-fold increase in sensitivity to methyl methanesulfonate, N-methyl-N-nitrosourea, and the chemotherapeutic drugs temozolomide and 1,3-bis(2-chloroethyl)-1-nitrosourea. These cells showed no increase in sensitivity to UV light or ionizing radiation. After treatment with methyl methanesulfonate, AAG knockdown HeLa cells were delayed in S phase but accumulated in G2-M. Our data support the hypothesis that ablation of AAG activity in human tumor cells may provide a useful strategy to enhance the efficacy of current chemotherapeutic regimens that include alkylating agents.

O6-Methylguanine DNA Methyltransferase Status Does Not Predict Response or Resistance to Alkylating Agents in Well-Differentiated Pancreatic Neuroendocrine Tumors.

PubMed

Raj, Nitya; Klimstra, David S; Horvat, Natally; Zhang, Liying; Chou, Joanne F; Capanu, Marinela; Basturk, Olca; Do, Richard Kinh Gian; Allen, Peter J; Reidy-Lagunes, Diane

2017-07-01

Alkylating agents have activity in well-differentiated pancreatic neuroendocrine tumors (WD panNETs). In glioblastoma multiforme, decreased activity of O-methylguanine DNA methyltransferase (MGMT) predicts response; in panNETs, MGMT relevance is unknown. We identified patients with WD panNETs treated with alkylating agents, determined best overall response by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, and performed MGMT activity testing. Fifty-six patients were identified; 26 (46%) of the 56 patients experienced partial response, 24 (43%) of 56 experienced stable disease, and 6 (11%) of 56 experienced progression of disease. O-methylguanine DNA methyltransferase status was available for 36 tumors. For tumors with partial response, 10 (67%) of 15 were MGMT deficient, and 5 (33%) of 15 were MGMT intact. For tumors with stable disease, 7 (47%) of 15 were MGMT deficient, and 8 (53%) of 15 were MGMT intact. For tumors with progression of disease, 3 (50%) of 6 were MGMT deficient, and 3 (50%) of 6 were MGMT intact. We observed response and resistance to alkylating agents in MGMT-deficient and MGMT-intact tumors. O-methylguanine DNA methyltransferase status should not guide alkylating agent therapy in WD panNETs.

Nucleotide excision repair is a potential therapeutic target in multiple myeloma

PubMed Central

Szalat, R; Samur, M K; Fulciniti, M; Lopez, M; Nanjappa, P; Cleynen, A; Wen, K; Kumar, S; Perini, T; Calkins, A S; Reznichenko, E; Chauhan, D; Tai, Y-T; Shammas, M A; Anderson, K C; Fermand, J-P; Arnulf, B; Avet-Loiseau, H; Lazaro, J-B; Munshi, N C

2018-01-01

Despite the development of novel drugs, alkylating agents remain an important component of therapy in multiple myeloma (MM). DNA repair processes contribute towards sensitivity to alkylating agents and therefore we here evaluate the role of nucleotide excision repair (NER), which is involved in the removal of bulky adducts and DNA crosslinks in MM. We first evaluated NER activity using a novel functional assay and observed a heterogeneous NER efficiency in MM cell lines and patient samples. Using next-generation sequencing data, we identified that expression of the canonical NER gene, excision repair cross-complementation group 3 (ERCC3), significantly impacted the outcome in newly diagnosed MM patients treated with alkylating agents. Next, using small RNA interference, stable knockdown and overexpression, and small-molecule inhibitors targeting xeroderma pigmentosum complementation group B (XPB), the DNA helicase encoded by ERCC3, we demonstrate that NER inhibition significantly increases sensitivity and overcomes resistance to alkylating agents in MM. Moreover, inhibiting XPB leads to the dual inhibition of NER and transcription and is particularly efficient in myeloma cells. Altogether, we show that NER impacts alkylating agents sensitivity in myeloma cells and identify ERCC3 as a potential therapeutic target in MM. PMID:28588253

Effect of the antitumoral alkylating agent 3-bromopyruvate on mitochondrial respiration: role of mitochondrially bound hexokinase.

PubMed

Rodrigues-Ferreira, Clara; da Silva, Ana Paula Pereira; Galina, Antonio

2012-02-01

The alkylating agent 3-Bromopyruvate (3-BrPA) has been used as an anti-tumoral drug due to its anti-proliferative property in hepatomas cells. This propriety is believed to disturb glycolysis and respiration, which leads to a decreased rate of ATP synthesis. In this study, we evaluated the effects of the alkylating agent 3-BrPA on the respiratory states and the metabolic steps of the mitochondria of mice liver, brain and in human hepatocarcinoma cell line HepG2. The mitochondrial membrane potential (ΔΨ(m)), O(2) consumption and dehydrogenase activities were rapidly dissipated/or inhibited by 3-BrPA in respiration medium containing ADP and succinate as respiratory substrate. 3-BrPA inhibition was reverted by reduced glutathione (GSH). Respiration induced by yeast soluble hexokinase (HK) was rapidly inhibited by 3-BrPA. Similar results were observed using mice brain mitochondria that present HK naturally bound to the outer mitochondrial membrane. When the adenine nucleotide transporter (ANT) was blocked by the carboxyatractiloside, the 3-BrPA effect was significantly delayed. In permeabilized human hepatoma HepG2 cells that present HK type II bound to mitochondria (mt-HK II), the inhibiting effect occurred faster when the endogenous HK activity was activated by 2-deoxyglucose (2-DOG). Inhibition of mt-HK II by glucose-6-phosphate retards the mitochondria to react with 3-BrPA. The HK activities recovered in HepG2 cells treated or not with 3-BrPA were practically the same. These results suggest that mitochondrially bound HK supporting the ADP/ATP exchange activity levels facilitates the 3-BrPA inhibition reaction in tumors mitochondria by a proton motive force-dependent dynamic equilibrium between sensitive and less sensitive SDH in the electron transport system.

Toxicity, Mutagenicity, and Mutational Spectra of Vinyl Chloride, 2- Chloroethylene Oxide, and Chloracetaldehyde in a Human Lymphoblastoid Line Expressing Cytochrome P450IIE1.

DTIC Science & Technology

1992-01-01

concluded that CEO was the alkylating agent involved in conversion of adenosine to l,N 6 -ethenoadenosine. 1,N6 - Ethenoadenosine was not produced by CEO...guanines as nearest neighbors upon the alkylation of a guanine residue in DNA. N-methyl-N- nitrosourea (MNU) was reacted with a synthetic polynucleotide...the alkylating agent MNNG or the intercalating agent ICR-191. In the study they determined that mutants comprising at least one percent of the total

DNA Damage Induced by Alkylating Agents and Repair Pathways

PubMed Central

Kondo, Natsuko; Takahashi, Akihisa; Ono, Koji; Ohnishi, Takeo

2010-01-01

The cytotoxic effects of alkylating agents are strongly attenuated by cellular DNA repair processes, necessitating a clear understanding of the repair mechanisms. Simple methylating agents form adducts at N- and O-atoms. N-methylations are removed by base excision repair, AlkB homologues, or nucleotide excision repair (NER). O6-methylguanine (MeG), which can eventually become cytotoxic and mutagenic, is repaired by O6-methylguanine-DNA methyltransferase, and O6MeG:T mispairs are recognized by the mismatch repair system (MMR). MMR cannot repair the O6MeG/T mispairs, which eventually lead to double-strand breaks. Bifunctional alkylating agents form interstrand cross-links (ICLs) which are more complex and highly cytotoxic. ICLs are repaired by complex of NER factors (e.g., endnuclease xeroderma pigmentosum complementation group F-excision repair cross-complementing rodent repair deficiency complementation group 1), Fanconi anemia repair, and homologous recombination. A detailed understanding of how cells cope with DNA damage caused by alkylating agents is therefore potentially useful in clinical medicine. PMID:21113301

Alkylating agents for Waldenstrom's macroglobulinaemia.

PubMed

Yang, Kun; Tan, Jianlong; Wu, Taixiang

2009-01-21

Waldenstrom's macroglobulinaemia (WM) is an uncommon B-cell lymphoproliferative disorder characterized by bone marrow infiltration and production of monoclonal immunoglobulin. Uncertainty remains if alkylating agents, such as chlorambucil, melphalan or cyclophosphamide, are an effective form of management. To assess the effects and safety of the alkylating agents on Waldenstrom's macroglobulinaemia (WM). We searched the Cochrane Central Register of Controlled Trials (Issue 1, 2008), MEDLINE (1966 to 2008), EMBASE (1980 to 2008), the Chinese Biomedical Base (1982 to 2008) and reference lists of articles.We also handsearched relevant conference proceedings from 1990 to 2008. Randomised controlled trials (RCTs) comparing alkylating agents given concomitantly with radiotherapy, splenectomy, plasmapheresis, stem-cell transplantation in patients with a confirmed diagnosis of WM. Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We collected adverse effects information from the trials. One trial involving 92 participants with pretreated/relapsed WM compared the effect of fludarabine versus the combination of cyclophosphamide (the alkylating agent), doxorubicin and prednisone (CAP). Compared to CAP, the Hazard ratio (HR) for deaths of treatment with fludarabine was estimated to be 1.04, with a standard error of 0.30 (95% CI 0.58 to 1.48) and it indicated that the mean difference of median survival time was -4.00 months, and 16.00 months for response duration. The relative risks (RR) of response rate was 2.80 (95% CI 1.10 to 7.12). There were no statistically difference in overall survival rate and median survival months, while on the basis of response rate and response duration, fludarabine seemed to be superior to CAP for pretreated/relapsed patients with macroglobulinaemia. Although alkylating agents have been used for decades they have never actually been tested in a proper randomised trial. This review demonstrated that there is currently no evidence to suggest that alkylating agents are effective in treating Waldenstrom's macroglobulinaemia.

Synthesis and biological evaluation of novel alkyl diamine linked bivalent β-carbolines as angiogenesis inhibitors.

PubMed

Chen, Wei; Zhang, Guoxian; Guo, Liang; Fan, Wenxi; Ma, Qin; Zhang, Xiaodong; Du, Runlei; Cao, Rihui

2016-11-29

We have synthesized and evaluated a series of novel alkyl diamine linked bivalent β-carbolines as potent angiogenesis inhibitors. The results demonstrated that most bivalent β-carbolines exhibited significant antiproliferative effects against human umbilical vein cell lines EA.HY926. Compound 4m was found to be the most potent antiproliferative agent with IC 50 value of 2.16 μM against EA.HY926 cell lines. Mechanism investigations revealed that compound 4m could significantly inhibit EA.HY926 cells migration and tube formation in a dose-dependent manner. Moreover, compound 4m also showed obvious angiogenesis inhibitory effects in CAM assay, and the antiangiogenetic potency was more potent than the reference drug Endostar. The bivalent β-carbolines might be served as candidates for the development of vascular targeting antitumor drugs. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Synthesis of 6-substituted 6H-indolo[2,3-b]quinolines as novel cytotoxic agents and topoisomerase II inhibitors.

PubMed

Kaczmarek, Lukasz; Luniewski, Wojciech; Zagrodzki, Bogdan; Godlewska, Joanna; Osiadacz, Jarosław; Wietrzyk, Joanna; Opolski, Adam; Peczyńska-Czoch, Wanda

2002-01-01

A systematic investigation into the impact of the substituents introduced into the indolo[2,3-b]quinoline system is described. The findings clearly demonstrate that the compounds bearing a methyl group or a longer aliphatic chain at the N-6 position are inactive against prokaryotic and eukaryotic cells. The introduction of alkyl-amino-alkyl substituent at the N-6 position of indolo[2,3-b]quinoline accounts for the appearance of the antimicrobial and.cytotoxic properties. The cytotoxicity against oral epidermoid carcinoma KB (ID50) is in the range from 2.0 to 9.0 microM, and the antimicrobial activity (MIC) falls between 0.03 and 0.50 mM. The structural relation within 6H-indolo[2,3-b]quinolines, concerning their antimicrobial and cytotoxic activity, corresponds well with their ability to bind DNA and to inhibit topoisomerase II activity.

Synthesis and Evaluation of Novel Oxyalkylated Derivatives of 2',4'-Dihydroxychalcone as Anti-Oomycete Agents against Bronopol Resistant Strains of Saprolegnia sp.

PubMed

Flores, Susana; Montenegro, Iván; Villena, Joan; Cuellar, Mauricio; Werner, Enrique; Godoy, Patricio; Madrid, Alejandro

2016-08-22

A series of novel oxyalkylchalcones substituted with alkyl groups were designed and synthesized, and the antioomycete activity of the series was evaluated in vitro against Saprolegnia strains. All tested O-alkylchalcones were synthesized by means of nucleophilic substitution from the natural compound 2',4'-dihydroxychalcone (1) and the respective alkyl bromide. The natural chalcone (1) and 10 synthetic oxyalkylchalcones (2-11) were tested against Saprolegnia parasitica and Saprolegnia australis. Among synthetic analogs, 2-hydroxy,4-farnesyloxychalcone (11) showed the most potent activity against Saprolegnia sp., with MIC and MOC values of 125 µg/mL (similar to bronopol at 150 µg/mL) and 175 µg/mL, respectively; however, 2',4'-dihydroxychalcone (1) was the strongest and most active molecule, with MIC and MOC values of 6.25 µg/mL and 12.5 µg/mL.

Novel multi-targeted agents for Alzheimer's disease: Synthesis, biological evaluation, and molecular modeling of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazoles.

PubMed

Ozadali-Sari, Keriman; Tüylü Küçükkılınç, Tuba; Ayazgok, Beyza; Balkan, Ayla; Unsal-Tan, Oya

2017-06-01

The present study describes the synthesis, pharmacological evaluation (BChE/AChE inhibition, Aβ antiaggregation, and neuroprotective effects), and molecular modeling studies of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazole derivatives. The alkyl-substituted derivatives exhibited selective inhibition on BChE with varying efficiency. Compounds 3b and 3d were found to be the most potent inhibitors of BChE with IC 50 values of 5.18 and 5.22μM, respectively. The kinetic studies revealed that 3b is a partial non-competitive BChE inhibitor. Molecular modeling studies also showed that the alkyl-substituted derivatives were able to reach the catalytic anionic site of the BChE. The compounds with an inhibitory effect on BChE were subsequently screened for their Aβ antiaggregating and neuroprotective activities. Compounds 3a and 3b exerted a potential neuroprotective effect against H 2 O 2 and Aβ-induced cytotoxicity in SH-SY5Y cells. Collectively, 3b was found as the most promising compound for the development of multi-target directed ligands against Alzheimer's disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Metal complexes of alkyl-aryl dithiocarbamates: Structural studies, anticancer potentials and applications as precursors for semiconductor nanocrystals

NASA Astrophysics Data System (ADS)

Andrew, Fartisincha P.; Ajibade, Peter A.

2018-03-01

Dithiocarbamates are versatile ligands able to stabilize wide range of metal ions in their various oxidation states with the partial double bond character of Csbnd N and Csbnd S of thioureide moiety. Variation of the substituents attached to the nitrogen atom of dithiocarbamate moiety generates various intermolecular interactions, which lead to different structural arrangement in the solid state. The presence of bulky substituents on the N atom obviates the supramolecular aggregation via secondary Msbnd S interactions whereas smaller substituents encourage such aggregation that results in their wide properties and applications. Over the past decades, the synthesis and structural studies of metal complexes of dithiocarbamates have received considerable attention as potential anticancer agents with various degree of DNA binding affinity and cytotoxicity and as single molecule precursors for the preparation of semiconductor nanocrystals. In this paper, we review the synthesis, structural studies, anticancer potency and the use of alkyl-phenyl dithiocarbamate complexes as precursors for the preparation of semiconductor nanocrystals. The properties of these compounds and activities are ascribed to be due to either the dithiocarbamate moieties, the nature or type of the substituents around the dithiocarbamate backbone and the central metal ions or combination of these factors.

Research on DNA methylation of human osteosarcoma cell MGMT and its relationship with cell resistance to alkylating agents.

PubMed

Guo, Jun; Cui, Qiu; Jiang, WeiHao; Liu, Cheng; Li, DingFeng; Zeng, Yanjun

2013-08-01

The objective of this study was to explore the O(6)-methylguanine-DNA methyltransferase (MGMT) gene methylation status and its protein expression, as well as the effects of demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-CdR) on MGMT gene expression and its resistance to alkylating agents, and to elucidate MGMT expression mechanism and significance in osteosarcoma. The human osteosarcoma cell lines Saos-2 and MG-63 were collected and treated with 5-Aza-CdR for 6 days. The cells not treated with 5-Aza-CdR were set as a negative control. The genomic DNA was extracted from the Saos-2 and MG-63 cells using methylation-specific PCR to detect the promoter CpG island methylation status of the MGMT gene. Cell sensitivity to alkylating agents before and after drug administration was detected by the MTT method. The variation in MGMT gene mRNA and protein was detected by reverse transcription PCR (RT-PCR) and Western blotting. The MGMT promoter gene of normal Saos-2 cells was methylated, with reduced MGMT mRNA and protein expression; the MGMT mRNA and protein expression of Saos-2 cells treated with 5-Aza-CdR was obviously enhanced, and its sensitivity to alkylating agents was reversed. Meanwhile, with promoter CpG island unmethylation of the MGMT gene, MGMT protein was expressed in the normal MG-63 cells and the MG-63 cells treated with 5-Aza-CdR, and both showed resistance to alkylating agents. The methylation status of the MGMT gene promoter in human osteosarcoma cells reflected the cells' ability to induce MGMT protein expression and can be used as a molecular marker to project the sensitivity of cancer tissues to alkylating agent drugs.

New coumarin carboxylates having trifluoromethyl, diethylamino and morpholino terminal groups: Synthesis and mesomorphic characterisations

NASA Astrophysics Data System (ADS)

Srinivasa, Hosapalya Thimmaiah; Harishkumar, Hosanagara Narayana; Palakshamurthy, Bandrehalli Siddagangappa

2017-03-01

New set of trifluromethyl, diethylamino and morpholino derived coumarin compounds were prepared by reacting various coumarin 3-carboxylic acids with various phenyl esters with peripheral alkyl, ester and polar cyano moieties in the presence of EDC.HCl/DMAP as esterification agent. The chemical structures of new coumarin derivatives were confirmed by standard spectroscopic techniques and mesomorphic behaviours were established by polarised optical microscopy (POM) and differential scanning calorimetry (DSC). Trifluoromethane and morpholino derivatives show SmA/Nematic phase, while diethylamino derivatives did not show liquid crystalline property.

Method for reactivating solid catalysts used in alkylation reactions

DOEpatents

Ginosar, Daniel M.; Thompson, David N.; Coates, Kyle; Zalewski, David J.; Fox, Robert V.

2003-06-17

A method for reactivating a solid alkylation catalyst is provided which can be performed within a reactor that contains the alkylation catalyst or outside the reactor. Effective catalyst reactivation is achieved whether the catalyst is completely deactivated or partially deactivated. A fluid reactivating agent is employed to dissolve catalyst fouling agents and also to react with such agents and carry away the reaction products. The deactivated catalyst is contacted with the fluid reactivating agent under pressure and temperature conditions such that the fluid reactivating agent is dense enough to effectively dissolve the fouling agents and any reaction products of the fouling agents and the reactivating agent. Useful pressures and temperatures for reactivation include near-critical, critical, and supercritical pressures and temperatures for the reactivating agent. The fluid reactivating agent can include, for example, a branched paraffin containing at least one tertiary carbon atom, or a compound that can be isomerized to a molecule containing at least one tertiary carbon atom.

Total Synthesis of Natural Products Using Hypervalent Iodine Reagents

NASA Astrophysics Data System (ADS)

Maertens, Gaetan; L'homme, Chloe; Canesi, Sylvain

2014-12-01

We present a review of natural product syntheses accomplished in our laboratory during the last five years. Each synthetic route features a phenol dearomatization promoted by an environmentally benign hypervalent iodine reagent. The dearomatizations demonstrate the “aromatic ring umpolung” concept, and involve stereoselective remodeling of the inert unsaturations of a phenol into a highly functionalized key intermediate that may contain a quaternary carbon center and a prochiral dienone system. Several new oxidative strategies were employed, including transpositions (1,3-alkyl shift and Prins-pinacol), a polycyclization, an ipso rearrangement, and direct nucleophilic additions at the phenol para position. Several alkaloids, heterocyclic compounds, and a polycyclic core have been achieved, including sceletenone (a serotonin reuptake inhibitor), acetylaspidoalbidine (an antitumor agent), fortucine (antiviral and antitumor), erysotramidine (curare-like effect), platensimycin (an antibiotic), and the main core of a kaurane diterpene (immunosuppressive agent and stimulator of apoptosis). These concise and in some cases enantioselective syntheses effectively demonstrate the importance of hypervalent iodine reagents in the total synthesis of bioactive natural products.

Acyl hydrazides as acyl donors for the synthesis of diaryl and aryl alkyl ketones.

PubMed

Akhbar, Ahmed R; Chudasama, Vijay; Fitzmaurice, Richard J; Powell, Lyn; Caddick, Stephen

2014-01-21

In this communication we describe a novel strategy for the formation of valuable diaryl and aryl alkyl ketones from acyl hydrazides. A wide variety of ketones are prepared and the mild reaction conditions allow for the use of a range of functionalities, especially in the synthesis of diaryl ketones.

Nitrosoureas: a review of experimental antitumor activity.

PubMed

Schabel, F M

1976-06-01

The chemical class of drugs known as the nitrosoureas are a recently developed group of very active alkylating-agent anticancer drugs which are best represented by BCNU, CCNU, and methyl-CCNU (meCCNU). The nitrosoureas are among the most active, if not the most active, anticancer drugs both quantitatively (log kill of sensitive tumor cells in vivo) and qualitatively (spectrum of mouse, rat, and hamster tumors responding to treatment). Therapeutic anticancer activity of the nitrosoureas has been consistently observed with oral as well as parenteral administration. The nitrosoureas are clearly the most active group of anticancer drugs observed against experimental meningeal leukemias and intracerebrally implanted transplantable primary tumors of central nervous system origin (eg, gliomas, ependymoblastomas, and astrocytomas in mice and hamsters). The nitrosoureas have been observed to be less than additive in lethal toxicity for vital normal cells in the mouse in combination with representatives of the other major classes of anticancer agents, eg, purine antagonists, pyrimidine antagonists, inhibitors of DNA polymerase(s) or ribonucleotide reductase(s), mitotic inhibitors, drugs that bind to or intercalate with DNA, and other alkylating agents. Therapeutic synergism against one or more transplantable or spontaneous tumors of mice, rats, or hamsters with one of several nitrosoureas in two-drug combinations with representatives of most of the major classes of anticancer agents listed above has been reported. With a number of advanced-stages mouse tumors, generally considered to be refractory to treatment with most anticancer agents, long-term cures have been obtained with combination-drug or combined-modality (surgery plus chemotherapy) treatment. The demonstrated lack of cross-resistance of several leukemias and solid tumors of mice selected for resistance to BCNU, meCCNU, or other alkylating agents suggests that the widely held opinion that all alkylating agents are very similar in biologic mechanism of action, and therefore resistance to one alkylating agent probably predicts cross-resistance to all alkylating agents, may no longer be tenable. If not, then alkylating-agent drug combinations, either used alone or combined with other treatment modalities (eg, surgery) which have been reported to result in therapeutic improvement in a number of experimental murine tumor systems, may be indicated for serious consideration as surgical adjuvant chemotherapy by surgeons or as primary therapy by medical oncologists.

Design, Synthesis, and Structure--Activity Relationship of New 2-Aryl-3,4-dihydro-β-carbolin-2-ium Salts as Antifungal Agents.

PubMed

Hou, Zhe; Zhu, Li-Fei; Yu, Xin-chi; Sun, Ma-Qiang; Miao, Fang; Zhou, Le

2016-04-13

Twenty-two 2-aryl-9-methyl-3,4-dihydro-β-carbolin-2-ium bromides along with four 9-demethylated derivatives were synthesized and characterized by spectroscopic analysis. By using the mycelium growth rate method, the compounds were evaluated for antifungal activities in vitro against six plant pathogenic fungi, and structure-activity relationships (SAR) were derived. Almost all of the compounds showed obvious inhibition activity on each of the fungi at 150 μM. For all of the fungi, 10 of the compounds showed average inhibition rates of >80% at 150 μM, and most of their EC50 values were in the range of 2.0-30.0 μM. SAR analysis showed that the substitution pattern of the N-aryl ring significantly influences the activity; N9-alkylation improves the activity, whereas aromatization of ring-C reduces the activity. It was concluded that the present research provided a series of new 2-aryl-9-alkyl-3,4-dihydro-β-carbolin-2-iums with excellent antifungal potency and structure optimization design for the development of new carboline antifungal agents.

Diastereoisomers of 2-benzyl-2, 3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol: potential anti-inflammatory agents.

PubMed

Sheridan, Helen; Walsh, John J; Cogan, Carina; Jordan, Michael; McCabe, Tom; Passante, Egle; Frankish, Neil H

2009-10-15

The synthesis and biological activity of the novel diastereoisomers of 2-benzyl-2,3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol is reported. The 2,2-coupled indane dimers were synthesised by coupling of the silyl enol ether of 1-indanone with the dimethyl ketal of 2-indanone. The coupled product was directly alkylated to give the racemic ketone which was reduced to the diastereoisomeric alcohols. The alcohols were separated and their relative stereochemistry was established by X-ray crystallography. These molecules demonstrate significant anti-inflammatory activity in vivo and in vitro and may represent a new class of anti-inflammatory agent.

Photoinduced, copper-catalyzed alkylation of amides with unactivated secondary alkyl halides at room temperature.

PubMed

Do, Hien-Quang; Bachman, Shoshana; Bissember, Alex C; Peters, Jonas C; Fu, Gregory C

2014-02-05

The development of a mild and general method for the alkylation of amides with relatively unreactive alkyl halides (i.e., poor substrates for SN2 reactions) is an ongoing challenge in organic synthesis. We describe herein a versatile transition-metal-catalyzed approach: in particular, a photoinduced, copper-catalyzed monoalkylation of primary amides. A broad array of alkyl and aryl amides (as well as a lactam and a 2-oxazolidinone) couple with unactivated secondary (and hindered primary) alkyl bromides and iodides using a single set of comparatively simple and mild conditions: inexpensive CuI as the catalyst, no separate added ligand, and C-N bond formation at room temperature. The method is compatible with a variety of functional groups, such as an olefin, a carbamate, a thiophene, and a pyridine, and it has been applied to the synthesis of an opioid receptor antagonist. A range of mechanistic observations, including reactivity and stereochemical studies, are consistent with a coupling pathway that includes photoexcitation of a copper-amidate complex, followed by electron transfer to form an alkyl radical.

Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases; Part 1: alkyl halide alkylations.

PubMed

Sorochinsky, Alexander E; Aceña, José Luis; Moriwaki, Hiroki; Sato, Tatsunori; Soloshonok, Vadim A

2013-10-01

Alkylations of chiral or achiral Ni(II) complexes of glycine Schiff bases constitute a landmark in the development of practical methodology for asymmetric synthesis of α-amino acids. Straightforward, easy preparation as well as high reactivity of these Ni(II) complexes render them ready available and inexpensive glycine equivalents for preparing a wide variety of α-amino acids, in particular on a relatively large scale. In the case of Ni(II) complexes containing benzylproline moiety as a chiral auxiliary, their alkylation proceeds with high thermodynamically controlled diastereoselectivity. Similar type of Ni(II) complexes derived from alanine can also be used for alkylation providing convenient access to quaternary, α,α-disubstituted α-amino acids. Achiral type of Ni(II) complexes can be prepared from picolinic acid or via recently developed modular approach using simple secondary or primary amines. These Ni(II) complexes can be easily mono/bis-alkylated under homogeneous or phase-transfer catalysis conditions. Origin of diastereo-/enantioselectivity in the alkylations reactions, aspects of practicality, generality and limitations of this methodology is critically discussed.

Regulation of DNA Alkylation Damage Repair: Lessons and Therapeutic Opportunities

PubMed Central

Soll, Jennifer M.; Sobol, Robert W.; Mosammaparast, Nima

2016-01-01

Alkylation chemotherapy is one of the most widely used systemic therapies for cancer. While somewhat effective, clinical responses and toxicities of these agents are highly variable. A major contributing factor for this variability is the numerous distinct lesions that are created upon alkylation damage. These adducts activate multiple repair pathways. There is mounting evidence that the individual pathways function cooperatively, suggesting that coordinated regulation of alkylation repair is critical to prevent toxicity. Furthermore, some alkylating agents produce adducts that overlap with newly discovered methylation marks, making it difficult to distinguish between bona fide damaged bases and so called ‘epigenetic’ adducts. We discuss new efforts aimed at deciphering the mechanisms that regulate these repair pathways, emphasizing their implications for cancer chemotherapy. PMID:27816326

Regio- and enantioselective palladium-catalyzed allylic alkylation of nitromethane with monosubstituted allyl substrates: synthesis of (R)-rolipram and (R)-baclofen.

PubMed

Yang, Xiao-Fei; Ding, Chang-Hua; Li, Xiao-Hui; Huang, Jian-Qiang; Hou, Xue-Long; Dai, Li-Xin; Wang, Pin-Jie

2012-10-19

The Pd-catalyzed asymmetric allylic alkylation (AAA) reaction of nitromethane with monosubstituted allyl substrates was realized for the first time to provide corresponding products in high yields with excellent regio- and enantioselectivities. The protocol was applied to the enantioselective synthesis of (R)-baclofen and (R)-rolipram.

Diastereoselective radical addition to γ-alkyl-α-methylene-γ-butyrolactams and the synthesis of a chiral pyroglutamic acid derivative.

PubMed

Yajima, Tomoko; Yoshida, Eriko; Hamano, Masako

2013-01-01

The cis- and trans-stereoselective radical additions to α-methylene-γ-alkyl- γ-lactams were investigated and the scope and limitation of the reaction were also revealed. This stereoselective radical reaction was used for synthesis of chiral pyroglutamic acid derivatives starting from a commercially available chiral amino acid.

Transition-Metal-Catalyzed C-H Alkylation Using Alkenes.

PubMed

Dong, Zhe; Ren, Zhi; Thompson, Samuel J; Xu, Yan; Dong, Guangbin

2017-07-12

Alkylation reactions represent an important organic transformation to form C-C bonds. In addition to conventional approaches with alkyl halides or sulfonates as alkylating agents, the use of unactivated olefins for alkylations has become attractive from both cost and sustainability viewpoints. This Review summarizes transition-metal-catalyzed alkylations of various carbon-hydrogen bonds (addition of C-H bonds across olefins) using regular olefins or 1,3-dienes up to May 2016. According to the mode of activation, the Review is divided into two sections: alkylation via C-H activation and alkylation via olefin activation.

Chemotherapy-induced pulmonary hypertension: role of alkylating agents.

PubMed

Ranchoux, Benoît; Günther, Sven; Quarck, Rozenn; Chaumais, Marie-Camille; Dorfmüller, Peter; Antigny, Fabrice; Dumas, Sébastien J; Raymond, Nicolas; Lau, Edmund; Savale, Laurent; Jaïs, Xavier; Sitbon, Olivier; Simonneau, Gérald; Stenmark, Kurt; Cohen-Kaminsky, Sylvia; Humbert, Marc; Montani, David; Perros, Frédéric

2015-02-01

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Protection against the Acute and Delayed Toxicity of Mustards and Mustard-Like Compounds.

DTIC Science & Technology

1983-09-01

Edition, A. G. Gilman, L. S. Goodman, and A. Gilman (eds.), Macmillan, New York, 1980, pp. 1256-1313. * 2. Ludlum, D. B., Alkylating Agents and the...chemical warfare agents . They are acutely toxic to the skin, respiratory tract, eyes, bone marrow, and, in large doses, to other organs as well...related to the alkylating activity of sulfur mustards and, specifically, to alkylation of DNA (1). Investigations of related compounds have led to the

Study of magnetization switching for MRAM based memory technologies

NASA Astrophysics Data System (ADS)

Pham, Huy

Amphibian alkaloids are attractive targets for synthesis due to their biological activity. An important class of amphibian alkaloids is the 2,5-disubstituted pyrrolidine-based family of compounds. There are many synthetic approaches for the preparation of the trans-2,5-disubstituted pyrrolidines, but methods for the construction of the cis-2,5-pyrrolidines are limited. Therefore, it was desired to develop an enantioselective approach for the preparation of cis-2,5-disubsituted pyrrolidines. (+)-Tropin-2-one derived from cocaine was used as starting material to exploit the inherent stereochemistry for construction of the cis-pyrrolidine ring. This permitted the unequivocal assignment of the absolute configuration of the target pyrrolidine. The structurally simple pyrrolidine alkaloid, 225H, was selected as a target to develop a general synthetic approach. The enantioselective synthesis of 225H was achieved in nine steps and good overall yield. The search for potent cannabinoid receptor partial agonist ligands as potential marijuana addiction therapeutic agents has led to an investigation of the synthesis of diaryl ether hybrid analogues of BAY 59-3074. A series of 2-(3-alkyl-5-hydroxyphenoxy)-6-(trifluoromethyl)benzonitriles, 3-(2-cyano-3-(trifluoromethyl)phenoxy)phenylalkanoates, and (3-(benzyloxy)phenoxy)-6-(trifluoromethyl)benzonitriles were synthesized and evaluated in vitro for CB1 affinity. The olivetol diaryl ether analogue was the most potent ligand of the alkyl series, but the diaryl ester analogues exhibited modest affinity for CB1 receptors. The most potent compound of the series was the 2-(3-(benzyloxy)phenoxy)-6-(trifluoromethyl)benzonitrile. Keywords. amphibian alkaloids, enantioselective synthesis, pyrrolidine, cannabinoid receptor, marijuana.

Safety Assessment of Alkyl PEG/PPG Ethers as Used in Cosmetics.

PubMed

Fiume, Monice M; Heldreth, Bart; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

2016-07-01

The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of 131 alkyl polyethylene glycol (PEG)/polypropylene glycol ethers as used in cosmetics, concluding that these ingredients are safe in the present practices of use and concentration described in this safety assessment when formulated to be nonirritating. Most of the alkyl PEG/PPG ethers included in this review are reported to function in cosmetics as surfactants, skin-conditioning agents, and/or emulsifying agents. The alkyl PEG/PPG ethers share very similar physiochemical properties as the alkyl PEG ethers, which were reviewed previously by the CIR Expert Panel and found safe when formulated to be nonirritating. The alkyl PEG ethers differ by the inclusion of PPG repeat units, which are used to fine-tune the surfactant properties of this group. The Panel relied heavily on data on analogous ingredients, extracted from the alkyl PEG ethers and PPG reports, when making its determination of safety. © The Author(s) 2016.

Anti-cancer agents based on N-acyl-2, 3-dihydro-1H-pyrrolo[2,3-b] quinoline derivatives and a method of making

DOEpatents

Gakh, Andrei; Krasavin, Mikhail; Karapetian, Ruben; Rufanov, Konstantin A; Konstantinov, Igor; Godovykh, Elena; Soldatkina, Olga; Sosnov, Andrey V

2013-04-16

The present disclosure relates to novel compounds that can be used as anti-cancer agents in the prostate cancer therapy. In particular, the invention relates to N-acyl derivatives of 2,3-dihydro-1H-pyrrolo[2,3-b]quinolines having the structural Formula (I), ##STR00001## stereoisomers, tautomers, racemics, prodrugs, metabolites thereof, or pharmaceutically acceptable salt and/or solvate thereof. The meaning of R1 is independently selected from H; C1-C6 Alkyl, cyclo-Alkyl or iso-Alkyl substituents; R2 is selected from C1-C6 Alkyl, cyclo-Alkyl or iso-Alkyl; substituted or non-substituted, fused or non-fused to substituted or non-substituted aromatic ring, aryl or heteroaryl groups. The invention also relates to methods for preparing said compounds, and to pharmaceutical compositions comprising said compounds.

The Impact of Commonly Used Alkylating Agents on Artifactual Peptide Modification.

PubMed

Hains, Peter G; Robinson, Phillip J

2017-09-01

Iodoacetamide is by far the most commonly used agent for alkylation of cysteine during sample preparation for proteomics. An alternative, 2-chloroacetamide, has recently been suggested to reduce the alkylation of residues other than cysteine, such as the N-terminus, Asp, Glu, Lys, Ser, Thr, and Tyr. Here we show that although 2-chloroacetamide reduces the level of off-target alkylation, it exhibits a range of adverse effects. The most significant of these is methionine oxidation, which increases to a maximum of 40% of all Met-containing peptides, compared with 2-5% with iodoacetamide. Increases were also observed for mono- and dioxidized tryptophan. No additional differences between the alkylating reagents were observed for a range of other post-translational modifications and digestion parameters. The deleterious effects were observed for 2-chloroacetamide from three separate suppliers. The adverse impact of 2-chloroacetamide on methionine oxidation suggests that it is not the ideal alkylating reagent for proteomics.

Synthesis and Anticancer Activity of 2-(Alkyl-, Alkaryl-, Aryl-, Hetaryl-)-[1,2,4]triazolo[1,5-c]quinazolines

PubMed Central

Kovalenko, Sergiy I.; Antypenko, Lyudmyla M.; Bilyi, Andriy K.; Kholodnyak, Sergiy V.; Karpenko, Olexandr V.; Antypenko, Olexii M.; Mykhaylova, Natalya S.; Los, Tetyana I.; Kolomoets, Olexandra S.

2013-01-01

The combinatorial library of novel potential anticancer agents, namely, 2-(alkyl-, alkaryl-, aryl-, hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines, was synthesized by the heterocyclization of the alkyl-, alkaryl-, aryl-, hetarylcarboxylic acid (3H-quinazoline-4-ylidene)hydrazides by oxidative heterocyclization of the 4-(arylidenehydrazino)quinazolines using bromine, and by the heterocyclization of N-(2-cyanophenyl)formimidic acid ethyl ester. The optimal method for synthesis of the s-triazolo[1,5-c]quinazolines appeared to be cyclocondensation of the corresponding carboxylic acid (3H-quinazoline-4-ylidene)hydrazides. The compounds’ structures were established by 1H, 13C NMR, LC- and EI-MS analysis. The in vitro screening of anticancer activity determined the most active compound to be 3,4,5-trimethoxy-N′-[quinazolin-4(3H)-ylidene]benzohydrazide (3.20) in micromolar concentrations with the GI50 level (MG_MID, GI50 is 2.29). Thus, the cancer cell lines whose growth is greatly inhibited by compound 3.20 are: non-small cell lung cancer (NCI-H522, GI50=0.34), CNS (SF-295, GI50=0.95), ovarian (OVCAR-3, GI50=0.33), prostate (PC-3, GI50=0.56), and breast cancer (MCF7, GI50=0.52), leukemia (K-562, GI50=0.41; SR, GI50=0.29), and melanoma (MDA-MB-435, GI50=0.31; SK-MEL-5, GI50=0.74; UACC-62, GI50=0.32). SAR-analysis is also discussed. PMID:23833709

'Petite' mutagenesis and mitotic crossing-over in yeast by DNA-targeted alkylating agents.

PubMed

Ferguson, L R; Turner, P M; Gourdie, T A; Valu, K K; Denny, W A

1989-12-01

Although the biological properties (cytotoxicity, mutagenicity and carcinogenicity) of alkylating agents result from their bonding interactions with DNA, such compounds generally do not show any special binding affinity for DNA. A series of acridine-linked aniline mustards of widely-varying alkylator reactivity have been designed as DNA-directed alkylating agents. We have considered whether such DNA targeting has an effect on mutagenic properties by evaluating this series of drugs in comparison with their untargeted counterparts for toxic, recombinogenic and mutagenic properties in Saccharomyces cerevisiae strain D5. The simple untargeted aniline mustards are effective inducers of mitotic crossing-over in this strain, but resemble other reported alkylators in being rather inefficient inducers of the "petite" or mitochondrial mutation in yeast. However, the majority of the DNA-targeted mustards were very efficient petite mutagens, while showing little evidence of mitotic crossing-over or other nuclear events. The 100% conversion of cells into petites and the lack of a differential between growing and non-growing cells are similar to the effects of the well characterised mitochondrial mutagen ethidium bromide. These data suggest very different modes of action between the DNA-targeted alkylators and their non-targeted counterparts.

Synthesis of a thiol-β-cyclodextrin, a potential agent for controlling enzymatic browning in fruits and vegetables.

PubMed

Manta, Carmen; Peralta-Altier, Gabriela; Gioia, Larissa; Méndez, María F; Seoane, Gustavo; Ovsejevi, Karen

2013-11-27

A thiol-β-cyclodextrin was synthesized by a simple and environmentally friendly three-step method comprising epoxy activation of β-cyclodextrin, thiosulfate-mediated oxirane opening, and further reduction of the S-alkyl thiosulfate to a thiol group. The final step was optimized by using thiopropyl-agarose, a solid phase reducing agent with many advantages over soluble ones. β-Cyclodextrin thiolation was confirmed by titration with a thiol-reactive reagent, NMR studies, and MALDI-TOF/TOF. Thiolated cyclodextrin had an average value of one thiol group per molecule. Thiol-β-cyclodextrin proved to be an excellent agent for controlling polyphenol oxidase activity. This copper-containing enzyme is responsible for browning in fruits and vegetables. Under the same conditions, thiol-β-cyclodextrin generated a reductive microenvironment that increased the antibrowning effect on Red Delicious apples compared to unmodified β-cyclodextrin.

Developing Ionic Liquid Know-How for the Design of Modular Functionality, Versatile Platforms, and New Synthetic Methodologies for Energetic Materials

DTIC Science & Technology

2013-12-05

Protocol for the Synthesis of Alkylated Imidazolium Salt Derivatives 1,3-Dimethylimidazolium chloride (1,3-diMe-IM][Cl]) (19c) and 1,2,3...C5’). A8. Hypergolic Ionic Liquids to Mill, Suspend, and Ignite Boron Nanoparticles Synthesis of 1-Butyl-3-methylimidazolium chloride ([1-Bu...3-methylimidazolium chloride , 5[Cl] D5. Zinc-assisted synthesis of imidazolium-tetrazolate bi-heterocyclic zwitterions with variable alkyl

Synthesis of m-Alkylphenols via a Ruthenium-Catalyzed C-H Bond Functionalization of Phenol Derivatives.

PubMed

Li, Gang; Gao, Panpan; Lv, Xulu; Qu, Chen; Yan, Qingkai; Wang, Ya; Yang, Suling; Wang, Junjie

2017-05-19

The first example of the synthesis of m-alkylphenols via a ruthenium-catalyzed C Ar -H bond functionalization of phenol derivatives with sec/tert-alkyl bromides is reported. Mechanistic studies indicated that the m-C Ar -H bond alkylation may involve a radical process and that a six-membered ruthenacycle complex was the active catalyst. Moreover, this approach can provide an expedited strategy for the atom-/step-economical synthesis of many noteworthy pharmaceuticals and other functional molecules.

Diastereoselective radical addition to γ-alkyl-α-methylene-γ-butyrolactams and the synthesis of a chiral pyroglutamic acid derivative

PubMed Central

Yoshida, Eriko; Hamano, Masako

2013-01-01

Summary The cis- and trans-stereoselective radical additions to α-methylene-γ-alkyl- γ-lactams were investigated and the scope and limitation of the reaction were also revealed. This stereoselective radical reaction was used for synthesis of chiral pyroglutamic acid derivatives starting from a commercially available chiral amino acid. PMID:23946839

Multi-catalysis cascade reactions based on the methoxycarbonylketene platform: diversity-oriented synthesis of functionalized non-symmetrical malonates for agrochemicals and pharmaceuticals.

PubMed

Ramachary, Dhevalapally B; Venkaiah, Chintalapudi; Reddy, Y Vijayendar; Kishor, Mamillapalli

2009-05-21

In this paper we describe new multi-catalysis cascade (MCC) reactions for the one-pot synthesis of highly functionalized non-symmetrical malonates. These metal-free reactions are either five-step (olefination/hydrogenation/alkylation/ketenization/esterification) or six-step (olefination/hydrogenation/alkylation/ketenization/esterification/alkylation), and employ aldehydes/ketones, Meldrum's acid, 1,4-dihydropyridine/o-phenylenediamine, diazomethane, alcohols and active ethylene/acetylenes, and involve iminium-, self-, self-, self- and base-catalysis, respectively. Many of the products have direct application in agricultural and pharmaceutical chemistry.

Copper(II)-catalyzed enantioselective hydrosilylation of halo-substituted alkyl aryl and heteroaryl ketones: asymmetric synthesis of (R)-fluoxetine and (S)-duloxetine.

PubMed

Zhou, Ji-Ning; Fang, Qiang; Hu, Yi-Hu; Yang, Li-Yao; Wu, Fei-Fei; Xie, Lin-Jie; Wu, Jing; Li, Shijun

2014-02-14

A set of reaction conditions has been established to facilitate the non-precious copper-catalyzed enantioselective hydrosilylation of a number of structurally diverse β-, γ- or ε-halo-substituted alkyl aryl ketones and α-, β- or γ-halo-substituted alkyl heteroaryl ketones under air to afford a broad spectrum of halo alcohols in high yields and good to excellent enantioselectivities (up to 99% ee). The developed procedure has been successfully applied to the asymmetric synthesis of antidepressant drugs (R)-fluoxetine and (S)-duloxetine, which highlighted its synthetic utility.

DNA injection and genetic recombination of alkylated bacteriophage T7 in the presence of nalidixic acid.

PubMed Central

Karska-Wysocki, B; Mamet-Bratley, M D; Przewlocki, G

1977-01-01

Marker rescue experiments with alkylated T7 bacteriophage carried out in the presence and in the absence of nalidixic acid suggest that the gradient in rescue is due to two alkylation-induced causes: a DNA injection defect and an interference with DNA synthesis. PMID:916036

Atorvastatin Downregulates In Vitro Methyl Methanesulfonate and Cyclophosphamide Alkylation-Mediated Cellular and DNA Injuries

PubMed Central

Christoni, Larissa S. A.; Justo, Graça; Soeiro, Maria N. C.

2018-01-01

Statins are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, and this class of drugs has been studied as protective agents against DNA damages. Alkylating agents (AAs) are able to induce alkylation in macromolecules, causing DNA damage, as DNA methylation. Our objective was to evaluate atorvastatin (AVA) antimutagenic, cytoprotective, and antigenotoxic potentials against DNA lesions caused by AA. AVA chemopreventive ability was evaluated using antimutagenicity assays (Salmonella/microsome assay), cytotoxicity, cell cycle, and genotoxicity assays in HepG2 cells. The cells were cotreated with AVA and the AA methyl methanesulfonate (MMS) or cyclophosphamide (CPA). Our datum showed that AVA reduces the alkylation-mediated DNA damage in different in vitro experimental models. Cytoprotection of AVA at low doses (0.1–1.0 μM) was observed after 24 h of cotreatment with MMS or CPA at their LC50, causing an increase in HepG2 survival rates. After all, AVA at 10 μM and 25 μM had decreased effect in micronucleus formation in HepG2 cells and restored cell cycle alterations induced by MMS and CPA. This study supports the hypothesis that statins can be chemopreventive agents, acting as antimutagenic, antigenotoxic, and cytoprotective components, specifically against alkylating agents of DNA. PMID:29849914

S - and N-alkylating agents diminish the fluorescence of fluorescent dye-stained DNA.

PubMed

Giesche, Robert; John, Harald; Kehe, Kai; Schmidt, Annette; Popp, Tanja; Balzuweit, Frank; Thiermann, Horst; Gudermann, Thomas; Steinritz, Dirk

2017-01-25

Sulfur mustard (SM), a chemical warfare agent, causes DNA alkylation, which is believed to be the main cause of its toxicity. SM DNA adducts are commonly used to verify exposure to this vesicant. However, the required analytical state-of-the-art mass-spectrometry methods are complex, use delicate instruments, are not mobile, and require laboratory infrastructure that is most likely not available in conflict zones. Attempts have thus been made to develop rapid detection methods that can be used in the field. The analysis of SM DNA adducts (HETE-G) by immunodetection is a convenient and suitable method. For a diagnostic assessment, HETE-G levels must be determined in relation to the total DNA in the sample. Total DNA can be easily visualized by the use of fluorescent DNA dyes. This study examines whether SM and related compounds affect total DNA staining, an issue that has not been investigated before. After pure DNA was extracted from human keratinocytes (HaCaT cells), DNA was exposed to different S- and N-alkylating agents. Our experiments revealed a significant, dose-dependent decrease in the fluorescence signal of fluorescent dye-stained DNA after exposure to alkylating agents. After mass spectrometry and additional fluorescence measurements ruled out covalent modifications of ethidium bromide (EthBr) by SM, we assumed that DNA crosslinks caused DNA condensation and thereby impaired access of the fluorescent dyes to the DNA. DNA digestion by restriction enzymes restored fluorescence, a fact that strengthened our hypothesis. However, monofunctional agents, which are unable to crosslink DNA, also decreased the fluorescence signal. In subsequent experiments, we demonstrated that protons produced during DNA alkylation caused a pH decrease that was found responsible for the reduction in fluorescence. The use of an appropriate buffer system eliminated the adverse effect of alkylating agents on DNA staining with fluorescent dyes. An appropriate buffer system is thus crucial for DNA quantification with fluorescent dyes in the presence of alkylating compounds. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Synthesis of benzimidazoles by PIDA-promoted direct C(sp2)-H imidation of N-arylamidines.

PubMed

Huang, Jinbo; He, Yimiao; Wang, Yong; Zhu, Qiang

2012-10-29

A metal-free synthesis of diversified benzimidazoles from N-arylamidines through a phenyliodine(III) diacetate (PIDA) promoted intramolecular direct C(sp(2))-H imidation has been developed. The reaction proceeds smoothly at 0 °C or ambient temperature to provide the desired products in good to excellent yields. The synthesis of 2-alkyl- or 2-alkyl-fused benzimidazoles, which are generally inaccessible by similar Pd- or Cu-catalyzed approaches, can also be achieved. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and Evaluation of Novel Oxyalkylated Derivatives of 2′,4′-Dihydroxychalcone as Anti-Oomycete Agents against Bronopol Resistant Strains of Saprolegnia sp.

PubMed Central

Flores, Susana; Montenegro, Iván; Villena, Joan; Cuellar, Mauricio; Werner, Enrique; Godoy, Patricio; Madrid, Alejandro

2016-01-01

A series of novel oxyalkylchalcones substituted with alkyl groups were designed and synthesized, and the antioomycete activity of the series was evaluated in vitro against Saprolegnia strains. All tested O-alkylchalcones were synthesized by means of nucleophilic substitution from the natural compound 2′,4′-dihydroxychalcone (1) and the respective alkyl bromide. The natural chalcone (1) and 10 synthetic oxyalkylchalcones (2–11) were tested against Saprolegnia parasitica and Saprolegnia australis. Among synthetic analogs, 2-hydroxy,4-farnesyloxychalcone (11) showed the most potent activity against Saprolegnia sp., with MIC and MOC values of 125 µg/mL (similar to bronopol at 150 µg/mL) and 175 µg/mL, respectively; however, 2′,4′-dihydroxychalcone (1) was the strongest and most active molecule, with MIC and MOC values of 6.25 µg/mL and 12.5 µg/mL. PMID:27556457

A new class of hybrid anticancer agents inspired by the synergistic effects of curcumin and genistein: Design, synthesis, and anti-proliferative evaluation.

PubMed

Chen, Qiao-Hong; Yu, Kevin; Zhang, Xiaojie; Chen, Guanglin; Hoover, Andrew; Leon, Francisco; Wang, Rubing; Subrahmanyam, Nithya; Addo Mekuria, Ermias; Harinantenaina Rakotondraibe, Liva

2015-10-15

Inspired by the synergistic effects of dietary natural products with different scaffolds on the inhibition of cancer cell proliferation, incorporation of central (1E,4E)-1,4-penta-dien-3-one linker (an optimal substitute for the central metabolically unstable diketone linker of curcumin), 1-alkyl-1H-imidazol-2-yl (a promising bioisostere of terminal aryl group in curcumin), and chromone (the common pharmacophore in genistein and quercetin) into one chemical entity resulted in ten new hybrid molecules, 3-((1E,4E)-5-(1-alkyl-1H-imidazol-2-yl)-3-oxopenta-1,4-dien-1-yl)-4H-chromen-4-ones. They were synthesized through a three-step transformation using acid-catalyzed aldol condensation as key step. The WST-1 cell proliferation assay showed that they have greater anti-proliferative potency than curcumin, quercetin, and genistein on both androgen-dependent and androgen-independent human prostate cancer cells. Published by Elsevier Ltd.

Total synthesis of (+/-)-taiwaniaquinol B via a domino intramolecular friedel-crafts acylation/carbonyl alpha-tert-alkylation reaction.

PubMed

Fillion, Eric; Fishlock, Dan

2005-09-28

The first synthesis of taiwaniaquinol B, a 6-nor-5(6-->7)abeoabietane-type diterpenoid exhibiting the uncommon fused 6-5-6 tricyclic carbon skeleton, was accomplished in 15 steps. A Lewis acid-promoted tandem intramolecular Friedel-Crafts/carbonyl alpha-tert-alkylation reaction was exploited as the core strategy for the synthesis of the sterically congested 1-indanone-containing tricyclic structure. This multiple carbon-carbon bond forming reaction exploits the unique reactivity of Meldrum's acid. The facile precursor synthesis makes this a useful methodology for the expedient modification and assembly of sterically congested 1-indanone-containing ring systems.

Synthesis, Biological Evaluation and Structure-Activity Relationships of a Novel Class of Apurinic/Apyrimidinic Endonuclease 1 Inhibitors

PubMed Central

Rai, Ganesha; Vyjayanti, Vaddadi N.; Dorjsuren, Dorjbal; Simeonov, Anton; Jadhav, Ajit; Wilson, David M.; Maloney, David J.

2012-01-01

APE1 is an essential protein that operates in the base excision repair (BER) pathway and is responsible for ≥95% of the total apurinic/apyrimidinic (AP) endonuclease activity in human cells. BER is a major pathway that copes with DNA damage induced by several anti-cancer agents, including ionizing radiation and temozolomide. Overexpression of APE1 and enhanced AP endonuclease activity has been linked to increased resistance of tumor cells to treatment with monofunctional alkylators, implicating inhibition of APE1 as a valid strategy for cancer therapy. We report herein the results of a focused medicinal chemistry effort around a novel APE1 inhibitor, N-(3-(benzo[d]thiazol-2-yl)-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide (3). Compound 3 and related analogs exhibit single-digit µM activity against the purified APE1 enzyme, comparable activity in HeLa whole cell extract assays, and potentiate the cytotoxicity of the alkylating agents methylmethane sulfonate and temozolomide. Moreover, this class of compounds possesses a generally favorable in vitro ADME profile, along with good exposure levels in plasma and brain following intraperitoneal dosing (30 mg/kg body weight) in mice. PMID:22455312

Synthesis of prostaglandins by conjugate addition and alkylation of a directed enolate ion. 4,5-allenyl prostaglandins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Patterson, J.W.

1990-09-28

Over the previous two decades many elegant syntheses of prostaglandins, which in more sophisticated forms, allow the stereospecific introduction of the various asymmetric carbons have been accomplished. However, among these approaches the cuprate addition/enolate alkylation of suitable cyclopentenone {sup 2} stands out because of brevity and convergence. The recent reports by Noyori{sup 3} and Corey{sup 4} and their colleagues have reduced to practice the conversion of 4-alkoxycyclopentenones to prostaglandin E{sub 2} (PGE{sub 2}) by conjugate addition of an organocopper derivative of the lower side chain followed by alkylation of the resulting carbanion with methyl 7-halohept-2-enoate. The subject of this papermore » is application of the Tardella tin enolate alkylation developed by Noyori to the synthesis of 4, 5-allenic prostaglandins, a pharmacologically important class of compounds. The authors results demonstrate that the tandem alkylation of an enone precursor with a cuprate reagent followed by alkylation of the corresponding tin enolate with bromide reagent is a viable synthetic method for 4,5-didehydro-PGE{sub 2}. Because the optically active forms of 1 and the vinyl iodide precursor of the PGE{sub 2} lower side chain have been employed to produce a single enantiomer of PGE{sub 2}, the extension of the methodology described here to the synthesis of single enantiomers of 4a awaits only the preparation of the separate enantiomers of allene 14.« less

Alkylation of enolates: An electrophilicity perspective

NASA Astrophysics Data System (ADS)

Elango, M.; Parthasarathi, R.; Subramanian, V.; Chattaraj, P. K.

Enolates are ambient nucleophiles, and alkylation can occur either at a carbon or at an oxygen site. It is known that the ratio of C/O alkylation depends significantly on various factors, including the type of enolate, alkylating agent, site of alkylation, and solvent environment. Analysis of regioselectivity and solvent effects on alkylation of lithium enolates is investigated using various reactivity descriptors, including generalized philicity. These results point out the reliability of both global and local reactivity descriptors in providing significant information about site selectivity and chemical reactivity of lithium enolates.

Endogenous sterol biosynthesis is important for mitochondrial function and cell morphology in procyclic forms of Trypanosoma brucei.

PubMed

Pérez-Moreno, Guiomar; Sealey-Cardona, Marco; Rodrigues-Poveda, Carlos; Gelb, Michael H; Ruiz-Pérez, Luis Miguel; Castillo-Acosta, Víctor; Urbina, Julio A; González-Pacanowska, Dolores

2012-10-01

Sterol biosynthesis inhibitors are promising entities for the treatment of trypanosomal diseases. Insect forms of Trypanosoma brucei, the causative agent of sleeping sickness, synthesize ergosterol and other 24-alkylated sterols, yet also incorporate cholesterol from the medium. While sterol function has been investigated by pharmacological manipulation of sterol biosynthesis, molecular mechanisms by which endogenous sterols influence cellular processes remain largely unknown in trypanosomes. Here we analyse by RNA interference, the effects of a perturbation of three specific steps of endogenous sterol biosynthesis in order to dissect the role of specific intermediates in proliferation, mitochondrial function and cellular morphology in procyclic cells. A decrease in the levels of squalene synthase and squalene epoxidase resulted in a depletion of cellular sterol intermediates and end products, impaired cell growth and led to aberrant morphologies, DNA fragmentation and a profound modification of mitochondrial structure and function. In contrast, cells deficient in sterol methyl transferase, the enzyme involved in 24-alkylation, exhibited a normal growth phenotype in spite of a complete abolition of the synthesis and content of 24-alkyl sterols. Thus, the data provided indicates that while the depletion of squalene and post-squalene endogenous sterol metabolites results in profound cellular defects, bulk 24-alkyl sterols are not strictly required to support growth in insect forms of T. brucei in vitro. Copyright © 2012 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

Synthesis and characterization of a glycine-modified heptamethine indocyanine dye for in vivo cancer-targeted near-infrared imaging

PubMed Central

Liu, Tao; Luo, Shenglin; Wang, Yang; Tan, Xu; Qi, Qingrong; Shi, Chunmeng

2014-01-01

Near-infrared (NIR) fluorescent sensors have emerged as promising molecular tools for cancer imaging and detection in living systems. However, cancer NIR fluorescent sensors are very challenging to develop because they are required to exhibit good specificity and low toxicity as an eligible contrast agent. Here, we describe the synthesis of a new heptamethine indocyanine dye (NIR-27) modified with a glycine at the end of each N-alkyl side chain, and its biological characterization for in vivo cancer-targeted NIR imaging. In addition to its high specificity, NIR-27 also shows lower cytotoxicity than indocyanine green, a nonspecific NIR probe widely used in clinic. These characteristics suggest that NIR-27 is a promising prospect as a new NIR fluorescent sensor for sensitive cancer detection. PMID:25246770

Poly(alkyl methacrylate) Brush-Grafted Silica Nanoparticles as Oil Lubricant Additives: Effects of Alkyl Pendant Groups on Oil Dispersibility, Stability, and Lubrication Property

DOE PAGES

Seymour, Bryan T.; Wright, Roger A. E.; Parrott, Alexander C.; ...

2017-07-03

This paper reports on the synthesis of a series of poly(alkyl methacrylate) brush-grafted, 23 nm silica nanoparticles (hairy NPs) and the study of the effect of alkyl pendant length on their use as oil lubricant additives for friction and wear reduction. The hairy NPs were prepared by surface-initiated reversible addition–fragmentation chain transfer polymerization from trithiocarbonate chain transfer agent (CTA)-functionalized silica NPs in the presence of a free CTA. We found that hairy NPs with sufficiently long alkyl pendant groups (containing >8 carbon atoms, such as 12, 13, 16, and 18 in this study) could be readily dispersed in poly(alphaolefin) (PAO),more » forming clear, homogeneous dispersions, and exhibited excellent stability at low and high temperatures as revealed by visual inspection and dynamic light scattering studies. Whereas poly(n-hexyl methacrylate) hairy NPs cannot be dispersed in PAO under ambient conditions or at 80 °C, interestingly, poly(2-ethylhexyl methacrylate) hairy NPs can be dispersed in PAO at 80 °C but not at room temperature, with a reversible clear-to-cloudy transition observed upon cooling. High-contact-stress ball-on-flat reciprocating sliding tribological tests at 100 °C showed significant reductions in both the coefficient of friction (up to 38%) and wear volume (up to 90% for iron flat) for transparent, homogeneous dispersions of hairy NPs in PAO at a concentration of 1.0 wt % compared with neat PAO. Finally, the formation of a load-bearing tribofilm at the rubbing interface was confirmed using scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy.« less

Poly(alkyl methacrylate) Brush-Grafted Silica Nanoparticles as Oil Lubricant Additives: Effects of Alkyl Pendant Groups on Oil Dispersibility, Stability, and Lubrication Property

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seymour, Bryan T.; Wright, Roger A. E.; Parrott, Alexander C.

This paper reports on the synthesis of a series of poly(alkyl methacrylate) brush-grafted, 23 nm silica nanoparticles (hairy NPs) and the study of the effect of alkyl pendant length on their use as oil lubricant additives for friction and wear reduction. The hairy NPs were prepared by surface-initiated reversible addition–fragmentation chain transfer polymerization from trithiocarbonate chain transfer agent (CTA)-functionalized silica NPs in the presence of a free CTA. We found that hairy NPs with sufficiently long alkyl pendant groups (containing >8 carbon atoms, such as 12, 13, 16, and 18 in this study) could be readily dispersed in poly(alphaolefin) (PAO),more » forming clear, homogeneous dispersions, and exhibited excellent stability at low and high temperatures as revealed by visual inspection and dynamic light scattering studies. Whereas poly(n-hexyl methacrylate) hairy NPs cannot be dispersed in PAO under ambient conditions or at 80 °C, interestingly, poly(2-ethylhexyl methacrylate) hairy NPs can be dispersed in PAO at 80 °C but not at room temperature, with a reversible clear-to-cloudy transition observed upon cooling. High-contact-stress ball-on-flat reciprocating sliding tribological tests at 100 °C showed significant reductions in both the coefficient of friction (up to 38%) and wear volume (up to 90% for iron flat) for transparent, homogeneous dispersions of hairy NPs in PAO at a concentration of 1.0 wt % compared with neat PAO. Finally, the formation of a load-bearing tribofilm at the rubbing interface was confirmed using scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy.« less

Synthesis of branched cores by poly-O-alkylation reaction under phase transfer conditions. A systematic study

NASA Astrophysics Data System (ADS)

Landeros, José M.; Silvestre, Hugo A.; Guadarrama, Patricia

2013-04-01

In the present paper is described a systematic study of poly-O-alkylation reactions of pentaerythritol (PE) and 1,1,1-tris(hydroxymethyl)ethane (TME) by 1,4 Michael addition, under phase transfer catalysis (PTC), considering the effect of: (1) the organophilicity of PTC (three different catalysts were tested), (2) PTC concentration (from catalytic to equimolar conditions), and (3) the regime of addition of reactants coexisting in the aqueous phase of the heterogeneous reaction system. The less organophilic transfer agent showed the best performance on these reactions. In our case, benzyltriethylammonium chloride (TEBAC) gathers the best features. The presence of NaOH as base, promotes the interfacial mechanism and not the bulk one. Out of the optimal range of concentration of NaOH (35-40%), competition between nucleophiles can occur, due to the saturation of the medium. Regarding the regime of addition of reactants, the scenario where NaOH and TEBAC are less time in contact, favors the formation of the desired products. Finally, the deprotection of tert-butyl groups of the poly-O-alkylated compounds is described, to get branched cores with terminal carboxylic acid groups in good yields (90-94%). Spectroscopic properties, such as IR, 1H and 13C NMR, of the synthesized compounds are also described.

B-Raf inhibitor vemurafenib in combination with temozolomide and fotemustine in the killing response of malignant melanoma cells.

PubMed

Roos, Wynand P; Quiros, Steve; Krumm, Andrea; Merz, Stephanie; Switzeny, Olivier Jérôme; Christmann, Markus; Loquai, Carmen; Kaina, Bernd

2014-12-30

In the treatment of metastatic melanoma, a highly therapy-refractory cancer, alkylating agents are used and, for the subgroup of BRAFV600E cancers, the B-Raf inhibitor vemurafenib. Although vemurafenib is initially beneficial, development of drug resistance occurs leading to tumor relapse, which necessitates the requirement for combined or sequential therapy with other drugs, including genotoxic alkylating agents. This leads to the question whether vemurafenib and alkylating agents act synergistically and whether chronic vemurafenib treatment alters the melanoma cell response to alkylating agents. Here we show that a) BRAFV600E melanoma cells are killed by vemurafenib, driving apoptosis, b) BRAFV600E melanoma cells are neither more resistant nor sensitive to temozolomide/fotemustine than non-mutant cells, c) combined treatment with vemurafenib plus temozolomide or fotemustine has an additive effect on cell kill, d) acquired vemurafenib resistance of BRAFV600E melanoma cells does not affect MGMT, MSH2, MSH6, PMS2 and MLH1, nor does it affect the resistance to temozolomide and fotemustine, e) metastatic melanoma biopsies obtained from patients prior to and after vemurafenib treatment did not show a change in the MGMT promoter methylation status and MGMT expression level. The data suggest that consecutive treatment with vemurafenib and alkylating drugs is a reasonable strategy for metastatic melanoma treatment.

B-Raf inhibitor vemurafenib in combination with temozolomide and fotemustine in the killing response of malignant melanoma cells

PubMed Central

Krumm, Andrea; Merz, Stephanie; Switzeny, Olivier Jérôme; Christmann, Markus; Loquai, Carmen; Kaina, Bernd

2014-01-01

In the treatment of metastatic melanoma, a highly therapy-refractory cancer, alkylating agents are used and, for the subgroup of BRAFV600E cancers, the B-Raf inhibitor vemurafenib. Although vemurafenib is initially beneficial, development of drug resistance occurs leading to tumor relapse, which necessitates the requirement for combined or sequential therapy with other drugs, including genotoxic alkylating agents. This leads to the question whether vemurafenib and alkylating agents act synergistically and whether chronic vemurafenib treatment alters the melanoma cell response to alkylating agents. Here we show that a) BRAFV600E melanoma cells are killed by vemurafenib, driving apoptosis, b) BRAFV600E melanoma cells are neither more resistant nor sensitive to temozolomide/fotemustine than non-mutant cells, c) combined treatment with vemurafenib plus temozolomide or fotemustine has an additive effect on cell kill, d) acquired vemurafenib resistance of BRAFV600E melanoma cells does not affect MGMT, MSH2, MSH6, PMS2 and MLH1, nor does it affect the resistance to temozolomide and fotemustine, e) metastatic melanoma biopsies obtained from patients prior to and after vemurafenib treatment did not show a change in the MGMT promoter methylation status and MGMT expression level. The data suggest that consecutive treatment with vemurafenib and alkylating drugs is a reasonable strategy for metastatic melanoma treatment. PMID:25557167

Quantitative assessment of the dose-response of alkylating agents in DNA repair proficient and deficient ames tester strains.

PubMed

Tang, Leilei; Guérard, Melanie; Zeller, Andreas

2014-01-01

Mutagenic and clastogenic effects of some DNA damaging agents such as methyl methanesulfonate (MMS) and ethyl methanesulfonate (EMS) have been demonstrated to exhibit a nonlinear or even "thresholded" dose-response in vitro and in vivo. DNA repair seems to be mainly responsible for these thresholds. To this end, we assessed several mutagenic alkylators in the Ames test with four different strains of Salmonella typhimurium: the alkyl transferases proficient strain TA1535 (Ogt+/Ada+), as well as the alkyl transferases deficient strains YG7100 (Ogt+/Ada-), YG7104 (Ogt-/Ada+) and YG7108 (Ogt-/Ada-). The known genotoxins EMS, MMS, temozolomide (TMZ), ethylnitrosourea (ENU) and methylnitrosourea (MNU) were tested in as many as 22 concentration levels. Dose-response curves were statistically fitted by the PROAST benchmark dose model and the Lutz-Lutz "hockeystick" model. These dose-response curves suggest efficient DNA-repair for lesions inflicted by all agents in strain TA1535. In the absence of Ogt, Ada is predominantly repairing methylations but not ethylations. It is concluded that the capacity of alkyl-transferases to successfully repair DNA lesions up to certain dose levels contributes to genotoxicity thresholds. Copyright © 2013 Wiley Periodicals, Inc.

Synthesis of (Silylamino)phosphines by the Wilburn Method.

DTIC Science & Technology

1982-08-01

by the addi- tion of two equivalents of an alkyl Grignard reagent at 0 0C affords the [bis(trimethylsilyl)aminoldialkylphosphines 1 -3 (eq 1). Simi...larly, the use of dichlorophenylphosphine and one equivalent of Grignard reagent permits the convenient preparation of the corres- ponding alkyl(phenyl...Received The importance of (silylamino)phosphines, e.g. (Me3Si)2NPMe2, as reagents for the synthesis of organo-substituted phosphazene 1 2,3 polymers

Activated N-nitrosocarbamates for regioselective synthesis of N-nitrosoureas.

PubMed

Martinez, J; Oiry, J; Imbach, J L; Winternitz, F

1982-02-01

A practical and convenient method for synthesizing antitumor compounds, N-alkyl-N-nitrosoureas, regioselectively nitrosated on the nitrogen atom bearing the alkyl group is proposed. N-Alkyl-N-nitrosocarbamates are interesting intermediates in these syntheses and yield, by reaction with amino compounds, the regioselectively nitrosated N-alkyl-N-nitrosoureas. As an interesting example, N,N'-bis[(2-chloroethyl)nitrosocarbamoyl]cystamine, a new attractive oncostatic derivative, has been prepared. The cytotoxic activity of these various compounds were tested on L1210 leukemia.

N-Alkyl Urea Hydroxamic Acids as a New Class of Peptide Deformylase Inhibitors with Antibacterial Activity

PubMed Central

Hackbarth, Corinne J.; Chen, Dawn Z.; Lewis, Jason G.; Clark, Kirk; Mangold, James B.; Cramer, Jeffrey A.; Margolis, Peter S.; Wang, Wen; Koehn, Jim; Wu, Charlotte; Lopez, S.; Withers III, George; Gu, Helen; Dunn, Elina; Kulathila, R.; Pan, Shi-Hao; Porter, Wilma L.; Jacobs, Jeff; Trias, Joaquim; Patel, Dinesh V.; Weidmann, Beat; White, Richard J.; Yuan, Zhengyu

2002-01-01

Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth and is a new target for the development of antibacterial agents. All previously reported PDF inhibitors with sufficient antibacterial activity share the structural feature of a 2-substituted alkanoyl at the P1′ site. Using a combination of iterative parallel synthesis and traditional medicinal chemistry, we have identified a new class of PDF inhibitors with N-alkyl urea at the P1′ site. Compounds with MICs of ≤4 μg/ml against gram-positive and gram-negative pathogens, including Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae, have been identified. The concentrations needed to inhibit 50% of enzyme activity (IC50s) for Escherichia coli Ni-PDF were ≤0.1 μM, demonstrating the specificity of the inhibitors. In addition, these compounds were very selective for PDF, with IC50s of consistently >200 μM for matrilysin and other mammalian metalloproteases. Structure-activity relationship analysis identified preferred substitutions resulting in improved potency and decreased cytotoxity. One of the compounds (VRC4307) was cocrystallized with PDF, and the enzyme-inhibitor structure was determined at a resolution of 1.7 Å. This structural information indicated that the urea compounds adopt a binding position similar to that previously determined for succinate hydroxamates. Two compounds, VRC4232 and VRC4307, displayed in vivo efficacy in a mouse protection assay, with 50% protective doses of 30.8 and 17.9 mg/kg of body weight, respectively. These N-alkyl urea hydroxamic acids provide a starting point for identifying new PDF inhibitors that can serve as antimicrobial agents. PMID:12183225

ALKBH7 drives a tissue and sex-specific necrotic cell death response following alkylation-induced damage

PubMed Central

Jordan, Jennifer J; Chhim, Sophea; Margulies, Carrie M; Allocca, Mariacarmela; Bronson, Roderick T; Klungland, Arne; Samson, Leona D; Fu, Dragony

2017-01-01

Regulated necrosis has emerged as a major cell death mechanism in response to different forms of physiological and pharmacological stress. The AlkB homolog 7 (ALKBH7) protein is required for regulated cellular necrosis in response to chemotherapeutic alkylating agents but its role within a whole organism is unknown. Here, we show that ALKBH7 modulates alkylation-induced cellular death through a tissue and sex-specific mechanism. At the whole-animal level, we find that ALKBH7 deficiency confers increased resistance to MMS-induced toxicity in male but not female mice. Moreover, ALKBH7-deficient mice exhibit protection against alkylation-mediated cytotoxicity in retinal photoreceptor and cerebellar granule cells, two cell types that undergo necrotic death through the initiation of the base excision repair pathway and hyperactivation of the PARP1/ARTD1 enzyme. Notably, the protection against alkylation-induced cerebellar degeneration is specific to ALKBH7-deficient male but not female mice. Our results uncover an in vivo role for ALKBH7 in mediating a sexually dimorphic tissue response to alkylation damage that could influence individual responses to chemotherapies based upon alkylating agents. PMID:28726787

Effect of ionic strength and cationic DNA affinity binders on the DNA sequence selective alkylation of guanine N7-positions by nitrogen mustards

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hartley, J.A.; Forrow, S.M.; Souhami, R.L.

Large variations in alkylation intensities exist among guanines in a DNA sequence following treatment with chemotherapeutic alkylating agents such as nitrogen mustards, and the substituent attached to the reactive group can impose a distinct sequence preference for reaction. In order to understand further the structural and electrostatic factors which determine the sequence selectivity of alkylation reactions, the effect of increase ionic strength, the intercalator ethidium bromide, AT-specific minor groove binders distamycin A and netropsin, and the polyamine spermine on guanine N7-alkylation by L-phenylalanine mustard (L-Pam), uracil mustard (UM), and quinacrine mustard (QM) was investigated with a modification of the guanine-specificmore » chemical cleavage technique for DNA sequencing. The result differed with both the nitrogen mustard and the cationic agent used. The effect, which resulted in both enhancement and suppression of alkylation sites, was most striking in the case of netropsin and distamycin A, which differed from each other. DNA footprinting indicated that selective binding to AT sequences in the minor groove of DNA can have long-range effects on the alkylation pattern of DNA in the major groove.« less

Active oligonucleotides incorporating alkylating an agent as potential sequence- and base selective modifier of gene expression.

PubMed

Sasaki, S

2001-04-01

A number of cross-linking (alkylating) agents have been developed and incorporated into the oligonulceotides for sequence selective control of gene expression. Recently, potential application of such active oligonucleotides has been expanding from use for improvement of inhibition efficiency to new biotechnology that may enable chemical alteration of genetic information. These interests in active oligonucleotides have encouraged the generation of new cross-linking agents that exhibit high efficiency for application of either in vitro or in vivo. This mini review summarizes structures of alkylating agents, in particular, a new basic skeleton for cross-linking, a 2'-deoxyribose derivative of 2-amino-6-vinylpurine that has been recently developed by the author's group. The 2-amino-6-vinylpurine has been shown to form a complex with cytidine under acidic conditions, and brings the vinyl and the amino reactive groups into proximity to achieve efficient alkylation. A new strategy was designed so that the reactivity of 2-amino-6-vinylpurine can be induced from the corresponding phenylsulfoxide derivative within a duplex with the complementary strand. The validity of the new strategy has been proven by achievement of cytidine-selective cross-linking with remarkably efficiency.

The antitumour activity of alkylating agents is not correlated with the levels of glutathione, glutathione transferase and O6-alkylguanine-DNA-alkyltransferase of human tumour xenografts. EORTC SPG and PAMM Groups.

PubMed

D'Incalci, M; Bonfanti, M; Pifferi, A; Mascellani, E; Tagliabue, G; Berger, D; Fiebig, H H

1998-10-01

Twenty-three human xenografts, including five colon, five gastric, nine lung (three small cell lung cancer) and four breast carcinomas, were investigated for their sensitivity to nitrosoureas, dacarbazine (DTIC), cyclophosphamide (CTX) and cisplatin (DDP). In 12 cases, at least one of the drugs produced complete or partial remission, in 2, a minor regression was observed and in the other 9, treatment was ineffective. The level of sensitivity to each drug, using a score from 1 to 5, was correlated to three biochemical parameters reported to be involved in resistance to alkylating agents: glutathione (GSH), glutathione transferase (GST) and O6-alkylguanine-DNA-alkyltransferase (AGT). A wide variability was found in these parameters in the xenografts investigated. No correlation was found between any of the three parameters and sensitivity to the drugs used or between sensitivity to one drug and to any of the other drugs tested. These results illustrate the complexity of the question of resistance to alkylating agents and indicate that, at least in xenografts, the biochemical parameters examined are not predictive of response to alkylating agents.

Drilling fluid containing a copolymer filtration control agent

DOE Office of Scientific and Technical Information (OSTI.GOV)

Enright, D.P.; Lucas, J.M.; Perricone, A.C.

1981-10-06

The invention relates to an aqueous drilling fluid composition, a filtration control agent for utilization in said aqueous drilling fluid, and a method of forming a filter cake on the wall of a well for the reduction of filtrate from said drilling fluid, by utilization of a copolymer of: (1) a (Meth) acrylamido alkyl sulfonic acid or alkali metal salt thereof; and (2) a (Meth) acrylamide or n-alkyl (Meth) acrylamide. The copolymer may be cross-linked with a quaternary ammonium salt cross-linking agent.

Syntheses of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells.

PubMed

Yang, Tianle; Chan, Noel Yan-Ki; Sauve, Anthony A

2007-12-27

A new two-step methodology achieves stereoselective synthesis of beta-nicotinamide riboside and a series of related amide, ester, and acid nucleosides. Compounds were prepared through a triacetylated-nicotinate ester nucleoside, via coupling of either ethylnicotinate or phenylnicotinate with 1,2,3,5-tetra-O-acetyl-beta-D-ribofuranose. Nicotinamide riboside, nicotinic acid riboside, O-ethylnicotinate riboside, O-methylnicotinate riboside, and several N-alkyl derivatives increased NAD+ concentrations from 1.2-2.7-fold in several mammalian cell lines. These findings establish bioavailability and potent effects of these nucleosides in stimulating the increase of NAD+ concentrations in mammalian cells.

Synthesis and Evaluation of Strychnos Alkaloids as MDR Reversal Agents for Cancer Cell Eradication

DTIC Science & Technology

2014-01-01

followed by magnesium in MeOH to afford 11 in 75% yield (one-pot). Alkylation with (Z)-2-iodobutenyl bromide23 and acyla- tion with bromoacetyl chloride...eluting with MeOH/CH2Cl2 (0.4:9.6? 1:9). The material was washed with a solution of 25% aq NaOH (10 mL), which afforded 24 mg (71%) of Table 2...with MeOH/CH2Cl2 (0.4:9.6? 1:9). The material was washed with a solution of 25% aq NaOH (10 mL), which afforded 90 mg (86%) of 2 as yellow liquid

Viral capsid mobility: a dynamic conduit for inactivation.

PubMed

Broo, K; Wei, J; Marshall, D; Brown, F; Smith, T J; Johnson, J E; Schneemann, A; Siuzdak, G

2001-02-27

Mass spectrometry and fluorescent probes have provided direct evidence that alkylating agents permeate the protein capsid of naked viruses and chemically inactivate the nucleic acid. N-acetyl-aziridine and a fluorescent alkylating agent, dansyl sulfonate aziridine, inactivated three different viruses, flock house virus, human rhinovirus-14, and foot and mouth disease virus. Mass spectral studies as well as fluorescent probes showed that alkylation of the genome was the mechanism of inactivation. Because particle integrity was not affected by selective alkylation (as shown by electron microscopy and sucrose gradient experiments), it was reasoned that the dynamic nature of the viral capsid acts as a conduit to the interior of the particle. Potential applications include fluorescent labeling for imaging viral genomes in living cells, the sterilization of blood products, vaccine development, and viral inactivation in vivo.

Profiling the nucleobase and structure selectivity of anticancer drugs and other DNA alkylating agents by RNA sequencing.

PubMed

Gillingham, Dennis; Sauter, Basilius

2018-05-06

Drugs that covalently modify DNA are components of most chemotherapy regimens, often serving as first-line treatments. Classically the chemical reactivity of DNA alkylators has been determined in vitro with short oligonucleotides. Here we use next generation RNA sequencing to report on the chemoselectivity of alkylating agents. We develop the method with the well-known clinically used DNA modifiying drugs streptozotocin and temozolomide, and then apply the technique to profile RNA modification with uncharacterized alkylation reactions such as with powerful electrophiles like trimethylsilyldiazomethane. The multiplexed and massively parallel format of NGS offers analyses of chemical reactivity in nucleic acids to be accomplished in less time with greater statistical power. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and antifungal activity of natural product-based 6-alkyl-2 3 4 5-tetrahydropyridines

USDA-ARS?s Scientific Manuscript database

Seven 6-alkyl-2,3,4,5-tetrahydropyridines (5a–5g) that mimic the natural products piperideines that were recently identified in the fire ant venom have been synthesized. Compounds 5c–5g with the C-6 alkyl chain lengths from C14 to C18 showed varying degrees of antifungal activities, with 5e (6-hexa...

Monoalkyl sulfates as alkylating agents in water, alkylsulfatase rate enhancements, and the “energy-rich” nature of sulfate half-esters

PubMed Central

Wolfenden, Richard; Yuan, Yang

2007-01-01

Alkyl sulfate monoesters are involved in cell signaling and structure. Alkyl sulfates are also present in many commercial detergents. Here, we show that monomethyl sulfate acts as an efficient alkylating agent in water, reacting spontaneously with oxygen nucleophiles >100-fold more rapidly than do alkylsulfonium ions, the usual methyl donors in living organisms. These reactions of methyl sulfate, which are much more rapid than its hydrolysis, are insensitive to the nature of the attacking nucleophile, with a Brønsted βnuc value of −0.01. Experiments at elevated temperatures indicate a rate constant of 2 × 10−11 s−1 for the uncatalyzed hydrolysis of methyl sulfate at 25°C (t1/2 = 1,100 y), corresponding to a rate enhancement of ≈1011-fold by a human alkylsulfatase. Equilibria of formation of methyl sulfate from methanol and sodium hydrogen sulfate indicate a group transfer potential (ΔG′pH7) of −8.9 kcal/mol for sulfate ester hydrolysis. The magnitude of that value, involving release of the strong acid HSO4−, helps to explain the need for harnessing the free energy of hydrolysis of two ATP molecules in activating sulfate for the biosynthesis of sulfate monoesters. The “energy-rich” nature of monoalkyl sulfate esters, coupled with their marked resistance to hydrolysis, renders them capable of acting as sulfating or alkylating agents under relatively mild conditions. These findings raise the possibility that, under appropriate circumstances, alkyl groups may undergo transfer from alkyl sulfate monoesters to biological target molecules. PMID:17182738

Design of a Photoredox Catalyst that Enables the Direct Synthesis of Carbamate-Protected Primary Amines via Photoinduced, Copper-Catalyzed N-Alkylation Reactions of Unactivated Secondary Halides.

PubMed

Ahn, Jun Myun; Peters, Jonas C; Fu, Gregory C

2017-12-13

Despite the long history of S N 2 reactions between nitrogen nucleophiles and alkyl electrophiles, many such substitution reactions remain out of reach. In recent years, efforts to develop transition-metal catalysts to address this deficiency have begun to emerge. In this report, we address the challenge of coupling a carbamate nucleophile with an unactivated secondary alkyl electrophile to generate a substituted carbamate, a process that has not been achieved effectively in the absence of a catalyst; the product carbamates can serve as useful intermediates in organic synthesis as well as bioactive compounds in their own right. Through the design and synthesis of a new copper-based photoredox catalyst, bearing a tridentate carbazolide/bisphosphine ligand, that can be activated upon irradiation by blue-LED lamps, we can achieve the coupling of a range of primary carbamates with unactivated secondary alkyl bromides at room temperature. Our mechanistic observations are consistent with the new copper complex serving its intended role as a photoredox catalyst, working in conjunction with a second copper complex that mediates C-N bond formation in an out-of-cage process.

Synthesis and fabrication of sized-controlled nanoparticles: Using surface self-assemblies as building blocks for developing supralattices on nanocomposite materials

NASA Astrophysics Data System (ADS)

Yee, Chanel Kitmon

2001-10-01

A general one-phase synthesis for self-assembling thiols onto gold, platinum, palladium and iridium nanoparticles using tetrahydrofuran (THF) as the solvent, and lithium triethylborohydride (superhydride) as the reducing agent, is presented. Using the same synthetic procedure gold nanoparticles functionalized with 11-hydroxyundecane-1-thiol and 4'-bromo-4-mercaptobiphenyl were prepared to show that the availability and reflexibility of this method could lead to surface fabrication with various type of facial moieties. Alkyl selenide- and alkyl thiolate-functionalized gold nanoparticles were also prepared by the same method at 6°C. The properties were compared to their counterparts made at 25°C. The formation of the Se-Au bond and S-Au bonds was investigated by transmission Fourier transform infrared spectroscopy (FTIR), while the bond nature in each case was examined by x-ray photoelectron spectroscopy (XPS). Particle size was determined by Transmission Electron Microscopy (TEM), and further confirmed by ultraviolet spectroscopy (UV). Superparamagnetic Fe and Fe2O3 nanoparticles were synthesized by ultrasound irradiation and post-fabricated with alkyl sulfonic acids of various chain lengths and octadecyl phosphonic acid. TEM reveals nanoparticles of 5--10 mn in diameter. FTIR spectra suggest that the alkyl chains are packed in a solid-like assembly with packing disorder increasing with the decreasing chain length. The octadecyl sulfonic acid coating displays the lowest magnetization within the sulfonic acid series, which may be explained by the high packing and ordering of the alkyl chains on the particle surface. The smallest value of magnetization in the OPA case suggests that the spin-state of surface Fe3+ ions is affected by the bonded surfactant, and that the phosphonate empty d-orbitals increase magnetic interactions between neighboring Fe3+ spins. To build superstructures beyond the monolayer level, a general route for the attachment of amino-terminated biomolecules to nanoparticles was proposed. Thiophene thiolate-functionalized platinum nanoparticles were prepared and reacted with nitrosonium tetrafluoroborate to provide the nitroso-functionalized nanoparticles. The reaction of the nitroso group with primary amines to yield strong N=N bonds might provide a general route for the attachment of amino-terminated biomolecules to nanoparticles. The attachment of two cytidine molecules to platinum nanoparticles was accomplished, and experimental data were provided to demonstrate the intended grafting reaction.

CC-1065 functional analogues possessing different electron-withdrawing substituents and leaving groups: synthesis, kinetics, and sequence specificity of reaction with DNA and biological evaluation.

PubMed

Wang, Y; Gupta, R; Huang, L; Lown, J W

1993-12-24

Antitumor agent CC-1065 functional analogues possessing different electron-withdrawing substituents and leaving groups have been synthesized. The extent and the relative rates of DNA cleavage following alkylation by these CPI structures and thermal treatment were determined independently by an ethidium binding assay and by agarose gel electrophoresis experiments. The anticipated preferential covalent binding to adenine sites within the minor groove was confirmed by sequencing determination of selected agents on high-resolution gels. Certain of the synthetic agents, unlike CC-1065, also bind covalently to G sites with weaker intensity. The cytotoxicities of these compounds were also determined against KB cells in vitro. Compounds bearing a bromo or nitro group in the benzene ring and a methylsulfonyl as a leaving group are 10 and 5 times more potent than their unsubstituted counterparts, respectively. Compounds bearing a methylsulfonyl as a leaving group are more potent than those bearing a chlorine.

Alkylation Damage by Lipid Electrophiles Targets Functional Protein Systems*

PubMed Central

Codreanu, Simona G.; Ullery, Jody C.; Zhu, Jing; Tallman, Keri A.; Beavers, William N.; Porter, Ned A.; Marnett, Lawrence J.; Zhang, Bing; Liebler, Daniel C.

2014-01-01

Protein alkylation by reactive electrophiles contributes to chemical toxicities and oxidative stress, but the functional impact of alkylation damage across proteomes is poorly understood. We used Click chemistry and shotgun proteomics to profile the accumulation of proteome damage in human cells treated with lipid electrophile probes. Protein target profiles revealed three damage susceptibility classes, as well as proteins that were highly resistant to alkylation. Damage occurred selectively across functional protein interaction networks, with the most highly alkylation-susceptible proteins mapping to networks involved in cytoskeletal regulation. Proteins with lower damage susceptibility mapped to networks involved in protein synthesis and turnover and were alkylated only at electrophile concentrations that caused significant toxicity. Hierarchical susceptibility of proteome systems to alkylation may allow cells to survive sublethal damage while protecting critical cell functions. PMID:24429493

O(6)-methylguanine DNA-methyltransferase (MGMT) overexpression in melanoma cells induces resistance to nitrosoureas and temozolomide but sensitizes to mitomycin C.

PubMed

Passagne, Isabelle; Evrard, Alexandre; Depeille, Philippe; Cuq, Pierre; Cupissol, Didier; Vian, Laurence

2006-03-01

Alkylating agents play an important role in the chemotherapy of malignant melanomas. The activity of alkylating agents depends on their capacity to form alkyl adducts with DNA, in some cases causing cross-linking of DNA strands. However, the use of these agents is limited by cellular resistance induced by the DNA repair enzyme O(6)-methylguanine DNA-methyltransferase (MGMT) which removes alkyl groups from alkylated DNA strands. To determine to what extent the expression of MGMT in melanoma cells induces resistance to alkylating agents, the human cell line CAL77 Mer- (i.e., MGMT deficient) were transfected with pcMGMT vector containing human MGMT cDNA. Several clones expressing MGMT at a high level were selected to determine their sensitivity to chemotherapeutic drugs. Melanoma-transfected cells were found to be significantly less sensitive to nitrosoureas (carmustine, fotemustine, streptozotocin) and temozolomide with an increase of IC(50) values between 3 and 14 when compared to parent cells. No difference in cell survival rates between MGMT-proficient and -deficient cells was observed for melphalan, chlorambucil, busulphan, thiotepa and cisplatin which preferentially induce N(7) guanine lesions. Surprisingly, MGMT overexpression increased the sensitivity of CAL77 cells to mitomycin C by approximately 10-fold. Treatment of clonal cell lines with buthionine-[S,R]-sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase which depletes cellular glutathione, completely reversed this unexpected increase in sensitivity to mitomycin C. This observation suggests that glutathione is involved in the sensitivity of MGMT-transfected cells to mitomycin C and may act synergistically with MGMT via an unknown mechanism.

Design and synthesis of novel carbazole tethered pyrrole derivatives as potent inhibitors of Mycobacterium tuberculosis.

PubMed

Surineni, Goverdhan; Yogeeswari, Perumal; Sriram, Dharmarajan; Kantevari, Srinivas

2015-02-01

A series of novel carbazole tethered pyrrole derivatives were designed by coupling core fragments of antitubercular agents, carbazole and substituted pyrrole in single molecular architecture. The synthesis of new analogues was achieved by FeCl3 mediated one pot three component condensation of 2-nitrovinylcarbazoles with aryl or alkyl amines and dimethylacetylene dicarboxylate (DMAD). All the new analogues 5a-l and 6a-l were fully characterized by their NMR and mass spectral data. Among the twenty four new compounds screened for in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv, dimethyl 1-(4-fluorophenyl)-4-(9-methyl-9H-carbazol-3-yl)-1H-pyrrole-2,3-dicarboxylate (5b) was found to be most active with MIC 3.13μg/mL and has shown low cytotoxicity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Regioselective and enantiospecific rhodium-catalyzed allylic alkylation reactions using copper(I) enolates: synthesis of (-)-sugiresinol dimethyl ether.

PubMed

Evans, P Andrew; Leahy, David K

2003-07-30

The transition metal-catalyzed allylic alkylation represents a fundamentally important cross-coupling reaction for the construction of ternary carbon stereogenic centers. We have developed a regioselective and enantiospecific rhodium-catalyzed allylic alkylation of acyclic unsymmetrical allylic alcohol derivatives using copper(I) enolates to prepare beta-substituted ketones. This protocol represents a convenient asymmetric Claisen rearrangement surrogate in which alpha-substituted enolates permit the introduction of an additional stereogenic center. The synthetic utility of this transformation was highlighted in the construction of a trans-1,2-disubstituted cyclohexene and the total synthesis of (-)-sugiresinol dimethyl ether. Finally, we anticipate that copper(I) enolates may prove useful nucleophiles in related metal-catalyzed reactions.

Chiral Brønsted Base-Promoted Nitroalkane Alkylation: Enantioselective Synthesis of sec-Alkyl-3-Substituted Indoles

PubMed Central

Dobish, Mark C.; Johnston, Jeffrey N.

2010-01-01

A Brønsted base-catalyzed reaction of nitroalkanes with alkyl electrophiles provides indole heterocycles substituted at C3 bearing a sec-alkyl group with good enantioselectivity (up to 90% ee). Denitration by hydrogenolysis provides a product with equally high ee. An indolenine intermediate is implicated in the addition step, and surprisingly, water cosolvent was found to have a beneficial effect in this step, leading to a one-pot protocol for elimination/enantioselective addition using PBAM, a bis(amidine) chiral nonracemic base. PMID:21090654

Catalyst-free dehydrative α-alkylation of ketones with alcohols: green and selective autocatalyzed synthesis of alcohols and ketones.

PubMed

Xu, Qing; Chen, Jianhui; Tian, Haiwen; Yuan, Xueqin; Li, Shuangyan; Zhou, Chongkuan; Liu, Jianping

2014-01-03

Direct dehydrative α-alkylation reactions of ketones with alcohols are now realized under simple, practical, and green conditions without using external catalysts. These catalyst-free autocatalyzed alkylation methods can efficiently afford useful alkylated ketone or alcohol products in a one-pot manner and on a large scale by CC bond formation of the in situ generated intermediates with subsequent controllable and selective Meerwein-Pondorf-Verley-Oppenauer-type redox processes. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The synthesis of 1,2-bis(1,5,9-triazacyclododecyl)ethane: a showcase for the importance of the linker length within bis(alkylating) reagents.

PubMed

Medina-Molner, Alfredo; Blacque, Olivier; Spingler, Bernhard

2007-11-08

The synthesis of 1,2-bis(1,5,9-triazacyclododecyl)ethane (1) showcases how different bis(alkylating) reagents change the reaction from an intra- to an intermolecular pathway. The isolation of the intermediate hexahydro-3a,6a-ethano-1H,4H,7H,9bH-9a-aza-3a,6a-diazoniaphenalene-3a,6a-diium (2) explained why initially the synthesis of 1 was not possible. Both isomers of 2 were found in solution. DFT calculations revealed that isomer 2a is 4.6 kcal/mol lower in energy than 2b. Synthesis of 1 was finally achieved by using oxalyl chloride.

A highly selective and sensitive "turn-on" fluorescence chemodosimeter for the detection of mustard gas.

PubMed

Raghavender Goud, D; Purohit, Ajay Kumar; Tak, Vijay; Dubey, Devendra Kumar; Kumar, Pravin; Pardasani, Deepak

2014-10-21

A new chemodosimetric protocol based on a tandem S-alkylation followed by desulfurisation reaction of rhodamine-thioamide with mustard gas is reported. The chemodosimeter is highly selective for potential DNA alkylating agents like sulfur mustard, over other simple alkyl halides with the limit of detection of 4.75 μM.

Trichloroacetimidates as Alkylating Reagents and Their Application in the Synthesis of Pyrroloindoline Natural Products and Synthesis of Small Molecule Inhibitors of Src Homology 2 Domain-Containing Inositol Phosphatase (SHIP)

NASA Astrophysics Data System (ADS)

Adhikari, Arijit A.

Trichloroacetimidates are known to be excellent alkylating agents when activated by a catalytic amount of a Bronsted or Lewis acid. Work described herein involved taking advantage of the favorable reactivity of trichloroacetimidates to establish several different synthetic protocols, including the application of these reagents in the synthesis of pyrroloindoline based natural products, 3,3'-disubstituted indolenines and benzylic trichloroacetamides. Initial investigations on the utilization of the reactivity of trichloroacetimidates found that diphenylmethyl trichloroacetimidate, which is a precursor to a highly stabilized carbocation, undergoes facile displacement with carboxylic acids providing the ester product without the need of any exogenous catalyst. Both hindered and unhindered carboxylic acids were esterified with high yields, with no preference for aromatic or aliphatic carboxylic acids. Carboxylic acids with unprotected hydroxyl groups or beta-lactam rings were esterified efficiently. Substrates that are highly prone to elimination or retro-aldol were also esterified in high yields. Carboxylic acids with highly enolizable alpha-stereocenters were esterified without any racemization. Mechanistic studies indicate that the carboxylic acid substrate itself is acidic enough to be effective at promoting the esterification reaction. During our studies on esterification with imidates it was found that these imidates also showed a tendency to undergo rearrangement to the corresponding trichloroacetamides. Two different sets of conditions, thermal and Lewis acid catalyzed, were established which provided these rearranged products with high yields. Various benzylic trichloroacetimidates were shown to undergo these transformations under the established conditions. Based on the observations discussed in this work a cationic mechanism is proposed. After the preliminary studies on alkylation of benzylic trichloroacetimidate with different nucleophiles, this chemistry was applied towards the synthesis of natural products and their analogs. The pyrroloindoline ring system is found in many alkaloids and cyclic peptides which mainly differ in the substitution at the C3a position. To provide rapid access to these natural products a diversity-oriented strategy was established via displacement of C3a-trichloroacetimidate pyrroloindoline. Carbon, oxygen, sulfur and nitrogen nucleophiles were all shown to undergo substitution reactions with these trichloroacetimidates in the presence of a Lewis acid catalyst. In order to demonstrate the utility of this new method it was applied towards the synthesis of arundinine and a formal synthesis of psychotriasine. Current investigations involve the application of this method towards the synthesis of a complex pyrroloindoline natural product kapakahine C and the progress made therein has been discussed. The reactivity of trichloroacetimidates was also investigated for the selective C3-alkylation of 2,3-disubstituted indoles to provide indolenines. Indolenines serve as useful intermediates in the synthesis of many complex alkaloids. Different benzylic and allylic trichloroacetimidates were shown to provide 3,3'-disubstituted indolenines with high yields in the presence of catalytic amounts of Lewis acids. Various substituted indoles were evaluated under these reaction conditions. This methodology was also applied towards the synthesis of the core tetracyclic ring system found in communesin natural products. In addition to the above work, synthesis of small molecule inhibitors of Src Homology 2 Domain-Containing Inositol Phosphatase (SHIP) has also been described. Aberrations in the phosphoinositide 3-kinase (PI3K) cellular signaling pathway can lead to diseased cellular states like cancer. Herein we have reported stereoselective synthesis of two quinoline based small molecule SHIP inhibitors. The lead compounds and their analogs were tested for their activities against SHIP by Malachite green assay and the discoveries made therein are discussed. In addition to this synthesis of a tryptamine based SHIP inhibitor has also been reported.

Synthesis and Crystallization Behavior of Surfactants with Hexamolybdate as the Polar Headgroup

DOE PAGES

Zhu, Li; Chen, Kun; Hao, Jian; ...

2015-06-12

For this paper, alkyl chains with different lengths were covalently grafted onto the surface of hexamolybdate through the postfunctionalization protocol of polyoxometalates. The obtained compounds represent typical structures of the so-called giant surfactants. Unexpectedly, those surfactants with hexamolybdates as polar headgroups are able to crystallize, while single-crystal X-ray diffraction reveals that the crystallization behavior of the surfactants is highly dependent on the length of the alkyl chains. For surfactants with comparatively short alkyl chains (C6 and C10), the alkyl chains prefer to interact with tetrabutylammonium, the countercation of hexamolybdate. However, the alkyl chains tend to pack with each other tomore » form a domain of alkyl chains in the surfactant with a longer alkyl chain (C18). Finally, the possible mechanism is that a long alkyl chain cannot be fully compatible with the short chain (C4) of tetrabutylammonium.« less

Safety Assessment of Amino Acid Alkyl Amides as Used in Cosmetics.

PubMed

Burnett, Christina L; Heldreth, Bart; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the product use, formulation, and safety data of 115 amino acid alkyl amides, which function as skin and hair conditioning agents and as surfactants-cleansing agents in personal care products. Safety test data on dermal irritation and sensitization for the ingredients with the highest use concentrations, lauroyl lysine and sodium lauroyl glutamate, were reviewed and determined to adequately support the safe use of the ingredients in this report. The Panel concluded that amino acid alkyl amides are safe in the present practices of use and concentration in cosmetics, when formulated to be nonirritating.

A detachable ester bond enables perfect Z-alkylations of olefins for the synthesis of tri- and tetrasubstituted alkenes.

PubMed

Nishikata, Takashi; Nakamura, Kimiaki; Inoue, Yuki; Ishikawa, Shingo

2015-06-25

2-Vinyl-substituted phenol and an alpha-bromoester undergo a tandem esterification-alkylation reaction in the presence of a Cu-amine catalyst system to produce benzene-fused lactone. Z-Alkylated styrene is obtained after hydrolysis of the lactone with perfect selectivity. The simple protocol developed in this work opens a new avenue in the multi-substitution chemistry of alkenes.

Asymmetric conjugate addition of Grignard reagents to pyranones.

PubMed

Mao, Bin; Fañanás-Mastral, Martín; Feringa, Ben L

2013-01-18

An efficient enantioselective synthesis of lactones was developed based on the catalytic asymmetric conjugate addition (ACA) of alkyl Grignard reagents to pyranones. The use of 2H-pyran-2-one for the first time in the ACA with Grignard reagents allows for a variety of further transformations to access highly versatile building blocks such as β-alkyl substituted aldehydes or β-bromo-γ-alkyl substituted alcohols with excellent regio- and stereoselectivity.

Highly efficient preparation of selectively isotope cluster-labeled long chain fatty acids via two consecutive C(sp3)-C(sp3) cross-coupling reactions.

PubMed

Lethu, Sébastien; Matsuoka, Shigeru; Murata, Michio

2014-02-07

An efficient synthesis involving two copper-catalyzed alkyl-alkyl coupling reactions has been designed to easily access doubly isotope-labeled fatty acids. Such NMR- and IR-active compounds were obtained in excellent overall yields and will be further used for determining the conformation of an alkyl chain of lipidic biomolecules upon interaction with proteins.

Synthesis and antiprotozoan evaluation of new alkyl-linked bis(2-thioxo-[1,3,5]thiadiazinan-3-yl) carboxylic acids.

PubMed

Coro, Julieta; Pérez, Rolando; Rodríguez, Hortensia; Suárez, Margarita; Vega, Celeste; Rolón, Miriam; Montero, David; Nogal, Juan José; Gómez-Barrio, Alicia

2005-05-16

Two new series of several alkyl-linked bis(2-thioxo-[1,3,5]thiadiazinan-3-yl) carboxylic acids were synthesized in a two step procedure from the corresponding alkyl bis-dithiocarbamic salt intermediary. The novel compounds were evaluated for their activity in vitro against Trypanosoma cruzi strain CL (clone CL B5) and Trichomonas vaginalis strain JH 31A.

Development of a general non-noble metal catalyst for the benign amination of alcohols with amines and ammonia.

PubMed

Cui, Xinjiang; Dai, Xingchao; Deng, Youquan; Shi, Feng

2013-03-11

The N-alkylation of amines or ammonia with alcohols is a valuable route for the synthesis of N-alkyl amines. However, as a potentially clean and economic choice for N-alkyl amine synthesis, non-noble metal catalysts with high activity and good selectivity are rarely reported. Normally, they are severely limited due to low activity and poor generality. Herein, a simple NiCuFeOx catalyst was designed and prepared for the N-alkylation of ammonia or amines with alcohol or primary amines. N-alkyl amines with various structures were successfully synthesized in moderate to excellent yields in the absence of organic ligands and bases. Typically, primary amines could be efficiently transformed into secondary amines and N-heterocyclic compounds, and secondary amines could be N-alkylated to synthesize tertiary amines. Note that primary and secondary amines could be produced through a one-pot reaction of ammonia and alcohols. In addition to excellent catalytic performance, the catalyst itself possesses outstanding superiority, that is, it is air and moisture stable. Moreover, the magnetic property of this catalyst makes it easily separable from the reaction mixture and it could be recovered and reused for several runs without obvious deactivation. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Modified Activated Carbon Perchlorate Sorbents

DTIC Science & Technology

2007-01-25

Yield 4.64 g. Methyl Chloride Alkylated Activated Carbon Methyl chloride (MeCl) treatment was carried out in a tube furnace generally in...with alkylation agents lowers the solution pH as the basic sites are alkylated . In the case of Me2SO4 treatment , the low slurry pH is believed to be...by Cannon and coworkers, the alkylated carbons are not significantly better. In the case of the SAI carbons, ammonia treatment does not result in a

Chemoselective synthesis of functional homocysteine residues in polypeptides and peptides.

PubMed

Gharakhanian, Eric G; Deming, Timothy J

2016-04-18

A methodology was developed for efficient, chemoselective transformation of methionine residues into stable, functional homocysteine derivatives. Methionine residues can undergo highly chemoselective alkylation reactions at low pH to yield stable sulfonium ions, which could then be selectively demethylated to give stable alkyl homocysteine residues. This mild, two-step process is chemoselective, efficient, tolerates many functional groups, and provides a means for creation of new functional biopolymers, site-specific peptide tagging, and synthesis of biomimetic and structural analogs of peptides.

Synthesis of new kojic acid based unnatural α-amino acid derivatives.

PubMed

Balakrishna, C; Payili, Nagaraju; Yennam, Satyanarayana; Uma Devi, P; Behera, Manoranjan

2015-11-01

An efficient method for the preparation of kojic acid based α-amino acid derivatives by alkylation of glycinate schiff base with bromokojic acids have been described. Using this method, mono as well as di alkylated kojic acid-amino acid conjugates have been prepared. This is the first synthesis of C-linked kojic acid-amino acid conjugate where kojic acid is directly linked to amino acid through a C-C bond. Copyright © 2015 Elsevier Ltd. All rights reserved.

Access to 6a-Alkyl Aporphines: Synthesis of (±)-N-Methylguattescidine.

PubMed

Ku, Angela F; Cuny, Gregory D

2016-10-21

(-)-N-Methylguattescidine (3) is an alkaloid recently isolated from Fissistigma latifolium and assigned as a rare example of a 6a-alkyl aporphine. Herein, we report the synthesis of (±)-3 and the des-hydroxyl derivative 4 using our previously reported ortho-phenol arylation methodology mediated by the XPhos precatalyst as a key synthetic step. In addition, substituents on the aryl halide portion of the ortho-phenol arylation substrates significantly influenced the formation of an oxidized side product.

Advanced asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid by alkylation/cyclization of newly designed axially chiral Ni(II) complex of glycine Schiff base.

PubMed

Kawashima, Aki; Shu, Shuangjie; Takeda, Ryosuke; Kawamura, Akie; Sato, Tatsunori; Moriwaki, Hiroki; Wang, Jiang; Izawa, Kunisuke; Aceña, José Luis; Soloshonok, Vadim A; Liu, Hong

2016-04-01

Asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid (vinyl-ACCA) is in extremely high demand due to the pharmaceutical importance of this tailor-made, sterically constrained α-amino acid. Here we report the development of an advanced procedure for preparation of the target amino acid via two-step SN2 and SN2' alkylation of novel axially chiral nucleophilic glycine equivalent. Excellent yields and diastereoselectivity coupled with reliable and easy scalability render this method of immediate use for practical synthesis of (1R,2S)-vinyl-ACCA.

Poly(ethyleneoxide) functionalization through alkylation

DOEpatents

Sivanandan, Kulandaivelu; Eitouni, Hany Basam; Li, Yan; Pratt, Russell Clayton

2015-04-21

A new and efficient method of functionalizing high molecular weight polymers through alkylation using a metal amide base is described. This novel procedure can also be used to synthesize polymer-based macro-initiators containing radical initiating groups at the chain-ends for synthesis of block copolymers.

Synthesis and evaluation of 1,7-diheteroarylhepta-1,4,6-trien-3-ones as curcumin-based anticancer agents.

PubMed

Wang, Rubing; Zhang, Xiaojie; Chen, Chengsheng; Chen, Guanglin; Zhong, Qiu; Zhang, Qiang; Zheng, Shilong; Wang, Guangdi; Chen, Qiao-Hong

2016-03-03

Thirty (1E,4E,6E)-1,7-diaryl-1,4,6-heptatrien-3-ones, featuring a central linear trienone linker and two identical nitrogen-containing heteroaromatic rings, were designed and synthesized as curcumin-based anticancer agents on the basis of their structural similarity to the enol-tautomer of curcumin, in addition to taking advantage of the possibly enhanced pharmacokinetic profiles contributed by the basic nitrogen-containing heteroaromatic rings. Their cytotoxicity and antiproliferative activity were evaluated towards both androgen-dependent and androgen-independent prostate cancer cell lines, as well as HeLa human cervical cancer cells. Among them, the ten most potent analogues are 5- to 36-fold more potent than curcumin in inhibiting cancer cell proliferation. The acquired structure-activity relationship data indicate (i) that (1E,4E,6E)-1,7-diaryl-1,4,6-heptatrien-3-ones represent a potential scaffold for development of curcumin-based agents with substantially improved cytotoxicity and anti-proliferative effect; and (ii) 1-alkyl-1H-imidazol-2-yl and 1-alkyl-1H-benzo[d]imidazole-2-yl serve as optimal heteroaromatic rings for increased in vitro potency of this scaffold. Two of most potent compounds displayed no apparent cytotoxicity toward MCF-10A normal mammary epithelial cells at 1 μM concentration. Treatment of PC-3 prostate cancer cells with the most potent compound led to appreciable cell cycle arrest at a G1/G0 phase and cell apoptosis induction. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Influence of DNA Repair on Nonlinear Dose-Responses for Mutation

PubMed Central

Johnson, George E.

2013-01-01

Recent evidence has challenged the default assumption that all DNA-reactive alkylating agents exhibit a linear dose-response. Emerging evidence suggests that the model alkylating agents methyl- and ethylmethanesulfonate and methylnitrosourea (MNU) and ethylnitrosourea observe a nonlinear dose-response with a no observed genotoxic effect level (NOGEL). Follow-up mechanistic studies are essential to understand the mechanism of cellular tolerance and biological relevance of such NOGELs. MNU is one of the most mutagenic simple alkylators. Therefore, understanding the mechanism of mutation induction, following low-dose MNU treatment, sets precedence for weaker mutagenic alkylating agents. Here, we tested MNU at 10-fold lower concentrations than a previous study and report a NOGEL of 0.0075 µg/ml (72.8nM) in human lymphoblastoid cells, quantified through the hypoxanthine (guanine) phosphoribosyltransferase assay (OECD 476). Mechanistic studies reveal that the NOGEL is dependent upon repair of O6-methylguanine (O6MeG) by the suicide enzyme O6MeG-DNA methyltransferase (MGMT). Inactivation of MGMT sensitizes cells to MNU-induced mutagenesis and shifts the NOGEL to the left on the dose axis. PMID:23288051

Influence of DNA repair on nonlinear dose-responses for mutation.

PubMed

Thomas, Adam D; Jenkins, Gareth J S; Kaina, Bernd; Bodger, Owen G; Tomaszowski, Karl-Heinz; Lewis, Paul D; Doak, Shareen H; Johnson, George E

2013-03-01

Recent evidence has challenged the default assumption that all DNA-reactive alkylating agents exhibit a linear dose-response. Emerging evidence suggests that the model alkylating agents methyl- and ethylmethanesulfonate and methylnitrosourea (MNU) and ethylnitrosourea observe a nonlinear dose-response with a no observed genotoxic effect level (NOGEL). Follow-up mechanistic studies are essential to understand the mechanism of cellular tolerance and biological relevance of such NOGELs. MNU is one of the most mutagenic simple alkylators. Therefore, understanding the mechanism of mutation induction, following low-dose MNU treatment, sets precedence for weaker mutagenic alkylating agents. Here, we tested MNU at 10-fold lower concentrations than a previous study and report a NOGEL of 0.0075 µg/ml (72.8nM) in human lymphoblastoid cells, quantified through the hypoxanthine (guanine) phosphoribosyltransferase assay (OECD 476). Mechanistic studies reveal that the NOGEL is dependent upon repair of O(6)-methylguanine (O(6)MeG) by the suicide enzyme O(6)MeG-DNA methyltransferase (MGMT). Inactivation of MGMT sensitizes cells to MNU-induced mutagenesis and shifts the NOGEL to the left on the dose axis.

The Effect of Different Coupling Agents on Nano-ZnO Materials Obtained via the Sol-Gel Process.

PubMed

Purcar, Violeta; Şomoghi, Raluca; Niţu, Sabina Georgiana; Nicolae, Cristian-Andi; Alexandrescu, Elvira; Gîfu, Ioana Cătălina; Gabor, Augusta Raluca; Stroescu, Hermine; Ianchiş, Raluca; Căprărescu, Simona; Cinteză, Ludmila Otilia

2017-12-12

Hybrid nanomaterials based on zinc oxide were synthesized via the sol-gel method, using different silane coupling agents: (3-glycidyloxypropyl)trimethoxysilane (GPTMS), phenyltriethoxysilane (PhTES), octyltriethoxysilane (OTES), and octadecyltriethoxysilane (ODTES). Morphological properties and the silane precursor type effect on the particle size were investigated using dynamic light scattering (DLS), environmental scanning electron microscopy (ESEM), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), and X-ray diffraction (XRD). The bonding characteristics of modified ZnO materials were investigated using Fourier transform infrared spectroscopy (FTIR). The final solutions were deposited on metallic substrate (aluminum) in order to realize coatings with various wettability and roughness. The morphological studies, obtained by ESEM and TEM analysis, showed that the sizes of the ZnO nanoparticles are changed as function of silane precursor used in synthesis. The thermal stability of modified ZnO materials showed that the degradation of the alkyl groups takes place in the 300-500 °C range. Water wettability study revealed a contact angle of 142 ± 5° for the surface covered with ZnO material modified with ODTES and showed that the water contact angle increases as the alkyl chain from the silica precursor increases. These modified ZnO materials, therefore, can be easily incorporated in coatings for various applications such as anti-corrosion and anti-icing.

Impact of topical application of sulfur mustard on mice skin and distant organs DNA repair enzyme signature.

PubMed

Sauvaigo, Sylvie; Sarrazy, Fanny; Batal, Mohamed; Caillat, Sylvain; Pitiot, Benoit; Mouret, Stéphane; Cléry-Barraud, Cécile; Boudry, Isabelle; Douki, Thierry

2016-01-22

Sulfur mustard (SM) is a chemical warfare agent that, upon topical application, damages skin and reaches internal organs through diffusion in blood. Two major toxic consequences of SM exposure are inflammation, associated with oxidative stress, and the formation of alkylated DNA bases. In the present study, we investigated the impact of exposure to SM on DNA repair, using two different functional DNA repair assays which provide information on several Base Excision Repair (BER) and Excision/Synthesis Repair (ESR) activities. BER activities were reduced in all organs as early as 4h after exposure, with the exception of the defense systems against 8-oxo-guanine and hypoxanthine which were stimulated. Interestingly, the resulting BER intermediates could activate inflammation signals, aggravating the inflammation triggered by SM exposure and leading to increased oxidative stress. ESR activities were found to be mostly inhibited in skin, brain and kidneys. In contrast, in the lung there was a general increase in ESR activities. In summary, exposure to SM leads to a significant decrease in DNA repair in most organs, concomitant with the formation of DNA damage. These synergistic genotoxic effects are likely to participate in the high toxicity of this alkylating agent. Lungs, possibly better equipped with repair enzymes to handle exogenous exposure, are the exception. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A New Class of Antibody-Drug Conjugates with Potent DNA Alkylating Activity.

PubMed

Miller, Michael L; Fishkin, Nathan E; Li, Wei; Whiteman, Kathleen R; Kovtun, Yelena; Reid, Emily E; Archer, Katie E; Maloney, Erin K; Audette, Charlene A; Mayo, Michele F; Wilhelm, Alan; Modafferi, Holly A; Singh, Rajeeva; Pinkas, Jan; Goldmacher, Victor; Lambert, John M; Chari, Ravi V J

2016-08-01

The promise of tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADC) has now been realized, evidenced by the approval of two ADCs, both of which incorporate highly cytotoxic tubulin-interacting agents, for cancer therapy. An ongoing challenge remains in identifying potent agents with alternative mechanisms of cell killing that can provide ADCs with high therapeutic indices and favorable tolerability. Here, we describe the development of a new class of potent DNA alkylating agents that meets these objectives. Through chemical design, we changed the mechanism of action of our novel DNA cross-linking agent to a monofunctional DNA alkylator. This modification, coupled with linker optimization, generated ADCs that were well tolerated in mice and demonstrated robust antitumor activity in multiple tumor models at doses 1.5% to 3.5% of maximally tolerated levels. These properties underscore the considerable potential of these purpose-created, unique DNA-interacting conjugates for broadening the clinical application of ADC technology. Mol Cancer Ther; 15(8); 1870-8. ©2016 AACR. ©2016 American Association for Cancer Research.

Divergent Synthesis of Solanidine and 22-epi-Solanidine.

PubMed

Hou, Ling-Li; Shi, Yong; Zhang, Zhi-Dan; Wu, Jing-Jing; Yang, Qing-Xiong; Tian, Wei-Sheng

2017-07-21

A divergent synthesis of solanidine and 22-epi-solanidine, two 25S natural steroidal alkaloids, from 25R-configured diosgenin acetate, is described. Initially, solanidine was synthesized through a series of transformations including a cascade ring-switching process of furostan-26-acid, an epimerization of C25 controlled by the conformation of six-membered lactone ring, an intramolecular Schmidt reaction, and an imine reduction/intramolecular aminolysis process. To address the epimerization issue during Schmidt reaction, an improved synthesis was developed, which also led to a synthesis of 22-epi-solanidine. In this synthesis, selective transformation of azido lactone to azido diol and amino diol was realized through a reduction relay tactic. The azido diol was transformed to solanidine via an intramolecular Schmidt reaction/N-alkylation/reduction process and to 22-epi-solanidine via an intramolecular double N-alkylation process.

A novel acetylation cycle of transcription co-activator Yes-associated protein that is downstream of Hippo pathway is triggered in response to SN2 alkylating agents.

PubMed

Hata, Shoji; Hirayama, Jun; Kajiho, Hiroaki; Nakagawa, Kentaro; Hata, Yutaka; Katada, Toshiaki; Furutani-Seiki, Makoto; Nishina, Hiroshi

2012-06-22

Yes-associated protein (YAP) is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes. Although cytoplasmic retention of YAP is known to be mediated by Hippo pathway-dependent phosphorylation, post-translational modifications that regulate YAP in the nucleus remain unclear. Here we report the discovery of a novel cycle of acetylation/deacetylation of nuclear YAP induced in response to S(N)2 alkylating agents. We show that after treatment of cells with the S(N)2 alkylating agent methyl methanesulfonate, YAP phosphorylation mediated by the Hippo pathway is markedly reduced, leading to nuclear translocation of YAP and its acetylation. This YAP acetylation occurs on specific and highly conserved C-terminal lysine residues and is mediated by the nuclear acetyltransferases CBP (CREB binding protein) and p300. Conversely, the nuclear deacetylase SIRT1 is responsible for YAP deacetylation. Intriguingly, we found that YAP acetylation is induced specifically by S(N)2 alkylating agents and not by other DNA-damaging stimuli. These results identify a novel YAP acetylation cycle that occurs in the nucleus downstream of the Hippo pathway. Intriguingly, our findings also indicate that YAP acetylation is involved in responses to a specific type of DNA damage.

A Novel Acetylation Cycle of Transcription Co-activator Yes-associated Protein That Is Downstream of Hippo Pathway Is Triggered in Response to SN2 Alkylating Agents*

PubMed Central

Hata, Shoji; Hirayama, Jun; Kajiho, Hiroaki; Nakagawa, Kentaro; Hata, Yutaka; Katada, Toshiaki; Furutani-Seiki, Makoto; Nishina, Hiroshi

2012-01-01

Yes-associated protein (YAP) is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes. Although cytoplasmic retention of YAP is known to be mediated by Hippo pathway-dependent phosphorylation, post-translational modifications that regulate YAP in the nucleus remain unclear. Here we report the discovery of a novel cycle of acetylation/deacetylation of nuclear YAP induced in response to SN2 alkylating agents. We show that after treatment of cells with the SN2 alkylating agent methyl methanesulfonate, YAP phosphorylation mediated by the Hippo pathway is markedly reduced, leading to nuclear translocation of YAP and its acetylation. This YAP acetylation occurs on specific and highly conserved C-terminal lysine residues and is mediated by the nuclear acetyltransferases CBP (CREB binding protein) and p300. Conversely, the nuclear deacetylase SIRT1 is responsible for YAP deacetylation. Intriguingly, we found that YAP acetylation is induced specifically by SN2 alkylating agents and not by other DNA-damaging stimuli. These results identify a novel YAP acetylation cycle that occurs in the nucleus downstream of the Hippo pathway. Intriguingly, our findings also indicate that YAP acetylation is involved in responses to a specific type of DNA damage. PMID:22544757

Asymmetric Synthesis of α-(Diarylmethyl) Alkyl Amines through Regioselective Lithiation of α-Diarylmethanes and the Diastereoselective Addition to Ellman's Imines.

PubMed

Reddy, Leleti Rajender; Kotturi, Sharadsrikar; Waman, Yogesh; Patel, Chirag; Danidharia, Megha; Shenoy, Rajesh

2018-06-15

A highly regio- and diastereoselective lithiation/addition of α-diarylmethanes to N-tert-butanesulfinylimines is reported. This methodology also affords the preparation of enantiomerically pure α-(diarylmethyl) alkyl amines bearing quaternary centers.

Stereospecific nickel-catalyzed cross-coupling reactions of benzylic ethers and esters.

PubMed

Tollefson, Emily J; Hanna, Luke E; Jarvo, Elizabeth R

2015-08-18

This Account presents the development of a suite of stereospecific alkyl-alkyl cross-coupling reactions employing nickel catalysts. Our reactions complement related nickel-catalyzed stereoconvergent cross-coupling reactions from a stereochemical and mechanistic perspective. Most reactions of alkyl electrophiles with low-valent nickel complexes proceed through alkyl radicals and thus are stereoablative; the correct enantioselective catalyst can favor the formation of one enantiomer. Our reactions, in contrast, are stereospecific. Enantioenriched ethers and esters are cleanly converted to cross-coupled products with high stereochemical fidelity. While mechanistic details are still to be refined, our results are consistent with a polar, two-electron oxidative addition that avoids the formation of radical intermediates. This reactivity is unusual for a first-row transition metal. The cross-coupling reactions engage a range of benzylic ethers and esters, including methyl ethers, tetrahydropyrans, tetrahydrofurans, esters, and lactones. Coordination of the arene substituent to the nickel catalyst accelerates the reactions. Arenes with low aromatic stabilization energies, such as naphthalene, benzothiophene, and furan, serve as the best ligands and provide the highest reactivity. Traceless directing groups that accelerate reactions of sluggish substrates are described, providing partial compensation for arene coordination. Kumada, Negishi, and Suzuki reactions provide incorporation of a broad range of transmetalating agents. In Kumada coupling reactions, a full complement of Grigard reagents, including methyl, n-alkyl, and aryl Grignard reagents, are employed. In reactions employing methylmagnesium iodide, ligation of the nickel catalyst by rac-BINAP or DPEphos provides the highest yield and stereospecificity. For all other Grignard reagents, Ni(dppe)Cl2 has emerged as the best catalyst. Negishi cross-coupling reactions employing dimethylzinc are reported as a strategy to increase the functional group tolerance of the reaction. We also describe Suzuki reactions using arylboronic esters. These reactions provided the first example in the series of a switch in stereochemical outcome. The reactions maintain stereospecificity, but reactions employing different achiral ligands provide opposite enantiomers of the product. Use of an N-heterocyclic carbene ligand, SIMes, provides inversion, consistent with our prior work in Kumada and Negishi coupling reactions. Use of the electron-rich phosphine PCy3, however, provides retention with stereospecificity, signaling a change in the mechanistic details. Potential applications of the reported cross-coupling reactions include the synthesis of medicinal agents containing the 2-arylalkane and 1,1-diarylalkane moieties, which are pharmacophores in medicinal chemistry. These moieties are found in compounds with activity against a broad range of indications, including cancer, heart disease, diabetes, osteoporosis, smallpox, tuberculosis, and insomnia. We highlight representative examples of bioactive compounds that we have prepared with high enantioselectivity employing our methods, as well as the discovery of a new anti-cancer agent.

Water-soluble conductive polymers

DOEpatents

Aldissi, Mahmoud

1989-01-01

Polymers which are soluble in water and are electrically conductive. The monomer repeat unit is a thiophene or pyrrole molecule having an alkyl group substituted for the hydrogen atom located in the beta position of the thiophene or pyrrole ring and having a surfactant molecule at the end of the alkyl chain. Polymers of this class having 8 or more carbon atoms in the alkyl chain exhibit liquid crystalline behavior, resulting in high electrical anisotropy. The monomer-to-monomer bonds are located between the carbon atoms which are adjacent to the sulfur or nitrogen atoms. The number of carbon atoms in the alkyl group may vary from 1 to 20 carbon atoms. The surfactant molecule consists of a sulfonate group, or a sulfate group, or a carboxylate group, and hydrogen or an alkali metal. Negative ions from a supporting electrolyte which may be used in the electrochemical synthesis of a polymer may be incorporated into the polymer during the synthesis and serve as a dopant to increase the conductivity.

Water-soluble conductive polymers

DOEpatents

Aldissi, Mahmoud

1990-01-01

Polymers which are soluble in water and are electrically conductive. The monomer repeat unit is a thiophene or pyrrole molecule having an alkyl group substituted for the hydrogen atom located in the beta position of the thiophene or pyrrole ring and having a surfactant molecule at the end of the alkyl chain. Polymers of this class having 8 or more carbon atoms in the alkyl chain exhibit liquid crystalline behavior, resulting in high electrical anisotropy. The monomer-to-monomer bonds are located between the carbon atoms which are adjacent to the sulfur or nitrogen atoms. The number of carbon atoms in the alkyl group may vary from 1 to 20 carbon atoms. The surfactant molecule consists of a sulfonate group, or a sulfate group, or a carboxylate group, and hydrogen or an alkali metal. Negative ions from a supporting electrolyte which may be used in the electrochemical synthesis of a polymer may be incorporated into the polymer during the synthesis and serve as a dopant to increase the conductivity.

Water-soluble conductive polymers

DOEpatents

Aldissi, M.

1988-02-12

Polymers which are soluble in water and are electrically conductive. The monomer repeat unit is a thiophene or pyrrole molecule having an alkyl group substituted for the hydrogen atom located in the beta position of the thiophene or pyrrole ring and having a surfactant molecule at the end of the alkyl chain. Polymers of this class having 8 or more carbon atoms in the alkyl chain exhibit liquid crystalline behavior, resulting in high electrical anisotropy. The monomer-to-monomer bonds are located between the carbon atoms which are adjacent to the sulfur or nitrogen atoms. The number of carbon atoms in the alkyl group may vary from 1 to 20 carbon atoms. The surfactant molecule consists of a sulfonate group, or a sulfate group, or a carboxylate group, and hydrogen or an alkali metal. Negative ions from a supporting electrolyte which may be used in the electrochemical synthesis of a polymer may be incorporated into the polymer during the synthesis and serve as a dopant to increase the conductivity.

Design and synthesis of some new 1-phenyl-3/4-[4-(aryl/heteroaryl/alkyl-piperazine1-yl)-phenyl-ureas as potent anticonvulsant and antidepressant agents.

PubMed

Mishra, Chandra Bhushan; Kumari, Shikha; Tiwari, Manisha

2016-05-01

A series of 1-phenyl-3/4-[4-(aryl/heteroaryl/alkyl-piperazine1-yl)-phenyl-urea derivatives (29-42) were designed, synthesized and evaluated for their anticonvulsant activity by using maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) seizure tests. The acute neurotoxicity was checked by rotarod assay. Most of the test compounds were found effective in both seizure tests. Compound 30 (1-{4-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3-phenyl-urea) exhibited marked anticonvulsant activity in MES as well as scPTZ tests. The phase II anticonvulsant quantification study of compound 30 indicates the ED50 value of 28.5 mg/kg against MES induced seizures. In addition, this compound also showed considerable protection against pilocarpine induced status epilepticus in rats. Seizures induced by 3-mercaptopropionic acid model and thiosemicarbazide were significantly attenuated by compound 30, which suggested its broad spectrum of anticonvulsant activity. Interestingly, compound 30 displayed better antidepressant activity than standard drug fluoxetine. Moreover, compound 30 appeared as a non-toxic chemical entity in sub-acute toxicity studies.

Copper-catalyzed transformation of ketones to amides via C(CO)-C(alkyl) bond cleavage directed by picolinamide.

PubMed

Ma, Haojie; Zhou, Xiaoqiang; Zhan, Zhenzhen; Wei, Daidong; Shi, Chong; Liu, Xingxing; Huang, Guosheng

2017-09-13

Copper catalyzed chemoselective cleavage of the C(CO)-C(alkyl) bond leading to C-N bond formation with chelation assistance of N-containing directing groups is described. Inexpensive Cu(ii)-acetate serves as a convenient catalyst for this transformation. This method highlights the emerging strategy to transform unactivated alkyl ketones into amides in organic synthesis and provides a new strategy for C-C bond cleavage.

Enantioselective synthesis of chiral oxazolines from unactivated ketones and isocyanoacetate esters by synergistic silver/organocatalysis.

PubMed

Martínez-Pardo, Pablo; Blay, Gonzalo; Muñoz, M Carmen; Pedro, José R; Sanz-Marco, Amparo; Vila, Carlos

2018-03-15

A multicatalytic approach that combines a bifunctional Brønsted base-squaramide organocatalyst and Ag + as Lewis acid has been applied in the reaction of unactivated ketones with tert-butyl isocyanoacetate to give chiral oxazolines bearing a quaternary stereocenter. The formal [3+2] cycloaddition provided high yields of the corresponding cis-oxazolines with good diastereoselectivity and excellent enantioselectivity, being applied to aryl-alkyl and alkyl-alkyl ketones.

Water Soluble Phosphane-Gold(I) Complexes. Applications as Recyclable Catalysts in a Three-component Coupling Reaction and as Antimicrobial and Anticancer Agents

PubMed Central

Elie, Benelita T.; Levine, Chaya; Ubarretxena-Belandia, Iban; Varela-Ramírez, Armando; Aguilera, Renato J.; Ovalle, Rafael; Contel, María

2013-01-01

Water-soluble compounds of the type [AuCl(PR3)] with alkyl-bis-(m-sulfonated-phenyl)-(mC6H4SO3Na)2 and dialkyl-(m-sulfonated-phenyl)-(mC6H4SO3Na) (R = nBu, Cp) phosphanes have been prepared. Dialkyl-phosphane compounds generate water-soluble nanoparticles of 10-15 nm radius when dissolved in water. These air-stable complexes have been evaluated as catalysts in the synthesis of propargylamines via a three-component coupling reaction of aldehydes, amines and alkynes in water. The antimicrobial activity of the new complexes against Gram-positive and Gram-negative bacteria and yeast has been evaluated. The new compounds display moderate to high antibacterial activity. The more lipophilic compounds are also potent against fungi. Their cytotoxic properties have been analyzed in vitro utilizing human Jurkat T-cell acute lymphoblastic leukemia cells. Compounds with dialkyl-(m-sulfonated-phenyl)-(mC6H4SO3Na) phosphanes displayed moderate to high cytotoxicity on this cell line. Death cell mechanism occurs mainly by early apoptosis. The catalytic/biological activity of the previously described compound with commercial m-trisulfonated-triphenylphosphine [AuCl(TPPTS)] (6) has been also evaluated to compare the effects of the higher basicity and lipophilicity of the alkyl- and di-alkyl-(m-sulfonated-phenyl) phosphanes on these new compounds. PMID:23524957

Characterization of "mini-nucleotides" as P2X receptor agonists in rat cardiomyocyte cultures. An integrated synthetic, biochemical, and theoretical study.

PubMed

Fischer, B; Yefidoff, R; Major, D T; Rutman-Halili, I; Shneyvays, V; Zinman, T; Jacobson, K A; Shainberg, A

1999-07-15

The design and synthesis of "mini-nucleotides", based on a xanthine-alkyl phosphate scaffold, are described. The physiological effects of the new compounds were evaluated in rat cardiac cell culture regarding Ca(2+) elevation and contractility. The results indicate biochemical and physiological profiles similar to those of ATP, although at higher concentrations. The biological target molecules of these "mini-nucleotides" were identified by using selective P2-R and A(1)-R antagonists and P2-R subtype selective agonists. On the basis of these results and of experiments in Ca(2+) free medium, in which [Ca(2+)](i) elevation was not observed, we concluded that interaction of the analogues is likely with P2X receptor subtypes, which causes Ca(2+) influx. Theoretical calculations analyzing electronic effects within the series of xanthine-alkyl phosphates were performed on reduced models at quantum mechanical levels. Calculated dipole moment vectors, electrostatic potential maps, and volume parameters suggest an explanation for the activity or inactivity of the synthesized derivatives and predict a putative binding site environment for the active agonists. Xanthine-alkyl phosphate analogues proved to be selective agents for activation of P2X-R subtypes, whereas ATP activated all P2-R subtypes in cardiac cells. Therefore, these analogues may serve as prototypes of selective drugs aiming at cardiac disorders mediated through P2X receptors.

Friedel-Crafts Alkylation Using Elemental Aluminum Catalyst: An Undergraduate Laboratory Experiment.

ERIC Educational Resources Information Center

Meeks, B. Spencer; Lucas, Anita R.

1989-01-01

Provides methodology for carrying out the synthesis of sec-butyltoluene by the Friedel-Crafts alkylation of toluene. Suggests using simple elemental aluminum as the catalyst in place of AlCl3 or amalgamated aluminum. Notes satisfactory results for both macro- and microscale operations. (MVL)

Polymerization of ethylene through reversible addition-fragmentation chain transfer (RAFT).

PubMed

Dommanget, Cédric; D'Agosto, Franck; Monteil, Vincent

2014-06-23

The present paper reports the first example of a controlled radical polymerization of ethylene using reversible addition-fragmentation chain transfer (RAFT) in the presence of xanthates (Alkyl-OC(=S)S-R) as controlling agents under relative mild conditions (70 °C, <200 bars). The specific reactivity of the produced alkyl-type propagating radicals induces a side fragmentation reaction of the stabilizing O-alkyl Z group of the controlling agents. This fragmentation, rarely observed in RAFT, was proven by NMR analyses. In addition, semicrystalline copolymers of ethylene and vinyl acetate were also prepared with a similar level of control. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

HTB140 melanoma cells under proton irradiation and/or alkylating agents

NASA Astrophysics Data System (ADS)

Korićanac, L.; Petrović, I.; Privitera, G.; Cuttone, G.; Ristić-Fira, A.

2007-09-01

Chemoresistance is a major problem in the treatment of malignant melanoma. The mainstay of treatment for melanoma is the DNA-alkylating agent dacarbazine (DTIC). Fotemustine (FM), a member of the chloroethylnitrosourea group of alkylating agents, has also demonstrated significant antitumor effects in malignant melanoma. However, the intrinsic and acquired resistance of melanoma limits the clinical application of these drugs. Melanomas are also extremely radioresistant. With the objective of enhancing growth inhibition of melanoma cells, combined treatments of FM or DTIC with proton irradiation have been investigated. These effects were studied on HTB140 melanoma cell viability and proliferation. Cells exposed to treatment with FM and protons have shown inhibition of cell growth and significant reduction of proliferation capacity compared to single irradiation or drug treatment. Treatment with DTIC and protons has shown improved growth inhibition compared to appropriate single drug treatment, while the effects of single proton irradiation have been the most pronounced.

Reduced DNA repair in mouse satellite DNA after treatment with methylmethanesulfonate, and N-methyl-N-nitrosourea.

PubMed Central

Bodell, W J; Banerjee, M R

1976-01-01

We have measured DNA repair in mouse satellite and main band DNA as resolved by Ag+-Cs2SO4 centrifugation in response to treatment with the alkylating agents, methyl methanesulfonate, and N-methyl-N-nitrosourea. We find that there is a statistically significant lower incorporation of 3H-Tdr into the satellite DNA as compared to the main band at varying periods after treatment with the alkylating agents. This suggests a reduced repair activity in the satellite DNA. We have measured the extent of binding of 14C-methyl methanesulfonate to the satellite, and main band DNA, and no difference in binding was observed, indicating that the reduced repair activity of satellite DNA is not due to a difference in binding of alkylating agents. We believe that the reduced incorporation of 3H-Tdr into satellite DNA may be due to its location in the condensed chromatin fraction. PMID:184436

1,6-Conjugate addition of zinc alkyls to para-quinone methides in a continuous-flow microreactor.

PubMed

Jadhav, Abhijeet S; Anand, Ramasamy Vijaya

2016-12-20

An efficient method for the synthesis of alkyl diarylmethanes through the 1,6-conjugate addition of dialkylzinc reagents to para-quinone methides (p-QMs) has been developed under continuous flow conditions using a microreactor. This protocol allows to access unsymmetrical alkyl diarylmethanes in moderate to excellent yields using a wide range of p-QMs and dialkylzinc reagents. Interestingly, this transformation worked well without the requirement of a catalyst.

Synthesis of 2-{(5-phenyl-1,3,4-Oxadiazol-2-yl)sulfanyl}-N-substituted acetamides as potential antimicrobial and hemolytic agents.

PubMed

Rehman, Aziz-ur; Abbasi, Muhammad Athar; Siddiqui, Sabahat Zahra; Ahmad, Irshad; Shahid, Muhammad; Subhani, Zinayyera

2016-05-01

A new series of N-substituted derivatives of 2-{(5-phenyl-1,3,4-Oxadiazol-2-yl)sulfanyl}acetamides was synthesized. The synthesis was carried out by converting benzoic acid (1) into ethyl benzoate (2), benzohydrazide (3) and then 5-pheny-1,3,4-Oxadiazol-2-thiol (4) step by st0ep. The target compounds 6a-p were synthesized by reaction of compound 4 with equimolar ratios of different N-alkyl/aryl substituted 2-bromoacetamide (5a-p) in the presence of DMF and sodium hydride (NaH). The spectral (EI-MS, IR, (1)H-NMR) characterization of all the synthesized compounds reveal their successful synthesis. The compounds were also screened for antimicrobial & hemolytic activity and most of them were found to be active against the selected microbial species at variable extent relative to reference standards. But 6h was the most active against the selected panel of microbes. This series showed less toxicity and may be considered for further biological screening and application trial except 6m, possessing higher cytotoxicity.

Pseudomonas putida AlkA and AlkB Proteins Comprise Different Defense Systems for the Repair of Alkylation Damage to DNA – In Vivo, In Vitro, and In Silico Studies

PubMed Central

Mielecki, Damian; Saumaa, Signe; Wrzesiński, Michał; Maciejewska, Agnieszka M.; Żuchniewicz, Karolina; Sikora, Anna; Piwowarski, Jan; Nieminuszczy, Jadwiga; Kivisaar, Maia; Grzesiuk, Elżbieta

2013-01-01

Alkylating agents introduce cytotoxic and/or mutagenic lesions to DNA bases leading to induction of adaptive (Ada) response, a mechanism protecting cells against deleterious effects of environmental chemicals. In Escherichia coli, the Ada response involves expression of four genes: ada, alkA, alkB, and aidB. In Pseudomonas putida, the organization of Ada regulon is different, raising questions regarding regulation of Ada gene expression. The aim of the presented studies was to analyze the role of AlkA glycosylase and AlkB dioxygenase in protecting P. putida cells against damage to DNA caused by alkylating agents. The results of bioinformatic analysis, of survival and mutagenesis of methyl methanesulfonate (MMS) or N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) treated P. putida mutants in ada, alkA and alkB genes as well as assay of promoter activity revealed diverse roles of Ada, AlkA and AlkB proteins in protecting cellular DNA against alkylating agents. We found AlkA protein crucial to abolish the cytotoxic but not the mutagenic effects of alkylans since: (i) the mutation in the alkA gene was the most deleterious for MMS/MNNG treated P. putida cells, (ii) the activity of the alkA promoter was Ada-dependent and the highest among the tested genes. P. putida AlkB (PpAlkB), characterized by optimal conditions for in vitro repair of specific substrates, complementation assay, and M13/MS2 survival test, allowed to establish conservation of enzymatic function of P. putida and E. coli AlkB protein. We found that the organization of P. putida Ada regulon differs from that of E. coli. AlkA protein induced within the Ada response is crucial for protecting P. putida against cytotoxicity, whereas Ada prevents the mutagenic action of alkylating agents. In contrast to E. coli AlkB (EcAlkB), PpAlkB remains beyond the Ada regulon and is expressed constitutively. It probably creates a backup system that protects P. putida strains defective in other DNA repair systems against alkylating agents of exo- and endogenous origin. PMID:24098441

Effect of the C-2 hydroxyl group on the mesomorphism of alkyl glycosides: synthesis and thermotropic behavior of alkyl 2-deoxy-D-arabino-hexopyranosides.

PubMed

Singh, Madan Kumar; Jayaraman, Narayanaswamy; Rao, D S Shankar; Prasad, S Krishna

2008-10-01

A homologous series of alkyl 2-deoxy-alpha-d-arabino-hexopyranosides and alkyl 2-deoxy-beta-d-arabino-hexopyranosides were synthesized, upon glycosylation of 1-alkanols (from C8 to C18 alkanols) with ethyl 2-deoxy-3,4,6-tri-O-acetyl-1-thio-d-arabino-hexopyranoside, followed by a deprotection. The thermotropic behavior of these new types of alkyl glycosides was investigated. It was observed that the beta-anomers of these alkyl glycosides, bearing nonyl to tetradecyl alkyl chain are mesomorphic, exhibiting monotropic smectic A phase. In contrast, the alpha-anomers are all non-mesomorphic. An effort to identify the liquid crystalline behavior of binary mixtures of the alpha- and beta-anomers was undertaken and it was found that mixtures containing equimolar amounts of the anomers exhibited mesomorphic behavior. A fine balance of the hydrophilic and hydrophobic components within the molecule is also found to be important for the alkyl 2-deoxy glycosides to form the mesophase.

Abiotic Organic Chemistry in Hydrothermal Systems.

NASA Astrophysics Data System (ADS)

Simoneit, B. R.; Rushdi, A. I.

2004-12-01

Abiotic organic chemistry in hydrothermal systems is of interest to biologists, geochemists and oceanographers. This chemistry consists of thermal alteration of organic matter and minor prebiotic synthesis of organic compounds. Thermal alteration has been extensively documented to yield petroleum and heavy bitumen products from contemporary organic detritus. Carbon dioxide, carbon monoxide, ammonia and sulfur species have been used as precursors in prebiotic synthesis experiments to organic compounds. These inorganic species are common components of hot spring gases and marine hydrothermal systems. It is of interest to further test their reactivities in reductive aqueous thermolysis. We have synthesized organic compounds (lipids) in aqueous solutions of oxalic acid, and with carbon disulfide or ammonium bicarbonate at temperatures from 175-400° C. The synthetic lipids from oxalic acid solutions consisted of n-alkanols, n-alkanoic acids, n-alkyl formates, n-alkanones, n-alkenes and n-alkanes, typically to C30 with no carbon number preferences. The products from CS2 in acidic aqueous solutions yielded cyclic thioalkanes, alkyl polysulfides, and thioesters with other numerous minor compounds. The synthesis products from oxalic acid and ammonium bicarbonate solutions were homologous series of n-alkyl amides, n-alkyl amines, n-alkanes and n-alkanoic acids, also to C30 with no carbon number predominance. Condensation (dehydration) reactions also occur under elevated temperatures in aqueous medium as tested by model reactions to form amide, ester and nitrile bonds. It is concluded that the abiotic formation of aliphatic lipids, condensation products (amides, esters, nitriles, and CS2 derivatives (alkyl polysulfides, cyclic polysulfides) is possible under hydrothermal conditions and warrants further studies.

Synergy of irofulven in combination with other DNA damaging agents: synergistic interaction with altretamine, alkylating, and platinum-derived agents in the MV522 lung tumor model.

PubMed

Kelner, Michael J; McMorris, Trevor C; Rojas, Rafael J; Estes, Leita A; Suthipinijtham, Pharnuk

2008-12-01

Irofulven (MGI 114, NSC 683863) is a semisynthetic derivative of illudin S, a natural product present in the Omphalotus illudins (Jack O'Lantern) mushroom. This novel agent produces DNA damage, that in contrast to other agents, is predominately ignored by the global genome repair pathway of the nucleotide excision repair (NER)(2) system. The aim of this study was to determine the antitumor activity of irofulven when administered in combination with 44 different DNA damaging agents, whose damage is in general detected and repaired by the genome repair pathway. The human lung carcinoma MV522 cell line and its corresponding xenograft model were used to evaluate the activity of irofulven in combination with different DNA damaging agents. Two main classes of DNA damaging agents, platinum-derived agents, and select bifunctional alkylating agents, demonstrated in vivo synergistic or super-additive interaction with irofulven. DNA helicase inhibiting agents also demonstrated synergy in vitro, but an enhanced interaction with irofulven could not be demonstrated in vivo. There was no detectable synergistic activity between irofulven and agents capable of inducing DNA cleavage or intercalating into DNA. These results indicate that the antitumor activity of irofulven is enhanced when combined with platinum-derived agents, altretamine, and select alkylating agents such as melphalan or chlorambucil. A common factor between these agents appears to be the production of intrastrand DNA crosslinks. The synergistic interaction between irofulven and other agents may stem from the nucleotide excision repair system being selectively overwhelmed at two distinct points in the pathway, resulting in prolonged stalling of transcription forks, and subsequent initiation of apoptosis.

Synthesis of 1-O-methylchlorogenic acid: reassignment of structure for MCGA3 isolated from bamboo (Phyllostachys edulis) leaves

USDA-ARS?s Scientific Manuscript database

The first synthesis of 1-O-methylchlorogenic acid is described. The short and efficient synthesis of this compound provides laboratory-scale quantities of the material to investigate its biological properties. The synthesis involved C-1 alkylation of the known (-)-4,5-cyclohexylidenequinic acid lact...

Direct N-alkylation of unprotected amino acids with alcohols

PubMed Central

Yan, Tao; Feringa, Ben L.; Barta, Katalin

2017-01-01

N-alkyl amino acids find widespread application as highly valuable, renewable building blocks. However, traditional synthesis methodologies to obtain these suffer from serious limitations, providing a major challenge to develop sustainable alternatives. We report the first powerful catalytic strategy for the direct N-alkylation of unprotected α-amino acids with alcohols. This method is highly selective, produces water as the only side product leading to a simple purification procedure, and a variety of α-amino acids are mono- or di-N-alkylated, in most cases with excellent retention of optical purity. The hydrophobicity of the products is tunable, and even simple peptides are selectively alkylated. An iron-catalyzed route to mono-N-alkyl amino acids using renewable fatty alcohols is also described that represents an ideal green transformation for obtaining fully bio-based surfactants. PMID:29226249

Removing polysaccharides-and saccharides-related coloring impurities in alkyl polyglycosides by bleaching with the H2O2/TAED/NaHCO3 system.

PubMed

Yanmei, Liu; Jinliang, Tao; Jiao, Sun; Wenyi, Chen

2014-11-04

The effect of H2O2/TAED/NaHCO3 system, namely NaHCO3 as alkaline agent with the (tetra acetyl ethylene diamine (TAED)) TAED-activated peroxide system, bleaching of alkyl polyglycosides solution was studied by spectrophotometry. The results showed that the optimal bleaching conditions about H2O2/TAED/NaHCO3 system bleaching of alkyl polyglycosides solution were as follows: molar ratio of TAED to H2O2 was 0.06, addition of H2O2 was 8.6%, addition of NaHCO3 was 3.2%, bleaching temperature of 50-65 °C, addition of MgO was 0.13%, and bleaching time was 8h. If too much amount of NaHCO3 was added to the system and maintained alkaline pH, the bleaching effect would be greatly reduced. Fixing molar ratio of TAED to H2O2 and increasing the amount of H2O2 were beneficial to improve the whiteness of alkyl polyglycosides, but adding too much amount of H2O2 would reduce the transparency. In the TAED-activated peroxide system, NaHCO3 as alkaline agent and buffer agent, could overcome the disadvantage of producing black precipitates when NaOH as alkaline agent. Copyright © 2014 Elsevier Ltd. All rights reserved.

Population pharmacokinetic (PK) analysis of laromustine, an emerging alkylating agent, in cancer patients.

PubMed

Nassar, Ala F; Wisnewski, Adam V; King, Ivan

2017-05-01

1. Alkylating agents are capable of introducing an alkyl group into nucleophilic sites on DNA or RNA through covalent bond. Laromustine is an active member of a relatively new class of sulfonylhydrazine prodrugs under development as antineoplastic alkylating agents, and displays significant single-agent activity. 2. This is the first report of the population pharmacokinetic analysis of laromustine, 106 patients, 66 with hematologic malignancies and 40 with solid tumors, participated in five clinical trials worldwide. Of these, 104 patients were included in the final NONMEM analysis. 3. The population estimates for total clearance (CL) and volume of distribution of the central compartment (V 1 ) were 96.3 L/h and 45.9 L, associated with high inter-patient variability of 52.9% and 79.8% and inter-occasion variability of 26.7% and 49.3%, respectively. The population estimates for Q and V 2 were 73.2 L/h and 29.9 L, and inter-patient variability in V 2 was 63.1%, respectively. 4. The estimate of V ss (75.8 L) exceeds total body water, indicating that laromustine is distributed to tissues. The half-life is short, less than 1 h, reflecting rapid clearance. Population PK analysis showed laromustine pharmacokinetics to be independent of dose and organ function with no effect on subsequent dosing cycles.

Pharmacology of dimethanesulfonate alkylating agents: busulfan and treosulfan.

PubMed

Galaup, Ariane; Paci, Angelo

2013-03-01

Among the dimethanesulfonates, busulfan, in combination with other alkylating agents or nucleoside analogues, is the cornerstone of high-dose chemotherapy. It is used, and followed hematopoietic stem cell transplantation, for the treatment of various hematologic malignancies and immunodeficiencies. Treosulfan, which is a hydrophilic analogue of busulfan, was the first dimethanesufonate registered for the treatment of ovarian cancer. Recently, treosulfan has been investigated for the treatment of hematologic malignancies in combination with the same second agents before hematopoietic stem cell transplantation. This work reviews the pharmacological data of these two dimethanesulfonates alkylating agents. Specifically, the article looks at their chemistry, metabolism, anticancer activity, and their pharmacokinetics and pharmacodynamics. Busulfan has been investigated widely for more than three decades leading to a large and precise handling of this agent with numerous studies on activity and pharmacokinetics and pharmacodynamics. In contrast, the behavior of treosulfan is still under investigation and not fully described. The complexity of treosulfan's metabolism and mechanism of action gives rise to the need of a deeper understanding of its pharmacological activity in a context of high-dose chemotherapy. Specifically, there is a great need to better understand its pharmacokinetics/pharmacodynamics relationship.

Extensive reprogramming of the genetic code for genetically encoded synthesis of highly N-alkylated polycyclic peptidomimetics.

PubMed

Kawakami, Takashi; Ishizawa, Takahiro; Murakami, Hiroshi

2013-08-21

Cyclic structures can increase the proteolytic stability and conformational rigidity of peptides, and N-alkylation of the peptide backbone can make peptides more cell-permeable and resistant to proteolysis. Therefore, cyclic N-alkyl amino acids are expected to be useful building blocks to increase simultaneously these pharmacological properties of peptides. In this study, we screened various cyclic N-alkyl amino acids for their ribosomal incorporation into peptides and identified cyclic N-alkyl amino acids that can be efficiently and successively incorporated. We also demonstrated genetic code reprogramming for reassigning 16 NNU codons to 16 different cyclic N-alkyl amino acids with high fidelity to synthesize highly N-alkylated polycyclic peptidomimetics and an mRNA-displayed library of completely N-alkylated polycyclic peptidomimetics by using our recently developed TRAP (transcription/translation coupled with association of puromycin linker) display. In vitro selection from a highly diverse library of such completely N-alkylated polycyclic peptidomimetics could become a powerful means to discover small-molecule ligands such as drug candidates that can be targeted to biomolecules inside living cells.

Replacing Conventional Carbon Nucleophiles with Electrophiles: Nickel-Catalyzed Reductive Alkylation of Aryl Bromides and Chlorides

PubMed Central

2012-01-01

A general method is presented for the synthesis of alkylated arenes by the chemoselective combination of two electrophilic carbons. Under the optimized conditions, a variety of aryl and vinyl bromides are reductively coupled with alkyl bromides in high yields. Under similar conditions, activated aryl chlorides can also be coupled with bromoalkanes. The protocols are highly functional-group tolerant (−OH, −NHTs, −OAc, −OTs, −OTf, −COMe, −NHBoc, −NHCbz, −CN, −SO2Me), and the reactions are assembled on the benchtop with no special precautions to exclude air or moisture. The reaction displays different chemoselectivity than conventional cross-coupling reactions, such as the Suzuki–Miyaura, Stille, and Hiyama–Denmark reactions. Substrates bearing both an electrophilic and nucleophilic carbon result in selective coupling at the electrophilic carbon (R–X) and no reaction at the nucleophilic carbon (R–[M]) for organoboron (−Bpin), organotin (−SnMe3), and organosilicon (−SiMe2OH) containing organic halides (X–R–[M]). A Hammett study showed a linear correlation of σ and σ(−) parameters with the relative rate of reaction of substituted aryl bromides with bromoalkanes. The small ρ values for these correlations (1.2–1.7) indicate that oxidative addition of the bromoarene is not the turnover-frequency determining step. The rate of reaction has a positive dependence on the concentration of alkyl bromide and catalyst, no dependence upon the amount of zinc (reducing agent), and an inverse dependence upon aryl halide concentration. These results and studies with an organic reductant (TDAE) argue against the intermediacy of organozinc reagents. PMID:22463689

Anticancer activity of botanical alkyl hydroquinones attributed to topoisomerase II poisoning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, C.-P.; Fang, W.-H.; Lin, L.-I.

2008-03-15

Cytotoxic alkyl hydroquinone compounds have been isolated from many plants. We previously isolated 3 structurally similar cytotoxic alkyl hydroquinone compounds from the sap of the lacquer tree Rhus succedanea L. belonging to the sumac family, which have a long history of medicinal use in Asia. Each has an unsaturated alkyl chain attached to the 2-position of a hydroquinone ring. One of these isolates, 10'(Z),13'(E),15'(E)-heptadecatrienylhydroquinone [HQ17(3)], being the most cytotoxic, was chosen for studying the anticancer mechanism of these compounds. We found that HQ17(3) was a topoisomerase (Topo) II poison. It irreversibly inhibited Topo II{alpha} activity through the accumulation of Topomore » II-DNA cleavable complexes. A cell-based assay showed that HQ17(3) inhibited the growth of leukemia HL-60 cells with an EC{sub 50} of 0.9 {mu}M, inhibited the topoisomerase-II-deficient cells HL-60/MX2 with an EC{sub 50} of 9.6 {mu}M, and exerted no effect on peripheral blood mononuclear cells at concentrations up to 50 {mu}M. These results suggest that Topo II is the cellular drug target. In HL-60 cells, HQ17(3) promptly inhibited DNA synthesis, induced chromosomal breakage, and led to cell death with an EC{sub 50} about one-tenth that of hydroquinone. Pretreatment of the cells with N-acetylcysteine could not attenuate the cytotoxicity and DNA damage induced by HQ17(3). However, N-acetylcysteine did significantly reduce the cytotoxicity of hydroquinone. In F344 rats, intraperitoneal injection of HQ17(3) for 28 days induced no clinical signs of toxicity. These results indicated that HQ17(3) is a potential anticancer agent, and its structural features could be a model for anticancer drug design.« less

Vinylcyclopropylacyl and polyeneacyl radicals. Intramolecular ketene alkyl radical additions in ring synthesis.

PubMed

De Boeck, Benoit; Herbert, Nicola M A; Harrington-Frost, Nicole M; Pattenden, Gerald

2005-01-21

Treatment of a variety of substituted vinylcyclopropyl selenyl esters, e.g. 11, with Bu(3)SnH-AIBN in refluxing benzene leads to the corresponding acyl radical intermediates, which undergo rearrangement and intramolecular cyclisations via their ketene alkyl radical equivalents producing cyclohexenones in 50-60% yield. By contrast, treatment of conjugated triene selenyl esters, e.g. 32, with Bu(3)SnH-AIBN produces substituted 2-cyclopentenones via intramolecular cyclisations of their ketene alkyl radical intermediates. Under the same radical-initiating conditions the selenyl esters derived from o-vinylbenzoic acid and o-vinylcinnamic acid undergo intramolecular cyclisations producing 1-indanone and 5,6-dihydrobenzocyclohepten-7-one respectively in 60-70% yields. A tandem radical cyclisation from the alpha,beta,gamma,delta-diene selenyl ester 31 provides an expeditious synthesis of the diquinane 35 in 69% yield.

Method For Reactivating Solid Catalysts Used For Alklation Reactions

DOEpatents

Ginosar, Daniel M.; Thompson, David N.; Coates, Kyle; Zalewski, David J.; Fox, Robert V.

2005-05-03

A method for reactivating a solid alkylation catalyst is provided which can be performed within a reactor that contains the alkylation catalyst or outside the reactor. Effective catalyst reactivation is achieved whether the catalyst is completely deactivated or partially deactivated. A fluid reactivating agent is employed to dissolve catalyst fouling agents and also to react with such agents and carry away the reaction products. The deactivated catalyst is contacted with the fluid reactivating agent under pressure and temperature conditions such that the fluid reactivating agent is dense enough to effectively dissolve the fouling agents and any reaction products of the fouling agents and the reactivating agent. Useful pressures and temperatures for reactivation include near-critical, critical, and supercritical pressures and temperatures for the reactivating agent. The fluid reactivating agent can include, for example, a branched paraffin containing at least one tertiary carbon atom, or a compound that can be isomerized to a molecule containing at least one tertiary carbon atom.

Recent Developments in the Use of Organoboranes in Organic Synthesis

ERIC Educational Resources Information Center

Cragg, G. M. L.

1969-01-01

Describes how the carbonylation of organoboranes in a suitable solvent can produce various alcohols, ketones, aldehydes and oxymethylation derivatives. The synthesis of alpha-alkylated ketone using alkylboranes is discussed. (RR)

Alkylating chemotherapy may exert a uniquely deleterious effect upon neo-antigen-targeting anticancer vaccination

PubMed Central

Litterman, Adam J; Dudek, Arkadiusz Z; Largaespada, David A

2013-01-01

Alkylating chemotherapy exerts both antineoplastic and immunostimulatory effects. However, in addition to depleting regulatory T cells (Treg), alkylating agents also mediate a long lasting antiproliferative effect on responder lymphocytes. Our recent findings indicate that this antiproliferative effect profoundly impairs vaccination-induced immune responses, especially in the case of vaccines that target specific tumor-associated neo-antigens that do not require Treg depletion. PMID:24251080

N-methylpurine DNA glycosylase inhibits p53-mediated cell cycle arrest and coordinates with p53 to determine sensitivity to alkylating agents

PubMed Central

Song, Shanshan; Xing, Guichun; Yuan, Lin; Wang, Jian; Wang, Shan; Yin, Yuxin; Tian, Chunyan; He, Fuchu; Zhang, Lingqiang

2012-01-01

Alkylating agents induce genome-wide base damage, which is repaired mainly by N-methylpurine DNA glycosylase (MPG). An elevated expression of MPG in certain types of tumor cells confers higher sensitivity to alkylation agents because MPG-induced apurinic/apyrimidic (AP) sites trigger more strand breaks. However, the determinant of drug sensitivity or insensitivity still remains unclear. Here, we report that the p53 status coordinates with MPG to play a pivotal role in such process. MPG expression is positive in breast, lung and colon cancers (38.7%, 43.4% and 25.3%, respectively) but negative in all adjacent normal tissues. MPG directly binds to the tumor suppressor p53 and represses p53 activity in unstressed cells. The overexpression of MPG reduced, whereas depletion of MPG increased, the expression levels of pro-arrest gene downstream of p53 including p21, 14-3-3σ and Gadd45 but not proapoptotic ones. The N-terminal region of MPG was specifically required for the interaction with the DNA binding domain of p53. Upon DNA alkylation stress, in p53 wild-type tumor cells, p53 dissociated from MPG and induced cell growth arrest. Then, AP sites were repaired efficiently, which led to insensitivity to alkylating agents. By contrast, in p53-mutated cells, the AP sites were repaired with low efficacy. To our knowledge, this is the first direct evidence to show that a DNA repair enzyme functions as a selective regulator of p53, and these findings provide new insights into the functional linkage between MPG and p53 in cancer therapy. PMID:22801474

N-methylpurine DNA glycosylase inhibits p53-mediated cell cycle arrest and coordinates with p53 to determine sensitivity to alkylating agents.

PubMed

Song, Shanshan; Xing, Guichun; Yuan, Lin; Wang, Jian; Wang, Shan; Yin, Yuxin; Tian, Chunyan; He, Fuchu; Zhang, Lingqiang

2012-08-01

Alkylating agents induce genome-wide base damage, which is repaired mainly by N-methylpurine DNA glycosylase (MPG). An elevated expression of MPG in certain types of tumor cells confers higher sensitivity to alkylation agents because MPG-induced apurinic/apyrimidic (AP) sites trigger more strand breaks. However, the determinant of drug sensitivity or insensitivity still remains unclear. Here, we report that the p53 status coordinates with MPG to play a pivotal role in such process. MPG expression is positive in breast, lung and colon cancers (38.7%, 43.4% and 25.3%, respectively) but negative in all adjacent normal tissues. MPG directly binds to the tumor suppressor p53 and represses p53 activity in unstressed cells. The overexpression of MPG reduced, whereas depletion of MPG increased, the expression levels of pro-arrest gene downstream of p53 including p21, 14-3-3σ and Gadd45 but not proapoptotic ones. The N-terminal region of MPG was specifically required for the interaction with the DNA binding domain of p53. Upon DNA alkylation stress, in p53 wild-type tumor cells, p53 dissociated from MPG and induced cell growth arrest. Then, AP sites were repaired efficiently, which led to insensitivity to alkylating agents. By contrast, in p53-mutated cells, the AP sites were repaired with low efficacy. To our knowledge, this is the first direct evidence to show that a DNA repair enzyme functions as a selective regulator of p53, and these findings provide new insights into the functional linkage between MPG and p53 in cancer therapy.

New Synthesis, Structure and Analgesic Properties of Methyl 1-R-4-Methyl-2,2-Dioxo-1H-2λ⁶,1-Benzothiazine-3-Carboxylates.

PubMed

Azotla-Cruz, Liliana; Lijanova, Irina V; Ukrainets, Igor V; Likhanova, Natalya V; Olivares-Xometl, Octavio; Bereznyakova, Natalya L

2017-01-12

According to the principles of the methodology of bioisosteric replacements a series of methyl 1-R-4-methyl-2,2-dioxo-1 H -2λ⁶,1-benzothiazine-3-carboxylates has been obtained as potential analgesics. In addition, a fundamentally new strategy for the synthesis of compounds of this chemical class involving the introduction of N -alkyl substituent at the final stage in 2,1-benzothiazine nucleus already formed has been proposed. Using nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry and X-ray diffraction analysis it has been proven that in the DMSO/K₂CO₃ system the reaction of methyl 4-methyl-2,2-dioxo-1 H -2λ⁶,1-benzothiazine-3-carboxylate and alkyl halides leads to formation of N -substituted derivatives with good yields regardless of the structure of the alkylating agent. The peculiarities of NMR (¹Н and 13 С) spectra of the compounds synthesized, their mass spectrometric behavior and the spatial structure are discussed. In N -benzyl derivative the ability to form a monosolvate with methanol has been found. According to the results of the pharmacological testing conducted on the model of the thermal tail-flick it has been determined that replacement of 4-ОН-group in methyl 1-R-4-hydroxy-2,2-dioxo-1 H -2λ⁶,1-benzothiazine-3-carboxylates for the methyl group is actually bioisosteric since all methyl 1-R-4-methyl-2,2-dioxo-1 H -2λ⁶,1-benzothiazine-3-carboxylates synthesized demonstrated a statistically significant analgesic effect. The majority of the substances can inhibit the thermal pain response much more effective than piroxicam in the same dose. Under the same conditions as an analgesic the N- methyl-substituted analog exceeds not only piroxicam, but more active meloxicam as well. Therefore, it deserves in-depth biological studies on other experimental models.

Gd-DTPA-Dopamine-Bisphytanyl Amphiphile: Synthesis, Characterisation and Relaxation Parameters of the Nanoassemblies and Their Potential as MRI Contrast Agents.

PubMed

Gupta, Abhishek; Willis, Scott A; Waddington, Lynne J; Stait-Gardner, Tim; de Campo, Liliana; Hwang, Dennis W; Kirby, Nigel; Price, William S; Moghaddam, Minoo J

2015-09-28

Here, a new amphiphilic magnetic resonance imaging (MRI) contrast agent, a Gd(III)-chelated diethylenetriaminepentaacetic acid conjugated to two branched alkyl chains via a dopamine spacer, Gd-DTPA-dopamine-bisphytanyl (Gd-DTPA-Dop-Phy), which is readily capable of self-assembling into liposomal nanoassemblies upon dispersion in an aqueous solution, is reported. In vitro relaxivities of the dispersions were found to be much higher than Magnevist, a commercially available contrast agent, at 0.47 T but comparable at 9.40 T. Analysis of variable temperature (17)O NMR transverse relaxation measurements revealed the water exchange of the nanoassemblies to be faster than that previously reported for paramagnetic liposomes. Molecular reorientation dynamics were probed by (1)H NMRD profiles using a classical inner and outer sphere relaxation model and a Lipari-Szabo "model-free" approach. High payloads of Gd(III) ions in the liposomal nanoassemblies made solely from the Gd-DTPA-Dop-Phy amphiphiles, in combination with slow molecular reorientation and fast water exchange makes this novel amphiphile a suitable candidate to be investigated as an advanced MRI contrast agent. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Design, synthesis and preliminary antimicrobial evaluation of n-alkyl chain tethered c-5 functionalized bis-isatins

USDA-ARS?s Scientific Manuscript database

A series of N-alkyl tethered C-5 functionalized bis-isatins were synthesized and evaluated for antimicrobial activity against pathogenic microorganisms. The preliminary evaluation studies revealed the compound 4t, with an optimal combination of bromo-substituent at the C-5 position of isatin ring al...

MICROWAVE-ASSISTED CHEMISTRY: SYNTHESIS OF AMINES AND HETEROCYCLES VIA CARBON-NITROGEN BOND FORMATION IN AQUEOUS MEDIA

EPA Science Inventory

Improved C-N bond formation under MW influence is demonstrated by a) solventless three-component coupling reaction to generate propargyl amines that uses only Cu (I); b) aqueous N-alkylation of amines by alkyl halides that proceeds expeditiously in the presence of NaOH to deliver...

Impact of Therapy Sequence with Alkylating Agents and MGMT Status in Patients with Advanced Neuroendocrine Tumors.

PubMed

Krug, Sebastian; Boch, Michael; Rexin, Peter; Gress, Thomas M; Michl, Patrick; Rinke, Anja

2017-05-01

Alkylating chemotherapeutics with either a streptozotocin-(STZ) or temozolomide-(TEM) backbone are routinely used in patients with progressive and unresectable pancreatic neuroendocrine tumors (PNET). In addition, dacarbazine (DTIC) was described as an alternative alkylating therapy option for PNETs. The optimal treatment sequence with alkylating compounds and a potential use of O6-methylguanine-DNA methyltransferase (MGMT) level as predictive biomarker have not yet been sufficiently elucidated. The aim of our study was the evaluation of therapy sequence with either STZ-based treatment followed by DTIC (group A) or the inverse schedule with upfront DTIC (group B) and to correlate MGMT status with clinicopathological characteristics and response to therapy. We retrospectively analyzed 28 patients with neuroendocrine tumors (NET) who were treated with STZ-based therapy and DTIC. Additionally, in a second group MGMT immunohistochemistry was performed from primary and metastatic tumor sites. For statistical evaluation Kaplan-Meier analysis, Cox regression methods and Fisher's exact test were used. There was no difference of objective response and disease control between either STZ-based therapy followed by DTIC treatment (group A) after progression or the reverse sequence (group B). Median time to progression (TTP) was estimated to be 21 months in both arms. First-line STZ-based chemotherapy was not superior to first-line DTIC treatment (16 vs. 13 months; p=0.8). MGMT status did not correlate with clinicopathological characteristics or response to therapy with these alkylating agents. Upfront chemotherapy with either STZ-based treatment or DTIC monotherapy showed similar efficacy and median TTP rates. In this study, MGMT protein expression assessed by immunohistochemistry did not play an important role as a predictive marker for alkylating agents. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Cross-Linking Interferes With Assessing Sulfur Mustard-Induced DNA Damage in Human Peripheral Blood Lymphocytes Using the Comet Assay

DTIC Science & Technology

2004-01-01

of SM to impede the migration of H,0 2 -damaged mal ian cell lethality with bifunctional alkylating agents . Chemr. Biol. Iriterui. 38:75-86.DNA is an...3100 Ricketts Point Road, Aberdeen Proving Ground, Maryland 21010-5400 N-3 position of adenine, and alkylation leads to depurination of Sulfur...mustard (SM) is a blistering agent that produces DNA DNA strands. Subsequent breakage of phosphodiester bonds at strand breaks. To detect SM-induced DNA

Maternal drug use: evaluation of risks to breast-fed infants.

PubMed

Kirksey, A; Groziak, S M

1984-01-01

This paper, based on a review of the literature, evaluates the risks to infants of maternal drug use during lactation. The potential harm of a particular drug to the breastfed infant is related both to the complex mechanism of milk synthesis and secretion and the mode of passage of the drug from plasma into milk. The 1st part of the paper discusses mammary cell and milk synthesis, milk secretion and composition, the mode of passage of drugs into milk, and factors influencing drug concentrations in milk. Drug concentrations in milk are dependent on 6 major factors: drug dosage, proportion bound in plasma, molecular weight, lipid solubility, degree of ionization, and pH difference between plasma and milk. Drugs that are weak acids are ionized to a greater extent and are more protein-bound than weak alkaline drugs. The 2nd part of the paper evaluates the risks to breastfed infants of selected pharmacons. Some categories of drugs that contain pharmacons that should be limited or avoided by nursing mothers are alkylating agents, analgesics and anti-inflammatory agents, anticoagulants, anticonvulsants, anti-infective agents, central nervous system stimulants, hormones, laxatives, minerals, provitamins, psychotherapeutic agents, thyroid affecting agents, and vitamins. The following precautions are suggested to minimize the risks of potentially harmful pharmacons: 1) all unnecessary medications should be avoided by nrusing mothers; 2) if medication is necessary during lactation, drug dosage should be controlled and the infant should be monitored for adverse symptoms; 3) drugs should be administered shortly after breastfeeding and the interval prolonged before the next feeding; and 4) if the infant must be fed soon after a potentially harmful drug has been taken by the mother, bottle feeding is recommended.

Preclinical studies of steroid-linked nitrosoureas in murine pancreatic adenocarcinoma PANO2.

PubMed

Papageorgiou, A; Lialiaris, Th; Stergiou, E; Stergiou, I; Tsigris, C; Kourti, A; Geromichalos, G; Stravoravdi, P; Trafalis, D; Athanassiou, A E; Pitsas, A; Camoutsis, Ch

2008-01-01

In earlier studies, this laboratory carried out research on the synthesis and anticancer evaluation of hybrid compounds, which combine two molecules in one such as homo-aza-steroidal esters (HASE) of carboxylic derivatives of N, N-bis (2-chloroethyl) aniline. In this combination, steroidal hormones are employed as carriers for transporting the alkylating agents to specific targeted tissues. Aiming to continue our research, we used alkylating agents, as nitrosoureas, instead of nitrogen mustards. In this work the N-[N- (2-chloroethyl)-N-nitroso-carbomoyl]-L-alanine (CNC-ala) has been used and was bound to 7 newly synthesized modified steroidal esters (carrier molecule) of nitrosourea and the hybrid molecules were tested for antitumor activity against PANO2 murine pancreatic adenocarcinoma. PANO2 adenocarcinoma was used in this study. C57Bl mice were used for chemotherapy evaluation. The activity was assessed from the inhibition of tumor growth and the oncostatic parameter T/C %. The antitumor activity displayed by 7 hybrid steroidal esters of nitrosourea was quite interesting. It was able to discern 4 of 7 compounds that exhibited considerable antitumor activity, increasing the lifespan of the tumor-bearing mice by inhibiting the tumor growth. The comparative study of 7 newly synthesized hybrid steroidal esters of nitrosourea shows that the antitumor effects of compound 7, which has an enlarged (7 carbon atoms) A-lactamic ring and nitrosourea esterified at the position 17, which seems to be the most appropriate for the connection of a DNA cross-linking amino acid derivative is superior.

Engineering acyclic stereocontrol in the alkylation of vinylglycine-derived dianions: asymmetric synthesis of higher alpha-vinyl amino acids.

PubMed

Berkowitz, D B; McFadden, J M; Sloss, M K

2000-05-19

A generalizable synthesis of higher L-alpha-vinyl amino acids is presented. The strategy pursued here involves the introduction of the amino acid side chain via the alkylation of a chiral, vinylglycine-derived dianionic dienolate, bearing the (-)-8-(beta-naphthyl)menthyl (d'Angelo) auxiliary. A model is presented that postulates a favored "exo-entended" conformation for this dienolate, leading to C(alpha)-alkylation at the si face. The model invokes internal amidate chelation to control ester enolate geometry and soft-soft interactions between the polarizable beta-naphthyl ring of the auxiliary and the extended pi-system of the dienolate to shield the re face. Heats of formation for four conformers of this dianion were calculated for their semiempirical optimized geometries (PM3). The results support the notion that in these vinylglycine-derived dianionic dienolates, "exo" conformations are considerable lower in energy than their "endo" counterparts, with the "exo-entended" conformation being most favorable. In fact, the d'Angelo auxiliary gives a greater degree of acyclic stereocontrol in this system when compared with the (-)-8-phenylmenthyl (Corey) and trans-2-(beta-naphthyl)cyclohexyl auxiliaries, using isobutyl iodide and benzyl bromide as model electrophiles. These dianions are generated from the corresponding dehydrobutyrine esters via sequential deprotonation with LDA and n-BuLi (2 equiv). When alkylations are carried out at -78 degrees C in THF-HMPA, they proceed in 65-81% yields, with both regiocontrol (deconjugative alpha-alkylation is preferred over gamma-alkylation) and a great degree of acyclic stereocontrol [91:9 to >/=98:2 diastereomeric ratios (10 examples)]. The auxiliary may be recovered in high yield (generally 90%) using a modification of Gassman's "anhydrous hydroxide" conditions, in which considerably higher temperatures are employed. Among the side chains introduced directly are those of butyrine, leucine, ornithine, phenylalanine, aspartate, valine, and norvaline. The lysine side chain is elaborated via a 4-step sequence from the alkylation product obtained with 1-chloro-4-iodobutane as electrophile. Importantly, to our knowledge, this work represents the first asymmetric synthesis of L-alpha-vinyl analogues of m-tyrosine, ornithine, and lysine, known time-dependent inhibitors for amino acid decarboxylases.

Dephosphorylation of receptor tyrosine kinases as target of regulation by radiation, oxidants or alkylating agents.

PubMed Central

Knebel, A; Rahmsdorf, H J; Ullrich, A; Herrlich, P

1996-01-01

Several non-physiologic agents such as radiation, oxidants and alkylating agents induce ligand-independent activation of numerous receptor tyrosine kinases (RTKs) and of protein tyrosine kinases at the inner side of the plasma membrane (e.g. Dévary et al., 1992; Sachsenmaier et al., 1994; Schieven et al., 1994; Coffer et al., 1995). Here we show additional evidence for the activation of epidermal growth factor receptor (EGFR), and we show activation of v-ErbB, ErbB2 and platelet-derived growth factor receptor. As a common principle of action the inducing agents such as UVC, UVB, UVA, hydrogen peroxide and iodoacetamide inhibit receptor tyrosine dephosphorylation in a thiol-sensitive and, with the exception of the SH-alkylating agent, reversible manner. EGFR dephosphorylation can also be modulated by these non-physiologic agents in isolated plasma membranes in the presence of Triton X-100. Further, substrate (EGFR) and phosphatase have been separated: a membrane preparation of cells that have been treated with epidermal growth factor (EGF) and whose dephosphorylating enzymes have been permanently destroyed by iodoacetamide can be mixed with a membrane preparation from untreated cells which re-establishes EGFR dephosphorylation. This dephosphorylation can be modulated in vitro by UV and thiol agents. We conclude that RTKs exhibit significant spontaneous protein kinase activity; several adverse agents target (an) essential SH-group(s) carried by (a) membrane-bound protein tyrosine phosphatase(s). Images PMID:8895576

Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes.

PubMed

Tran, Thai Q; Ishak Gabra, Mari B; Lowman, Xazmin H; Yang, Ying; Reid, Michael A; Pan, Min; O'Connor, Timothy R; Kong, Mei

2017-11-01

Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death. In addition, low glutamine-induced DNA damage is abolished in ALKBH deficient cells. Importantly, we show that glutaminase inhibitors, 6-Diazo-5-oxo-L-norleucine (DON) or CB-839, hypersensitize cancer cells to alkylating agents both in vitro and in vivo. Together, the crosstalk between glutamine metabolism and the DNA repair pathway identified in this study highlights a potential role of metabolic stress in genomic instability and therapeutic response in cancer.

Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes

PubMed Central

Tran, Thai Q.; Ishak Gabra, Mari B.; Lowman, Xazmin H.; Yang, Ying; Reid, Michael A.; Pan, Min; O’Connor, Timothy R.

2017-01-01

Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death. In addition, low glutamine-induced DNA damage is abolished in ALKBH deficient cells. Importantly, we show that glutaminase inhibitors, 6-Diazo-5-oxo-L-norleucine (DON) or CB-839, hypersensitize cancer cells to alkylating agents both in vitro and in vivo. Together, the crosstalk between glutamine metabolism and the DNA repair pathway identified in this study highlights a potential role of metabolic stress in genomic instability and therapeutic response in cancer. PMID:29107960

Generation of an endogenous DNA-methylating agent by nitrosation in Escherichia coli.

PubMed Central

Taverna, P; Sedgwick, B

1996-01-01

Escherichia coli ada ogt mutants, which are totally deficient in O6-methylguanine-DNA methyltransferases, have an increased spontaneous mutation rate. This phenotype is particularly evident in starving cells and suggests the generation of an endogenous DNA alkylating agent under this growth condition. We have found that in wild-type cells, the level of the inducible Ada protein is 20-fold higher in stationary-phase and starving cells than in rapidly growing cells, thus enhancing the defense of these cells against DNA damage. The increased level of Ada in stationary cells is dependent on RpoS, a stationary-phase-specific sigma subunit of RNA polymerase. We have also identified a potential source of the mutagenic agent. Nitrosation of amides and related compounds can generate directly acting methylating agents and can be catalyzed by bacteria] enzymes. E. coli moa mutants, which are defective in the synthesis of a molybdopterin cofactor required by several reductases, are deficient in nitrosation activity. It is reported here that a moa mutant shows reduced generation of a mutagenic methylating agent from methylamine (or methylurea) and nitrite added to agar plates. Moreover, a moa mutation eliminates much of the spontaneous mutagenesis in ada ogt mutants. These observations indicate that the major endogenous mutagen is not S-adenosylmethionine but arises by bacterially catalyzed nitrosation. PMID:8752326

Focus on Fotemustine.

PubMed

De Rossi, A; Rossi, L; Laudisi, A; Sini, V; Toppo, L; Marchesi, F; Tortorelli, G; Leti, M; Turriziani, M; Aquino, A; Bonmassar, E; De Vecchis, L; Torino, F

2006-12-01

Fotemustine is a cytotoxic alkylating agent, belonging to the group of nitrosourea family. Its mechanism of action is similar to that of other nitrosoureas, characterized by a mono-functional/bi-functional alkylating activity. Worth of consideration is the finding that the presence of high levels of the DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT) in cancer cells confers drug resistance. In different clinical trials Fotemustine showed a remarkable antitumor activity as single agent, and in association with other antineoplastic compounds or treatment modalities. Moreover, its toxicity is generally considered acceptable. The drug has been employed in the treatment of metastatic melanoma, and, on the basis of its pharmacokinetic properties, in brain tumors, either primitive or metastatic. Moreover, Fotemustine shows pharmacodynamic properties similar to those of mono-functional alkylating compounds (e.g. DNA methylating drugs, such as Temozolomide), that have been recently considered for the management of acute refractory leukaemia. Therefore, it is reasonable to assume that this agent could be a good candidate to play a potential role in haematological malignancies.

O-Alkylated heavy atom carbohydrate probes for protein X-ray crystallography: Studies towards the synthesis of methyl 2-O-methyl-L-selenofucopyranoside.

PubMed

Sommer, Roman; Hauck, Dirk; Varrot, Annabelle; Imberty, Anne; Künzler, Markus; Titz, Alexander

2016-01-01

Selenoglycosides are used as reactive glycosyl donors in the syntheses of oligosaccharides. In addition, such heavy atom analogs of natural glycosides are useful tools for structure determination of their lectin receptors using X-ray crystallography. Some lectins, e.g., members of the tectonin family, only bind to carbohydrate epitopes with O-alkylated ring hydroxy groups. In this context, we report the first synthesis of an O -methylated selenoglycoside, specifically methyl 2- O -methyl-L-selenofucopyranoside, a ligand of the lectin tectonin-2 from the mushroom Laccaria bicolor . The synthetic route required a strategic revision and further optimization due to the intrinsic lability of alkyl selenoglycosides, in particular for the labile fucose. Here, we describe a successful synthetic access to methyl 2- O -methyl-L-selenofucopyranoside in 9 linear steps and 26% overall yield starting from allyl L-fucopyranoside.

Poly(1-Vinyl-1,2,4-triazolium) Poly(Ionic Liquid)s: Synthesis and the Unique Behavior in Loading Metal Ions.

PubMed

Zhang, Weiyi; Yuan, Jiayin

2016-07-01

Herein, the synthesis of a series of poly(4-alkyl-1-vinyl-1,2,4-triazolium) poly(ionic liquid)s is reported either via straightforward free radical polymerization of their corresponding ionic liquid monomers or via anion metathesis of the polymer precursors bearing halide as counter anion. The ionic liquid monomers are first prepared via N-alkylation reaction of commercially available 1-vinyl-1,2,4-triazole with alkyl iodides, followed by anion metathesis with targeted fluorinated anions. The thermal properties and solubilities of these poly(ionic liquid)s have been systematically investigated. Interestingly, it is found that the poly(4-ethyl-1-vinyl-1,2,4-triazolium) poly(ionic liquid) exhibited an improved loading capacity of transition metal ions in comparison with its imidazolium counterpart. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and testing of hypergolic ionic liquids for chemical propulsion

NASA Astrophysics Data System (ADS)

Stovbun, S. V.; Shchegolikhin, A. N.; Usachev, S. V.; Khomik, S. V.; Medvedev, S. P.

2017-06-01

Synthesis of new highly energetic ionic liquids (ILs) is described, and their hypergolic ignition properties are tested. The synthesized ILs combine the advantages of conventional rocket propellants with the energy characteristics of acetylene derivatives. To this end, N-alkylated imidazoles (alkyl = ethyl, butyl) have been synthesized and alkylated with propargyl bromide. The desired ionic liquids have been produced by metathesis using Ag dicyanamide. Modified hypergolic drop tests with white fuming nitric acid have been performed for N-ethyl (IL-1) and N-butyl propargylimidazolium (IL-2) ionic liquids. In the modified drop tests, high-speed shadowgraph imaging is used to visualize the process, and the temperature rise due to ignition is monitored with a two-color photodetector. It is shown that the ignition delay is shorter for IL-1 as compared to IL-2. The ignition of IL-1 occurs in two stages, whereas the combustion of IL-2 proceeds smoothly without secondary flashes.

Synthesis and antifungal activities of 3-alkyl substituted thieno[2,3-d]pyrimidinones

NASA Astrophysics Data System (ADS)

Wang, H. M.; Deng, S. H.; Zheng, A. H.; Zhang, Q. Y.; Chen, X. B.; Zeng, X. H.; Hu, Y. G.

2016-08-01

The 3-aryl substituted thieno[2,3-d]pyrimidinones 3 by sequential reaction of iminophosphorane 1, aromatic isocyanates and various nucleophiles (HY), found some compounds showed good antitumor and antibacterial activities. Meanwhile, aliphatic isocyanates were applied in the reaction to prepare 3-alkyl substituted thieno[2,3- d]pyrimidinones, but there are no reports of their antifungal activities. As a continuation of our research for new biologically active heterocycles, we herein wish to report a facile synthesis and antifungal activities of 3-alkyl substituted thieno[2,3-d]pyrimidinones 6 via easily accessible iminophosphorane 1. The growth inhibitory effect of one concentration (50mg/L) of compounds 6 against five fungus(Fusarium oxysporium, Rhizoctonia solani, Colletotrichum gossypii, Gibberella zeae and Dothiorella gregaria) in vitro was tested by the method of toxic medium. Compound 6d showed the best inhibition rate against Gibberella zeae with 85.68%.

Dimers of coumarin-1,2,3-triazole hybrids bearing alkyl spacer: Design, microwave-assisted synthesis, molecular docking and evaluation as antimycobacterial and antimicrobial agents

NASA Astrophysics Data System (ADS)

Ashok, Dongamanti; Gundu, Srinivas; Aamate, Vikas Kumar; Devulapally, Mohan Gandhi; Bathini, Raju; Manga, Vijjulatha

2018-04-01

The present study demonstrated the synthesis of new series of coumarin-1,2,3-triazole hybrids under microwave irradiation method. Several dimers of coumarin based 1,2,3-triazole derivatives were synthesized and their antimycobacterial and antimicrobial activities were investigated. The antimycobacterial activity screening results revealed that compounds 6i and 6j were the most active against Mycobacterium tuberculosis H37Rv strain. The active compounds were further evaluated for cytotoxicity with HEK cell lines and exhibited less % of inhibition. The same synthetic hybrids were evaluated for their antimicrobial activity against various bacterial strains and fungal strains and compounds 6e, 6h, 6i and 6j were found to be the most promising antimicrobial potent molecules. Furthermore, the active compounds against Mycobacterium tuberculosis were evaluated for their molecular docking studies against pantothenate synthetase (PS) enzyme of MTB and the docking results are in well agreement with the antitubercular evaluation results.

Synthesis and evaluation of anticonvulsant activities of some new arylhexahydropyrimidine-2,4-diones.

PubMed

Caliş, U; Köksal, M

2001-01-01

In this study, some new 3-alkyl-6-arylhexahydropyrimidine-2,4-dione derivatives were synthesized as anticonvulsant agents. 6-Arylhexahydropyrimidine-2,4-diones which were used as starting materials in the synthesis of the compounds were prepared in acidic media by the cyclization of potassium cyanate and the appropriate ureido acids that were gained by the reaction of beta-aminoacids, malonic acid and ammonium acetate. The structures of the synthesized compounds were confirmed by UV, IR, 1H-NMR and elementary analysis. Their anticonvulsant activities were determined by maximal electroshock (MES), subcutaneous metrazol (scMet) and rotorod toxicity tests for neurological deficits. According to the activity studies, 3-arylalkyl-6-(p-chlorophenyl) derivatives were found to be protective against scMet, whereas 6-phenyl derivatives were not. 6-Phenyl-3-(2-morpholinoethyl)hexahydropyrimidine-2,4-dione was the only compound determined to be active against MES at 300 mg/kg dose at half an hour.

Induction by alkylating agents of sister chromatid exchanges and chromatid breaks in Fanconi's anemia.

PubMed

Latt, S A; Stetten, G; Juergens, L A; Buchanan, G R; Gerald, P S

1975-10-01

Sister chromatid exchanges, which may reflect chromosome repair in response to certain types of DNA damage, provide a means of investigating the increased chromosome fragility characteristic of Fanconi's anemia. By a recently developed technique using 33258 Hoechst and 5-bromodeoxyuridine, it was observed that the baseline frequency of sister chromatid exchanges in phytohemagglutinin-stimulated lymphocytes from four males with Fanconi's anemia differed little from that of normal lymphocytes. However, addition of the bifunctional alkylating agent mitomycin C (0.01 or 0.03 mug/ml) to the Fanconi's anemia cells during culture induces less than half of the increase in exchanges found in identically treated normal lymphocytes. This reduced increment in exchanges in accompanied by a partial suppression of mitosis and a marked increase in chromatid breaks and rearrangements. Many of these events occur at sites of incomplete chromatid interchange. The increase in sister chromatid exchanges induced in Fanconi's anemia lymphocytes by the monofunctional alkylating agent ethylmethane sulfonate (0.25 mg/ml) was slightly less than that in normal cells. Lymphocytes from two sets of parents of the patients with Fanconi's anemia exhibited a normal response to alkylating agents, while dermal fibroblasts from two different patients with Fanconi's anemia reacted to mitomycin C with an increase in chromatid breaks, but a nearly normal increment of sister chromatid exchanges. The results suggest that chromosomal breaks and rearrangements in Fanconi's anemia lymphocytes may result from a defect in a form of repair of DNA damage.

Synthesis of an acid addition salt of delta-aminolevulinic acid from 5-bromo levulinic acid esters

DOEpatents

Moens, L.

1999-05-25

A process is disclosed for preparing an acid addition salt of delta-aminolevulinic acid comprising. The process involves dissolving a lower alkyl 5-bromolevulinate and an alkali metal diformylamide in an organic solvent selected from the group consisting of acetonitrile, methanol, tetrahydrofuran, 2-methyltetrahydrofuran and methylformate or mixtures to form a suspension of an alkyl 5-(N,N-diformylamino) levulinate ester; and hydrolyzing the alkyl 5-(N,N-diformylamino) levulinate with an inorganic acid to form an acid addition salt of delta-amino levulinic acid.

Synthesis of an acid addition salt of delta-aminolevulinic acid from 5-bromo levulinic acid esters

DOEpatents

Moens, Luc

1999-01-01

A process of preparing an acid addition salt of delta-aminolevulinic acid comprising: dissolving a lower alkyl 5-bromolevulinate and an alkali metal diformylamide in an organic solvent selected from the group consisting of acetonitrile, methanol, tetrahydrofuran, 2-methyltetrahydrofuran and methylformate or mixtures thereof to form a suspension of an alkyl 5-(N,N-diformylamino) levulinate ester; and hydrolyzing said alkyl 5-(N,N-diformylamino) levulinate with an inorganic acid to form an acid addition salt of delta-amino levulinic acid.

Speciation of Reactive Sulfur Species and their Reactions with Alkylating Agents: Do we have any clue about what is present inside the cell?

PubMed

Bogdándi, Virág; Ida, Tomoaki; Sutton, Thomas R; Bianco, Christopher; Ditrói, Tamás; Koster, Grielof; Henthorn, Hillary A; Minnion, Magda; Toscano, John P; van der Vliet, Albert; Pluth, Michael D; Feelisch, Martin; Fukuto, Jon M; Akaike, Takaaki; Nagy, Péter

2018-06-17

Posttranslational modifications of cysteine (Cys) residues represent a major aspect of redox biology, and their reliable detection is key in providing mechanistic insights. The metastable character of these modifications and cell lysis-induced artifactual oxidation render current state-of-the-art protocols to rely on alkylation-based stabilization of labile Cys derivatives before cell/tissue rupture. An untested assumption in these procedures is that for all Cys derivatives alkylation rates are faster than their dynamic interchange. However, when the interconversion of Cys derivatives is not rate-limiting, then electrophilic labeling is under Curtin-Hammett control and hence the final alkylated mixture may not represent the speciation that prevailed before alkylation. We here present evidence that in the majority of cases, the speciation of alkylated polysulfide/thiol derivatives indeed depends on the experimental conditions. Our results reveal that alkylation perturbs sulfur speciation in both a concentration- and time-dependent manner, and that strong alkylating agents can cleave polysulfur chains. Moreover, we show that labeling of sulfenic acids with dimedone also affects Cys speciation, suggesting that part of the endogenous pool of products previously believed to represent sulfenic acid species may in fact represent polysulfides. These observations were obtained using buffered aqueous solutions of inorganic-, organic-, cysteine-, glutathione- and GAPDH-polysulfide species. Additional experiments in human plasma and serum revealed that monobromobimane can extract sulfide from the endogenous sulfur pool by shifting speciation equilibria, suggesting caution should be exercised when interpreting experimental results using this tool. We highlight methodological caveats potentially arising from these pitfalls and conclude that current derivatization strategies often fail to adequately capture physiologic speciation of sulfur species. This article is protected by copyright. All rights reserved.

Distinct pathways for repairing mutagenic lesions induced by methylating and ethylating agents

PubMed Central

Negishi, Tomoe

2013-01-01

DNA alkylation damage can be repaired by nucleotide excision repair (NER), base excision repair (BER) or by direct removal of alkyl groups from modified bases by O 6-alkylguanine DNA alkyltransferase (AGT; E.C. 2.1.1.63). DNA mismatch repair (MMR) is also likely involved in this repair. We have investigated alkylation-induced mutagenesis in a series of NER- or AGT-deficient Escherichia coli strains, alone or in combination with defects in the MutS, MutL or MutH components of MMR. All strains used contained the Fʹprolac from strain CC102 (FʹCC102) episome capable of detecting specifically lac GC to AT reverse mutations resulting from O 6-alkylguanine. The results showed the repair of O 6-methylguanine to be performed by AGT ≫ MMR > NER in order of importance, whereas the repair of O 6-ethylguanine followed the order NER > AGT > MMR. Studies with double mutants showed that in the absence of AGT or NER repair pathways, the lack of MutS protein generally increased mutant frequencies for both methylating and ethylating agents, suggesting a repair or mutation avoidance role for this protein. However, lack of MutL or MutH protein did not increase alkylation-induced mutagenesis under these conditions and, in fact, reduced mutagenesis by the N-alkyl-N-nitrosoureas MNU and ENU. The combined results suggest that little or no alkylation damage is actually corrected by the mutHLS MMR system; instead, an as yet unspecified interaction of MutS protein with alkylated DNA may promote the involvement of a repair system other than MMR to avoid a mutagenic outcome. Furthermore, both mutagenic and antimutagenic effects of MMR were detected, revealing a dual function of the MMR system in alkylation-exposed cells. PMID:23446177

Bioinspired Supramolecular Enzymatic Systems

DTIC Science & Technology

2012-09-28

bearing alkyl chains of various lengths (methyl, ethyl, propyl , butyl, Figure 34. Synthesis of a catalytically active RPM for the hydrolysis...signal or product production. The multidisciplinary work accomplished integrated efforts and expertise in organic and inorganic chemical synthesis ...MURI grant period, Mirkin, Hupp, Stoddart, Ratner, and Nguyen made significant headway into the synthesis and study of supramolecular allosteric

The synthesis and biological evaluation of new DNA-directed alkylating agents, phenyl N-mustard-4-anilinoquinoline conjugates containing a urea linker.

PubMed

Marvania, Bhavin; Kakadiya, Rajesh; Christian, Wilson; Chen, Tai-Lin; Wu, Ming-Hsi; Suman, Sharda; Tala, Kiran; Lee, Te-Chang; Shah, Anamik; Su, Tsann-Long

2014-08-18

We synthesized a series of phenyl N-mustard-4-anilinoquinoline conjugates to study their antitumorigenic effects. These agents were prepared by the condensation of 4-[N,N-bis(2-chloroethyl)amino]phenyl isocyanate with 6-amino-4-methylamino or 4-anilinoquinolines. The structure-activity relationship (SAR) studies revealed that the C2-methylquinoline derivatives (18a-o) were generally more cytotoxic than the C2-phenylquinoline conjugates (23a-d) in inhibiting the cell growth of various human tumor cell lines in vitro. However, the methylamino or aniline substituents at C4 of quinoline did not influence the cytotoxic effects. The title conjugates were capable of inducing DNA cross-linking and promoting cell-cycle arrest at the G2/M phase. This study demonstrates that phenyl N-mustard-4-anilinoquinoline conjugates are generally more potent than phenyl N-mustard-4-anilinoquinazoline conjugates against the cell growth of various tumor cell-lines. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Biomolecule conjugation strategy using novel water-soluble phosphine-based chelating agents

DOEpatents

Katti, Kattesh V.; Gali, Hariprasad; Volkert, Wynn A.

2004-08-24

This invention describes a novel strategy to produce phosphine-functionalized biomolecules (e.g. peptides or proteins) for potential use in the design and development of site-specific radiopharmaceuticals for diagnosis or therapy of specific cancers. Hydrophilic alkyl phosphines, in general, tend to be oxidatively unstable. Therefore, incorporation of such phosphine functionalities on peptide (and other biomolecule) backbones, without oxidizing the P.sup.III centers, is difficult. In this context this discovery reports on a new technology by which phosphines, in the form of bifunctional chelating agents, can be directly incorporated on biomolecular backbones using manual synthetic or solid phase peptide synthesis methodologies. The superior ligating abilities of phosphine ligands, with various diagnostically (e.g. TC-99m) or therapeutically (e.g. Re186/188, Rh-105, Au-199) useful radiometals, coupled with the findings that the resulting complexes demonstrate high in vivo stability makes this approach useful in the development of radiolabeled biomolecules for applications in the design of tumor-specific radiopharmaceuticals.

A "by-productless" cellulose foaming agent for use in imidazolium ionic liquids.

PubMed

Scott, Janet L; Unali, Gianfranco; Perosa, Alvise

2011-03-14

Cellulose foams, or sponges, are produced from solutions in ionic liquids by the aqueous acid mediated decomposition of 1-alkyl-3-methylimidazolium-2-carboxylates, where the alkyl group and acid may be selected such that the by-product is the ionic liquid solvent: a by-productless foaming.

Phase II study of Cloretazine for the treatment of adults with recurrent glioblastoma multiforme1

PubMed Central

Badruddoja, Michael A.; Penne, Kara; Desjardins, Annick; Reardon, David A.; Rich, Jeremy N.; Quinn, Jennifer A.; Sathornsumetee, Sith; Friedman, Allan H.; Bigner, Darell D.; Herndon, James E.; Cahill, Ann; Friedman, Henry S.; Vredenburgh, James J.

2007-01-01

Cloretazine (VNP40101M) is a newly synthesized alkylating agent belonging to a novel class of alkylating agents called 1,2-bis(sulfonyl)hydrazines. Agents that belong to this class do not produce vinylating and chloroethylating species, and hence this class of alkylating agents is thought to have minimal systemic toxicity. Cloretazine produces two short-lived active species: 1,2-bis(methylsulfonyl)-1-(2-chloroethyl) hydrazine (a chloroethylating species) and a thiophilic carbamoylating methylisocyanate species. The chloroethylating species preferentially produces lesions at the O6 position of guanine. The methylisocyanate species may inhibit O6-alkylguanine-DNA alkyltransferase, an important mechanism of resistance against alkylating agents. The purpose of this study was to determine the efficacy and tolerability of Cloretazine in patients with recurrent glioblastoma multiforme. The basis for the determination of efficacy was the proportion of patients alive without evidence of disease progression six months after initiation of treatment. Patients with recurrent glioblastoma multiforme received Cloretazine (300 mg/m2) intravenously every six weeks. Radiographic response, survival data, and toxicity were assessed. Thirty-two patients were enrolled. Median age was 56 years; 24 patients (75%) were men. At six months, two patients were alive and progression free, so the six-month progression-free survival (PFS) was 6%. The median PFS was 6.3 weeks. There were no objective radiographic responses. Twelve patients had stable disease for at least one cycle, but only two patients received more than three cycles. Nine patients experienced grade 4 thrombocytopenia and three patients experienced grade 4 neutropenia. Cloretazine administered every six weeks was relatively well tolerated, although this schedule has insignificant activity for patients with recurrent glioblastoma multiforme PMID:17108065

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

PubMed Central

Klapacz, Joanna; Pottenger, Lynn H.; Engelward, Bevin P.; Heinen, Christopher D.; Johnson, George E.; Clewell, Rebecca A.; Carmichael, Paul L.; Adeleye, Yeyejide; Andersen, Melvin E.

2016-01-01

From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations. PMID:27036068

Genetic abnormalities in leukemia secondary to treatment in patients with Hodgkin's disease.

PubMed

Salas, Consuelo; Pérez-Vera, Patricia; Frías, Sara

2011-01-01

Hodgkin's disease has been treated mainly with two chemotherapy schedules, MOPP (nitrogen mustard, Oncovin, procarbazine and prednisone), which includes alkylating agents, and ABVD (adriamycin, bleomycin, vinblastine and dacarbazine), which includes topoisomerase II inhibitors, either with or without radiation therapy. Due to the types of agents used, patients with Hodgkin's disease often develop secondary leukemias. The alkylating agents included in the MOPP scheme were the first drugs associated with the development of therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML); both entities are the result of the clonal selection of cells with accumulated genomic lesions induced by antineoplastic therapy. In patients who developed t-MDS and t-AML, eight alternative routes with specific cytogenetic and molecular changes have been identified, and the routes are related to the type of therapy, alkylating agents or DNA topoisomerase II inhibitors. At the cytogenetic level, patients treated with alkylating agents show deletion 5q/monosomy 5 and deletion 7q/monosomy 7; in contrast, those who were treated with topoisomerase II inhibitors show 11q23 translocations involving the MLL gene. At the molecular level, there are two types of mutations: Class I, which alter the RAS-BRAF signal transduction pathways and increase cell proliferation; Class II, which disrupt genes that encode transcription factors and NPM1 that are involved in cell differentiation, and the inactivation of p53 tumor suppressor gene. Knowledge of the genetic alterations in these conditions is important for the classification, treatment and prognosis of patients as well as essential for increasing the knowledge of the biology of these diseases, which leads to identifying potential therapeutic targets.

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents.

PubMed

Klapacz, Joanna; Pottenger, Lynn H; Engelward, Bevin P; Heinen, Christopher D; Johnson, George E; Clewell, Rebecca A; Carmichael, Paul L; Adeleye, Yeyejide; Andersen, Melvin E

2016-01-01

From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance of a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations. Copyright © 2015 Elsevier B.V. All rights reserved.

Activation of the chemosensing transient receptor potential channel A1 (TRPA1) by alkylating agents.

PubMed

Stenger, Bernhard; Zehfuss, Franziska; Mückter, Harald; Schmidt, Annette; Balszuweit, Frank; Schäfer, Eva; Büch, Thomas; Gudermann, Thomas; Thiermann, Horst; Steinritz, Dirk

2015-09-01

The transient receptor potential ankyrin 1 (TRPA1) cation channel is expressed in different tissues including skin, lung and neuronal tissue. Recent reports identified TRPA1 as a sensor for noxious substances, implicating a functional role in the molecular toxicology. TRPA1 is activated by various potentially harmful electrophilic substances. The chemical warfare agent sulfur mustard (SM) is a highly reactive alkylating agent that binds to numerous biological targets. Although SM is known for almost 200 years, detailed knowledge about the pathophysiology resulting from exposure is lacking. A specific therapy is not available. In this study, we investigated whether the alkylating agent 2-chloroethyl-ethylsulfide (CEES, a model substance for SM-promoted effects) and SM are able to activate TRPA1 channels. CEES induced a marked increase in the intracellular calcium concentration ([Ca(2+)]i) in TRPA1-expressing but not in TRPA1-negative cells. The TRP-channel blocker AP18 diminished the CEES-induced calcium influx. HEK293 cells permanently expressing TRPA1 were more sensitive toward cytotoxic effects of CEES compared with wild-type cells. At low CEES concentrations, CEES-induced cytotoxicity was prevented by AP18. Proof-of-concept experiments using SM resulted in a pronounced increase in [Ca(2+)]i in HEK293-A1-E cells. Human A549 lung epithelial cells, which express TRPA1 endogenously, reacted with a transient calcium influx in response to CEES exposure. The CEES-dependent calcium response was diminished by AP18. In summary, our results demonstrate that alkylating agents are able to activate TRPA1. Inhibition of TRPA1 counteracted cellular toxicity and could thus represent a feasible approach to mitigate SM-induced cell damage.

Hypoxia-Activated Alkylating Agents in BRCA1-Mutant Ovarian Serous Carcinoma.

PubMed

Conroy, Michael; Borad, Mitesh J; Bryce, Alan H

2017-07-26

Breast cancer 1 antigen (BRCA 1) and breast cancer 2 antigen (BRCA2) genes play a significant role in deoxyribonucleic acid (DNA) repair by means of interstrand crosslink repair, and deleterious germline mutations of these are responsible for most hereditary breast and ovarian cancers. Therapeutic strategies which specifically target interstrand crosslink repair can therefore be helpful in patients with harmful mutations. We describe two patients with advanced ovarian cancer and deleterious BRCA1 mutations who were treated with TH-302, a hypoxia-activated alkylating agent.

[The biochemical mechanisms of the action of N-alkyl-N-nitrosoureas. The possible reasons for drug resistance to these compounds].

PubMed

Syrkin, A B; Gorbacheva, L B

1996-01-01

N-alkyl-N-nitrosoureas exhibit a wide spectrum of antitumor activity. They react as alkylating agents at nucleophilic sites in purine and pyrimidine moieties of DNA. The predominant site of this alkylation is N7 of guanine, which is followed by the site N3 of adenine and 06 of guanine. The formation and persistence of 0(6)-alkylguanine (0(6)-AG) may be of primary importance in cytotoxicity of the nitrosoureas. 0(6)-AG adducts of DNA of the tumor cells are repaired by protein 0(6)-alkylguanine-DNA transferase (0(6)-AGT) which transfers the alkyl group to internal cysteine residue being the acceptor protein for the alkyl group in an irreversible transfer reaction. 0(6)-AGT can protect the tumor cells against 0(6)-AG adducts by the way of inhibiting the formation of the DNA interstrand cross-links 0(6)-AGT plays an important role in the drug resistance because it repairs the DNA alkyl adducts at the 0(6) position of guanine. The 0(6)-AGT activity inversely correlates with the cytotoxic effect of the nitrosoureas. The agents like 0(6)-methylguanosine, 0(6)-methyl-2'-deoxyguanosine, and some 0(6)-benzylated guanine derivatives are effective inactivators of 0(6)-AGT, and thus can be used to enhance the cytotoxicity of N-nitrosoureas. The activation of 0(6)-AGT and other repairing enzymes such as alpha and beta DNA-polymerases as well as an increase in the level of reduced glutathione may be used in developing the resistance to the nitrosoureas.

Synthesis of 3-alkyl naphthalenes as novel estrogen receptor ligands

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fang, Jing; Akwabi-Ameyaw, Adwoa; Britton, Jonathan E.

2009-06-24

A series of estrogen receptor ligands based on a 3-alkyl naphthalene scaffold was synthesized using an intramolecular enolate-alkyne cycloaromatization as the key step. Several of these compounds bearing a C6-OH group were shown to be high affinity ligands. All compounds had similar ER{alpha} and ER{beta} binding affinity ranging from micromolar to low nanomolar.

Molecular modeling studies and synthesis of novel quinoxaline derivatives with potential anticancer activity as inhibitors of c-Met kinase.

PubMed

Abbas, Hebat-Allah S; Al-Marhabi, Aisha R; Eissa, Sally I; Ammar, Yousry A

2015-10-15

In an effort to develop potent anti-cancer agents, we have synthesized some substituted quinoxaline derivatives. Reaction of 6-bromo-3-methylquinoxalin-2(1H)-one 1 with aromatic aldehydes furnished the styryl derivatives 2a-e. Alkylation of 1 with ethyl chloroacetate produced the N-alkyl derivatives 3. Hydrazinolysis of the ester derivative 3 with hydrazine hydrate afforded the hydrazide derivative 4. In addition, chlorination of 1 with phosphorus oxychloride afforded the 2-chloro derivative 5 which was used as a key intermediate for the synthesis of substituted quinoxaline derivatives 6-8, N-pyrazole derivative 9, tetrazolo[1,5-a]quinoxaline derivative 10 and Schiff base derivatives 13, 15 via reaction with several nucleophiles reagents. Docking methodologies were used to predict their binding conformation to explain the differences of their tested biological activities. All the tested compounds were screened in vitro for their cytotoxic effect on three tumor cell lines. Some new quinoxaline derivatives were studied as inhibitors of c-Met kinase, a receptor associated with high tumor grade and poor prognosis in a number of human cancers. Compounds 2e, 4, 7a, 12a, 12b and 13 showed the highest binding affinity with CDOCKER energy score, while showed the lowest IC50 values against three types of cancer cell lines. It is worth to mention that, compounds 2e, 7a, 12b and 13 showed comparable inhibition activity to the reference drug, while compounds 4 and 12a showed a more potent inhibition activity than Doxorubicin. Copyright © 2015 Elsevier Ltd. All rights reserved.

Impact of gender on efficacy and acute toxicity of alkylating agent -based chemotherapy in Ewing sarcoma: secondary analysis of the Euro-Ewing99-R1 trial.

PubMed

van den Berg, Henk; Paulussen, Michael; Le Teuff, Gwénaël; Judson, Ian; Gelderblom, Hans; Dirksen, Uta; Brennan, Bernadette; Whelan, Jeremy; Ladenstein, Ruth Lydia; Marec-Berard, Perrine; Kruseova, Jarmila; Hjorth, Lars; Kühne, Thomas; Brichard, Benedicte; Wheatley, Keith; Craft, Alan; Juergens, Heribert; Gaspar, Nathalie; Le Deley, Marie-Cécile

2015-11-01

Based on the randomised Euro-EWING99-R1 trial, vincristine, adriamycin, cyclophosphamide (VAC) may be able to replace vincristine, adriamycin, ifosfamide (VAI) in the treatment of standard-risk Ewing sarcoma. However some heterogeneity of treatment effect by gender was observed. The current exploratory study aimed at investigating the influence of gender on treatment efficacy and acute toxicity. Impact of gender on event-free survival (EFS), acute toxicity by course, switches between treatment arms and cumulative dose of alkylating agents was evaluated in multivariable models adjusted for age including terms to test for heterogeneity of treatment effect by gender. The analysis of the EFS was performed on the intention-to-treat population. EFS did not significantly differ between the 509 males and 347 females (p=0.33), but an interaction in terms of efficacy was suspected between treatment and gender (p=0.058): VAC was associated with poorer EFS than VAI in males, hazard ratio (HR) (VAC/VAI)=1.37 [95% confidence interval (CI), 0.98-1.90], contrasting with HR=0.81 [95%CI, 0.53-1.24] in females. Severe toxicity was more frequent in females, whatever the toxicity type. Thirty patients switched from VAI to VAC (9/251 males, 4%, and 21/174 females, 12%) mostly due to renal toxicity, and three from VAC to VAI (2/258 males, 0.8%, and 1/173 females, 0.6%). A reduction of alkylating agent cumulative dose >20% was more frequent in females (15% versus 9%, p=0.005), with no major difference between VAC and VAI (10% versus 13%, p=0.15). Differences of acute toxicity rate and cumulative doses of alkylating agents could not explain the marginal interaction observed in the Euro-EWING99-R1 trial data. Effects of gender-dependent polymorphism/activity of metabolic enzymes (e.g. known for CYP2B6) of ifosfamide versus cyclophosphamide should be explored. External data are required to further evaluate whether there is heterogeneity of alkylating agent effect by gender. NCT00987636 and EudraCT 2008-003658-13. Copyright © 2015 Elsevier Ltd. All rights reserved.

Selective sp3 C-H alkylation via polarity-match-based cross-coupling.

PubMed

Le, Chip; Liang, Yufan; Evans, Ryan W; Li, Ximing; MacMillan, David W C

2017-07-06

The functionalization of carbon-hydrogen (C-H) bonds is one of the most attractive strategies for molecular construction in organic chemistry. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in organic molecules and its availability for functionalization at almost any stage in a synthetic sequence. Although many C-H functionalization reactions involve C(sp 3 )-C(sp 2 ) coupling, there is a growing demand for C-H alkylation reactions, wherein sp 3 C-H bonds are replaced with sp 3 C-alkyl groups. Here we describe a polarity-match-based selective sp 3 C-H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodology simultaneously uses three catalytic cycles to achieve hydridic C-H bond abstraction (enabled by polarity matching), alkyl halide oxidative addition, and reductive elimination to enable alkyl-alkyl fragment coupling. The sp 3 C-H alkylation is highly selective for the α-C-H of amines, ethers and sulphides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry.

Cobalt-catalyzed cross-coupling reactions of alkyl halides with allylic and benzylic Grignard reagents and their application to tandem radical cyclization/cross-coupling reactions.

PubMed

Ohmiya, Hirohisa; Tsuji, Takashi; Yorimitsu, Hideki; Oshima, Koichiro

2004-11-05

Details of cobalt-catalyzed cross-coupling reactions of alkyl halides with allylic Grignard reagents are disclosed. A combination of cobalt(II) chloride and 1,2-bis(diphenylphosphino)ethane (DPPE) or 1,3-bis(diphenylphosphino)propane (DPPP) is suitable as a precatalyst and allows secondary and tertiary alkyl halides--as well as primary ones--to be employed as coupling partners for allyl Grignard reagents. The reaction offers a facile synthesis of quaternary carbon centers, which has practically never been possible with palladium, nickel, and copper catalysts. Benzyl, methallyl, and crotyl Grignard reagents can all couple with alkyl halides. The benzylation definitely requires DPPE or DPPP as a ligand. The reaction mechanism should include the generation of an alkyl radical from the parent alkyl halide. The mechanism can be interpreted in terms of a tandem radical cyclization/cross-coupling reaction. In addition, serendipitous tandem radical cyclization/cyclopropanation/carbonyl allylation of 5-alkoxy-6-halo-4-oxa-1-hexene derivatives is also described. The intermediacy of a carbon-centered radical results in the loss of the original stereochemistry of the parent alkyl halides, creating the potential for asymmetric cross-coupling of racemic alkyl halides.

Selective sp3 C-H alkylation via polarity-match-based cross-coupling

NASA Astrophysics Data System (ADS)

Le, Chip; Liang, Yufan; Evans, Ryan W.; Li, Ximing; MacMillan, David W. C.

2017-07-01

The functionalization of carbon-hydrogen (C-H) bonds is one of the most attractive strategies for molecular construction in organic chemistry. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in organic molecules and its availability for functionalization at almost any stage in a synthetic sequence. Although many C-H functionalization reactions involve C(sp3)-C(sp2) coupling, there is a growing demand for C-H alkylation reactions, wherein sp3 C-H bonds are replaced with sp3 C-alkyl groups. Here we describe a polarity-match-based selective sp3 C-H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodology simultaneously uses three catalytic cycles to achieve hydridic C-H bond abstraction (enabled by polarity matching), alkyl halide oxidative addition, and reductive elimination to enable alkyl-alkyl fragment coupling. The sp3 C-H alkylation is highly selective for the α-C-H of amines, ethers and sulphides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry.

Enantioconvergent Cross-Couplings of Racemic Alkylmetal Reagents with Unactivated Secondary Alkyl Electrophiles: Catalytic Asymmetric Negishi α-Alkylations of N-Boc-pyrrolidine

PubMed Central

Cordier, Christopher J.; Lundgren, Rylan J.; Fu, Gregory C.

2013-01-01

Although enantioconvergent alkyl-alkyl couplings of racemic electrophiles have been developed, there have been no reports of the corresponding reactions of racemic nucleophiles. Herein, we describe Negishi cross-couplings of racemic α-zincated N-Boc-pyrrolidine with unactivated secondary halides, thus providing a one-pot, catalytic asymmetric method for the synthesis of a range of 2-alkylpyrrolidines (an important family of target molecules) from N-Boc-pyrrolidine, a commercially available precursor. Preliminary mechanistic studies indicate that two of the most straightforward mechanisms for enantioconvergence (a dynamic kinetic resolution of the organometallic coupling partner and a simple β-hydride elimination/β-migratory insertion pathway) are unlikely to be operative. PMID:23869442

Effect of polyester blends in hydroentangled raw and bleached cotton nonwoven fabrics on the adsorption of alkyl-dimethyl-benzyl-ammonium chloride

USDA-ARS?s Scientific Manuscript database

The adsorption kinetics and isotherms of alkyl-dimethyl-benzyl-ammonium chloride (ADBAC), a cationic surfactant commonly employed as an antimicrobial agent, on hydroentangled nonwoven fabrics (applicable for wipes) including raw cotton, bleached cotton, and their blends with polyester (PES) were stu...

Photo-triggered fluorescent theranostic prodrugs as DNA alkylating agents for mechlorethamine release and spatiotemporal monitoring.

PubMed

Cao, Yanting; Pan, Rong; Xuan, Weimin; Wei, Yongyi; Liu, Kejian; Zhou, Jiahong; Wang, Wei

2015-06-28

We describe a new theranostic strategy for selective delivery and spatiotemporal monitoring of mechlorethamine, a DNA alkylating agent. A photo-responsive prodrug is designed and composed of a photolabile o-nitrophenylethyl group, a DNA alkylating mechlorethamine drug and a coumarin fluorophore. Masking of the "N" in mechlorethamine in a positively charged state in the prodrug renders it inactive, non-toxic, selective and non-fluorescent. Indeed, the stable prodrug shows negligible cytotoxicity towards normal cells with and without UV activation and is completely non-fluorescent. However, upon photo-irradiation, the active mechlorethamine is released and induces efficient DNA cross-links, accompanied by a strong fluorescence enhancement (152 fold). Furthermore, DNA cross-linking activity from the release can be transformed into anticancer activity observed in in vitro studies of tumor cells. Importantly, the drug release progress and the movement can be conveniently monitored by fluorescence spectroscopy. The mechanistic study proves that the DNA cross-linking activity is mainly due to the release of DNA alkylating mechlorethamine. Altogether, the studies show the power of the theranostic strategy for efficient therapy in cancer treatment.

Management of patients with multiple myeloma: emphasizing the role of high-dose therapy.

PubMed

Kyle, R A

2001-06-01

Treatment for multiple myeloma should not be given until the patient is symptomatic or at risk for the occurrence of complications of the disease. If the patient is younger than 70 years, the physician should seriously consider an autologous peripheral blood stem cell transplant. Most physicians initially administer vincristine/doxorubicin/dexamethasone (VAD) for 3 to 4 months and then collect the stem cells before exposure to alkylating agents. Following stem cell collection, one may proceed with high-dose chemotherapy and then infusion of the stem cells, or one can administer alkylating agents until a plateau is reached and delay transplantation until progressive disease occurs. There is no difference in overall survival between early and late transplantation, but the former avoids the cost and inconvenience of alkylating agent therapy. Double or tandem autologous stem cell transplants may produce better results, but the evidence is not strong. Almost all patients have a relapse after an autologous stem cell transplant, so efforts are being made to prolong the response with a2-interferon or dendritic cell therapy. Allogeneic bone marrow transplantation is feasible for only 5%-10% of patients, but the mortality is high and it is curative in only a small fraction of patients. Treatment with melphalan and prednisone results in an objective response in 50%-60% of patients. Combinations of alkylating agents produce a higher response rate, but there is no survival benefit. Thalidomide produces an objective response in about one third of patients with refractory disease. It currently is being studied in conjunction with dexamethasone for conventional initial therapy.

Glutathione Depletion Induced by c-Myc Downregulation Triggers Apoptosis on Treatment with Alkylating Agents1

PubMed Central

Biroccio, Annamaria; Benassi, Barbara; Fiorentino, Francesco; Zupi, Gabriella

2004-01-01

Abstract Here we investigate the mechanism(s) involved in the c-Myc-dependent drug response of melanoma cells. By using three M14-derived c-Myc low-expressing clones, we demonstrate that alkylating agents, cisplatin and melphalan, trigger apoptosis in the c-Myc antisense transfectants, but not in the parental line. On the contrary, topoisomerase inhibitors, adriamycin and camptothecin, induce apoptosis to the same extent regardless of c-Myc expression. Because we previously demonstrated that c-Myc downregulation decreases glutathione (GSH) content, we evaluated the role of GSH in the apoptosis induced by the different drugs. In control cells treated with one of the alkylating agents or the others, GSH depletion achieved by l-buthionine-sulfoximine preincubation opens the apoptotic pathway. The apoptosis proceeded through early Bax relocalization, cytochrome c release, and concomitant caspase-9 activation, whereas reactive oxygen species production and alteration of mitochondria membrane potential were late events. That GSH was determining in the c-Myc-dependent drug-induced apoptosis was demonstrated by altering the intracellular GSH content of the c-Myc low-expressing cells up to the level of controls. Indeed, GSH ethyl ester-mediated increase of GSH abrogated apoptosis induced by cisplatin and melphalan by inhibition of Bax/cytochrome c redistribution. The relationship among c-Myc, GSH content, and the response to alkylating agent has been also evaluated in the M14 Myc overexpressing clones as well as in the melanoma JR8 c-Myc antisense transfectants. All together, these results demonstrate that GSH plays a key role in governing c-Myc-dependent drug-induced apoptosis. PMID:15153331

Cellular response to alkylating agent MNNG is impaired in STAT1-deficients cells.

PubMed

Ah-Koon, Laurent; Lesage, Denis; Lemadre, Elodie; Souissi, Inès; Fagard, Remi; Varin-Blank, Nadine; Fabre, Emmanuelle E; Schischmanoff, Olivier

2016-10-01

The SN 1 alkylating agents activate the mismatch repair system leading to delayed G2 /M cell cycle arrest and DNA repair with subsequent survival or cell death. STAT1, an anti-proliferative and pro-apoptotic transcription factor is known to potentiate p53 and to affect DNA-damage cellular response. We studied whether STAT1 may modulate cell fate following activation of the mismatch repair system upon exposure to the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Using STAT1-proficient or -deficient cell lines, we found that STAT1 is required for: (i) reduction in the extent of DNA lesions, (ii) rapid phosphorylation of T68-CHK2 and of S15-p53, (iii) progression through the G2 /M checkpoint and (iv) long-term survival following treatment with MNNG. Presence of STAT1 is critical for the formation of a p53-DNA complex comprising: STAT1, c-Abl and MLH1 following exposure to MNNG. Importantly, presence of STAT1 allows recruitment of c-Abl to p53-DNA complex and links c-Abl tyrosine kinase activity to MNNG-toxicity. Thus, our data highlight the important modulatory role of STAT1 in the signalling pathway activated by the mismatch repair system. This ability of STAT1 to favour resistance to MNNG indicates the targeting of STAT1 pathway as a therapeutic option for enhancing the efficacy of SN1 alkylating agent-based chemotherapy. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the Childhood Cancer Survivor Study.

PubMed

Green, Daniel M; Nolan, Vikki G; Goodman, Pamela J; Whitton, John A; Srivastava, DeoKumar; Leisenring, Wendy M; Neglia, Joseph P; Sklar, Charles A; Kaste, Sue C; Hudson, Melissa M; Diller, Lisa R; Stovall, Marilyn; Donaldson, Sarah S; Robison, Leslie L

2014-01-01

Estimation of the risk of adverse long-term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses. We compared the performance of the Cyclophosphamide Equivalent Dose (CED), a unit for quantifying alkylating agent exposure independent of study population, to the AAD. Comparisons included associations from three Childhood Cancer Survivor Study (CCSS) outcome analyses, receiver operator characteristic (ROC) curves and goodness of fit based on the Akaike's Information Criterion (AIC). The CED and AAD performed essentially identically in analyses of risk for pregnancy among the partners of male CCSS participants, risk for adverse dental outcomes among all CCSS participants and risk for premature menopause among female CCSS participants, based on similar associations, lack of statistically significant differences between the areas under the ROC curves and similar model fit values for the AIC between models including the two measures of exposure. The CED is easily calculated, facilitating its use for patient counseling. It is independent of the drug dose distribution of a particular patient population, a characteristic that will allow direct comparisons of outcomes among epidemiological cohorts. We recommend the use of the CED in future research assessing cumulative alkylating agent exposure. © 2013 Wiley Periodicals, Inc.

Isolation and characterization of Escherichia coli K-12 mutants unable to induce the adaptive response to simple alkylating agents.

PubMed Central

Jeggo, P

1979-01-01

When Esherichia coli cells are exposed to a low level of simple alkylating agents, they induce the adaptive response which renders them more resistant to the killing and the mutagenic effects of the same or other alkylating agents. This paper describes the isolation of one strain that was deficient in mutagenic adaptation and five that were deficient in both mutagenic and killing adaptation, confirming previous suggestions that killing and mutagenic adaptation are, at least to some extent, separable. These six strains have been called Ada mutants. They were more sensitive to the killing and mutagenic effects of N-methy-N'-nitro-N-nitrosoguanidine (MNNG) than the unadapted Ada+ parent. Thus, the adaptation pathway is responsible for circumventing some alkylation-induced damage even in cells that are preinduced. The increase in mutation frequency seen in Ada cells treated with MNNG was the same whether the cells were lexA+ or lexA, showing that the extra mutations found in Ada- strains do not depend upon the SOS pathway. Ada strains accumulated more O6-methyl guanine lesions than the Ada+ parent on prolonged exposure to MNNG, and this supports the idea that O6-methyl guanine is the most important lesion for MNNG-induced mutagenesis. The ada mutations have been shown to map in the 47 to 53-min region of the E. coli chromosome. PMID:383692

Versatile Synthesis of Stable, Functional Polypeptides via Reaction with Epoxides.

PubMed

Gharakhanian, Eric G; Deming, Timothy J

2015-06-08

Methodology was developed for efficient alkylation of methionine residues using epoxides as a general strategy to introduce a wide range of functional groups onto polypeptides. Use of a spacer between epoxide and functional groups further allowed addition of sterically demanding functionalities. Contrary to other methods to alkylate methionine residues, epoxide alkylations allow the reactions to be conducted in wet protic media and give sulfonium products that are stable against dealkylation. These functionalizations are notable since they are chemoselective, utilize stable and readily available epoxides, and allow facile incorporation of an unprecedented range of functional groups onto simple polypeptides using stable linkages.

Synthesis and Reactivity of Alkyl-1,1,1-trisphosphonate Esters

PubMed Central

Smits, Jacqueline P.; Wiemer, David F.

2011-01-01

The α–trisphosphonic acid esters provide a unique spatial arrangement of three phosphonate groups, and may represent an attractive motif for inhibitors of enzymes that utilize di- or triphosphate substrates. To advance studies of this unique functionality, a general route to alkyl derivatives of the parent system (R = H) has been developed. A set of new α-alkyl-1,1,1-trisphosphonate esters has been prepared through phosphinylation and subsequent oxidation of tetraethyl alkylbisphosphonates, and the reactivity of these new compounds has been studied in representative reactions that afford additional examples of this functionality. PMID:21916407

Benzylation of Nitroalkanes Using Copper-Catalyzed Thermal Redox Catalysis: Toward the Facile C-Alkylation of Nitroalkanes

PubMed Central

Gildner, Peter G.; Gietter, Amber A. S.; Cui, Di; Watson, Donald A.

2012-01-01

The C-alkylation of nitroalkanes under mild conditions has been a significant challenge in organic synthesis for more than a century. Herein, we report a simple Cu(I) catalyst, generated in situ, that is highly effective for C-benzylation of nitroalkanes using abundant benzyl bromides and related heteroaromatic compounds. This process, which we believe proceeds via a thermal redox mechanism, allows access to a variety of complex nitroalkanes under mild reaction conditions and represents the first step towards developing a general catalytic system for the alkylation of nitroalkanes. PMID:22691127

The reaction of Grignard reagents with Bunte salts: a thiol-free synthesis of sulfides.

PubMed

Reeves, Jonathan T; Camara, Kaddy; Han, Zhengxu S; Xu, Yibo; Lee, Heewon; Busacca, Carl A; Senanayake, Chris H

2014-02-21

S-Alkyl, S-aryl, and S-vinyl thiosulfate sodium salts (Bunte salts) react with Grignard reagents to give sulfides in good yields. The S-alkyl Bunte salts are prepared from odorless sodium thiosulfate by an SN2 reaction with alkyl halides. A Cu-catalyzed coupling of sodium thiosulfate with aryl and vinyl halides was developed to access S-aryl and S-vinyl Bunte salts. The reaction is amenable to a broad structural array of Bunte salts and Grignard reagents. Importantly, this route to sulfides avoids the use of malodorous thiol starting materials or byproducts.

Total Synthesis of Adunctin B.

PubMed

Dethe, Dattatraya H; Dherange, Balu D

2018-03-16

Total synthesis of (±)-adunctin B, a natural product isolated from Piper aduncum (Piperaceae), has been achieved using two different strategies, in seven and three steps. The efficient approach features highly atom economical and diastereoselective Friedel-Crafts acylation, alkylation reaction and palladium catalyzed Wacker type oxidative cyclization.

Asymmetric Synthesis of 1,2,9,9a-Tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI)

PubMed Central

Lajiness, James P.; Boger, Dale L.

2011-01-01

A short, asymmetric synthesis of the 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI) analogue of the CC-1065 and duocarmycin DNA alkylation subunits is described. Treatment of iodo-epoxide 5, prepared by late-stage alkylation of 4 with (S)-glycidal-3-nosylate, with EtMgBr at room temperature directly provides the optically pure alcohol 6 in 87% yield (99% ee) derived from selective metal–halogen exchange and subsequent regioselective intramolecular 6-endo-tet cyclization. The use of MeMgBr or i-PrMgBr also provides the product in high yields (82–87%), but requires larger amounts of the Grignard reagent to effect metal–halogen exchange and cyclization. Direct transannular spirocyclization of 7 following O-debenzylation of 6 provides N-Boc-CBI. This approach represents the most efficient (9-steps, 31% overall) and effective (99% ee) route to the optically pure CBI alkylation subunit yet described. PMID:21192653

Regioselective and stereospecific acylation across oxirane- and silyloxy systems as a novel strategy to the synthesis of enantiomerically pure mono-, di- and triglycerides.

PubMed

Stamatov, Stephan D; Stawinski, Jacek

2007-12-07

A trifluoroacetate-catalyzed opening of the oxirane ring of glycidyl derivatives bearing allylic acyl or alkyl functionalities with trifluoroacetic anhydride (TFAA), provides an efficient entry to configurationally homogeneous 1(3)-acyl- or 1(3)-O-alkyl-sn-glycerols. Selective introduction of tert-butyldimethylsilyl- (TBDMS), or triisopropylsilyl- (TIPS) transient protections at the terminal sites within these key intermediates secures 1(3)-acyl- or 1(3)-O-alkyl-3(1)-O-TBDMS (or TIPS)-sn-glycerols as general bifunctional precursors to 1,2(2,3)-diacyl-, 1(3)-O-alkyl-2-acyl- and 1,3-diacyl-sn-glycerols and hence triester isosters. Incorporation of a requisite acyl residue at the central carbon of the silylated synthons with a subsequent Et(3)N.3HF-promoted, direct trichloroacetylation across the siloxy system by trichloroacetic anhydride (TCAA), followed by cleavage of the trichloroacetyl group, affords the respective 1,2(2,3)-diacyl- or 1(3)-O-alkyl-2-acyl-sn-glycerols. Alternatively, a reaction sequence involving: (i) attachment of a trichloroacetyl fragment at the stereogenic C2-centre of the monosilylated glycerides; (ii) replacement of the silyl moiety by a short- or long-chain carboxylic acid residue by means of the acylating agent: tetra-n-butylammonium bromide (TBABr)-carboxylic acid anhydride (CAA)-trimethylsilyl bromide (TMSBr); and (iii) removal of the trichloroacetyl replacement, provides pure 1,3-diacyl-sn-glycerols. The TBABr-CAA-TMSBr reagent system allows also a one-step conversion of 1,2-diacylglycerol silyl ethers into homochiral triglycerides with predefined asymmetry and degree of unsaturation. These compounds can also be accessed via a two-step one-pot approach where the trichloroacetyl derivatives of 1,2(2,3)- or 1,3-diacyl-sn-glycerols serve as triester building blocks for establishing the third ester bond at preselected C3(1)- or C2-positions within the glycerol skeleton at the very last synthetic stage. In all instances, the target compounds were produced under mild conditions, in high enantiomeric purity, and in practically quantitative yields.

Inhibition of thioredoxin reductase but not of glutathione reductase by the major classes of alkylating and platinum-containing anticancer compounds.

PubMed

Witte, Anne-Barbara; Anestål, Karin; Jerremalm, Elin; Ehrsson, Hans; Arnér, Elias S J

2005-09-01

Mammalian thioredoxin reductase (TrxR) is important for cell proliferation, antioxidant defense, and redox signaling. Together with glutathione reductase (GR) it is the main enzyme providing reducing equivalents to many cellular processes. GR and TrxR are flavoproteins of the same enzyme family, but only the latter is a selenoprotein. With the active site containing selenocysteine, TrxR may catalyze reduction of a wide range of substrates, but can at the same time easily be targeted by electrophilic compounds due to the extraordinarily high reactivity of a selenolate moiety. Here we addressed the inhibition of the enzyme by major anticancer alkylating agents and platinum-containing compounds and we compared it to that of GR. We confirmed prior studies suggesting that the nitrosourea carmustine can inhibit both GR and TrxR. We next found, however, that nitrogen mustards (chlorambucil and melphalan) and alkyl sulfonates (busulfan) efficiently inhibited TrxR while these compounds, surprisingly, did not inhibit GR. Inhibitions were concentration and time dependent and apparently irreversible. Anticancer anthracyclines (daunorubicin and doxorubicin) were, in contrast to the alkylating agents, not inhibitors but poor substrates of TrxR. We also found that TrxR, but not GR, was efficiently inhibited by both cisplatin, its monohydrated complex, and oxaliplatin. Carboplatin, in contrast, could not inhibit any of the two enzymes. These findings lead us to conclude that representative compounds of the major classes of clinically used anticancer alkylating agents and most platinum compounds may easily target TrxR, but not GR. The TrxR inhibition should thereby be considered as a factor that may contribute to the cytotoxicity seen upon clinical use of these drugs.

Cytotoxic and apoptotic effects of bortezomib and gefitinib compared to alkylating agents on human glioblastoma cells.

PubMed

Pédeboscq, Stéphane; L'Azou, Béatrice; Passagne, Isabelle; De Giorgi, Francesca; Ichas, François; Pometan, Jean-Paul; Cambar, Jean

2008-01-01

Glioblastoma is a malignant astrocytic tumor with a median survival of about 12 months for which new therapeutic strategies are required. We therefore examined the cytotoxicity of anticancer drugs with different mechanisms of action on two human glioblastoma cell lines expressing various levels of EGFR (epidermal growth factor receptor). Apoptosis induced by these anticancer agents was evaluated by flow cytometry. The cytotoxicity of alkylating drugs followed a dose-effect curve and cytotoxicity index values were lower with carboplatin than with BCNU and temozolomide. Anti-EGFR gefitinib (10 microM) cytotoxicity on DBTRG.05-MG expressing high levels of EGFR was significantly higher than on U87-MG expressing low levels of EGFR. Carboplatin and temozolomide cytotoxicity was potentiated with the addition of gefitinib on DBTRG.05-MG. Among the anticancer agents tested, the proteasome inhibitor bortezomib was the most cytotoxic with very low IC50 on the two cell lines. Moreover, all anticancer drugs tested induced apoptosis in a concentration-dependent manner. Bortezomib proved to be a more potent inductor of apoptosis than gefitinib and alkylating agents. These results show the efficacy of bortezomib and of the association between conventional chemotherapy and gefitinib on glioblastoma cells and therefore suggest the interest of these molecules in the treatment of glioblastoma.

Enantioselective modular synthesis of cyclohexenones: total syntheses of (+)-crypto- and (+)-infectocaryone.

PubMed

Franck, Géraldine; Brödner, Kerstin; Helmchen, Günter

2010-09-03

A modular synthesis of cyclohexenones is described and applied to the first enantioselective total syntheses of (+)-crypto- and (+)-infectocaryone. Key steps in the synthesis of cyclohexenones are an iridium-catalyzed allylic alkylation, nucleophilic allylation, and ring-closing metathesis. On the way to (+)-cryptocaryone, a catch and release strategy involving an iodolactonization/elimination and a regioselective C-acylation were used.

Low-cost synthesis and physical characterization of thieno[3,4-c]pyrrole-4,6-dione-based polymers.

PubMed

Berrouard, Philippe; Dufresne, Stéphane; Pron, Agnieszka; Veilleux, Justine; Leclerc, Mario

2012-09-21

The improved synthesis of thieno[3,4-c]pyrrole-4,6-dione (TPD) monomers, including Gewald thiophene ring formation, a Sandmeyer-type reaction, and neat condensation with an amine, is presented. This protocol enables faster, cheaper, and more efficient preparation of TPD units in comparison to traditional methods. Furthermore, a series of TPD homo- and pseudohomopolymers bearing various alkyl chains was synthesized via a direct heteroarylation polymerization (DHAP) procedure. UV-visible absorption and powder X-ray diffraction measurements revealed the relationship between the ratio of branched to linear alkyl chains and the optoelectronic properties of the polymers as well as their packing in the solid state.

New Therapeutic Approaches for Waldenstrom Macroglobulinemia

PubMed Central

Stedman, Jennifer; Roccaro, Aldo; Leleu, Xavier; Ghobrial, Irene M.

2011-01-01

Waldenstrom Macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of the bone marrow (BM) with lymphoplasmacytic cells, as well as detection of an IgM monoclonal gammopathy in the serum. WM is an incurable disease, with an overall medial survival of only 5-6 years. First-line therapy of WM has been based on single-agent or combination therapy with alkylator agents (e.g. chlorambucil or cyclophasphamide), nucleoside analogues (cladribine or fludarabine), and the monoclonal antibody rituximab. Novel therapeutic agents that have demonstrated efficacy in WM include thalidomide, lenalidomide, bortezomib, everolimus, Atacicept, and perifosine. The range of the ORR to these agents is between 25-80%. Ongoing and planned future clinical trials include those using PKC inhibitors such as enzastaurin, new proteasome inhibitors such as carfilzomib, histone deacetylase inhibitors such as panobinostat, humanized CD20 antibodies such as Ofatumumab, and additional alkylating agents such as bendamustine. These agents, when compared to traditional chemotherapeutic agents, may lead in the future to higher responses, longer remissions and better quality of life for patients with WM. PMID:21869855

Synthesis of a Simplified Version of Stable Bulky and Rigid Cyclic (Alkyl)(Amino)Carbenes (CAACs), and Catalytic Activity of the Ensuing Gold(I) Complex in the Three-Component Preparation of 1,2-Dihydroquinoline Derivatives

PubMed Central

Zeng, Xiaoming; Frey, Guido D.; Kinjo, Rei; Donnadieu, Bruno; Bertrand, Guy

2009-01-01

A 95/5 mixture of cis and trans 2,4-dimethyl-3-cyclohexenecarboxaldehyde (trivertal), a common fragrance and flavor material produced in bulk quantities, serves as the precursor for the synthesis of a stable spirocyclic (alkyl)(amino)carbene, in which the 2-methyl-substituted cyclohexenyl group provides steric protection to an ensuing metal. The efficiency of this carbene as ligand for transition metal based catalysts is first illustrated by the gold(I) catalyzed hydroamination of internal alkynes with secondary dialkyl amines, a process with little precedent. The feasibility of this reaction allows for significantly enlarging the scope of the one-pot three-component synthesis of 1,2-dihydroquinoline derivatives, and related nitrogen-containing heterocycles. Indeed, two different alkynes were used, which include an internal alkyne for the first step. PMID:19456108

[Combi-molecules: a global approach towards better chemoselectivity and chemosensitivity].

PubMed

Matheson, Stéphanie; Qiu, Qiyu; Brahimi, Fouad; Dudouit, Fabienne; Banerjee, Ranjita; Rachid, Zakaria; Jean-Claude, Bertrand J

2004-12-01

It is now known that tumour cells possess many signaling pathways to repair damage inflicted by alkylating agents. However, most of these cytotoxic agents only target DNA and this does not suffice to induce sustained antiproliferative activity. Furthermore, the efficacy of antitumour alkylating agents is hampered by a lack of selectivity for tumour tissues. To circumvent these problems, we recently designed a novel strategy termed combi-targeting that sought to synthesize compounds capable of not only damaging DNA, but also blocking signaling associated with aggressive proliferation. The first prototypes described herein can block signaling associated with the epidermal growth factor receptor (EGFR) and significantly damage DNA. In addition to their binary EGFR/DNA targeting properties, we demonstrated that their effects are selective for cells to which EGFR has conferred a proliferative advantage. These novel agents with mixed targeting properties are termed "combi-molecules".

Selective sp3 C–H alkylation via polarity-match-based cross-coupling

PubMed Central

Le, Chip; Liang, Yufan; Evans, Ryan W.; Li, Ximing; MacMillan, David W. C.

2017-01-01

The functionalization of carbon–hydrogen (C–H) bonds is one of the most attractive strategies for molecular construction in organic chemistry. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in organic molecules and its availability for functionalization at almost any stage in a synthetic sequence1. Although many C–H functionalization reactions involve C(sp3)–C(sp2) coupling, there is a growing demand for C–H alkylation reactions, wherein sp3 C–H bonds are replaced with sp3 C–alkyl groups. Here we describe a polarity-match-based selective sp3 C–H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodology simultaneously uses three catalytic cycles to achieve hydridic C–H bond abstraction (enabled by polarity matching), alkyl halide oxidative addition, and reductive elimination to enable alkyl–alkyl fragment coupling. The sp3 C–H alkylation is highly selective for the α-C–H of amines, ethers and sulphides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry. PMID:28636596

Female cancer survivors exposed to alkylating-agent chemotherapy have unique reproductive hormone profiles.

PubMed

Johnson, Lauren; Sammel, Mary D; Schanne, Allison; Lechtenberg, Lara; Prewitt, Maureen; Gracia, Clarisa

2016-12-01

To evaluate reproductive hormone patterns in women exposed to alkylating-agent chemotherapy. Prospective cohort. University hospital. Normally menstruating mid-reproductive-age women (20-35 years old) who had previously been exposed to alkylating-agent chemotherapy for cancer treatment were compared with two healthy control populations: similarly-aged women and late-reproductive-age women (43-50 years old). Subjects collected daily urine samples for one cycle. Integrated urinary pregnanediol glucuronide (PDG) and estrone conjugate (E1c) and urinary excretion of gonadotropins (FSH and LH). Thirty-eight women (13 survivors, 11 same-age control subjects, 14 late-reproductive-age control subjects) provided 1,082 urine samples. Cycle length, luteal phase length, and evidence of luteal activity were similar among the groups. As expected, ovarian reserve was impaired in cancer survivors compared with same-age control subjects but similar between survivors and late-reproductive-age control subjects. In contrast, survivors had total and peak PDG levels that were similar to same-age control subjects and higher than those observed in late-reproductive-age control subjects. Survivors had higher E1c levels than both same-age and late-reproductive-age control subjects. There was no difference in urinary gonadotropins among the groups. Women exposed to alkylating agents have a unique reproductive hormone milieu that is not solely explained by age or ovarian reserve. The urinary hormone profile observed in survivors appears more similar to same-age control subjects than to late-reproductive-age women with similar ovarian reserve, which may suggest that age plays a more important role than ovarian reserve in the follicular dynamics of survivors. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Stereospecific nickel-catalyzed cross-coupling reactions of alkyl ethers: enantioselective synthesis of diarylethanes.

PubMed

Taylor, Buck L H; Swift, Elizabeth C; Waetzig, Joshua D; Jarvo, Elizabeth R

2011-01-26

Secondary benzylic ethers undergo stereospecific substitution reactions with Grignard reagents in the presence of nickel catalysts. Reactions proceed with inversion of configuration and high stereochemical fidelity. This reaction allows for facile enantioselective synthesis of biologically active diarylethanes from readily available optically enriched carbinols.

Synthesis of Nitriles via Palladium-Catalyzed Water Shuffling from Amides to Acetonitrile

PubMed Central

Zhang, Wandi; Haskins, Christopher W.; Yang, Yang; Dai, Mingji

2014-01-01

Palladium-catalyzed synthesis of nitriles from amides has been described. Two similar, but complementary reaction conditions have been identified to convert various amides including α,β,γ,δ-unsaturated amides, cinnamides, aromatic amides and alkyl amides to the corresponding nitriles in good to excellent yield. PMID:25316145

Synthesis of nitriles via palladium-catalyzed water shuffling from amides to acetonitrile.

PubMed

Zhang, Wandi; Haskins, Christopher W; Yang, Yang; Dai, Mingji

2014-12-07

Palladium-catalyzed synthesis of nitriles from amides has been described. Two similar, but complementary reaction conditions have been identified to convert various amides including α,β,γ,δ-unsaturated amides, cinnamides, aromatic amides and alkyl amides to the corresponding nitriles in good to excellent yield.

The Two Faces of Sulfinates: Illustrating Umpolung Reactivity

ERIC Educational Resources Information Center

Tapia-Pineda, Adabelia; Perez-Arrieta, Carlos; Silva-Cuevas, Carolina; Paleo, Ehecatl; Lujan-Montelongo, J. Armando

2016-01-01

A simple, microscale experiment was developed with the aim of demonstrating the concept of umpolung in synthetic organic chemistry. Starting from a common alkyl sulfinate, students perform a polarity inversion by performing a Grignard-based sulfoxide synthesis and a Mannich-type formamide synthesis. The products are purified without chromatography…

Selected Alkylating Agents Can Overcome Drug Tolerance of G0-like Tumor Cells and Eradicate BRCA1-Deficient Mammary Tumors in Mice.

PubMed

Pajic, Marina; Blatter, Sohvi; Guyader, Charlotte; Gonggrijp, Maaike; Kersbergen, Ariena; Küçükosmanoğlu, Aslι; Sol, Wendy; Drost, Rinske; Jonkers, Jos; Borst, Piet; Rottenberg, Sven

2017-11-15

Purpose: We aimed to characterize and target drug-tolerant BRCA1-deficient tumor cells that cause residual disease and subsequent tumor relapse. Experimental Design: We studied responses to various mono- and bifunctional alkylating agents in a genetically engineered mouse model for BRCA1/p53 -mutant breast cancer. Because of the large intragenic deletion of the Brca1 gene, no restoration of BRCA1 function is possible, and therefore, no BRCA1-dependent acquired resistance occurs. To characterize the cell-cycle stage from which Brca1 -/- ;p53 -/- mammary tumors arise after cisplatin treatment, we introduced the fluorescent ubiquitination-based cell-cycle indicator (FUCCI) construct into the tumor cells. Results: Despite repeated sensitivity to the MTD of platinum drugs, the Brca1 -mutated mammary tumors are not eradicated, not even by a frequent dosing schedule. We show that relapse comes from single-nucleated cells delaying entry into the S-phase. Such slowly cycling cells, which are present within the drug-naïve tumors, are enriched in tumor remnants. Using the FUCCI construct, we identified nonfluorescent G 0 -like cells as the population most tolerant to platinum drugs. Intriguingly, these cells are more sensitive to the DNA-crosslinking agent nimustine, resulting in an increased number of multinucleated cells that lack clonogenicity. This is consistent with our in vivo finding that the nimustine MTD, among several alkylating agents, is the most effective in eradicating Brca1 -mutated mouse mammary tumors. Conclusions: Our data show that targeting G 0 -like cells is crucial for the eradication of BRCA1/p53-deficient tumor cells. This can be achieved with selected alkylating agents such as nimustine. Clin Cancer Res; 23(22); 7020-33. ©2017 AACR . ©2017 American Association for Cancer Research.

Stability of solutions of antineoplastic agents during preparation and storage for in vitro assays. General considerations, the nitrosoureas and alkylating agents.

PubMed

Bosanquet, A G

1985-01-01

In vitro drug sensitivity of tumour biopsies is currently being determined using a variety of methods. For these chemosensitivity assays many drugs are required at short notice, and this in turn means that the drugs must generally be stored in solution. There are, however, a number of potential problems associated with dissolving and storing drugs for in vitro use, which include (a) drug adsorption; (b) effects of freezing; (c) drug stability under the normal conditions of dilution and setting up of an in vitro assay; and (d) insolubility of drugs in normal saline (NS) or phosphate-buffered saline (PBS). These problems are considered in general, and some recommendations for use of solutions of drugs in in vitro assays are suggested. The nitrosoureas and alkylating agents are also investigated in greater detail in this respect. The nitrosoureas are found to be very labile in PBS at pH 7, with 5% degradation (t0.95) occurring in 10-50 min at room temperature. These values are increased about 10-fold on refrigeration and about 5- to 10-fold on reduction of the pH of the medium to pH 4-5. At pH 7 and room temperature, t0.95 is observed in under 1 h with the alkylating agents nitrogen mustard, chlorambucil, melphalan, 2,5-diaziridinyl-3,6-bis(2-hydroxyethylamino)-1,4-benzoquinone (BZQ), dibromodulcitol, dibromomannitol, treosulphan, and procarbazine. Of the other alkylating agents, 4-hydroperoxycylophosphamide (sometimes used in vitro in place of cyclophosphamide), busulphan, dianhydrogalactitol, aziridinylbenzoquinone (AZQ), and dacarbazine have a t0.95 of between 2 and 24 h, while ifosfamide and pentamethylmelamine are both stable in aqueous solution for greater than 7 days. About half the drugs studied in detail have been stored frozen in solution for in vitro use, although very little is known about their stability under these conditions.

Synthesis of N4-(Substituted phenyl)-N4-alkyl/desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines and Identification of New Microtubule Disrupting Compounds that are Effective against Multidrug Resistant Cells1

PubMed Central

Gangjee, Aleem; Zaware, Nilesh; Devambatla, Ravi Kumar Vyas; Raghavan, Sudhir; Westbrook, Cara D.; Dybdal-Hargreaves, Nicholas F.; Hamel, Ernest; Mooberry, Susan L.

2013-01-01

A series of fourteen N4-(substituted phenyl)-N4-methyl/desmethyl-9H-pyrimido[4,5-b]indole-2,4-diamines was synthesized as potential microtubule targeting agents. The synthesis involved a Fisher indole cyclization of 2-amino-6-hydrazinylpyrimidin-4(3H)-one with cyclohexanone, followed by oxidation, chlorination and displacement with appropriate anilines. Compounds 6, 14 and 15 had low nanomolar potency against MDA-MB-435 tumor cells and depolymerized microtubules. Compound 6 additionally had nanomolar GI50 values against 57 of the NCI 60-tumor panel cell lines. Mechanistic studies showed that 6 inhibited tubulin polymerization and [3H]colchicine binding to tubulin. The most potent compounds were all effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, which have been associated with clinical drug reisistence. Modeling studies provided the potential interactions of 6, 14 and 15 within the colchicine site. PMID:23332369

Small molecule inhibitors of ERCC1-XPF protein-protein interaction synergize alkylating agents in cancer cells.

PubMed

Jordheim, Lars Petter; Barakat, Khaled H; Heinrich-Balard, Laurence; Matera, Eva-Laure; Cros-Perrial, Emeline; Bouledrak, Karima; El Sabeh, Rana; Perez-Pineiro, Rolando; Wishart, David S; Cohen, Richard; Tuszynski, Jack; Dumontet, Charles

2013-07-01

The benefit of cancer chemotherapy based on alkylating agents is limited because of the action of DNA repair enzymes, which mitigate the damage induced by these agents. The interaction between the proteins ERCC1 and XPF involves two major components of the nucleotide excision repair pathway. Here, novel inhibitors of this interaction were identified by virtual screening based on available structures with use of the National Cancer Institute diversity set and a panel of DrugBank small molecules. Subsequently, experimental validation of the in silico screening was undertaken. Top hits were evaluated on A549 and HCT116 cancer cells. In particular, the compound labeled NSC 130813 [4-[(6-chloro-2-methoxy-9-acridinyl)amino]-2-[(4-methyl-1-piperazinyl)methyl

Advances in Development of Antimicrobial Peptidomimetics as Potential Drugs.

PubMed

Molchanova, Natalia; Hansen, Paul R; Franzyk, Henrik

2017-08-29

The rapid emergence of multidrug-resistant pathogens has evolved into a global health problem as current treatment options are failing for infections caused by pan-resistant bacteria. Hence, novel antibiotics are in high demand, and for this reason antimicrobial peptides (AMPs) have attracted considerable interest, since they often show broad-spectrum activity, fast killing and high cell selectivity. However, the therapeutic potential of natural AMPs is limited by their short plasma half-life. Antimicrobial peptidomimetics mimic the structure and biological activity of AMPs, but display extended stability in the presence of biological matrices. In the present review, focus is on the developments reported in the last decade with respect to their design, synthesis, antimicrobial activity, cytotoxic side effects as well as their potential applications as anti-infective agents. Specifically, only peptidomimetics with a modular structure of residues connected via amide linkages will be discussed. These comprise the classes of α-peptoids ( N -alkylated glycine oligomers), β-peptoids ( N -alkylated β-alanine oligomers), β³-peptides, α/β³-peptides, α-peptide/β-peptoid hybrids, α/γ N -acylated N -aminoethylpeptides (AApeptides), and oligoacyllysines (OAKs). Such peptidomimetics are of particular interest due to their potent antimicrobial activity, versatile design, and convenient optimization via assembly by standard solid-phase procedures.

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

PubMed Central

Focken, Thilo

2014-01-01

Summary A review of the synthesis of natural products and bioactive compounds adopting phosphonamide anion technology is presented highlighting the utility of phosphonamide reagents in stereocontrolled bond-forming reactions. Methodologies utilizing phosphonamide anions in asymmetric alkylations, Michael additions, olefinations, and cyclopropanations will be summarized, as well as an overview of the synthesis of the employed phosphonamide reagents. PMID:25246946

Regeneration of polyborazylene

DOEpatents

Davis, Benjamin L.; Gordon, John C.

2010-12-07

Method of producing ammonia borane, comprising providing polyborazylene; digesting the polyborazylene with a dithiol-containing agent to produce a boro-sulfide compound and a byproduct; converting the byproduct to the boro-sulfide product of step (b) by reaction with a first alkyl-tin hydride; and, converting the boro-sulfide compound produced in steps (b) and (c) to ammonia borane by reaction with a second alkyl-tin hydride.

Method for producing hydrophobic aerogels

DOEpatents

Hrubesh, Lawrence W.; Poco, John F.; Coronado, Paul R.

1999-01-01

A method for treating a dried monolithic aerogel containing non-dispersed particles, with an organometallic surface modifying agent to produce hydrophobic aerogels. The dried, porous hydrophobic aerogels contain a protective layer of alkyl groups, such as methyl groups, on the modified surfaces of the pores of the aerogel. The alkyl groups at the aerogel surface typically contain at least one carbon-metal bond per group.

Safety Assessment of Alkyl PEG Sulfosuccinates as Used in Cosmetics.

PubMed

Johnson, Wilbur; Heldreth, Bart; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

2015-09-01

The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed the safety of alkyl polyethylene glycol (PEG) sulfosuccinates, which function in cosmetics mostly as surfactants/cleansing agents. Although these ingredients may cause ocular and skin irritation, dermal penetration is unlikely because of the substantial polarity and molecular size of these ingredients. The Panel considered the negative oral carcinogenicity and reproductive and developmental toxicity data on chemically related laureths (PEG lauryl ethers) and negative repeated dose toxicity and skin sensitization data on disodium laureth sulfosuccinate supported the safety of these alkyl PEG sulfosuccinates in cosmetic products, but. The CIR Expert Panel concluded that the alkyl PEG sulfosuccinates are safe in the present practices of use and concentration when formulated to be nonirritating. © The Author(s) 2015.

Synthesis and biological evaluation of novel N-phenyl ureidobenzenesulfonate derivatives as potential anticancer agents. Part 2. Modulation of the ring B.

PubMed

Gagné-Boulet, Mathieu; Moussa, Hanane; Lacroix, Jacques; Côté, Marie-France; Masson, Jean-Yves; Fortin, Sébastien

2015-10-20

DNA double strand-breaks (DSBs) are the most deleterious lesions that can affect the genome of living beings and are lethal if not quickly and properly repaired. Recently, we discovered a new family of anticancer agents designated as N-phenyl ureidobenzenesulfonates (PUB-SOs) that are blocking the cells cycle progression in S-phase and inducing DNA DSBs. Previously, we have studied the effect of several modifications on the molecular scaffold of PUB-SOs on their cytocidal properties. However, the effect of the nature and the position of substituents on the aromatic ring B is still poorly studied. In this study, we report the preparation and the biological evaluation of 45 new PUB-SO derivatives substituted by alkyl, alkoxy, halogen and nitro groups at different positions on the aromatic ring B. All PUB-SOs were active in the submicromolar to low micromolar range (0.24-20 μM). The cell cycle progression analysis showed that PUB-SOs substituted at position 2 by alkyl, halogen or nitro groups or substituted at position 4 by a hydroxyl group arrest the cell cycle progression in S-phase. Interestingly, all others PUB-SOs substituted at positions 3 and 4 arrested the cell cycle in G2/M-phase. PUB-SOs arresting the cell cycle progression in S-phase also induced the phosphorylation of H2AX (γH2AX) which is indicating the generation of DNA DSBs. We evidenced that few modifications on the ring B of PUB-SOs scaffold lead to cytocidal derivatives arresting the cell cycle in S-phase and inducing γH2AX and DSBs. In addition, this study shows that these new anticancer agents are promising and could be used as alternative to circumvent some of the biopharmaceutical complications that might be encountered during the development of PUB-SOs. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Sensitization to radiation and alkylating agents by inhibitors of poly(ADP-ribose) polymerase is enhanced in cells deficient in DNA double-strand break repair.

PubMed

Löser, Dana A; Shibata, Atsushi; Shibata, Akiko K; Woodbine, Lisa J; Jeggo, Penny A; Chalmers, Anthony J

2010-06-01

As single agents, chemical inhibitors of poly(ADP-ribose) polymerase (PARP) are nontoxic and have clinical efficacy against BRCA1- and BRCA2-deficient tumors. PARP inhibitors also enhance the cytotoxicity of ionizing radiation and alkylating agents but will only improve clinical outcomes if tumor sensitization exceeds effects on normal tissues. It is unclear how tumor DNA repair proficiency affects the degree of sensitization. We have previously shown that the radiosensitizing effect of PARP inhibition requires DNA replication and will therefore affect rapidly proliferating tumors more than normal tissues. Because many tumors exhibit defective DNA repair, we investigated the impact of double-strand break (DSB) repair integrity on the sensitizing effects of the PARP inhibitor olaparib. Sensitization to ionizing radiation and the alkylating agent methylmethane sulfonate was enhanced in DSB repair-deficient cells. In Artemis(-/-) and ATM(-/-) mouse embryo fibroblasts, sensitization was replication dependent and associated with defective repair of replication-associated damage. Radiosensitization of Ligase IV(-/-) mouse embryo fibroblasts was independent of DNA replication and is explained by inhibition of "alternative" end joining. After methylmethane sulfonate treatment, PARP inhibition promoted replication-independent accumulation of DSB, repair of which required Ligase IV. Our findings predict that the sensitizing effects of PARP inhibitors will be more pronounced in rapidly dividing and/or DNA repair defective tumors than normal tissues and show their potential to enhance the therapeutic ratio achieved by conventional DNA-damaging agents.

Synergistic effects of N-ethyl-N-nitrosourea (an alkylating agent with a low Swain-Scott substrate constant) and X-rays in the stamen hairs of Tradescantia clone BNL 4430.

PubMed

Shima, N; Ichikawa, S

1997-01-01

The mutagenic interaction between N-ethyl-N-nitrosourea (ENU) and X-rays was tested in the stamen hairs of Tradescantia clone BNL 4430, a blue/pink heterozygote. ENU, a monofunctional alkylating agent with a low Swain-Scott substrate constant (s) of 0.26, exhibited a strong cytotoxicity. ENU-induced somatic pink mutation frequency per 10(4) hair-cell divisions increased with increasing ENU dose, with a slope of 1.243 on a log-log graph, the slope value being similar to that for X-ray-induced mutation frequency. Three out of five combined treatments with ENU and X-rays produced mutation frequencies significantly higher than those expected from the additive effects of the two mutagens. Clear synergistic effects were detected when relatively higher X-ray doses were applied, resembling those confirmed earlier between methyl methanesulfonate (MMS) and X-rays, although the s value for ENU is very much smaller than that (0.88) for MMS. It is therefore concluded that mutagenic interactions between alkylating agents and X-rays do not have any clear relationship with the s values.

Antioxidant and antigenotoxic role of recombinant human erythropoeitin against alkylating agents: cisplatin and mitomycin C in cultured Vero cells.

PubMed

Rjiba-Touati, Karima; Ayed-Boussema, Imen; Soualeh, Nidhal; Achour, Abdellatif; Bacha, Hassen; Abid, Salwa

2013-08-01

Cisplatin (CDDP) and mitomycin C (MMC), two alkylating agents used against various solid tumours, are a common source of acute kidney injury. Thus, strategies for minimizing CDDP and MMC toxicity are of a clinical interest. In this study, we aimed to investigate the protective role of recombinant human erythropoietin (rhEPO) against oxidative stress and genotoxicity induced by CDDP and MMC in cultured Vero cells. Three types of treatments were performed: (i) cells were treated with rhEPO 24 h before exposure to CDDP/MMC (pre-treatment), (ii) cells were treated with rhEPO and CDDP/MMC simultaneously (co-treatment), (iii) cells were treated with rhEPO 24 h after exposure to CDDP/MMC (post-treatment). Our results showed that rhEPO decreased the reactive oxygen species levels, the malondialdehyde levels and ameliorated glutathione (reduced and oxidized glutathione) modulation induced by CDDP and MMC in cultured Vero cells. Furthermore, rhEPO administration prevented alkylating agents-induced DNA damage accessed by comet test. Altogether, our results suggested a protective role of rhEPO, against CDDP- and MMC-induced oxidative stress and genotoxicity, especially in pre-treatment condition.

Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study.

PubMed

Green, Daniel M; Liu, Wei; Kutteh, William H; Ke, Raymond W; Shelton, Kyla C; Sklar, Charles A; Chemaitilly, Wassim; Pui, Ching-Hon; Klosky, James L; Spunt, Sheri L; Metzger, Monika L; Srivastava, DeoKumar; Ness, Kirsten K; Robison, Leslie L; Hudson, Melissa M

2014-10-01

Few data define the dose-specific relation between alkylating agent exposure and semen variables in adult survivors of childhood cancer. We undertook this study to test the hypothesis that increased exposure to alkylating agents would be associated with decreased sperm concentration in a cohort of adult male survivors of childhood cancer who were not exposed to radiation therapy for their childhood cancer. We did semen analysis on 214 adult male survivors of childhood cancer (median age 7·7 years [range 0·01-20·3] at diagnosis, 29·0 years [18·4-56·1] at assessment, and a median of 21·0 years [10·5-41·6] since diagnosis) who had received alkylating agent chemotherapy but no radiation therapy. Alkylating agent exposure was estimated using the cyclophosphamide equivalent dose (CED). Odds ratios (ORs) and 95% CIs for oligospermia (sperm concentration >0 and <15 million per mL) and azoospermia were calculated with logistic regression modelling. Azoospermia was noted in 53 (25%) of 214 participants, oligospermia in 59 (28%), and normospermia (sperm concentration ≥15 million per mL) in 102 (48%) participants. 31 (89%) of 35 participants who received CED less than 4000 mg/m(2) were normospermic. CED was negatively correlated with sperm concentration (correlation coefficient=-0·37, p<0·0001). Mean CED was 10 830 mg/m(2) (SD 7274) in patients with azoospermia, 8480 mg/m(2) (4264) in patients with oligospermia, and 6626 mg/m(2) (3576) in patients with normospermia. In multivariable analysis, CED was significantly associated with an increased risk per 1000 mg/m(2) CED for azoospermia (OR 1·22, 95% CI 1·11-1·34), and for oligospermia (1·14, 1·04-1·25), but age at diagnosis and age at assessment were not. Impaired spermatogenesis was unlikely when the CED was less than 4000 mg/m(2). Although sperm concentration decreases with increasing CED, there was substantial overlap of CED associated with normospermia, oligospermia, and azoospermia. These data can inform pretreatment patient counselling and use of fertility preservation services. US National Cancer Institute, American Lebanese Syrian Associated Charities. Copyright © 2014 Elsevier Ltd. All rights reserved.

A Click Chemistry-Based Proteomic Approach Reveals that 1,2,4-Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile.

PubMed

Ismail, Hanafy M; Barton, Victoria E; Panchana, Matthew; Charoensutthivarakul, Sitthivut; Biagini, Giancarlo A; Ward, Stephen A; O'Neill, Paul M

2016-05-23

In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism of action. This is important since it will influence cross-resistance risks between the different classes. Here we investigate this proposition using novel clickable 1,2,4-trioxolane activity based protein-profiling probes (ABPPs). ABPPs with potent antimalarial activity were able to alkylate protein target(s) within the asexual erythrocytic stage of Plasmodium falciparum (3D7). Importantly, comparison of the alkylation fingerprint with that generated from an artemisinin ABPP equivalent confirms a highly conserved alkylation profile, with both endoperoxide classes targeting proteins in the glycolytic, hemoglobin degradation, antioxidant defence, protein synthesis and protein stress pathways, essential biological processes for plasmodial survival. The alkylation signatures of the two chemotypes show significant overlap (ca. 90 %) both qualitatively and semi-quantitatively, suggesting a common mechanism of action that raises concerns about potential cross-resistance liabilities.

N1-Alkylated 3,4-dihydropyrimidine-2(1H)-ones: Convenient one-pot selective synthesis and evaluation of their calcium channel blocking activity.

PubMed

Singh, Kamaljit; Arora, Divya; Poremsky, Elizabeth; Lowery, Jazmyne; Moreland, Robert S

2009-05-01

It has been found that selective N1-alkylation of 3,4-dihydropyrimidine-2(1H)-ones can be achieved under solvent-less, mild phase transfer catalytic (PTC) conditions with tetrabutylammonium hydrogen sulfate and 50% aqueous NaOH as the catalyst and base, respectively. The procedure is tolerant to substitutional variation at key diversity points on the pyrimidinone moiety.

Synthesis and Crystal Structures of Benzimidazole-2-thione Derivatives by Alkylation Reactions.

PubMed

El Ashry, El Sayed H; El Kilany, Yeldez; Nahas, Nariman M; Barakat, Assem; Al-Qurashi, Nadia; Ghabbour, Hazem A; Fun, Hoong-Kun

2015-12-22

Alkylated, benzylated and bromoalkylated benzimidazole-thione that intramolecularly heterocyclized to 3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazole were synthesized. The chemical structure of the synthesized product was characterized by Infra Red, ¹H-NMR, (13)C-NMR, and Mass spectroscopy. Furthermore, the molecular structures of 8 and 9 were confirmed by X-ray single crystallography in different space groups, Pbca and P2₁/c, respectively.

Total synthesis of (+)-batzelladine A and (-)-batzelladine D via [4 + 2]-annulation of vinyl carbodiimides with N-alkyl imines.

PubMed

Arnold, Michael A; Day, Kenneth A; Durón, Sergio G; Gin, David Y

2006-10-11

A diastereoselective [4 + 2]-annulation of vinyl carbodiimides with chiral N-alkyl imines has been developed to access the stereochemically rich polycyclic guanidine cores of the batzelladine alkaloids. Application of this strategy, together with additional key steps such as long-range directed hydrogenation and diastereoselective intramolecular iodo-amination, led to highly convergent total syntheses of (-)-batzelladine D and (+)-batzelladine A with excellent stereocontrol.

Synthesis of 4-alkyl and 4-(beta-alkylvinyl) derivatives of primaquine as potential antimalarials.

PubMed

Carroll, F I; Berrang, B D; Linn, C P

1979-11-01

4(beta-Alkylvinyl)-6-methoxy-8-nitroquinolines (6) were prepared from 6-methoxy-8-nitroquinoline-4-carboxaldehyde (5) via a Wittig reaction. Stannous chloride reduction of 6 gave 4-(beta-alkylvinyl)-8-amino-6-methoxyquinolines (8), whereas catalytic reduction of 6 using Raney nickel catalyst gave 4-alkyl-8-amino-6-methoxyquinolines (7). Alkylation of 7 and 8 with 4-iodo-1-phthalimidopentane, followed by removal of the phthaloyl-protecting group with hydrazine, gave 4-alkyl and 4-(beta-alkylvinyl) derivatives of primiquine, respectively. These compounds were evaluated for antimalarial activity against P. berghei and P. berghei yoelii in mice and against P. cynomolgi in rhesus monkeys. Several of the compounds were active in the P. bergheii yoelii screen. None of the compounds showed significant activity in the other two screens.

Cu/Mn bimetallic catalysis enables carbonylative Suzuki-Miyaura coupling with unactivated alkyl electrophiles.

PubMed

Pye, Dominic R; Cheng, Li-Jie; Mankad, Neal P

2017-07-01

A bimetallic system consisting of Cu-carbene and Mn-carbonyl co-catalysts was employed for carbonylative C-C coupling of arylboronic esters with alkyl halides, allowing for the convergent synthesis of ketones. The system operates under mild conditions and exhibits complementary reactivity to Pd catalysis. The method is compatible with a wide range of arylboronic ester nucleophiles and proceeds smoothly for both primary and secondary alkyl iodide electrophiles. Preliminary mechanistic experiments corroborate a hypothetical catalytic mechanism consisting of co-dependent cycles wherein the Cu-carbene co-catalyst engages in transmetallation to generate an organocopper nucleophile, while the Mn-carbonyl co-catalyst activates the alkyl halide electrophile by single-electron transfer and then undergoes reversible carbonylation to generate an acylmanganese electrophile. The two cycles then intersect with a heterobimetallic, product-releasing C-C coupling step.

Metal-free, mild, nonepimerizing, chemo- and enantio- or diastereoselective N-alkylation of amines by alcohols via oxidation/imine-iminium formation/reductive amination: a pragmatic synthesis of octahydropyrazinopyridoindoles and higher ring analogues.

PubMed

Khan, Imran A; Saxena, Anil K

2013-12-06

A mild step and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure has been developed via oxidation/imine-iminium formation/reduction cascade using TEMPO-BAIB-HEH-Brønsted acid catalysis in DMPU as solvent and a stoichiometric amount of amine. The optimized conditions were further extended for the nonenzymatic kinetic resolution of the chiral amine thus formed under nonenzymatic in situ hydrogen-transfer conditions using VAPOL-derived phosphoric acid (VAPOL-PA) as the Brønsted acid catalyst. The enantioselective cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring analogues.

Alkyl phospholipid antihypertensive agents in method of lowering blood pressure

DOEpatents

Snyder, Fred L.; Blank, Merle L.; Muirhead, Ernest E.; Leach, deceased, Byron E.; Byers, Lawrence W.

1988-01-01

The composition of this invention is 1-O-alkyl-2-acetoyl-sn-glycero-3-phosphocholine, having the ionic structural formula; ##STR1## wherein R is saturated alkyl having 9-21 carbon atoms, or salts or hydrates of the composition. Preferably R has 13-19 carbon atoms and most preferably R has 15 carbon atoms. The composition of this invention is useful for reducing hypertension in warm-blooded animals, including humans, when administered either orally or by injection or innoculation, e.g., intravenous injection. The composition can be prepared from naturally occurring lipids or synthetically from commercially available material.

DNA Repair Modulates The Vulnerability of The Developing Brain to Alkylating Agents

PubMed Central

Kisby, G.E.; Olivas, A.; Park, T.; Churchwell, M.; Doerge, D.; Samson, L. D.; Gerson, S.L.; Turker, M.S.

2009-01-01

Neurons of the developing brain are especially vulnerable to environmental agents that damage DNA (i.e., genotoxicants), but the mechanism is poorly understood. The focus of the present study is to demonstrate that DNA damage plays a key role in disrupting neurodevelopment. To examine this hypothesis, we compared the cytotoxic and DNA damaging properties of the methylating agents methylazoxymethanol (MAM) and dimethyl sulfate (DMS) and the mono- and bifunctional alkylating agents chloroethylamine (CEA) and nitrogen mustard (HN2), in granule cell neurons derived from the cerebellum of neonatal wild type mice and three transgenic DNA repair strains. Wild type cerebellar neurons were significantly more sensitive to the alkylating agents DMS and HN2 than neuronal cultures treated with MAM or the half-mustard CEA. Parallel studies with neuronal cultures from mice deficient in alkylguanine DNA glycosylase (Aag-/-) or O6-methylguanine methyltransferase (Mgmt-/-), revealed significant differences in the sensitivity of neurons to all four genotoxicants. Mgmt-/- neurons were more sensitive to MAM and HN2 than the other genotoxicants and wild type neurons treated with either alkylating agent. In contrast, Aag-/- neurons were for the most part significantly less sensitive than wild type or Mgmt-/- neurons to MAM and HN2. Aag-/- neurons were also significantly less sensitive than wild type neurons treated with either DMS or CEA. Granule cell development and motor function were also more severely disturbed by MAM and HN2 in Mgmt-/- mice than in comparably treated wild type mice. In contrast, cerebellar development and motor function were well preserved in MAM treated Aag-/- or MGMT overexpressing (MgmtTg+) mice, even as compared with wild type mice suggesting that AAG protein increases MAM toxicity, whereas MGMT protein decreases toxicity. Surprisingly, neuronal development and motor function were severely disturbed in MgmtTg+ mice treated with HN2. Collectively, these in vitro and in vivo studies demonstrate that the type of DNA lesion and the efficiency of DNA repair are two important factors that determine the vulnerability of the developing brain to long-term injury by a genotoxicant. PMID:19162564

Synthesis and Antibacterial Activities of Antibacterial Peptides with a Spiropyran Fluorescence Probe

PubMed Central

Chen, Lei; Zhu, Yu; Yang, Danling; Zou, Rongfeng; Wu, Junchen; Tian, He

2014-01-01

In this report, antibacterial peptides1-3 were prepared with a spiropyran fluorescence probe. The probe exhibits a change in fluorescence when isomerized from a colorless spiro-form (spiropyran, Sp) to a colored open-form (merocyanine, Mc) under different chemical environments, which can be used to study the mechanism of antimicrobial activity. Peptides 1-3 exhibit a marked decrease in antimicrobial activity with increasing alkyl chain length. This is likely due to the Sp-Mc isomers in different polar environments forming different aggregate sizes in TBS, as demonstrated by time-dependent dynamic light scattering (DLS). Moreover, peptides 1-3 exhibited low cytotoxicity and hemolytic activity. These probe-modified peptides may provide a novel approach to study the effect of structural changes on antibacterial activity, thus facilitating the design of new antimicrobial agents to combat bacterial infection. PMID:25358905

Design, Synthesis, and Biological Evaluation of Peptidomimetic N-Substituted Cbz-4-Hyp-Hpa-Amides as Novel Inhibitors of Plasmodium falciparum.

PubMed

Bacherikov, Valeriy A; Chittiboyina, Amar G; Avery, Mitchell A

2017-08-01

A new series of peptidomimetic N-substituted Cbz-4-Hyp-Hpa-amides were designed, synthesized, and evaluated for inhibition of the Plasmodium falciparum. Substituents on the N-atom of the amide group were selected alkyl-, allyl-, aryl-, 2-hydroxyethyl-, 2-cyanoethyl-, cyanomethyl-, 2-hydroxyethyl-, 2,2-diethoxyethyl-, or 2-ethoxy-2-oxoethylamino groups, and about of 40 new compounds were synthesized and evaluated for antiplasmodial activity in vitro. Antimalarial activity has been investigated as for the final peptide mimetics, and their immediate predecessors, carrying TBDMS or TBDPS protecting groups on 4-hydroxyproline residue and 18 derivatives exhibited toxicity against P. falciparum. Of these agents, compound 23e was shown to have potent antimalarial activity with IC 50 528 ng/ml. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

Structure-based design of nitrosoureas containing tyrosine derivatives as potential antimelanoma agents.

PubMed

Gadjeva, Vesselina

2002-04-01

Two new nitrosoureas (TNUs), containing tyrosine derivatives as carriers of nitrosourea cytotoxic group have been synthesised. The physicochemical properties such as half-life time (tau(0.5)), alkylating and carbamoylating activities were determined. The nitrosoureas showed a higher inhibiting effect on the DOPA-oxidase activity of mushroom tyrosinase than that of the antitumour drug N'-cyclohexyl-N-(2-chloroethyl)-N-nitrosourea (lomustine, CCNU). In vitro cytotoxic effects of newly synthesised tyrosine containing nitrosoureas have been studied and compared to those of CCNU. A higher cytotoxicity to B16 melanoma cells than to YAC-1 and to lymphocytes was demonstrated for the tyrosine containing nitrosoureas in comparison with CCNU. Based on the results presented, we accept that a new trend for synthesis of more selective and less toxic nitrosourea derivatives as potential antimelanomic drugs might be developed.

A concise entry into nonsymmetrical alkyl polyamines.

PubMed

Pirali, Tracey; Callipari, Grazia; Ercolano, Emanuela; Genazzani, Armando A; Giovenzana, Giovanni Battista; Tron, Gian Cesare

2008-10-02

The synthesis of nonsymmetrical polyamines (PAs) has, up to now, been problematic due to lengthy synthetic procedures, lack of regioselectivity, and very poor atom economy. An innovative synthetic protocol for nonsymmetrical PAs using a modified Ugi reaction ( N-split Ugi) which simplifies the synthesis of these tricky compounds is described. We believe that this new synthesis may open the door for the generation of new and pharmacologically active PAs.

Alkylation of acetohydroxyacid synthase I from Escherichia coli K-12 by 3-bromopyruvate: evidence for a single active site catalyzing acetolactate and acetohydroxybutyrate synthesis.

PubMed Central

Silverman, P M; Eoyang, L

1987-01-01

Acetohydroxyacid synthase I (AHAS I) purified from Escherichia coli K-12 was irreversibly inactivated by incubation with 3-bromopyruvate. Inactivation was specific, insofar as bromoacetate and iodoacetate were much less effective than bromopyruvate. Inactivation was accompanied by incorporation of radioactivity from 3-bromo[2-14C]pyruvate into acid-insoluble material. More than 95% of the incorporated radioactivity coelectrophoresed with the 60-kilodalton IlvB subunit of the enzyme through a sodium dodecyl sulfate-polyacrylamide gel; less than 5% coelectrophoresed with the 11.2-kilodalton IlvN subunit. The stoichiometry of incorporation at nearly complete inactivation was 1 mol of 14C per mol of IlvB polypeptide. These data indicate that bromopyruvate inactivates AHAS I by alkylating an amino acid at or near a single active site located in the IlvB subunit of the enzyme. We confirmed that this alkylation inactivated both AHAS reactions normally catalyzed by AHAS I. These results provide the first direct evidence that AHAS I catalyzes both acetohydroxybutyrate and acetolactate synthesis from the same active site. Images PMID:3294793

Synthesis and characterization of a novel long-alkyl-chain ester-substituted benzimidazole gelator and its octan-1-ol solvate.

PubMed

Geiger, H Cristina; Zick, Patricia L; Roberts, William R; Geiger, David K

2017-04-01

The synthesis of a novel benzimidazole derivative with a long-chain-ester substituent, namely methyl 8-[4-(1H-benzimidazol-2-yl)phenoxy]octanoate, (3), is reported. Ester (3) shows evidence of aggregation in solution and weak gelation ability with toluene. The octan-1-ol solvate, methyl 8-[4-(1H-benzimidazol-2-yl)phenoxy]octanoate octan-1-ol monosolvate, C 22 H 26 N 2 O 3 ·C 8 H 18 O, (4), exhibits a four-molecule hydrogen-bonded motif in the solid state, with N-H...O hydrogen bonds between benzimidazole molecules and O-H...N hydrogen bonds between the octan-1-ol solvent molecules and the benzimidazole unit. The alkyl chains of the ester and the octan-1-ol molecules are in unfolded conformations. The phenylene ring is canted by 10.27 (6)° from the plane of the benzimidazole ring system. H...C contacts make up 20.7% of the Hirshfeld surface coverage. Weak C-H...π interactions involving the benzimidazole alkyl chain and three aromatic rings are observed.

Stereospecific Nickel-Catalyzed Cross-Coupling Reactions of Alkyl Grignard Reagents and Identification of Selective Anti-Breast Cancer Agents**

PubMed Central

Osborne, Charlotte A.; Moore, Curtis E.; Morrissette, Naomi S.; Jarvo, Elizabeth R.

2014-01-01

β-Hydrogen-containing alkyl Grignard reagents were used in a stereospecific nickel-catalyzed cross-coupling reaction to form sp3–sp3 carbon–carbon bonds. Aryl Grignard reagents were also utilized to synthesize 1,1-diarylalkanes. Several compounds synthesized by this method exhibited selective inhibition of proliferation of MCF-7 breast cancer cells. PMID:24478275

ALKYL PYROPHOSPHATE METAL SOLVENT EXTRACTANTS AND PROCESS

DOEpatents

Long, R.L.

1958-09-30

A process is presented for the recovery of uranium from aqueous mineral acidic solutions by solvent extraction. The extractant is a synmmetrical dialkyl pyrophosphate in which the alkyl substituents have a chain length of from 4 to 17 carbon atoms. Mentioned as a preferred extractant is dioctyl pyrophosphate. The uranium is precipitated irom the organic extractant phase with an agent such as HF, fluoride salts. alcohol, or ammonia.

Silibinin derivatives as anti-prostate cancer agents: Synthesis and cell-based evaluations.

PubMed

Vue, Bao; Zhang, Sheng; Zhang, Xiaojie; Parisis, Konstantinos; Zhang, Qiang; Zheng, Shilong; Wang, Guangdi; Chen, Qiao-Hong

2016-02-15

This study aims to systematically explore the alkylation effect of 7-OH in silibinin and 2,3-dehydrosilibinin on the antiproliferative potency toward three prostate cancer cell lines. Eight 7-O-alkylsilibinins, eight 7-O-alkyl-2,3-dehydrosilibinins, and eight 3,7-O-dialkyl-2,3-dehydrosilibinins have been synthesized from commercially available silibinin for the in vitro cell-based evaluation. The WST-1 cell proliferation assay indicates that nineteen out of twenty-four silibinin derivatives have significantly improved antiproliferative potency when compared with silibinin. 7-O-Methylsilibinin (2) and 7-O-ethylsilibinin (3) have been identified as the most potent compounds with 98- and 123-fold enhanced potency against LNCaP human androgen-dependent prostate cancer cell line. Among 2,3-dehydrosilibinin derivatives, 7-O-methyl-2,3-dehydrosilibinin (10) and 7-O-ethyl-2,3-dehydrosilibinin (11) have been identified as the optimal compounds with the highest potency towards both androgen-dependent LNCaP and androgen-independent PC-3 prostate cancer cell lines. 7-O-Ethyl-2,3-dehydrosilibinin (11) was demonstrated to arrest PC-3 cell cycle at the G0/G1 phase and to induce PC-3 cell apoptosis. The findings in this study suggest that antiproliferative potency of silibinin and 2,3-dehydrosilibinin can be appreciably enhanced through suitable chemical modifications on the phenolic hydroxyl group at C-7 and that introduction of a chemical moiety with the potential to improve bioavailability through a linker to 7-OH in silibinin and 2,3-dehydrosilibinin would be a feasible strategy for the development of silibinin derivatives as anti-prostate cancer agents. Published by Elsevier Masson SAS.

Effect of alkyl glycerophosphate on the activation of peroxisome proliferator-activated receptor gamma and glucose uptake in C2C12 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsukahara, Tamotsu, E-mail: ttamotsu@shinshu-u.ac.jp; Haniu, Hisao; Matsuda, Yoshikazu

Highlights: •Alkyl-LPA specifically interacts with PPARγ. •Alkyl-LPA treatments induces lipid accumulation in C2C12 cells. •Alkyl-LPA enhanced glucose uptake in C2C12 cells. •Alkyl-LPA-treated C2C12 cells express increased amounts of GLUT4 mRNA. •Alkyl-LPA is a novel therapeutic agent that can be used for the treatment of obesity and diabetes. -- Abstract: Studies on the effects of lipids on skeletal muscle cells rarely examine the effects of lysophospholipids. Through our recent studies, we identified select forms of phospholipids, such as alkyl-LPA, as ligands for the intracellular receptor peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ is a nuclear hormone receptor implicated in many human diseases,more » including diabetes and obesity. We previously showed that alkyl-LPA is a specific agonist of PPARγ. However, the mechanism by which the alkyl-LPA–PPARγ axis affects skeletal muscle cells is poorly defined. Our objective in the present study was to determine whether alkyl-LPA and PPARγ activation promotes glucose uptake in skeletal muscle cells. Our findings indicate that PPARγ1 mRNA is more abundant than PPARγ2 mRNA in C2C12 cells. We showed that alkyl-LPA (3 μM) significantly activated PPARγ and increased intracellular glucose levels in skeletal muscle cells. We also showed that incubation of C2C12 cells with alkyl-LPA led to lipid accumulation in the cells. These findings suggest that alkyl-LPA activates PPARγ and stimulates glucose uptake in the absence of insulin in C2C12 cells. This may contribute to the plasma glucose-lowering effect in the treatment of insulin resistance.« less

O6-methylguanine-DNA methyltransferase activity is associated with response to alkylating agent therapy and with MGMT promoter methylation in glioblastoma and anaplastic glioma

PubMed Central

Bobola, Michael S.; Alnoor, Mohammad; Chen, John Y.-S.; Kolstoe, Douglas D.; Silbergeld, Daniel L.; Rostomily, Robert C.; Blank, A.; Chamberlain, Marc C.; Silber, John R.

2014-01-01

Background CpG methylation in the O6-methylguanine-DNA methyltransferase (MGMT) promoter is associated with better outcome following alkylating agent chemotherapy in glioblastoma (GBM) and anaplastic glioma (AG). To what extent improved response reflects low or absent MGMT activity in glioma tissue has not been unequivocally assessed. This information is central to developing anti-resistance therapies. Methods We examined the relationship of MGMT activity in 91 GBMs and 84 AGs with progression-free survival (PFS) following alkylator therapy and with promoter methylation status determined by methylation-specific PCR (MSP). Results Cox regression analysis revealed that GBMs with high activity had a significantly greater risk for progression in dichotomous (P ≤ 0.001) and continuous (P ≤ 0.003) models, an association observed for different alkylator regimens, including concurrent chemo-radiation with temozolomide. Analysis of MGMT promoter methylation status in 47 of the GBMs revealed that methylated tumors had significantly lower activity (P ≤ 0.005) and longer PFS (P ≤ 0.036) compared to unmethylated tumors, despite overlapping activities. PFS was also significantly greater in methylated vs. unmethylated GBMs with comparable activity (P ≤ 0.005), and among unmethylated tumors with less than median activity (P ≤ 0.026), suggesting that mechanisms in addition to MGMT promote alkylator resistance. Similar associations of MGMT activity with PFS and promoter methylation status were observed for AGs. Conclusions Our results provide strong support for the hypotheses that MGMT activity promotes alkylator resistance and reflects promoter methylation status in malignant gliomas. General significance MGMT activity is an attractive target for anti-resistance therapy regardless of methylation status. PMID:25558448

Synthesis of benzo-fused 1-azabicyclo[m.n.0]alkanes via the Schmidt reaction: a formal synthesis of gephyrotoxin.

PubMed

Pearson, W H; Fang, W

2000-10-20

The intramolecular capture of benzocyclobutyl, benzocyclopentyl, and benzocyclohexyl carbocations 7 by azides produces spirocyclic aminodiazonium ions 8, which undergo 1,2-C-to-N rearrangement with loss of dinitrogen to produce benzo-fused iminium ions resulting from either aryl (9) or alkyl (10) migration to the electron-deficient nitrogen atom. Reduction of the iminium ions affords regioisomeric benzo-fused 1-azabicyclo[m.n.0]alkanes, e.g., benzopyrrolizidines, benzoindolizidines, benzoquinolizidines, or perhydrobenzo[f]pyrrolo[1,2-a]azepines in two regioisomeric versions, anilines (e.g., 11-14) and benzylic amines (e.g., 15-18), the result of aryl and alkyl migrations, respectively. Generally, aryl migration is preferred, despite modeling that shows that the lowest energy aminodiazonium ions are those where the departing dinitrogen is preferentially antiperiplanar to the migrating alkyl group rather than the aryl group. The utility of this methodology was illustrated by a formal synthesis of the alkaloid gephyrotoxin 4. A dependence on the efficiency and regioselectivity of the Schmidt reaction upon subtle changes in the structure of the cation precursor was observed, necessitating the exploration of a variety of substrates. Fortunately, these materials were easily made. Ultimately, the azido-alkene 81 bearing a 2-bromoethyl side-chain was useful for the Schmidt reaction, producing the known benzo-fused indolizidine 49, which had been transformed by Ito et al. into gephyrotoxin 4. The synthesis of 49 required nine steps (five purifications) from commercially available 4-methoxy-1-indanone 60 and proceeded in 22% overall yield.

4-Alkylated homoibotenic acid (HIBO) analogues: versatile pharmacological agents with diverse selectivity profiles towards metabotropic and ionotropic glutamate receptor subtypes.

PubMed

Madsen, Ulf; Pickering, Darryl S; Nielsen, Birgitte; Bräuner-Osborne, Hans

2005-01-01

4-Alkylated analogues of homoibotenic acid (HIBO) have previously shown high potency and selectivity at ionotropic and metabotropic glutamic acid receptor (iGluR and mGluR) subtypes. Compounds with different selectivity profiles are valuable pharmacological tools for neuropharmacological studies, and the series of 4-alkyl-HIBO analogues have been extended in this paper in the search for versatile agents. Pharmacological characterization of five new analogues, branched and unbranched 4-alkyl-HIBO analogues, have been carried out. The present compounds are all weak antagonists at Group I mGluRs (mGluR1 and 5) presenting only small differences in potencies (Ki values ranging from 89 to 670 microM). Affinities were studied at native and cloned iGluRs, and the compounds described show preference for the AMPA receptor subtypes GluR1 and 2 over GluR3 and 4. However, compared to previous 4-alkyl-HIBO analogues, these compounds show a remarkably high affinity for the Kain preferring subtype GluR5. The observed GluR5 affinities were either similar or higher compared to their GluR1 and 2 affinity. Isopropyl-HIBO showed the highest affinity for GluR5 (Ki=0.16 microM), and represents a unique compound with high affinity towards the three subtypes GluR1, 2 and 5. In general, these compounds represent new selectivity profiles compared to previously reported Glu receptor analogues.

Synthesis of 6-alkyluridines from 6-cyanouridine via zinc(II) chloride-catalyzed nucleophilic substitution with alkyl Grignard reagents.

PubMed

Shih, Yu-Chiao; Yang, Ya-Ying; Lin, Chun-Chi; Chien, Tun-Cheng

2013-04-19

6-Cyanouracil derivatives underwent a direct nucleophilic substitution reaction with alkyl Grignard reagents in the presence of zinc(II) chloride as a catalyst to form the corresponding 6-alkyluracils. This methodology is applicable to sugar-protected 6-cyanouridine and 6-cyano-2'-deoxyuridine without the protection at the N(3)-imide and provides a facile and general access to versatile 6-alkyluracil and 6-alkyluridine derivatives.

Total Synthesis of (+)-Batzelladine A and (−)-Batzelladine D via [4 + 2]-Annulation of Vinyl Carbodiimides with N-Alkyl Imines

PubMed Central

Arnold, Michael A.; Day, Kenneth A.; Durón, Sergio G.; Gin, David Y.

2008-01-01

A diastereoselective [4 + 2]-annulation of vinyl carbodiimides with chiral N-alkyl imines has been developed to access the stereochemically rich polycyclic guanidine cores of the batzelladine alkaloids. Application of this strategy, together with additional key steps such as long-range directed hydrogenation and diastereoselective intramolecular iodo-amination, led to highly convergent total syntheses of (−)-batzelladine D and (+)-batzelladine A with excellent stereocontrol. PMID:17017806

Synthesis of 1-[bis(trifluoromethyl)phosphine]-1'-oxazolinylferrocene ligands and their application in regio- and enantioselective Pd-catalyzed allylic alkylation of monosubstituted allyl substrates.

PubMed

Lai, Zeng-Wei; Yang, Rong-Fei; Ye, Ke-Yin; Sun, Hongbin; You, Shu-Li

2014-01-01

A class of novel, easily accessible and air-stable 1-[bis(trifluoromethyl)phosphine]-1'-oxazolinylferrocene ligands has been synthesized from ferrocene. It became apparent that these ligands can be used in the regio- and enantioselective Pd-catalyzed allylic alkylation of monosubstituted allyl substrates in a highly efficient manner. Excellent regio- and enantioselectivity could be obtained for a wide range of substrates.

Differential chemosensitivity to antifolate drugs between RAS and BRAF melanoma cells

PubMed Central

2014-01-01

Background The importance of the genetic background of cancer cells for the individual susceptibility to cancer treatments is increasingly apparent. In melanoma, the existence of a BRAF mutation is a main predictor for successful BRAF-targeted therapy. However, despite initial successes with these therapies, patients relapse within a year and have to move on to other therapies. Moreover, patients harbouring a wild type BRAF gene (including 25% with NRAS mutations) still require alternative treatment such as chemotherapy. Multiple genetic parameters have been associated with response to chemotherapy, but despite their high frequency in melanoma nothing is known about the impact of BRAF or NRAS mutations on the response to chemotherapeutic agents. Methods Using cell proliferation and DNA methylation assays, FACS analysis and quantitative-RT-PCR we have characterised the response of a panel of NRAS and BRAF mutant melanoma cell lines to various chemotherapy drugs, amongst them dacarbazine (DTIC) and temozolomide (TMZ) and DNA synthesis inhibitors. Results Although both, DTIC and TMZ act as alkylating agents through the same intermediate, NRAS and BRAF mutant cells responded differentially only to DTIC. Further analysis revealed that the growth-inhibitory effects mediated by DTIC were rather due to interference with nucleotide salvaging, and that NRAS mutant melanoma cells exhibit higher activity of the nucleotide synthesis enzymes IMPDH and TK1. Importantly, the enhanced ability of RAS mutant cells to use nucleotide salvaging resulted in resistance to DHFR inhibitors. Conclusion In summary, our data suggest that the genetic background in melanoma cells influences the response to inhibitors blocking de novo DNA synthesis, and that defining the RAS mutation status could be used to stratify patients for the use of antifolate drugs. PMID:24941944

Oxidative 1,2-carboamination of alkenes with alkyl nitriles and amines toward γ-amino alkyl nitriles

NASA Astrophysics Data System (ADS)

Liu, Yan-Yun; Yang, Xu-Heng; Song, Ren-Jie; Luo, Shenglian; Li, Jin-Heng

2017-04-01

Difunctionalization of alkenes has become a powerful tool for quickly increasing molecular complexity in synthesis. Despite significant progress in the area of alkene difunctionalization involving the incorporation of a nitrogen atom across the C-C double bonds, approaches for the direct 1,2-carboamination of alkenes to produce linear N-containing molecules are scarce and remain a formidable challenge. Here we describe a radical-mediated oxidative intermolecular 1,2-alkylamination of alkenes with alkyl nitriles and amines involving C(sp3)-H oxidative functionalization catalysed by a combination of Ag2CO3 with iron Lewis acids. This three-component alkene 1,2-alkylamination method is initiated by the C(sp3)-H oxidative radical functionalization, which enables one-step formation of two new chemical bonds, a C-C bond and a C-N bond, to selectively produce γ-amino alkyl nitriles.

Isomeric Detergent Comparison for Membrane Protein Stability: Importance of Inter-Alkyl-Chain Distance and Alkyl Chain Length

PubMed Central

Cho, Kyung Ho; Hariharan, Parameswaran; Mortensen, Jonas S.; Du, Yang; Nielsen, Anne K.; Byrne, Bernadette; Kobilka, Brian K.; Loland, Claus J.; Guan, Lan

2017-01-01

Membrane proteins encapsulated by detergent micelles are widely used for structural study. Because of their amphipathic property, detergents have the ability to maintain protein solubility and stability in an aqueous medium. However, conventional detergents have serious limitations in their scope and utility, particularly for eukaryotic membrane proteins and membrane protein complexes. Thus, a number of new agents have been devised; some have made significant contributions to membrane protein structural studies. However, few detergent design principles are available. In this study, we prepared meta and ortho isomers of the previously reported para-substituted xylene-linked maltoside amphiphiles (XMAs), along with alkyl chain-length variation. The isomeric XMAs were assessed with three membrane proteins, and the meta isomer with a C12 alkyl chain was most effective at maintaining solubility/stability of the membrane proteins. We propose that interplay between the hydrophile–lipophile balance (HLB) and alkyl chain length is of central importance for high detergent efficacy. In addition, differences in inter-alkyl-chain distance between the isomers influence the ability of the detergents to stabilise membrane proteins. PMID:27981750

Intramolecular homolytic displacements. 30. Functional decarbonylative transformations of aldehydes via homolytically induced decomposition of unsaturated peroxyacetals

PubMed

Degueil-Castaing; Moutet; Maillard

2000-06-30

Homolytically induced decompositions of unsaturated peroxyacetals, synthesized from aldehydes, gave alkoxyalkoxyl radicals that yielded alkyl radicals by rapid beta-scission. The latter radicals could react with several types of "transfer agents" to smoothly bring about homolytic decarbonylative functional group transformations of aldehydes into halides, hydrocarbons, xanthates, alkanenitriles, 2-alkyl-3-chloromaleic anhydrides, 1-phenylalk-1-ynes, and ethyl 2-alkylpropenoates.

Radiation-induced transmethylation and transsulfuration in the system DNA-methionine

NASA Astrophysics Data System (ADS)

Köhnlein, W.; Merwitz, O.; Ohneseit, P.

Evidence is presented for the radiation-induced transmethylation and transsulfuration in a DNA-methionine model system. The extent of such alkylation of DNA is found to be comparable with that of alkylating agents. Therefore, both processes could be initial steps in radiation carcinogenesis. The protective effect of methionine on DNA strand breaks, due to scavenging of OH radicals, causes the formation of methyl and thiyl radicals.

Palladium-Catalyzed Asymmetric Alkylation in the Synthesis of Cyclopentanoid and Cycloheptanoid Core Structures Bearing All-Carbon Quaternary Stereocenters

PubMed Central

Hong, Allen Y.; Bennett, Nathan B.; Krout, Michael R.; Jensen, Thomas; Harned, Andrew. M.

2011-01-01

General catalytic asymmetric routes toward cyclopentanoid and cycloheptanoid core structures embedded in numerous natural products have been developed. The central stereoselective transformation in our divergent strategies is the enantioselective decarboxylative alkylation of seven-membered β-ketoesters to form α-quaternary vinylogous esters. Recognition of the unusual reactivity of β-hydroxyketones resulting from the addition of hydride or organometallic reagents enabled divergent access to γ-quaternary acylcyclopentenes through a ring contraction pathway or γ-quaternary cycloheptenones through a carbonyl transposition pathway. Synthetic applications of these compounds were explored through the preparation of mono-, bi-, and tricyclic derivatives that can serve as valuable intermediates for the total synthesis of complex natural products. This work complements our previous work with cyclohexanoid systems. PMID:22347731

Synthesis of hydroxyphthioceranic acid using a traceless lithiation-borylation-protodeboronation strategy

NASA Astrophysics Data System (ADS)

Rasappan, Ramesh; Aggarwal, Varinder K.

2014-09-01

In planning organic syntheses, disconnections are most often made adjacent to functional groups, which assist in C-C bond formation. For molecules devoid of obvious functional groups this approach presents a problem, and so functionalities must be installed temporarily and then removed. Here we present a traceless strategy for organic synthesis that uses a boronic ester as such a group in a one-pot lithiation-borylation-protodeboronation sequence. To realize this strategy, we developed a methodology for the protodeboronation of alkyl pinacol boronic esters that involves the formation of a boronate complex with a nucleophile followed by oxidation with Mn(OAc)3 in the presence of the hydrogen-atom donor 4-tert-butylcatechol. Iterative lithiation-borylation-protodeboronation allows the coupling of smaller fragments to build-up long alkyl chains. We employed this strategy in the synthesis of hydroxyphthioceranic acid, a key component of the cell-wall lipid of the virulent Mycobacterium tuberculosis, in just 14 steps (longest linear sequence) with full stereocontrol.

INCREASE IN THE CHEMOTHERAPEUTIC COEFFICIENT OF MECHLORETHAMINE BY THE ACTION OF THE RADIOPROTECTIVE AGENT SODIUM DIETHYLDITHIOCARBAMATE (in Italian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cima, L; Pozza, F

1963-01-01

In mice of the SMZ strain the protective effect of various kinds of radioprotectant agents against the toxicity of the alkylating agent mechiorethamine (HN2) was investigated. HN2 was injected subcutaneously in doses of 6 mg/kg, corresponding to the LD/sub 99/6/. The most effective protective agent tested was the chelating agent Na diethyldithiocarbamate (DEDTC), which when injected intraperitoneally in doses of 335 mg/kg raised the 4-day survival rate to 90% from a control value of 20%. Other chelating agents were less effective, showing the specific action of the dithiocarbamate anion: tetraethylthiuram disulfide (disulfiram), 2-guanidinothiazolidone, and diethylamine. Moderately effective against the toxicitymore » of HN2 were (in decreasing order): reserpine, chlorpromazine, propylene glycol, malononitrile, glutathione, cysteamine, oxytocin, and Na ethylenediaminetatraacetate. Tryptamine was ineffective and cysteine augmented the toxicity of HN2. DEDTC did not modify the carcinostatic effect of HN2 against Ehrlich ascites tumor and thus, by markedly reducing the toxicity of HN2, enhances the therapeutic index of HN2 3 fold. The protective effect of DEDTC and the other radioprotectant agents against HN2 suggest that alkylating agents and ionizing radiation have analogous effects on tissue constituents. (H.H.D.)« less

Thiol-ene/oxidation tandem reaction under visible light photocatalysis: synthesis of alkyl sulfoxides.

PubMed

Guerrero-Corella, Andrea; María Martinez-Gualda, Ana; Ahmadi, Fereshteh; Ming, Enrique; Fraile, Alberto; Alemán, José

2017-09-19

The photocatalyzed synthesis of sulfoxides from alkenes and thiols has been carried out using Eosin Y. This is a metal-free method which uses a low catalyst loading, atmospheric oxygen as the oxidant, and visible light conditions (green light). A mechanism has been proposed that is consistent with the experimental results.

Synthesis of functionalized chromenes from Meldrum's acid, 4-hydroxycoumarin, and ketones or aldehydes.

PubMed

Sabbaghan, Maryam; Yavari, Issa; Hossaini, Zinatossadat

2010-11-01

An efficient synthesis of 4-alkyl-4-methyl-3,4-dihydro-2H,5H-pyrano[3,2-c]chromene-2,5-dione or 4-aryl-3,4-dihydro-2H,5H-pyrano[3,2-c]chromene-2,5-diones via reaction 4-hydroxycoumarin with Meldrum's acid and ketones or aldehydes is described.

SOLVENT EXTRACTION PROCESS FOR THE RECOVERY OF METALS FROM PHOSPHORIC ACID

DOEpatents

Bailes, R.H.; Long, R.S.

1958-11-01

> A solvent extraction process is presented for recovering metal values including uranium, thorium, and other lanthanide and actinide elements from crude industrial phosphoric acid solutions. The process conslsts of contacting said solution with an immisclble organic solvent extractant containing a diluent and a material selected from the group consisting of mono and di alkyl phosphates, alkyl phosphonates and alkyl phosphites. The uranlum enters the extractant phase and is subsequently recovered by any of the methods known to the art. Recovery is improved if the phosphate solution is treated with a reducing agent such as iron or aluminum powder prior to the extraction step.

Towards of Vanadium Pentoxide Nanotubes and Thiols using Gold Nanoparticles

NASA Astrophysics Data System (ADS)

Lavayen, V.; Gonzalez, G.; Cardenas, G.; Sotomayor Torres, C. M.

2005-09-01

The template-directed synthesis is a promising route to realise 1-D nanostructures, an example of which is the formation of vanadium pentoxide nanotubes. In this work we report the interchange of long alkyl amines with alkyl thiols, this reaction was followed using gold nanoparticles prepared by the Chemical Liquid Deposition (CLD) method. The diameter of the gold clusters was 9 Å with a stability of about 85 days. SEM, TEM, EDAX and electron diffraction was the techniques used for the characterization of the reactions.

Synthesis of acid addition salt of delta-aminolevulinic acid from 5-bromo levulinic acid esters

DOEpatents

Moens, Luc

2003-06-24

A process of preparing an acid addition salt of delta-aminolevulinc acid comprising: a) dissolving a lower alkyl 5-bromolevulinate and hexamethylenetetramine in a solvent selected from the group consisting of water, ethyl acetate, chloroform, acetone, ethanol, tetrahydrofuran and acetonitrile, to form a quaternary ammonium salt of the lower alkyl 5-bromolevulinate; and b) hydrolyzing the quaternary ammonium salt with an inorganic acid to form an acid addition salt of delta-aminolevulinic acid.

Synthesis of 1-[bis(trifluoromethyl)phosphine]-1’-oxazolinylferrocene ligands and their application in regio- and enantioselective Pd-catalyzed allylic alkylation of monosubstituted allyl substrates

PubMed Central

Lai, Zeng-Wei; Yang, Rong-Fei; Ye, Ke-Yin

2014-01-01

Summary A class of novel, easily accessible and air-stable 1-[bis(trifluoromethyl)phosphine]-1’-oxazolinylferrocene ligands has been synthesized from ferrocene. It became apparent that these ligands can be used in the regio- and enantioselective Pd-catalyzed allylic alkylation of monosubstituted allyl substrates in a highly efficient manner. Excellent regio- and enantioselectivity could be obtained for a wide range of substrates. PMID:24991277

Molecular characterization of an adaptive response to alkylating agents in the opportunistic pathogen Aspergillus fumigatus.

PubMed

O'Hanlon, Karen A; Margison, Geoffrey P; Hatch, Amy; Fitzpatrick, David A; Owens, Rebecca A; Doyle, Sean; Jones, Gary W

2012-09-01

An adaptive response to alkylating agents based upon the conformational change of a methylphosphotriester (MPT) DNA repair protein to a transcriptional activator has been demonstrated in a number of bacterial species, but this mechanism appears largely absent from eukaryotes. Here, we demonstrate that the human pathogen Aspergillus fumigatus elicits an adaptive response to sub-lethal doses of the mono-functional alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). We have identified genes that encode MPT and O(6)-alkylguanine DNA alkyltransferase (AGT) DNA repair proteins; deletions of either of these genes abolish the adaptive response and sensitize the organism to MNNG. In vitro DNA repair assays confirm the ability of MPT and AGT to repair methylphosphotriester and O(6)-methylguanine lesions respectively. In eukaryotes, the MPT protein is confined to a select group of fungal species, some of which are major mammalian and plant pathogens. The evolutionary origin of the adaptive response is bacterial and rooted within the Firmicutes phylum. Inter-kingdom horizontal gene transfer between Firmicutes and Ascomycete ancestors introduced the adaptive response into the Fungal kingdom. Our data constitute the first detailed characterization of the molecular mechanism of the adaptive response in a lower eukaryote and has applications for development of novel fungal therapeutics targeting this DNA repair system.

Molecular characterization of an adaptive response to alkylating agents in the opportunistic pathogen Aspergillus fumigatus

PubMed Central

O’Hanlon, Karen A.; Margison, Geoffrey P.; Hatch, Amy; Fitzpatrick, David A.; Owens, Rebecca A.; Doyle, Sean; Jones, Gary W.

2012-01-01

An adaptive response to alkylating agents based upon the conformational change of a methylphosphotriester (MPT) DNA repair protein to a transcriptional activator has been demonstrated in a number of bacterial species, but this mechanism appears largely absent from eukaryotes. Here, we demonstrate that the human pathogen Aspergillus fumigatus elicits an adaptive response to sub-lethal doses of the mono-functional alkylating agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG). We have identified genes that encode MPT and O6-alkylguanine DNA alkyltransferase (AGT) DNA repair proteins; deletions of either of these genes abolish the adaptive response and sensitize the organism to MNNG. In vitro DNA repair assays confirm the ability of MPT and AGT to repair methylphosphotriester and O6-methylguanine lesions respectively. In eukaryotes, the MPT protein is confined to a select group of fungal species, some of which are major mammalian and plant pathogens. The evolutionary origin of the adaptive response is bacterial and rooted within the Firmicutes phylum. Inter-kingdom horizontal gene transfer between Firmicutes and Ascomycete ancestors introduced the adaptive response into the Fungal kingdom. Our data constitute the first detailed characterization of the molecular mechanism of the adaptive response in a lower eukaryote and has applications for development of novel fungal therapeutics targeting this DNA repair system. PMID:22669901

HeLa Cells Containing a Truncated Form of DNA Polymerase Beta are More Sensitized to Alkylating Agents than to Agents Inducing Oxidative Stress.

PubMed

Khanra, Kalyani; Chakraborty, Anindita; Bhattacharyya, Nandan

2015-01-01

The present study was aimed at determining the effects of alkylating and oxidative stress inducing agents on a newly identified variant of DNA polymerase beta (polβ Δ208-304) specific for ovarian cancer. Pol β Δ208-304 has a deletion of exons 11-13 which lie in the catalytic part of enzyme. We compared the effect of these chemicals on HeLa cells and HeLa cells stably transfected with this variant cloned into in pcDNAI/neo vector by MTT, colony forming and apoptosis assays. Polβ Δ208-304 cells exhibited greater sensitivity to an alkylating agent and less sensitivity towards H2O2 and UV when compared with HeLa cells alone. It has been shown that cell death in Pol β Δ208-304 transfected HeLa cells is mediated by the caspase 9 cascade. Exon 11 has nucleotidyl selection activity, while exons 12 and 13 have dNTP selection activity. Hence deletion of this part may affect polymerizing activity although single strand binding and double strand binding activity may remain same. The lack of this part may adversely affect catalytic activity of DNA polymerase beta so that the variant may act as a dominant negative mutant. This would represent clinical significance if translated into a clinical setting because resistance to radiation or chemotherapy during the relapse of the disease could be potentially overcome by this approach.

Effect of chemotherapy with alkylating agents on the yield of CD34+ cells in patients with multiple myeloma. Results of the Spanish Myeloma Group (GEM) Study.

PubMed

de la Rubia, Javier; Bladé, Joan; Lahuerta, Juan-José; Ribera, Josep M; Martínez, Rafael; Alegre, Adrián; García-Laraña, José; Fernández, Pascual; Sureda, Anna; de Arriba, Felipe; Carrera, Dolores; Besalduch, Joan; García Boyero, Raimundo; Palomera Bernal, Luis; Hernández, Miguel T; García, Paz Ribas; Pérez-Calvo, Javier; Alcalá, Antonio; Casado, Luis Felipe; San Miguel, Jesús

2006-05-01

Although alkylating agents are clearly beneficial in multiple myeloma (MM), their deleterious effect on bone marrow hematopoietic progenitor cells usually precludes their use as front-line therapy in patients scheduled to undergo autologous stem cell transplantation (ASCT). We analyzed the impact of first-line chemotherapy with alkylating agents on stem cell collection in MM patients. Seven hundred and eighty-nine patients included in the Spanish multicenter protocol GEM-2000 underwent mobilization therapy after four courses of alternating VBMCP/VBAD chemotherapy. The mobilization regimens consisted of standard or high-dose granulocyte colony-stimulating factor (G-CSF) in 551 (70%) patients, and chemotherapy and G-CSF in 206 (26%) patients. The CD34+ cell yield was lower than 4x10(6)/kg in 388 patients (49%), and equal or greater than 4x10(6)/kg in 401 patients (51%). Multivariate analysis indicated that advanced age (p<0.0001) and longer interval between diagnosis and mobilization (p=0.012) were the two variables associated with a lower CD34+ cell yield. Significant differences in CD34+ cell yield were not observed between the mobilization regimens. Of the 789 patients included in the protocol, 726 (92%) underwent the planned ASCT, whereas 25 (3%) patients did not because of the low number of CD34+ cells collected. Following ASCT, 0.5x10(9) neutrophils/L could be recovered after 11 days (median time; range, 5-71 days) and 20x10(9) platelets/L could be recovered after 12 days (median time; range, 6-69 days). A short-course of therapy with alkylating agents according to the GEM-2000 protocol was associated with an appropriate CD34+ cell collection, and allowed the planned ASCT to be performed in the majority of MM patients.

Synthesis of Quaternary Carbon Stereogenic Centers through Enantioselective Cu-Catalyzed Allylic Substitutions with Vinylaluminum Reagents

PubMed Central

Gao, Fang; McGrath, Kevin P.; Lee, Yunmi; Hoveyda, Amir H.

2010-01-01

Catalytic enantioselective allylic substitution (EAS) reactions, which involve the use of alkyl- or aryl-substituted vinylaluminum reagents and afford 1,4-dienes containing a quaternary carbon stereogenic center at their C-3 site, are disclosed. The C–C bond forming transformations are promoted by 0.5–2.5 mol % of sulfonate bearing chiral bidentate N-heterocyclic carbene (NHC) complexes, furnishing the desired products efficiently (66–97% yield of isolated products) and in high site- (>98% SN2′) and enantioselectivity [up to 99:1 enantiomer ratio (er)]. To the best of our knowledge, the present report puts forward the first cases of allylic substitution reactions that result in the generation of all-carbon quaternary stereogenic centers through the addition of a vinyl unit. The aryl- and vinyl-substituted vinylaluminum reagents, which cannot be prepared in high efficiency through direct reaction with diisobutylaluminum hydride, are accessed through a recently introduced Ni-catalyzed reaction of the corresponding terminal alkynes with the same inexpensive metal-hydride agent. Sequential Ni-catalyzed hydrometallations and Cu-catalyzed C–C bond forming reactions allow for efficient and selective synthesis of a range of enantiomerically enriched EAS products, which cannot cannot be accessed by previously disclosed strategies (due to inefficient vinylmetal synthesis or low reactivity and/or selectivity with Si-substituted derivatives). The utility of the protocols developed is demonstrated through a concise enantioselective synthesis of natural product bakuchiol. PMID:20860365

Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies

PubMed Central

Behenna, Douglas C.; Mohr, Justin T.; Sherden, Nathaniel H.; Marinescu, Smaranda C.; Harned, Andrew M.; Tani, Kousuke; Seto, Masaki; Ma, Sandy; Novák, Zoltán; Krout, Michael R.; McFadden, Ryan M.; Roizen, Jennifer L.; Enquist, John A.; White, David E.; Levine, Samantha R.; Petrova, Krastina V.; Iwashita, Akihiko; Virgil, Scott C.; Stoltz, Brian M.

2012-01-01

α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursors: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center. PMID:22083969

Enantioselective Synthesis of Chiral α-Azido and α-Aryloxy Quaternary Stereogenic Centers via the Phase-Transfer-Catalyzed α-Alkylation of α-Bromomalonates, Followed by SN2 Substitution.

PubMed

Kim, Doyoung; Ha, Min Woo; Hong, Suckchang; Park, Cheonhyoung; Kim, Byungsoo; Yang, Jewon; Park, Hyeung-Geun

2017-05-05

A new efficient synthetic method for chiral α-azido-α-alkylmalonates and α-aryloxy-α-alkylmalonates was developed. The enantioselective α-alkylation of diphenylmethyl tert-butyl α-bromomalonate under phase-transfer catalytic conditions [(S,S)-3,4,5-trifluorophenyl-NAS bromide, 50% KOH, toluene, and -40 °C) provided the corresponding α-bromo-α-alkylmalonates in high chemical yields (≤98%) and high optical yields (≤99% ee). The resulting α-alkylated products were converted to α-azido-α-alkylmalonates (≤96%, ≤97% ee) and α-aryloxy-α-alkylmalonates (≤79%, ≤93% ee) by S N 2 substitution with sodium azide and aryloxides, respectively.

Stereo-specific Synthesis of Analogs of Nerve Agents And Their Utilization For Selection And Characterization of Paraoxonase (PON1) Catalytic Scavengers

PubMed Central

Ashani, Y.; Gupta, R.D.; Goldsmith, M.; Silman, I.; Sussman, J.L.; Tawfik, D. S.; Leader, H.

2010-01-01

Fluorogenic organophosphate inhibitors of acetylcholinesterase (AChE) homologous in structure to nerve agents provide useful probes for high throughput screening of mammalian paraoxonase (PON1) libraries generated by directed evolution of an engineered PON1 variant with wild-type like specificity (rePON1). Wt PON1 and rePON1 hydrolyze preferentially the less-toxic RP enantiomers of nerve agents and of their fluorogenic surrogates containing the fluorescent leaving group, 3-cyano-7-hydroxy-4-methylcoumarin (CHMC). To increase the sensitivity and reliability of the screening protocol so as to directly select rePON1 clones displaying stereo-preference towards the toxic SP enantiomer, and to determine accurately Km and kcat values for the individual isomers, two approaches were used to obtain the corresponding SP and RP isomers: (a) stereo-specific synthesis of the O-ethyl, O-n-propyl, and O-i-propyl analogs; (b) enzymic resolution of a racemic mixture of O-cyclohexyl methylphosphonylated CHMC. The configurational assignments of the SP and RP isomers, as well as their optical purity, were established by X-ray diffraction, reaction with sodium fluoride, hydrolysis by selected rePON1 variants, and inhibition of AChE. The SP configuration of the tested surrogates was established for the enantiomer with the more potent anti-AChE activity, with SP/RP inhibition ratios of 10–100, whereas the RP isomers of the O-ethyl and O-n-propyl were hydrolyzed by wt rePON1 about 600- and 70-fold faster, respectively, than the SP counterpart. Wt rePON1-induced RP/SP hydrolysis ratios for the O-cyclohexyl and O-i-propyl analogs are estimated to be ≫1000. The various SP enantiomers of O-alkyl-methylphosphonyl esters of CHMC provide suitable ligands for screening rePON1 libraries, and can expedite identification of variants with enhanced catalytic proficiency towards the toxic nerve agents. PMID:20303930

Synthesis of Alkyl-Glycerolipids Standards for Gas Chromatography Analysis: Application for Chimera and Shark Liver Oils

PubMed Central

Pinault, Michelle; Guimaraes, Cyrille; Couthon, Hélène; Thibonnet, Jérôme; Fontaine, Delphine; Chantôme, Aurélie; Chevalier, Stephan; Jaffrès, Paul-Alain; Vandier, Christophe

2018-01-01

Natural O-alkyl-glycerolipids, also known as alkyl-ether-lipids (AEL), feature a long fatty alkyl chain linked to the glycerol unit by an ether bond. AEL are ubiquitously found in different tissues but, are abundant in shark liver oil, breast milk, red blood cells, blood plasma, and bone marrow. Only a few AEL are commercially available, while many others with saturated or mono-unsaturated alkyl chains of variable length are not available. These compounds are, however, necessary as standards for analytical methods. Here, we investigated different reported procedures and we adapted some of them to prepare a series of 1-O-alkyl-glycerols featuring mainly saturated alkyl chains of various lengths (14:0, 16:0, 17:0, 19:0, 20:0, 22:0) and two monounsaturated chains (16:1, 18:1). All of these standards were fully characterized by NMR and GC-MS. Finally, we used these standards to identify the AEL subtypes in shark and chimera liver oils. The distribution of the identified AEL were: 14:0 (20–24%), 16:0 (42–54%) and 18:1 (6–16%) and, to a lesser extent, (0.2–2%) for each of the following: 16:1, 17:0, 18:0, and 20:0. These standards open the possibilities to identify AEL subtypes in tumours and compare their composition to those of non-tumour tissues. PMID:29570630

Effect of Anti-Parasite Chemotherapeutic Agents on Immune Reactions.

DTIC Science & Technology

1980-08-01

observations). Similar effects of a number of other alkylating agents have been noticed (9, and personal observa- tions). Similarly, corticosteroids inhibit...Wellham, L. L., and Sigel, M. M. Ef- fect of anti-cancer chemotherapeutic agents on immune reactions of mice. I. Comparison of two nitrosoureas . J...7 D-Ri138 852 EFFECT OF ANTI-PARASITE CHEMOTHERAPEUTIC AGENTS ON i/i IMMUNE REACTIONS(U) SOUTH CAROLINA UNIV COLUMBIA DEPT OF MICROBIOLOGY AND

Insight into microbial mannosidases: a review.

PubMed

Chauhan, Prakram Singh; Gupta, Naveen

2017-03-01

Mannan is the major constituent of hemicelluloses in softwoods. Mannan hydrolyzing enzymes cleave the 1,4-β-mannopyranosyl linkages of the hetero-1,4-β-d-mannans to yield mannose. β-Mannosidases are mandatory for the complete depolymerization of mannan, these are exo-acting enzymes, which acts on non-reducing end of mannooligomers and on mannobiose removing mannose residues. Some plants and actinomycetes produce mannosidases but mainly these enzymes are produced by bacteria and fungi. The majority of microorganisms produce these enzymes extracellularly and their activity is in a wide range of pH and temperature. They have found potential applications in bioethanol production, synthesis of alkyl glycosides and, as pharmaceutical agents. Comprehensive information will be helpful for the effective understanding and application of these enzymes. This manuscript is an exhaustive review of microbial mannosidases reported to date. All the aspects such as sources, production conditions, characterization, cloning and biotechnological applications are considered.

Synthesis and biological evaluation of novel quinazoline-sulfonamides as anti-cancer agents.

PubMed

Poudapally, Suresh; Battu, Shankar; Velatooru, Loka Reddy; Bethu, Murali Satyanarayana; Janapala, Venkateswara Rao; Sharma, Somesh; Sen, Subhabrata; Pottabathini, Narender; Iska, Vijaya Bhaskara Reddy; Katangoor, Vidya

2017-05-01

A robust economic approach to N-(quinazoline-4-yl)sulfonamides was developed and synthesized different aryl, hetero aryl, alkyl and cyclopropyl sulfonamides in excellent yields. All the compounds were evaluated for cytotoxic affinity to SKOV3, DU145, THP1, U937, and COLO205 cell lines. Interesting to find that the bulkiness of substituent at C-2 position of quinazoline forces the molecule to flip around in order to bind in the active site, when compared to the binding preference of previously known quinazoline compounds. Among the 21 compounds synthesized 2b, 2d, 2e, 2h, 2i, 3c, 3d, 3f, 3g and 3h found to be active on all the cell lines tested with IC 50 values <10µg/mL. Performed docking simulations to understand the binding preference of various C-2 substituted quinazoline sulfonamides. Copyright © 2017 Elsevier Ltd. All rights reserved.

Key factor affecting the structural and textural properties of ZSM-5/MCM-41 composite

NASA Astrophysics Data System (ADS)

Boukoussa, Bouhadjar; Aouad, Nafissa; Hamacha, Rachida; Bengueddach, Abdelkader

2015-03-01

ZSM-5/MCM-41 micro/mesoporous composite materials were synthesized by the hydrothermal technique with alkali-treated ZSM-5 zeolite as source of silica and aluminum and characterized by various physico-chemical techniques such as X-ray diffraction (XRD), nitrogen sorption at 77 K, transmission electronic microscopy (TEM), FTIR spectroscopy and NH3 temperature programmed desorption (TPD) techniques. The effect of concentration of CTAB in the synthesis of these solids has been investigated, the mesopore volume, surface area and surface acidity decrease with increasing the concentration of CTAB. Increasing the CTAB concentration causes the recrystallization of zeolite ZSM-5 and it disadvantage the formation of mesoporous materials MCM-41. The catalytic activity of ZSM-5/MCM-41 materials has been evaluated in the Friedel-Crafts acylation of anisole with benzoyl chloride as alkylating agent. The results revealed the reaction to be influenced by surface area, pore volume and surface acidity.

Binding of chemical warfare agent simulants as guests in a coordination cage: contributions to binding and a fluorescence-based response.

PubMed

Taylor, Christopher G P; Piper, Jerico R; Ward, Michael D

2016-05-07

Cubic coordination cages act as competent hosts for several alkyl phosphonates used as chemical warfare agent simulants; a range of cage/guest structures have been determined, contributions to guest binding analysed, and a fluorescent response to guest binding demonstrated.

21 CFR 178.3400 - Emulsifiers and/or surface-active agents.

Code of Federal Regulations, 2014 CFR

2014-04-01

... paperboard. α-[p-(1,1,3,3-Tetramethylbutyl)phenyl] omega-hydroxypoly(oxyethylene) produced by the... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Emulsifiers and/or surface-active agents. 178.3400... substances: List of substances Limitations α-Alkyl-, α-alkenyl-, and α-alkylaryl-omega-hydroxypoly...

Toward efficient Zn(II)-based artificial nucleases.

PubMed

Boseggia, Elisa; Gatos, Maddalena; Lucatello, Lorena; Mancin, Fabrizio; Moro, Stefano; Palumbo, Manlio; Sissi, Claudia; Tecilla, Paolo; Tonellato, Umberto; Zagotto, Giuseppe

2004-04-14

A series of cis-cis-triaminocyclohexane Zn(II) complex-anthraquinone intercalator conjugates, designed in such a way to allow their easy synthesis and modification, have been investigated as hydrolytic cleaving agents for plasmid DNA. The ligand structure comprises a triaminocyclohexane platform linked by means of alkyl spacers of different length (from C(4) to C(8)) to the anthraquinone group which may intercalate the DNA. At a concentration of 5 microM, the complex of the derivative with a C(8) alkyl spacer induces the hydrolytic stand scission of supercoiled DNA with a rate of 4.6 x 10(-6) s(-1) at pH 7 and 37 degrees C. The conjugation of the metal complex with the anthraquinone group leads to a 15-fold increase of the cleavage efficiency when compared with the anthraquinone lacking Zn-triaminocyclohexane complex. The straightforward synthetic procedure employed, allowing a systematic change of the spacer length, made possible to gain more insight on the role of the intercalating group in determining the reactivity of the systems. Comparison of the reactivity of the different complexes shows a remarkable increase of the DNA cleaving efficiency with the length of the spacer. In the case of too-short spacers, the advantages due to the increased DNA affinity are canceled due to the incorrect positioning of the reactive group, thus leading to cleavage inhibition.

Concise synthesis of the hasubanan alkaloid (±)-cepharatine A using a Suzuki coupling reaction to effect o,p-phenolic coupling.

PubMed

Magnus, Philip; Seipp, Charles

2013-09-20

Suzuki coupling of 10 and 11 resulted in 9, which was O-alkylated to provide 12. Treatment of 12 with CsF in DMF resulted in the formation of the completed core structure 13 in a single step. Reductive amination of 13 completed the synthesis of (±)-cepharatine A, 4.

Acylation, Diastereoselective Alkylation, and Cleavage of an Oxazolidinone Chiral Auxiliary: A Multistep Asymmetric Synthesis Experiment for Advanced Undergraduates

ERIC Educational Resources Information Center

Smith, Thomas E.; Richardson, David P.; Truran, George A.; Belecki, Katherine; Onishi, Megumi

2008-01-01

An introduction to the concepts and experimental techniques of diastereoselective synthesis using a chiral auxiliary is described. The 4-benzyl-2-oxazolidinone chiral auxiliary developed by Evans is acylated with propionic anhydride under mild conditions using DMAP as an acyl transfer catalyst. Deprotonation with NaN(TMS)[subscript 2] at -78…

Spin-Center Shift-Enabled Direct Enantioselective α-Benzylation of Aldehydes with Alcohols.

PubMed

Nacsa, Eric D; MacMillan, David W C

2018-03-07

Nature routinely engages alcohols as leaving groups, as DNA biosynthesis relies on the removal of water from ribonucleoside diphosphates by a radical-mediated "spin-center shift" (SCS) mechanism. Alcohols, however, remain underused as alkylating agents in synthetic chemistry due to their low reactivity in two-electron pathways. We report herein an enantioselective α-benzylation of aldehydes using alcohols as alkylating agents based on the mechanistic principle of spin-center shift. This strategy harnesses the dual activation modes of photoredox and organocatalysis, engaging the alcohol by SCS and capturing the resulting benzylic radical with a catalytically generated enamine. Mechanistic studies provide evidence for SCS as a key elementary step, identify the origins of competing reactions, and enable improvements in chemoselectivity by rational photocatalyst design.

Synthesis and biological properties of novel 2-aminopyrimidin-4(3H)-ones highly potent against HIV-1 mutant strains.

PubMed

Mai, Antonello; Artico, Marino; Rotili, Dante; Tarantino, Domenico; Clotet-Codina, Imma; Armand-Ugón, Mercedes; Ragno, Rino; Simeoni, Silvia; Sbardella, Gianluca; Nawrozkij, Maxim B; Samuele, Alberta; Maga, Giovanni; Esté, José A

2007-11-01

Following the disclosure of dihydro-alkoxy-, dihydro-alkylthio-, and dihydro-alkylamino-benzyl-oxopyrimidines (DABOs, S-DABOs, and NH-DABOs) as potent and selective anti-HIV-1 agents belonging to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, we report here the synthesis and biological evaluation of a novel series of DABOs bearing a N,N-disubstituted amino group or a cyclic amine at the pyrimidine-C2 position, a hydrogen atom or a small alkyl group at C5 and/or at the benzylic position, and the favorable 2,6-difluorobenzyl moiety at the C6 position (F2-N,N-DABOs). The new compounds were highly active up to the subnanomolar level against both wt HIV-1 and the Y181C mutant and at the submicromolar to nanomolar range against the K103N and Y188L mutant strains. Such derivatives were more potent than S-DABOs, NH-DABOs, and nevirapine and efavirenz were chosen as reference drugs. The higher inhibitor adaptability to the HIV-1 RT non-nucleoside binding site (NNBS) may account for the higher inhibitory effect exerted by the new molecules against the mutated RTs.

Chemical structure of carbamoylating groups and their relationship to bone marrow toxicity and antiglioma activity of bifunctionally alkylating and carbamoylating nitrosoureas.

PubMed

Ali-Osman, F; Giblin, J; Berger, M; Murphy, M J; Rosenblum, M L

1985-09-01

Although the antitumor effects of chloroethylnitrosoureas have been shown to be due primarily to DNA-DNA cross-linking by the alkylating moieties of these agents, the basis of the often accompanying bone marrow toxicity has been more controversial. We report on the relative bone marrow toxicity of four model nitrosoureas with different alkylating and carbamoylating activities: 1,3-bis(2-chloroethyl)-1-nitrosourea; 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea; chlorozotozin, (2-[3-(2-chloroethyl)-3 -nitrosoureido]-2-deoxy-D-glucopyranose); and -3-(beta-D-glucopyranosyl)-1-nitrosourea. Inhibitions of DNA, RNA, and protein synthesis in murine bone marrow cells and of colony growth of myeloid precursor cells (granulocyte-macrophage colony-forming units) were used as in vitro end points of myelotoxicity. Further, we determined the antiglioma activity of the four nitrosoureas on two human gliomas in a clonogenic tumor cell assay and studied the effect of the non-nitrosourea carbamoylators potassium cyanate, chloroethyl isocyanate, cyclohexyl isocyanate, ethyl isocyanate, and ethyl isothiocyanate on granulocyte-macrophage colony-forming units. The results show that, at equivalent drug exposures, clonogenic glioma cell kill was significant and comparative for 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea, and chlorozotocin; 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea showed little activity. In contrast, granulocyte-macrophage colony-forming unit toxicity was low with chlorozotocin and 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea and very high with 1,3-bis(2-chloroethyl)-1-nitrosourea and 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea. Of the isocyanates, bone marrow toxicity was highest with chloroethyl isocyanate and cyclohexyl isocyanate, intermediate with ethyl isocyanate, and lowest with KOCN and ethyl isothiocyanate. Our results indicate that (a) bifunctional alkylation is essential for antiglioma activity of nitrosoureas and (b) myelosuppression is at least partly linked with carbamoylation but that structural entities in the carbamoylating isocyanate rather than a quantitative degree of carbamoylation determine the degree of potential myelotoxicity.

Isomeric Detergent Comparison for Membrane Protein Stability: Importance of Inter-Alkyl-Chain Distance and Alkyl Chain Length.

PubMed

Cho, Kyung Ho; Hariharan, Parameswaran; Mortensen, Jonas S; Du, Yang; Nielsen, Anne K; Byrne, Bernadette; Kobilka, Brian K; Loland, Claus J; Guan, Lan; Chae, Pil Seok

2016-12-14

Membrane proteins encapsulated by detergent micelles are widely used for structural study. Because of their amphipathic property, detergents have the ability to maintain protein solubility and stability in an aqueous medium. However, conventional detergents have serious limitations in their scope and utility, particularly for eukaryotic membrane proteins and membrane protein complexes. Thus, a number of new agents have been devised; some have made significant contributions to membrane protein structural studies. However, few detergent design principles are available. In this study, we prepared meta and ortho isomers of the previously reported para-substituted xylene-linked maltoside amphiphiles (XMAs), along with alkyl chain-length variation. The isomeric XMAs were assessed with three membrane proteins, and the meta isomer with a C 12 alkyl chain was most effective at maintaining solubility/stability of the membrane proteins. We propose that interplay between the hydrophile-lipophile balance (HLB) and alkyl chain length is of central importance for high detergent efficacy. In addition, differences in inter-alkyl-chain distance between the isomers influence the ability of the detergents to stabilise membrane proteins. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chain length effects on the vibrational structure and molecular interactions in the liquid normal alkyl alcohols

NASA Astrophysics Data System (ADS)

Kiefer, Johannes; Wagenfeld, Sabine; Kerlé, Daniela

2018-01-01

Alkyl alcohols are widely used in academia, industry, and our everyday lives, e.g. as cleaning agents and solvents. Vibrational spectroscopy is commonly used to identify and quantify these compounds, but also to study their structure and behavior. However, a comprehensive investigation and comparison of all normal alkanols that are liquid at room temperature has not been performed, surprisingly. This study aims at bridging this gap with a combined experimental and computational effort. For this purpose, the alkyl alcohols from methanol to undecan-1-ol have been analyzed using infrared and Raman spectroscopy. A detailed assignment of the individual peaks is presented and the influence of the alkyl chain length on the hydrogen bonding network is discussed. A 2D vibrational mapping allows a straightforward visualization of the effects. The conclusions drawn from the experimental data are backed up with results from Monte Carlo simulations using the simulation package Cassandra.

Safety Assessment of Alkyl Ethylhexanoates as Used in Cosmetics.

PubMed

Fiume, Monice; Heldreth, Bart; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

2015-01-01

The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) assessed the safety of 16 alkyl ethylhexanoates for use in cosmetics, concluding that these ingredients are safe in cosmetic formulations in the present practices of use and concentrations when formulated to be nonirritating. The alkyl ethylhexanoates primarily function as skin-conditioning agents in cosmetics. The highest concentration of use reported for any of the alkyl ethylhexanoates is 77.3% cetyl ethylhexanoate in rinse-off formulations used near the eye, and the highest leave-on use reported is 52% cetyl ethylhexanoate in lipstick formulations. The Panel reviewed available animal and clinical data related to these ingredients, and the similarities in structure, properties, functions, and uses of ingredients from previous CIR assessments on constituent alcohols that allowed for extrapolation of the available toxicological data to assess the safety of the entire group. © The Author(s) 2015.

Incorporation of N-amidino-pyroglutamic acid into peptides using intramolecular cyclization of alpha-guanidinoglutaric acid.

PubMed

Burov, Sergey; Moskalenko, Yulia; Dorosh, Marina; Shkarubskaya, Zoya; Panarin, Evgeny

2009-11-01

N-terminal modification of peptides by unnatural amino acids significantly affects their enzymatic stability, conformational properties and biological activity. Application of N-amidino-amino acids, positively charged under physiological conditions, can change peptide conformation and its affinity to the corresponding receptor. In this article, we describe synthesis of short peptides, containing a new building block-N-amidino-pyroglutamic acid. Although direct guanidinylation of pyroglutamic acid and oxidation of N-amidino-proline using RuO(4) did not produce positive results, N-amidino-Glp-Phe-OH was synthesized on Wang polymer by cyclization of alpha-guanidinoglutaric acid residue. In the course of synthesis, it was found that literature procedure of selective Boc deprotection using TMSOTf/TEA reagent is accompanied by concomitant side reaction of triethylamine alkylation by polymer linker fragment. It should be mentioned that independently from cyclization time and coupling agent (DIC or HCTU), the lactam formation was incomplete. Separation of the cyclic product from the linear precursor was achieved by HPLC in ammonium formate buffer at pH 6. HPLC analysis showed N-amidino-Glp-Phe-OH stability at acidic and physiological pH and fast ring opening in water solution at pH 9. The suggested method of N-amidino-Glp residue formation can be applied in the case of short peptide chains, whereas synthesis of longer ones will require fragment condensation approach.

Synthesis of S-linked trisaccharide glycal of derhodinosylurdamycin A: Discovery of alkyl thiocyanate as an efficient electrophile for stereoselective sulfenylation of 2-deoxy glycosyl lithium.

PubMed

Acharya, Padam P; Baryal, Kedar N; Reno, Cristin E; Zhu, Jianglong

2017-08-07

Stereoselective synthesis of S-linked trisaccharide glycal of angucycline antitumor antibiotic derhodinosylurdamycin A is described. The synthesis has been accomplished employing our previously reported umpolung S-glycosylation strategy - stereoselective sulfenylation of 2-deoxy glycosyl lithium. It was found that sugar-derived thiocyanate was a better electrophile than corresponding asymmetric disulfide in this type of stereoselective sulfenylation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Stereospecific nickel-catalyzed cross-coupling reactions of alkyl Grignard reagents and identification of selective anti-breast-cancer agents.

PubMed

Yonova, Ivelina M; Johnson, A George; Osborne, Charlotte A; Moore, Curtis E; Morrissette, Naomi S; Jarvo, Elizabeth R

2014-02-24

Alkyl Grignard reagents that contain β-hydrogen atoms were used in a stereospecific nickel-catalyzed cross-coupling reaction to form C(sp(3))-C(sp(3)) bonds. Aryl Grignard reagents were also utilized to synthesize 1,1-diarylalkanes. Several compounds synthesized by this method exhibited selective inhibition of proliferation of MCF-7 breast cancer cells. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Novel Thioredoxin Inhibitors for Breast Cancer Therapy

DTIC Science & Technology

2001-07-01

of TH-223, the cesium salt of diol 3 16] was alkylated and cyclized under oxidative conditions. All of these compounds have been fully characterized...selectivity for Trx-1 over TrxR. Alkylation at the phenol as shown in the SR-series of analogs mostly abolished activity, with the exception of SR...with either MDA-MB 231 or MCF-7 cells were quite active as antiproliferative agents . Generally, MCF-7 cells were slightly more sensitive than the p53

Cu/Mn bimetallic catalysis enables carbonylative Suzuki–Miyaura coupling with unactivated alkyl electrophiles† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc01170a Click here for additional data file.

PubMed Central

Pye, Dominic R.; Cheng, Li-Jie

2017-01-01

A bimetallic system consisting of Cu-carbene and Mn-carbonyl co-catalysts was employed for carbonylative C–C coupling of arylboronic esters with alkyl halides, allowing for the convergent synthesis of ketones. The system operates under mild conditions and exhibits complementary reactivity to Pd catalysis. The method is compatible with a wide range of arylboronic ester nucleophiles and proceeds smoothly for both primary and secondary alkyl iodide electrophiles. Preliminary mechanistic experiments corroborate a hypothetical catalytic mechanism consisting of co-dependent cycles wherein the Cu-carbene co-catalyst engages in transmetallation to generate an organocopper nucleophile, while the Mn-carbonyl co-catalyst activates the alkyl halide electrophile by single-electron transfer and then undergoes reversible carbonylation to generate an acylmanganese electrophile. The two cycles then intersect with a heterobimetallic, product-releasing C–C coupling step. PMID:28966784

Preparation and use of tetra-alkyl cobalt dicarbollide for extraction of cesium and strontium into hydrocarbon solvents

DOEpatents

Miller, Rebecca L.; Pinkerton, Anthony B.; Abney, Kent D.; Kinkead, Scott A.

1997-01-01

Preparation and use of tetra-C-alkyl cobalt dicarbollide for extraction of cesium and strontium into hydrocarbon solvents. Tetra-C-alkyl derivatives of cobalt dicarbollide, Co(C.sub.2 R.sub.2 B.sub.9 H.sub.9).sub.2.sup.- (CoB.sub.2 R.sub.4.sup.- ; R=CH.sub.3 and C.sub.6 H.sub.13) are demonstrated to be significant cesium and strontium extractants from acidic and alkaline solutions into non-toxic organic solvent systems. Extractions using mesitylene and diethylbenzene are compared to those with nitrobenzene as the organic phase. CoB.sub.2 -hexyl.sub.4.sup.- in diethylbenzene shows improved selectivity (10.sup.4) for Cs over Na in acidic solution. In dilute alkaline solution, CoB.sub.2 -hexyl.sub.4.sup.- extracts Cs less efficiently, but more effectively removes Sr from higher base concentrations. A general synthesis of tetra-C-alkyl cobalt dicarbollides is described.

Preparation and use of tetra-alkyl cobalt dicarbollide for extraction of cesium and strontium into hydrocarbon solvents

DOEpatents

Miller, R.L.; Pinkerton, A.B.; Abney, K.D.; Kinkead, S.A.

1997-02-11

Preparation and use of tetra-C-alkyl cobalt dicarbollide for extraction of cesium and strontium into hydrocarbon solvents. Tetra-C-alkyl derivatives of cobalt dicarbollide, Co(C{sub 2}R{sub 2}B{sub 9}H{sub 9}){sub 2}{sup {minus}}(CoB{sub 2}R{sub 4}{sup {minus}}; R=CH{sub 3} and C{sub 6}H{sub 13}) are demonstrated to be significant cesium and strontium extractants from acidic and alkaline solutions into non-toxic organic solvent systems. Extractions using mesitylene and diethylbenzene are compared to those with nitrobenzene as the organic phase. CoB{sub 2}-hexyl{sub 4}{sup {minus}} in diethylbenzene shows improved selectivity (10{sup 4}) for Cs over Na in acidic solution. In dilute alkaline solution, CoB{sub 2}-hexyl{sub 4}{sup {minus}} extracts Cs less efficiently, but more effectively removes Sr from higher base concentrations. A general synthesis of tetra-C-alkyl cobalt dicarbollides is described. 6 figs.

Decontamination of chemical and biological warfare agents with a single multi-functional material.

PubMed

Amitai, Gabi; Murata, Hironobu; Andersen, Jill D; Koepsel, Richard R; Russell, Alan J

2010-05-01

We report the synthesis of new polymers based on a dimethylacrylamide-methacrylate (DMAA-MA) co-polymer backbone that support both chemical and biological agent decontamination. Polyurethanes containing the redox enzymes glucose oxidase and horseradish peroxidase can convert halide ions into active halogens and exert striking bactericidal activity against gram positive and gram negative bacteria. New materials combining those biopolymers with a family of N-alkyl 4-pyridinium aldoxime (4-PAM) halide-acrylate co-polymers offer both nucleophilic activity for the detoxification of organophosphorus nerve agents and internal sources of halide ions for generation of biocidal activity. Generation of free bromine and iodine was observed in the combined material resulting in bactericidal activity of the enzymatically formed free halogens that caused complete kill of E. coli (>6 log units reduction) within 1 h at 37 degrees C. Detoxification of diisopropylfluorophosphate (DFP) by the polyDMAA MA-4-PAM iodide component was dose-dependent reaching 85% within 30 min. A subset of 4-PAM-halide co-polymers was designed to serve as a controlled release reservoir for N-hydroxyethyl 4-PAM (HE 4-PAM) molecules that reactivate nerve agent-inhibited acetylcholinesterase (AChE). Release rates for HE 4-PAM were consistent with hydrolysis of the HE 4-PAM from the polymer backbone. The HE 4-PAM that was released from the polymer reactivated DFP-inhibited AChE at a similar rate to the oxime antidote 4-PAM. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

β-Glucoside Activators of Mung Bean UDP-Glucose: β-Glucan Synthase 1

PubMed Central

Callaghan, Theresa; Ross, Peter; Weinberger-Ohana, Patricia; Benziman, Moshe

1988-01-01

n-Alkyl (C6-C12) β-d-monoglucopyranosides have been found to be highly potent activators of mung bean β-glucan synthase in vitro, increasing the Vmax of the enzyme as much as 60-fold and with Ka values as low as 10 micromolar. Activation is highly specific for the β-linked terminal glucose residue; other alkyl glycosides such as, octyl-α-glucoside, dodecyl β-maltoside, 6-lauryl sucrose, 6-lauryl glucose, which lack this structure, are ineffective as activators. Based on the similarities in their structure and effects on β-glucan synthesis under a variety of conditions, it is proposed that the alkyl β-glucosides are structural analogs of the native glucolipid activator of β-glucan synthase isolated from mung bean extracts. PMID:16666039

Asymmetric 1,2-perfluoroalkyl migration: easy access to enantioenriched α-hydroxy-α-perfluoroalkyl esters.

PubMed

Wang, Pan; Feng, Liang-Wen; Wang, Lijia; Li, Jun-Fang; Liao, Saihu; Tang, Yong

2015-04-15

This study has led to the development of a novel, highly efficient, 1,2-perfluoro-alkyl/-aryl migration process in reactions of hydrate of 1-perfluoro-alkyl/-aryl-1,2-diketones with alcohols, which are promoted by a Zn(II)/bisoxazoline and form α-perfluoro-alkyl/-aryl-substituted α-hydroxy esters. With (-)-8-phenylmenthol as the alcohol, the corresponding menthol esters are generated in high yields with excellent levels of diastereoselectivity. The mechanistic studies show that the benzilic ester-type rearrangement reaction takes place via an unusual 1,2-migration of electron-deficient trifluoromethyl group rather than the phenyl group. The overall process serves as a novel, efficient, and simple approach for the synthesis of highly enantioenriched, biologically relevant α-hydroxy-α-perfluoroalkyl carboxylic acid derivatives.

The Eschenmoser coupling reaction under continuous-flow conditions

PubMed Central

Singh, Sukhdeep; Köhler, J Michael; Schober, Andreas

2011-01-01

Summary The Eschenmoser coupling is a useful carbon–carbon bond forming reaction which has been used in various different synthesis strategies. The reaction proceeds smoothly if S-alkylated ternary thioamides or thiolactames are used. In the case of S-alkylated secondary thioamides or thiolactames, the Eschenmoser coupling needs prolonged reaction times and elevated temperatures to deliver valuable yields. We have used a flow chemistry system to promote the Eschenmoser coupling under enhanced reaction conditions in order to convert the demanding precursors such as S-alkylated secondary thioamides and thiolactames in an efficient way. Under pressurized reaction conditions at about 220 °C, the desired Eschenmoser coupling products were obtained within 70 s residence time. The reaction kinetics was investigated and 15 examples of different building block combinations are given. PMID:21915222

Beyond alkyl transfer: Synthesis of main group metal (Mg, Ca, Zn) silyl and tris(oxazolinyl)borato complexes and their stoichiometric and catalytic reactions with borane Lewis acids and carbonyls

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lampland, Nicole Lynn

2015-05-09

Recently, the fundamental knowledge of main group metal chemistry has grown. This progress is crucial for the further development of main group metal compounds in silicon chemistry and catalysis and for advancing their applications as green alternatives to many rare earth and transition metal compounds. This thesis focuses on reactivity beyond the welldocumented alkyl-transfer applications for main group metals, and it highlights examples of reactions with Lewis acids and the reduction of carbonyls.

Stereoselective synthesis, spectral and antimicrobial studies of some cyanoacetyl hydrazones of 3-alkyl-2,6-diarylpiperidin-4-ones

NASA Astrophysics Data System (ADS)

Velayutham Pillai, M.; Rajeswari, K.; Vidhyasagar, T.

2014-11-01

A series of novel cyanoacetyl hydrazones of 3-alkyl-2,6-diarylpiperidin-4-ones were synthesized stereoselectively and characterized by IR, Mass, 1H NMR, 13C NMR, 1H-1H COSY and 1H-13C COSY spectra. The stereochemistry of the synthesized compounds was established using NMR spectra. Antimicrobial screening of the synthesized compounds revealed their antibacterial and antifungal potencies. Growth inhibition of Enterobacter Aerogenes by compound 15 was found to be superior to the standard drug.

Synthetic Method for Oligonucleotide Block by Using Alkyl-Chain-Soluble Support.

PubMed

Matsuno, Yuki; Shoji, Takao; Kim, Shokaku; Chiba, Kazuhiro

2016-02-19

A straightforward method for the synthesis of oligonucleotide blocks using a Cbz-type alkyl-chain-soluble support (Z-ACSS) attached to the 3'-OH group of 3'-terminal nucleosides was developed. The Z-ACSS allowed for the preparation of fully protected deoxyribo- and ribo-oligonucleotides without chromatographic purification and released dimer- to tetramer-size oligonucleotide blocks via hydrogenation using a Pd/C catalyst without significant loss or migration of protective groups such as 5'-end 4,4'-dimethoxtrityl, 2-cyanoethyl on internucleotide bonds, or 2'-TBS.

One-pot synthesis of keto thioethers by palladium/gold-catalyzed click and pinacol reactions.

PubMed

Cadu, Alban; Watile, Rahul A; Biswas, Srijit; Orthaber, Andreas; Sjöberg, Per J R; Samec, Joseph S M

2014-11-07

An atom-efficient synthesis of keto thioethers was devised via tandem gold/palladium catalysis. The reaction proceeds through a regioselective thiol attack at the β-position of the alcohol, followed by an alkyl, aryl, or benzyl 1,2-shift. Both acyclic and cyclic systems were studied, in the latter case leading to the ring expansion of cyclic substrates.

Reactions of in situ generated N-Boc nitrones with aromatic and heteroaromatic grignard reagents: application to the synthesis of zileuton.

PubMed

Guinchard, Xavier; Denis, Jean-Noël

2008-03-07

A new class of alpha-aromatic-N-hydroxylamines has been prepared by reaction of tert-butyl (phenylsulfonyl)alkyl-N-hydroxycarbamates with aromatic and heteroaromatic Grignard reagents. Reactions proceed via a base-assisted elimination of the phenylsulfonyl group leading to N-Boc nitrones. This methodology has been applied to the synthesis of zileuton.

Chemoselective room temperature E1cB N-N cleavage of oxazolidinone hydrazides from enantioselective aldehyde α-hydrazination: synthesis of (+)-1,4-dideoxyallonojirimycin.

PubMed

Ferreira, Jasmin; Rees-Jones, Sophie C M; Ramaotsoa, Valerie; Msutu, Ath'enkosi; Hunter, Roger

2016-02-07

Room temperature E1cB N-N cleavage of oxazolidinone hydrazides via N-alkylation with diethyl bromomalonate and potassium or caesium carbonate as base in acetonitrile is presented. The new method has a much improved chemoselectivity, which is illustrated by a concise total synthesis of the piperidine iminosugar (+)-1,4-dideoxyallonojirimycin.

A convenient synthesis of tetrabenzo[de,hi,mn,qr]naphthacene from readily available 1,2-di(phenanthren-4-yl)ethyne.

PubMed

Mukherjee, Anupam; Pati, Kamalkishore; Liu, Rai-Shung

2009-08-21

We report here a convenient synthesis of tetrabenzo[de,hi,mn,qr]naphthacenes from 1,2-di(phenanthren-4-yl)ethynes through initial Brønsted acid-catalyzed hydroarylation, followed by FeCl(3)-oxidative coupling reactions. This new method is applicable to tetrabenzo[de,hi,mn,qr]naphthacenes bearing various alkyl substituents.

Anti-biofilm action of nitric oxide-releasing alkyl-modified poly(amidoamine) dendrimers against Streptococcus mutans.

PubMed

Backlund, Christopher J; Worley, Brittany V; Schoenfisch, Mark H

2016-01-01

The effect of nitric oxide (NO)-releasing dendrimer hydrophobicity on Streptococcus mutans killing and biofilm disruption was examined at pH 7.4 and 6.4, the latter relevant to dental caries. Generation 1 (G1) poly(amidoamine) (PAMAM) dendrimers were modified with alkyl epoxides to generate propyl-, butyl-, hexyl-, octyl-, and dodecyl-functionalized dendrimers. The resulting secondary amines were reacted with NO to form N-diazeniumdiolate NO donor-modified dendrimer scaffolds (total NO ∼1μmol/mg). The bactericidal action of the NO-releasing dendrimers against both planktonic and biofilm-based S. mutans proved greatest with increasing alkyl chain length and at lower pH. Improved bactericidal efficacy at pH 6.4 was attributed to increased scaffold surface charge that enhanced dendrimer-bacteria association and ensuing membrane damage. For shorter alkyl chain (i.e., propyl and butyl) dendrimer modifications, increased antibacterial action at pH 6.4 was due to faster NO-release kinetics from proton-labile N-diazeniumdiolate NO donors. Octyl- and dodecyl-modified PAMAM dendrimers proved most effective for eradicating S. mutans biofilms with NO release mitigating dendrimer scaffold cytotoxicity. We report the antibacterial and anti-biofilm efficacy of dual-action nitric oxide (NO)-releasing dendrimers against S. mutans, an etiological agent in dental caries. This work was undertaken to enhance the anti-biofilm action of these scaffolds by employing various alkyl chain modifications. Furthermore, we evaluated the ability of NO to eradicate cariogenic biofilms. We found that at the lower pH associated with dental caries (pH ∼6.4), NO has a more pronounced antibacterial effect for alkyl modifications less capable of biofilm penetration and membrane disruption. Of greatest significance, we introduce dendrimers as a new macromolecular antibacterial agent against the cariogenic bacteria S. mutans. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Synthesis of γ-Valerolactone from Carbohydrates and its Applications.

PubMed

Zhang, Zehui

2016-01-01

γ-Valerolactone (GVL) is a valuable chemical intermediate that can be obtained by catalytic reduction of levulinic acid (LA) or alkyl levulinates (AL). There are many reports on the synthesis of GVL from LA or AL. However, the demand for the large-scale synthesis of GVL requires more environmentally friendly and cost-effective production processes. This article focuses on the recent advance in the synthesis of GVL from carbohydrates or lignocellulosic biomass. In addition, application of GVL as the reaction solvents, fuel additives, and as precursor for the synthesis of jet fuel and polymer monomers is also discussed. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Phellilane L, Sesquiterpene Metabolite of Phellinus linteus: Isolation, Structure Elucidation, and Asymmetric Total Synthesis.

PubMed

Ota, Koichiro; Yamazaki, Ikuma; Saigoku, Takahiro; Fukui, Mei; Miyata, Tomoki; Kamaike, Kazuo; Shirahata, Tatsuya; Mizuno, Fumi; Asada, Yoshihisa; Hirotani, Masao; Ino, Chieko; Yoshikawa, Takafumi; Kobayashi, Yoshinori; Miyaoka, Hiroaki

2017-12-01

A new cyclopropane-containing sesquiterpenoid, phellilane L (1), was isolated from the medicinal mushroom Phellinus linteus ("Meshimakobu" in Japanese), a member of the Hymenochaetaceae family and a well-known fungus that is widely used in East Asia. The planar structure of 1 was determined on the basis of spectroscopic analysis. The authors achieved the first total synthesis of 1. Our protecting group-free synthesis features a highly stereoselective one-pot synthesis involving an intermolecular alkylation/cyclization/lactonization strategy for construction of the key cyclopropane-γ-lactone intermediate. Additionally, our synthesis determined the absolute configuration of phellilane L (1).

How cyclophosphamide at environmentally relevant concentration influences Daphnia magna life history and its proteome.

PubMed

Grzesiuk, Małgorzata; Mielecki, Damian; Pilżys, Tomasz; Garbicz, Damian; Marcinkowski, Michał; Grzesiuk, Elżbieta

2018-01-01

The waste of commonly used medicines is known to contaminate freshwater ecosystems. Pharmaceuticals can be toxic, mutagenic, or modifying to freshwater organisms even at low concentrations if consider their permanent presence in the environment. Chemotherapeutics used to treat cancer, and in particular alkylating agents, contribute significantly to this form of pollution, the latter introducing cytotoxic and/or mutagenic lesions to the DNA and RNA of organisms which can be disruptive to their cells. The aim of the present study was to investigate the influence of the alkylating anticancer agent cyclophosphamide (CP) on Daphnia magna clones. We evaluated the life history parameters and protein profiles of this crustacean following exposure to environmentally relevant CP concentration of 10 ng L-1. Even at this low concentration, the alkylating agent caused modification of the life history parameters and proteome profile of the Daphnia. These changes were clone-specific and involved growth rate, age at first reproduction, neonate number, and proteins related to cell cycle and redox state regulation. The disturbance caused by pharmaceuticals contaminating freshwater ecosystem is probably weaker and unlikely to be cytotoxic in character due to the high dilution of these substances in the water. However, our results indicate that prolonged exposure of organisms to these toxins may lead to modifications on the organismal and molecular levels with unpredictable significance for the entire ecosystem.

Mutagenic synergism detected between dimethyl sulfate and X-rays but not found between N-methyl-N-nitrosourea and X-rays in the stamen hairs of Tradescantia clone BNL 4430.

PubMed

Shima, N; Ichikawa, S

1995-09-01

Mutagenic interactions with X-rays of two monofunctional alkylating agents, dimethyl sulfate (DMS) and N-methyl-N-nitrosourea (MNU), were studied in the stamen hairs of Tradescantia clone BNL 4430, a blue/pink heterozygote. The young inflorescence-bearing shoots with roots cultivated in the nutrient solution circulating growth chamber were used as tester plants. Synergism between two different mutagens was judged to have occurred when the mutation frequency observed after applying the two mutagens concurrently was statistically significantly higher than the mutation frequency expected from the additive effects of the two mutagens. Clear synergistic effects in inducing somatic pink mutations were detected with all combinations of doses of DMS and X-rays examined, even in a relatively low X-ray dose range (down to 299 mGy), resembling those confirmed earlier between ethyl methanesulfonate (EMS) and X-rays, but somewhat differing from the synergisms observed earlier between methyl methanesulfonate (MMS) and X-rays. On the other hand, no mutagenic synergism was detected between MNU and X-rays, even in a relatively high X-ray dose range (up to 862 mGy). The presence or absence of mutagenic synergisms of these alkylating agents with X-rays could be related to the action mechanism of each alkylating agent.

Therapeutic journery of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives.

PubMed

Singh, Rajesh K; Kumar, Sahil; Prasad, D N; Bhardwaj, T R

2018-05-10

Cancer is considered as one of the most serious health problems today. The discovery of nitrogen mustard as an alkylating agent in 1942, opened a new era in the cancer chemotherapy. This valuable class of alkylating agent exerts its biological activity by binding to DNA, cross linking two strands, preventing DNA replication and ultimate cell death. At the molecular level, nitrogen lone pairs of nitrogen mustard generate a strained intermediate "aziridinium ion" which is very reactive towards DNA of tumor cell as well as normal cell resulting in various adverse side effects alogwith therapeutic implications. Over the last 75 years, due to its high reactivity and peripheral cytotoxicity, numerous modifications have been made in the area of nitrogen mustard to improve its efficacy as well as enhancing drug delivery specifically to tumor cells. This review mainly discusses the medicinal chemistry aspects in the development of various classes of nitrogen mustards (mechlorethamine, chlorambucil, melphalan, cyclophosphamide and steroidal based nitrogen mustards). The literature collection includes the historical and the latest developments in these areas. This comprehensive review also attempted to showcase the recent progress in the targeted delivery of nitrogen mustards that includes DNA directed nitrogen mustards, antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), nitrogen mustard activated by glutathione transferase, peptide based nitrogen mustards and CNS targeted nitrogen mustards. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Downregulation of hPMC2 imparts chemotherapeutic sensitivity to alkylating agents in breast cancer cells.

PubMed

Krishnamurthy, Nirmala; Liu, Lili; Xiong, Xiahui; Zhang, Junran; Montano, Monica M

2015-01-01

Triple negative breast cancer cell lines have been reported to be resistant to the cyotoxic effects of temozolomide (TMZ). We have shown previously that a novel protein, human homolog of Xenopus gene which Prevents Mitotic Catastrophe (hPMC2) has a role in the repair of estrogen-induced abasic sites. Our present study provides evidence that downregulation of hPMC2 in MDA-MB-231 and MDA-MB-468 breast cancer cells treated with temozolomide (TMZ) decreases cell survival. This increased sensitivity to TMZ is associated with an increase in number of apurinic/apyrimidinic (AP) sites in the DNA. We also show that treatment with another alkylating agent, BCNU, results in an increase in AP sites and decrease in cell survival. Quantification of western blot analyses and immunofluorescence experiments reveal that treatment of hPMC2 downregulated cells with TMZ results in an increase in γ-H2AX levels, suggesting an increase in double strand DNA breaks. The enhancement of DNA double strand breaks in TMZ treated cells upon downregulation of hPCM2 is also revealed by the comet assay. Overall, we provide evidence that downregulation of hPMC2 in breast cancer cells increases cytotoxicity of alkylating agents, representing a novel mechanism of treatment for breast cancer. Our data thus has important clinical implications in the management of breast cancer and brings forth potentially new therapeutic strategies.

PML expression in soft tissue sarcoma: prognostic and predictive value in alkylating agents/antracycline-based first line therapy.

PubMed

Vincenzi, Bruno; Santini, Daniele; Schiavon, Gaia; Frezza, Anna Maria; Silletta, Marianna; Crucitti, Pierfilippo; Casali, Paolo; Dei Tos, Angelo P; Rossi, Sabrina; Rizzo, Sergio; Badalamenti, Giuseppe; Tomasino, Rosa Maria; Russo, Antonio; Butrynski, James E; Tonini, Giuseppe

2012-04-01

Soft tissue sarcomas are aggressive tumors representing <1% of all adult neoplasms. Aim of our study was to evaluate promyelocytic leukemia gene expression value as prognostic factor and as a factor predicting response to alkylating agents/antracycline-based first line therapy. One hundred eleven patients affected by locally advanced and metastatic soft tissue sarcoma were selected. PML expression was evaluated by immunohistochemical analysis in pathological samples and in the corresponding normal tissue from each case. PML immunohistochemical results were correlated with prognosis and with radiological response to alkylating agents/antracycline-based first line therapy. PML expression was significantly reduced in synovial sarcomas (P < 0.0001), in myofibroblastic sarcomas (P < 0.0001), angiosarcomas (P < 0.0001), in leiomyosarcomas (P = 0.003), in mixoid liposarcomas (P < 0.0001), and in dedifferentiated liposarcomas (P < 0.0001). No significant difference was found for pleomorphic sarcoma [31.8 (95% CI: 16.7-41.0); P = 0.21]. and pleomorphic liposarcomas (P = 0.51). Loss of PML expression was found to be statistically correlated with TTP (P < 0.0001), median duration of response (P = 0.007), and OS (P = 0.02). No correlation was observed between PML expression and treatment efficacy. PML IHC expression is down-regulated in synovial sarcomas, myofibroblastic sarcomas, angiosarcomas, liposarcoma, and leiomyosarcomas and its expression correlated with prognosis. Copyright © 2011 Wiley Periodicals, Inc.

Toward Hypoxia-Selective DNA-Alkylating Agents Built by Grafting Nitrogen Mustards onto the Bioreductively Activated, Hypoxia-Selective DNA-Oxidizing Agent 3-Amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine)

PubMed Central

2015-01-01

Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a heterocyclic di-N-oxide that undergoes enzymatic deoxygenation selectively in the oxygen-poor (hypoxic) cells found in solid tumors to generate a mono-N-oxide metabolite. This work explored the idea that the electronic changes resulting from the metabolic deoxygenation of tirapazamine analogues might be exploited to activate a DNA-alkylating species selectively in hypoxic tissue. Toward this end, tirapazamine analogues bearing nitrogen mustard units were prepared. In the case of the tirapazamine analogue 18a bearing a nitrogen mustard unit at the 6-position, it was found that removal of the 4-oxide from the parent di-N-oxide to generate the mono-N-oxide analogue 17a did indeed cause a substantial increase in reactivity of the mustard unit, as measured by hydrolysis rates and DNA-alkylation yields. Hammett sigma values were measured to quantitatively assess the magnitude of the electronic changes induced by metabolic deoxygenation of the 3-amino-1,2,4-benzotriazine 1,4-dioxide heterocycle. The results provide evidence that the 1,2,4-benzotiazine 1,4-dioxide unit can serve as an oxygen-sensing prodrug platform for the selective unmasking of bioactive agents in hypoxic cells. PMID:25029663

Toward hypoxia-selective DNA-alkylating agents built by grafting nitrogen mustards onto the bioreductively activated, hypoxia-selective DNA-oxidizing agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine).

PubMed

Johnson, Kevin M; Parsons, Zachary D; Barnes, Charles L; Gates, Kent S

2014-08-15

Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a heterocyclic di-N-oxide that undergoes enzymatic deoxygenation selectively in the oxygen-poor (hypoxic) cells found in solid tumors to generate a mono-N-oxide metabolite. This work explored the idea that the electronic changes resulting from the metabolic deoxygenation of tirapazamine analogues might be exploited to activate a DNA-alkylating species selectively in hypoxic tissue. Toward this end, tirapazamine analogues bearing nitrogen mustard units were prepared. In the case of the tirapazamine analogue 18a bearing a nitrogen mustard unit at the 6-position, it was found that removal of the 4-oxide from the parent di-N-oxide to generate the mono-N-oxide analogue 17a did indeed cause a substantial increase in reactivity of the mustard unit, as measured by hydrolysis rates and DNA-alkylation yields. Hammett sigma values were measured to quantitatively assess the magnitude of the electronic changes induced by metabolic deoxygenation of the 3-amino-1,2,4-benzotriazine 1,4-dioxide heterocycle. The results provide evidence that the 1,2,4-benzotiazine 1,4-dioxide unit can serve as an oxygen-sensing prodrug platform for the selective unmasking of bioactive agents in hypoxic cells.

Synthesis of structurally diverse benzosuberene analogues and their biological evaluation as anti-cancer agents

PubMed Central

Tanpure, Rajendra P.; George, Clinton S.; Strecker, Tracy E.; Devkota, Laxman; Tidmore, Justin K.; Lin, Chen-Ming; Herdman, Christine A.; MacDonough, Matthew T.; Sriram, Madhavi; Chaplin, David J.; Trawick, Mary Lynn; Pinney, Kevin G.

2014-01-01

Diversely functionalized, fused aryl-alkyl ring systems hold a prominent position as well-established molecular frameworks for a variety of anti-cancer agents. The benzosuberene (6,7 fused, also referred to as dihydro-5H-benzo[7]annulene and benzocycloheptene) ring system has emerged as a valuable molecular core component for the development of inhibitors of tubulin assembly, which function as antiproliferative anti-cancer agents and, in certain cases, as vascular disrupting agents (VDAs). Both a phenolic-based analogue (known as KGP18, compound 39) and its corresponding amine-based congener (referred to as KGP156, compound 45), which demonstrate strong inhibition of tubulin assembly (low micromolar range) and potent cytotoxicity (picomolar range for KGP18 and nanomolar range for KGP156) are noteworthy examples of such benzosuberene-based compounds. In order to extend the structure-activity relationship (SAR) knowledge base related to benzosuberene anti-cancer agents, a series of eleven analogues (including KGP18) were prepared in which the methoxylation pattern on the pendant aryl ring as well as functional group incorporation on the fused aryl ring were varied. The synthetic approach to these compounds featured a sequential Wittig olefination, reduction, Eaton's reagent-mediated cyclization strategy to achieve the core benzosuberone intermediate, and represented a higher-yielding synthesis of KGP18 (which we prepared previously through a ring-expansion strategy). Incorporation of a fluorine or chlorine atom at the 1-position of the fused aryl ring or replacement of one of the methoxy groups with hydrogen (on the pendant aryl ring of KGP18) led to benzosuberene analogues that were both strongly inhibitory against tubulin assembly (IC50 approximately 1.0 M) and strongly cytotoxic against selected human cancer cell lines (for example, GI50 = 5.47 nM against NCI-H460 cells with fluorobenzosuberene analogue 37). A water-soluble phosphate prodrug salt of KGP18 (referred to as KGP265, compound 44) and a water-soluble serinamide salt (compound 48) of KGP156 were also synthesized and evaluated in this study. PMID:24183586

The Fanconi anemia (FA) pathway confers glioma resistance to DNA alkylating agents.

PubMed

Chen, Clark C; Taniguchi, Toshiyasu; D'Andrea, Alan

2007-05-01

DNA alkylating agents including temozolomide (TMZ) and 1,3-bis[2-chloroethyl]-1-nitroso-urea (BCNU) are the most common form of chemotherapy in the treatment of gliomas. Despite their frequent use, the therapeutic efficacy of these agents is limited by the development of resistance. Previous studies suggest that the mechanism of this resistance is complex and involves multiple DNA repair pathways. To better define the pathways contributing to the mechanisms underlying glioma resistance, we tested the contribution of the Fanconi anemia (FA) DNA repair pathway. TMZ and BCNU treatment of FA-proficient cell lines led to a dose- and time-dependent increase in FANCD2 mono-ubiquitination and FANCD2 nuclear foci formation, both hallmarks of FA pathway activation. The FA-deficient cells were more sensitive to TMZ/BCNU relative to their corrected, isogenic counterparts. To test whether these observations were pertinent to glioma biology, we screened a panel of glioma cell lines and identified one (HT16) that was deficient in the FA repair pathway. This cell line exhibited increased sensitivity to TMZ and BCNU relative to the FA-proficient glioma cell lines. Moreover, inhibition of FA pathway activation by a small molecule inhibitor (curcumin) or by small interference RNA suppression caused increased sensitivity to TMZ/BCNU in the U87 glioma cell line. The BCNU sensitizing effect of FA inhibition appeared additive to that of methyl-guanine methyl transferase inhibition. The results presented in this paper underscore the complexity of cellular resistance to DNA alkylating agents and implicate the FA repair pathway as a determinant of this resistance.

Alkyl chitosan film-high strength, functional biomaterials.

PubMed

Lu, Li; Xing, Cao; Xin, Shen; Shitao, Yu; Feng, Su; Shiwei, Liu; Fusheng, Liu; Congxia, Xie

2017-11-01

Biofilm with strong tensile strength is a topic item in the area of tissue engineering, medicine engineering, and so forth. Here we introduced an alkyl chitosan film with strong tensile strength and its possibility for an absorbable anticoagulation material in vivo was tested in the series of blood test, such as dynamic coagulation time, plasma recalcification time and hemolysis. Alkyl chitosan film was a better biomaterial than traditional chitosan film in the anticoagulation, tissue compatibility and cell compatibility. The unique trait of alkyl chitosan film may be for its greater contact angle and hydrophobicity ability to reduce the adsorption capacity for the blood component and the activity of fibrinolytic enzymes, enhance the antibacterial capacity than chitosan film. Moreover, none of chitosan film or butyl chitosan film exhibited quick inflammation or other disadvantage and degraded quickly by implanted test. Therefore, Alkyl chitosan film is of prospective properties as an implantable, absorbable agent for tissue heals, and this material need further research. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3034-3041, 2017. © 2017 Wiley Periodicals, Inc.

Reevaluation of the effect of ellagic acid on N-methyl-N-nitrosourea DNA alkylation and mutagenicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lord, H.L.; Josephy, P.D.; Snieckus, V.A.

N-Methyl-N-nitrosourea (MNU) is a reactive, mutagenic methylating agent. MNU methylates DNA at various sites, including guanine N{sup 7}, guanine O{sup 6}, and adenine N{sup 3}. Dixit and Gold ((1986) Proc. Natl, Acad. Sci. U.S.A. 83, 8039-8043) reported that ellagic acid, a phenolic natural product, inhibited the mutagenicity of MNU in Salmonella typhimurium strain TA 100, inhibited salmon sperm DNA alkylation by ({sup 3}H)MNU, and also greatly reduced the ratio of guanine O{sup 6} to guanine N{sup 7} alkylation. We have examined the MNU-induced alkylation of calf thymus DNA and evaluated the effect of ellagic acid on this binding. Ellagic acidmore » had only a slight effect on total alkylation and did not alter the ratio of methylation at guanine-O{sup 6} and -N{sup 7} positions. In further experiments, ellagic acid did not significantly inhibit MNU mutagenicity. These findings do not support the potential use of ellagic acid as an inhibitor of biological damage induced by nitrosoureas.« less

Synthesis and characterization of chitosan alkyl urea.

PubMed

Wang, Jing; Jiang, Ji-Zhou; Chen, Wei; Bai, Zheng-Wu

2016-07-10

Chitosan is a versatile material employed for various purposes in many fields including the development of chiral stationary phases for enantioseparation. Chitosan alkyl urea is a kind of intermediate used to prepare enantioseparation materials. In order to synthesize the intermediates, in the present work, a new way to prepare chitosan alkyl urea has been established: chitosan was first reacted with methyl chloroformate yielding N-methoxyformylated chitosan, which was then converted to chitosan alkyl urea through amine-ester exchange reaction. With a large excess of methyl chloroformate and primary amine of low stereohindrance, the amino group in chitosan could be almost completely converted to ureido group. The as-prepared chitosan alkyl urea derivatives were characterized by IR, (1)H NMR, (13)C NMR,(1)H-(1)H COSY and (1)H-(13)C HSQC NMR spectra. The chemical shifts of hydrogen and carbon atoms of glucose unit were assigned. It was found that the degree of substitution was obviously lower if cyclopropyl amine, aniline, tert-butyl amine and diethyl amine were used as reactants for the amine-ester exchange reaction. The reason was explained with the aid of theoretical calculations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Solid-Phase Synthesis of Diverse Peptide Tertiary Amides By Reductive Amination

PubMed Central

Pels, Kevin; Kodadek, Thomas

2015-01-01

The synthesis of libraries of conformationally-constrained peptide-like oligomers is an important goal in combinatorial chemistry. In this regard an attractive building block is the N-alkylated peptide, also known as peptide tertiary amide (PTA). PTAs are strongly biased conformationally due to allylic 1,3 strain interactions. We report here an improved synthesis of these species on solid supports through the use of reductive amination chemistry using amino acid-terminated, bead-displayed oligomers and diverse aldehydes. The utility of this chemistry is demonstrated by the synthesis of a library of 10,000 mixed peptoid-PTA oligomers. PMID:25695359

Solid-phase synthesis of diverse peptide tertiary amides by reductive amination.

PubMed

Pels, Kevin; Kodadek, Thomas

2015-03-09

The synthesis of libraries of conformationally constrained peptide-like oligomers is an important goal in combinatorial chemistry. In this regard an attractive building block is the N-alkylated peptide, also known as a peptide tertiary amide (PTA). PTAs are conformationally constrained because of allylic 1,3 strain interactions. We report here an improved synthesis of these species on solid supports through the use of reductive amination chemistry using amino acid-terminated, bead-displayed oligomers and diverse aldehydes. The utility of this chemistry is demonstrated by the synthesis of a library of 10,000 mixed peptoid-PTA oligomers.

Mutagenicity and clastogenicity of extracts of Helicobacter pylori detected by the Ames test and in the micronucleus test using human lymphoblastoid cells.

PubMed

Arimoto-Kobayashi, Sakae; Ohta, Kaori; Yuhara, Yuta; Ayabe, Yuka; Negishi, Tomoe; Okamoto, Keinosuke; Nakajima, Yoshihiro; Ishikawa, Takeshi; Oguma, Keiji; Otsuka, Takanao

2015-07-01

Epidemiological studies have demonstrated a close association between infection with Helicobacter pylori (H.pylori) and the development of gastric carcinoma. Chronic H.pylori infection increases the frequency of mutation in gastric epithelial cells. However, the mechanism by which infection of H.pylori leads to mutation in gastric epithelial cells is unclear. We suspected that components in H.pylori may be related to the mutagenic response associated with DNA alkylation, and could be detected with the Ames test using a more sensitive strain for alkylating agents. Our investigation revealed that an extract of H.pylori was mutagenic in the Ames test with Salmonella typhimurium YG7108, which is deficient in the DNA repair of O(6)-methylguanine. The extract of H.pylori may contain methylating or alkylating agents, which might induce O (6)-alkylguanine in DNA. Mutagenicity of the alkylating agents N-methyl-N-nitrosourea (MNU) and N-methyl-N'-nitro-N-nitrosoguanidine in the Ames test with S.typhimurium TA1535 was enhanced significantly in the presence of the extract of H.pylori. The tested extracts of H.pylori resulted in a significant induction of micronuclei in human-derived lymphoblastoid cells. Heat instability and dialysis resistance of the extracts of H.pylori suggest that the mutagenic component in the extracts of H.pylori is a heat-unstable large molecule or a heat-labile small molecule strongly attached or adsorbed to a large molecule. Proteins in the extracts of H.pylori were subsequently fractionated using ammonium sulphate precipitation. However, all fractions expressed enhancing effects toward MNU mutagenicity. These results suggest the mutagenic component is a small molecule that is absorbed into proteins in the extract of H.pylori, which resist dialysis. Continuous and chronic exposure of gastric epithelial cells to the alkylative mutagenic component from H.pylori chronically infected in the stomach might be a causal factor in the gastric carcinogenesis associated with H.pylori. © The Author 2015. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Nature of the Elimination of the Penicillinase Plasmid from Staphylococcus aureus by Surface-Active Agents

PubMed Central

Sonstein, Stephen A.; Baldwin, J. N.

1972-01-01

Growth of Stapylococcus aureus in various ionic surface-active agents resulted in loss of the ability to produce penicillinase, whereas growth in nonionic surface-active agents had no effect on penicillinase production. The curing effect of various alkyl sulfates was found to be dependent upon the chain length. Curing by surface-active agents could be inhibited by magnesium. Reciprocal transduction experiments showed that curing by a surface-active agent was a property of the plasmid, not of the bacterial strain in which the plasmic resides. PMID:4204903

Formation of N-alkylpyrroles via intermolecular redox amination.

PubMed

Pahadi, Nirmal K; Paley, Miranda; Jana, Ranjan; Waetzig, Shelli R; Tunge, Jon A

2009-11-25

A wide variety of aldehydes, ketones, and lactols undergo redox amination when allowed to react with 3-pyrroline in the presence of a mild Brønsted acid catalyst. This reaction utilizes the inherent reducing power of 3-pyrroline to perform the equivalent of a reductive amination to form alkyl pyrroles. In doing so, the reaction avoids stoichiometric reducing agents that are typically associated with reductive aminations. Moreover, the redox amination protocol allows access to alkyl pyrroles that cannot be made via standard reductive amination.

Method for removing elemental sulfur in sour gas wells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sample, T.E. Jr.

1975-09-30

A process is described for removing sulfur deposits from sour gas wells. The formation, well, and surface equipment are contacted with a chemical composition whose aqueous solution will solubilize the sulfur by primary chemical reaction and contains a wetting agent to facilitate and accelerate the sulfur dissolution and removal. The wetting agent or surfactant may be any of a wide variety of surface-active substances such as soaps, sodium or ammonium salts of alkyl or alkyl-aryl sulfates and sulfonates. Nonionic surfactants are preferred, such as ethoxylated substituted phenols. The aqueous solvents are capable of chemically reacting with sulfur to form water-solublemore » sulfur derivatives and include aqueous solutions of alkalies, bases (both inorganic and organic), ammonia, sulfites, bisulfites, etc. (6 claims)« less

ON DEVELOPING CLEANER ORGANIC UNIT PROCESSES

EPA Science Inventory

Organic waste products, potentially harmful to the human health and the environment, are primarily produced in the synthesis stage of manufacturing processes. Many such synthetic unit processes, such as halogenation, oxidation, alkylation, nitration, and sulfonation are common to...

Synthesis of alkyl- and aryl-amino-substituted anthraquinone derivatives by microwave-assisted copper(0)-catalyzed Ullmann coupling reactions.

PubMed

Baqi, Younis; Müller, Christa E

2010-05-01

This protocol describes the efficient, generally applicable Ullmann coupling reaction of bromaminic acid with alkyl- or aryl-amines in phosphate buffer under microwave irradiation using elemental copper as a catalyst. The reaction leads to a number of biologically active compounds. As a prototypical example, the synthesis of a new, potent antagonist of human platelet P2Y(12) receptors, which has potential as an antithrombotic drug, is described in detail. The optimized protocol includes a description of an appropriate reaction setup, thin layer chromatography for monitoring the reaction and a procedure for the isolation, purification and characterization of the anticipated product. The reaction is performed without the use of a glove box and there is no requirement for an inert atmosphere. The reaction typically proceeds within 2-30 min, the protocol, including workup, generally takes 1-3 h to complete.

Synthesis and evaluation of ethylnitrosoureas of substituted naphthalimides as anticancer compounds.

PubMed

Pain, Anindita; Samanta, Suva; Dutta, Sushanta; Saxena, Ajit K; Shanmugavel, Mutiah; Sharma, Madhunika; Qazi, Gulam N; Sanyal, Utpal

2007-01-01

Four new ethylnitrosourea derivatives of substituted naphthalimides 3a-d have been synthesized from the respective N-(2-ethylamino) naphthalimides. Their chemical alkylating activity compared with the clinical drug CCNU and an experimental compound Mitonafide indicated that they possess lower alkylating activity than CCNU and comparable activity with the latter. Their anti-tumor efficacies were assessed in vivo in two murine ascites tumors namely Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times (MST) of drug treated (T) over untreated control (C) mice. CCNU and Mitonafide were used as positive controls for comparison. The representative compound 3a has displayed marginal anti-tumoral activity in these tumors. Three compounds were further screened in vitro in 4 different human tumor cell lines but no significant activity was observed in those lines. These compounds moderately inhibit the synthesis of DNA and RNA in S-180 tumor cells.

Safety Assessment of Alkyl Esters as Used in Cosmetics.

PubMed

Fiume, Monice M; Heldreth, Bart A; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

2015-09-01

The Cosmetic Ingredient Review Expert Panel (Panel) assessed the safety of 237 alkyl esters for use in cosmetics. The alkyl esters included in this assessment have a variety of reported functions in cosmetics, with skin-conditioning agent being the most common function. The Panel reviewed available animal and clinical data in making its determination of safety on these ingredients, and where there were data gaps, similarity in structure, properties, functions, and uses of these ingredients allowed for extrapolation of the available toxicological data to assess the safety of the entire group. The Panel concluded that these ingredients are safe in cosmetic formulations in the present practices of use and concentration when formulated to be nonirritating. © The Author(s) 2015.

Synthesis, structure, theoretical and experimental in vitro antioxidant/pharmacological properties of α-aryl, N-alkyl nitrones, as potential agents for the treatment of cerebral ischemia.

PubMed

Samadi, Abdelouahid; Soriano, Elena; Revuelta, Julia; Valderas, Carolina; Chioua, Mourad; Garrido, Ignacio; Bartolomé, Begoña; Tomassolli, Isabelle; Ismaili, Lhassane; González-Lafuente, Laura; Villarroya, Mercedes; García, Antonio G; Oset-Gasque, María J; Marco-Contelles, José

2011-01-15

The synthesis, structure, theoretical and experimental in vitro antioxidant properties using the DPPH, ORAC, and benzoic acid, as well as preliminary in vitro pharmacological activities of (Z)-α-aryl and heteroaryl N-alkyl-nitrones 6-15, 18, 19, 21, and 23, is reported. In the in vitro antioxidant activity, for the DPPH radical test, only nitrones bearing free phenol groups gave the best RSA (%) values, nitrones 13 and 14 showing the highest values in this assay. In the ORAC analysis, the most potent radical scavenger was nitrone indole 21, followed by the N-benzyl benzene-type nitrones 10 and 15. Interestingly enough, the archetypal nitrone 7 (PBN) gave a low RSA value (1.4%) in the DPPH test, or was inactive in the ORAC assay. Concerning the ability to scavenge the hydroxyl radical, all the nitrones studied proved active in this experiment, showing high values in the 94-97% range, the most potent being nitrone 14. The theoretical calculations for the prediction of the antioxidant power, and the potential of ionization confirm that nitrones 9 and 10 are among the best compounds in electron transfer processes, a result that is also in good agreement with the experimental values in the DPPH assay. The calculated energy values for the reaction of ROS (hydroxyl, peroxyl) with the nitrones predict that the most favourable adduct-spin will take place between nitrones 9, 10, and 21, a fact that would be in agreement with their experimentally observed scavenger ability. The in vitro pharmacological analysis showed that the neuroprotective profile of the target molecules was in general low, with values ranging from 0% to 18.7%, in human neuroblastoma cells stressed with a mixture of rotenone/oligomycin-A, being nitrones 18, and 6-8 the most potent, as they show values in the range 24-18.4%. Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.

Synthesis of Spiro Indole-2-Ones Using Three Component Reaction of N-Alkylisatins and Triphenylphosphonium Intermediates.

PubMed

Moradi, Ali Varasteh

2017-01-01

A simple and efficient procedure is achieved for the synthesis of indole-2-one derivatives via three-component reaction of N-alkylisatin, activated acetylenic compounds and alkyl bromide in the presence of triphenylphosphine in water under two conditions; room temperature and microwave irradiation. All chemicals used in this work were prepared from Fluka (Buchs, Switzerland) and were used without further purification. N-alkylisatin were synthesized in the laboratory in the procedure that is reported in the literature. Electrothermal 9100 apparatus is employed for measuring of melting points of products. Elemental analyses for C, H, and N were performed with Heraeus CHN-O-Rapid analyzer. Mass spectra were recorded on a FINNIGAN-MAT 8430 spectrometer operating at an ionization potential of 70 eV. Measurement of IR spectra was performed by Shimadzu IR-460 spectrometer. 1H, and 13C NMR spectra were evaluated with a BRUKER DRX- 500 AVANCE spectrometer at 500.1 and 125.8 MHz, respectively. The results were demonstrated that simple mixing of N-alkylisatin, dialkyl acetylenedicarboxylate and alkyl bromides in the presence of triphenylphosphine by using of microwave condition is the efficient method for preparation of indole derivatives in good yields. In the optimized reaction conditions, water is solvent and temperature of the mixture of reaction is 80 oC. In this study, the reaction of activated acetylenic compounds with N-alkylisatin and alkyl bromide in the presence of triphenylphosphine is investigated which is led to a facile synthesis of some functionalized indoles. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Development of A Concise Synthesis of (−)-Oseltamivir (Tamiflu®)

PubMed Central

Trost, Barry M.; Zhang, Ting

2011-01-01

We report a full account of our work towards the development of an eight-step synthesis of anti-influenza drug (−)-oseltamivir (Tamiflu®) from commercially available starting material. The final synthetic route proceeds with an overall yield of 30 %. Key transformations include a novel palladium-catalyzed asymmetric allylic alkylation reaction (Pd-AAA) as well as a rhodium-catalyzed chemo-, regio-, and stereoselective aziridination reaction. PMID:21365707

Room-temperature synthesis of two-dimensional ultrathin gold nanowire parallel array with tunable spacing.

PubMed

Morita, Clara; Tanuma, Hiromitsu; Kawai, Chika; Ito, Yuki; Imura, Yoshiro; Kawai, Takeshi

2013-02-05

A series of long-chain amidoamine derivatives with different alkyl chain lengths (CnAA where n is 12, 14, 16, or 18) were synthesized and studied with regard to their ability to form organogels and to act as soft templates for the production of Au nanomaterials. These compounds were found to self-assemble into lamellar structures and exhibited gelation ability in some apolar solvents. The gelation concentration, gel-sol phase transition temperature, and lattice spacing of the lamellar structures in organic solvent all varied on the basis of the alkyl chain length of the particular CnAA compound employed. The potential for these molecules to function as templates was evaluated through the synthesis of Au nanowires (NWs) in their organogels. Ultrathin Au NWs were obtained from all CnAA/toluene gel systems, each within an optimal temperature range. Interestingly, in the case of C12AA and C14AA, it was possible to fabricate ultrathin Au NWs at room temperature. In addition, two-dimensional parallel arrays of ultrathin Au NWs were self-assembled onto TEM copper grids as a result of the drying of dispersion solutions of these NWs. The use of CnAA compounds with differing alkyl chain lengths enabled precise tuning of the distance between the Au NWs in these arrays.

The Grignard Reagent: Preparation, Structure, and Some Reactions.

ERIC Educational Resources Information Center

Orchin, Milton

1989-01-01

The Grignard reagent used in the laboratory synthesis of organic compounds is the product resulting from the reaction of an alkyl or aryl halide with elemental magnesium. Describes the structure, formation, and some reactions of the reagent. (YP)

EXPEDITIOUS SYNTHESIS OF IONIC LIQUIDS USING ULTRASOUND AND MICROWAVE IRRADIATION

EPA Science Inventory

Environmentally friendlier preparations of ionic liquids have been developed that proceed expeditiously under the influence of microwave or ultrasound irradiation conditions using neat reactants, alkylimidazoles and alkyl halides. A number of useful ionic liquids have been prepar...

The Catalytic Enantioselective Total Synthesis of (+)-Liphagal**

PubMed Central

Day, Joshua J.; McFadden, Ryan M.; Virgil, Scott C.; Kolding, Helene; Alleva, Jennifer L.; Stoltz, Brian M.

2012-01-01

Ring a ding: The first catalytic enantioselective total synthesis of the meroterpenoid natural product (+)-liphagal is disclosed. The approach showcases a variety of technology including enantioselective enolate alkylation, a photochemical alkyne-alkene [2+2] reaction, microwave-assisted metal catalysis, and an intramolecular aryne capture cyclization reaction. Pivotal to the successful completion of the synthesis was a sequence involving ring expansion from a [6-5-4] tricycle to a [6-7] bicyclic core followed by stereoselective hydrogenation of a sterically occluded tri-substituted olefin to establish the trans homodecalin system found in the natural product. PMID:21671325

The translesion polymerase Rev3L in the tolerance of alkylating anticancer drugs.

PubMed

Roos, Wynand Paul; Tsaalbi-Shtylik, Anastasia; Tsaryk, Roman; Güvercin, Fatma; de Wind, Niels; Kaina, Bernd

2009-10-01

Temozolomide and fotemustine, representing methylating and chloroethylating agents, respectively, are used in the treatment of glioma and malignant melanoma. Because chemoresistance of these tumors is a common phenomenon, identification of the underlying mechanisms is needed. Here we show that Rev3L, the catalytic subunit of the translesion DNA polymerase zeta, mediates resistance to both temozolomide and fotemustine. Rev3L knockout cells are hypersensitive to both agents. It is remarkable that cells heterozygous for Rev3L showed an intermediate sensitivity. Rev3L is not involved in the tolerance of the toxic O6-methylguanine lesion. However, a possible role of Rev3L in the tolerance of O6-chloroethylguanine or the subsequently formed N1-guanine-N3-cytosine interstrand cross-link is shown. Rev3L had no influence on base excision repair (BER) of the N-alkylation lesions but is very likely to be involved in the tolerance of N-alkylations or apurinic/apyrimidinic sites originating from them. We also show that Rev3L exerts its protective effect in replicating cells and that loss of Rev3L leads to a significant increase in DNA double-strand breaks after temozolomide and fotemustine treatment. These data show that Rev3L contributes to temozolomide and fotemustine resistance, thus acting in concert with O6-methylguanine-DNA methyltransferase, BER, mismatch repair, and double-strand break repair in defense against simple alkylating anticancer drugs.

Studies on a Total Synthesis of the Microbial Immunosuppresive Agent FR901483

PubMed Central

Kropf, Jeffrey E.; Meigh, Ivona C.; Bebbington, Magnus W.P.; Weinreb, Steven M.

2008-01-01

A strategy is outlined for construction of the fungal immunosuppressant FR901483 (1). It was possible to convert 1,4-cyclohexanedione monoethylene ketal in five simple steps to iodoacetamide ketone 10, which was cyclized in good yield to the key bridged keto lactam 11 containing the A/B 2-azabicyclo[3.3.1]nonane ring system of the natural product. This intermediate could be transformed to N-Boc lactam 16, whose derived enolate underwent stereoselective hydroxylation with the Davis oxaziridine to produce alcohol 17 having the desired C-2 configuration. Compound 17 was then converted in three steps to alkoxy carbamate 20. The N-acyliminium ion derived from intermediate 20 could be alkylated in good overall yield with p-methoxybenzylmagnesium chloride to afford a 5:4 mixure of the desired PMB product 21 and the epimer 23. In an attempt to improve the stereoselectivity in this alkylation, the inverted C-4 protected alcohol N-Boc lactam 33 was prepared and its enolate was hydroxylated. Inexplicably, the product of this reaction was the undesired equatorial alcohol 34. Some model systems were investigated towards annulation of the C-ring of the natural product. It was found that homoallylic amine 40 could be cyclized with PhSCl in the presence of silica gel to generate the desired 5-endo tetracyclic product 42 in moderate yield. This cyclization protocol was also successfully applied to the actual FR901483 system 22, leading to the requisite tricycle 43. PMID:16496992

Chiral alkylated-aniline as a noninvasive fluorescence sensor: Spectroscopic and molecular modeling studies

NASA Astrophysics Data System (ADS)

Sengupta, Bidisha; Mukherjee, Chirantan Sen; Chakraborty, Sandipan; Muhammad, Maria Jones; Gladney, William; Armstrong, George

2017-12-01

Aniline, heterocyclic aromatic amines, and arylamines are known carcinogens. Recently aniline mustard has come into prominence as a novel anticancer agent. In this project, microwave irradiation has been used to synthesize an optically active alkylated aniline namely 2,6-dimethyl-4-(1-(p-tolyl)ethyl)aniline (abbreviated DMPA). The presence of quartet and doublet peaks in NMR and a single chromatogram in HPLC verified that the final product DMPA, prepared from the synthesis reactions, had no major impurities. By using a Lux chiral column in HPLC, two peaks have been detected in the chromatogram, which correspond to two enantiomers of the chiral aniline derivative. Fluorescence spectroscopic measurements on DMPA indicated conspicuous dependence of its emission behavior on the polarity (in terms of the empirical polarity parameter ET(30)) of the homogeneous solvents used, a property important for an optical sensor. The nature of the emission profiles, along with the relevant parameter namely wavelength at emission maximum (λemmax) is used to infer the distribution, binding and microenvironment of the DMPA molecules in human serum albumin protein (HSA). DMPA is weakly fluorescent in aqueous buffer medium, with a dramatic enhancement in the fluorescence emission in the presence of HSA. Molecular modeling studies have been carried out on the two enantiomers (R and S) of DMPA with HSA. The implications of these findings are examined in relation to the potentialities of DMPA as a novel fluorescence sensor for biological systems.

Chiral alkylated-aniline as a noninvasive fluorescence sensor: Spectroscopic and molecular modeling studies.

PubMed

Sengupta, Bidisha; Mukherjee, Chirantan Sen; Chakraborty, Sandipan; Muhammad, Maria Jones; Gladney, William; Armstrong, George

2017-12-05

Aniline, heterocyclic aromatic amines, and arylamines are known carcinogens. Recently aniline mustard has come into prominence as a novel anticancer agent. In this project, microwave irradiation has been used to synthesize an optically active alkylated aniline namely 2,6-dimethyl-4-(1-(p-tolyl)ethyl)aniline (abbreviated DMPA). The presence of quartet and doublet peaks in NMR and a single chromatogram in HPLC verified that the final product DMPA, prepared from the synthesis reactions, had no major impurities. By using a Lux chiral column in HPLC, two peaks have been detected in the chromatogram, which correspond to two enantiomers of the chiral aniline derivative. Fluorescence spectroscopic measurements on DMPA indicated conspicuous dependence of its emission behavior on the polarity (in terms of the empirical polarity parameter E T (30)) of the homogeneous solvents used, a property important for an optical sensor. The nature of the emission profiles, along with the relevant parameter namely wavelength at emission maximum (λ em max ) is used to infer the distribution, binding and microenvironment of the DMPA molecules in human serum albumin protein (HSA). DMPA is weakly fluorescent in aqueous buffer medium, with a dramatic enhancement in the fluorescence emission in the presence of HSA. Molecular modeling studies have been carried out on the two enantiomers (R and S) of DMPA with HSA. The implications of these findings are examined in relation to the potentialities of DMPA as a novel fluorescence sensor for biological systems. Copyright © 2017 Elsevier B.V. All rights reserved.

Design and in vitro activities of N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, novel small molecule Hypoxia Inducible Factor-1 (HIF-1) pathway inhibitors and anti-cancer agents

PubMed Central

Mun, Jiyoung; Jabbar, Adnan Abdul; Devi, Narra Sarojini; Yin, Shaoman; Wang, Yingzhe; Tan, Chalet; Culver, Deborah; Snyder, James P.; Van Meir, Erwin G.; Goodman, Mark M.

2013-01-01

The Hypoxia Inducible Factor (HIF) pathway is an attractive target for cancer as it controls tumor adaptation to growth under hypoxia and mediates chemo- and radiation resistance. We previously discovered 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, as a novel small molecule HIF-1 pathway inhibitor in a high-throughput cell-based assay, but its in vivo delivery is hampered by poor aqueous solubility (0.009 μM in water; logP7.4: 3.7). Here we describe the synthesis of twelve N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, which were designed to possess optimal lipophilicities and aqueous solubilities by in silico calculations. Experimental logP7.4 values of 8 of the 12 new analogs ranged from 1.2 ∼ 3.1. Aqueous solubilities of 3 analogs were measured, among which the most soluble N-[(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-2-sulfonamide had an aqueous solubility of 80 μM, e.g. a solubility improvement of ∼9,000-fold. The pharmacological optimization had minimal impact on drug efficacy as the compounds retained IC50 values at or below 5 μM in our HIF-dependent reporter assay. PMID:22746274

Comparative toxicity of mono- and bifunctional alkylating homologues of sulphur mustard in human skin keratinocytes.

PubMed

Sawyer, Thomas W; McNeely, Karin; Louis, Kristen; Lecavalier, Pierre; Song, Yanfeng; Villanueva, Mercy; Clewley, Robin

2017-05-01

Sulphur mustard (bis(2-chloroethyl) sulphide; agent H) is a vesicant chemical warfare (CW) agent whose mechanism of action is not known with any certainty and for which there are no effective antidotes. It has a pronounced latent period before signs and symptoms of poisoning appear which it shares with the nitrogen mustards, and that differentiates it from other classes of vesicant agents. Sulphur mustard, the sulphur mustard CW agents Q (1,2-bis(2-chloroethylthio) ethane) and T (1,1 bis(2-chloroethylthioethyl) ether), the H partial hydrolysis product hemi-sulphur mustard (2-chloroethyl 2-hydroxyethyl sulphide; HSM), and the commercially available 2-chloroethyl ethyl sulphide (CEES) were characterized with respect to their toxicity in first passage cultures of proliferating human skin keratinocytes, the target cell of H-induced skin vesication. Agents H and T were equitoxic and half as toxic as agent Q. Hemi-sulphur mustard and CEES were approximately six times and seventeen times, respectively less cytotoxic than H. 2-Chloroethyl ethyl sulphide was only slightly less toxic in confluent cultures compared to actively proliferating cells. In contrast, the toxicity of H, Q, T and HSM significantly decreased as the cultures became confluent, paralleling the decreasing sensitivity of skin keratinocytes to H as they leave the basement membrane of the skin. The toxicity of CEES was maximal by 24h. In contrast, the maximal toxicity of the other four agents occurred at 48h, mirroring the latent period observed for these agents in vivo. The markedly different characteristics of toxicity between CEES and the other four test compounds indicate that it is likely that different mechanisms of action are operative between them. Caution should therefore be taken when interpreting the results of studies utilizing CEES as a simulant for the mechanistic study of H, or in the elucidation of medical countermeasures against this CW agent. It is also notable that the toxicity characteristics of the mono-alkylating HSM mirrors those of H, Q and T, suggesting that the bi-alkylating characteristics of these latter compounds may not play as large a role in their toxic effects as commonly thought. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Inhibition of autophagy enhances DNA damage-induced apoptosis by disrupting CHK1-dependent S phase arrest

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liou, Jong-Shian; Wu, Yi-Chen; Yen, Wen-Yen

2014-08-01

DNA damage has been shown to induce autophagy, but the role of autophagy in the DNA damage response and cell fate is not fully understood. BO-1012, a bifunctional alkylating derivative of 3a-aza-cyclopenta[a]indene, is a potent DNA interstrand cross-linking agent with anticancer activity. In this study, BO-1012 was found to reduce DNA synthesis, inhibit S phase progression, and induce phosphorylation of histone H2AX on serine 139 (γH2AX) exclusively in S phase cells. Both CHK1 and CHK2 were phosphorylated in response to BO-1012 treatment, but only depletion of CHK1, but not CHK2, impaired BO-1012-induced S phase arrest and facilitated the entry ofmore » γH2AX-positive cells into G2 phase. CHK1 depletion also significantly enhanced BO-1012-induced cell death and apoptosis. These results indicate that BO-1012-induced S phase arrest is a CHK1-dependent pro-survival response. BO-1012 also resulted in marked induction of acidic vesicular organelle (AVO) formation and microtubule-associated protein 1 light chain 3 (LC3) processing and redistribution, features characteristic of autophagy. Depletion of ATG7 or co-treatment of cells with BO-1012 and either 3-methyladenine or bafilomycin A1, two inhibitors of autophagy, not only reduced CHK1 phosphorylation and disrupted S phase arrest, but also increased cleavage of caspase-9 and PARP, and cell death. These results suggest that cells initiate S phase arrest and autophagy as pro-survival responses to BO-1012-induced DNA damage, and that suppression of autophagy enhances BO-1012-induced apoptosis via disruption of CHK1-dependent S phase arrest. - Highlights: • Autophagy inhibitors enhanced the cytotoxicity of a DNA alkylating agent, BO-1012. • BO-1012-induced S phase arrest was a CHK1-dependent pro-survival response. • Autophagy inhibition enhanced BO-1012 cytotoxicity via disrupting the S phase arrest.« less

Stereoregulations of pyrimidinone based chiral auxiliary in aldol and alkylation reactions: a convenient route to oxyneolignans.

PubMed

Chouhan, Mangilal; Sharma, Ratnesh; Nair, Vipin A

2012-11-16

(S)-4-Isopropyl-1-phenyltetrahydropyrimidin-2(1H)-one was synthesized and evaluated as a chiral auxiliary for asymmetric acetate and propionate aldol reactions, by generation of titanium and lithium enolates, affording excellent yields and stereoselectivities for syn and anti aldol diastereomers, respectively. High stereoselectivities were also obtained in lithium mediated alkylation reactions. The application of the auxiliary was exemplified in the asymmetric synthesis of a natural oxyneolignan, (+)-(7S,8S)-4-hydroxy-3,3',5'-trimethoxy-8',9'-dinor-8,4'-oxyneoligna-7,9-diol-7'-oic acid.

Strategies for the solid-phase diversification of poly-L-proline-type II peptide mimic scaffolds and peptide scaffolds through guanidinylation.

PubMed

Flemer, Stevenson; Wurthmann, Alexander; Mamai, Ahmed; Madalengoitia, José S

2008-10-03

A strategy for the solid-phase diversification of PPII mimic scaffolds through guanidinylation is presented. The approach involves the synthesis N-Pmc-N'-alkyl thioureas as diversification reagents. Analogues of Fmoc-Orn(Mtt)-OH can be incorporated into a growing peptide chain on Wang resin. Side chain deprotection with 1% TFA/CH2Cl2 followed by EDCI-mediated reaction of N-Pmc-N'-alkyl thioureas with the side chain amine affords arginine analogues with modified guanidine head groups. The scope, limitations, and incidental chemistry are discussed.

Targeting neddylation induces DNA damage and checkpoint activation and sensitizes chronic lymphocytic leukemia B cells to alkylating agents.

PubMed

Paiva, C; Godbersen, J C; Berger, A; Brown, J R; Danilov, A V

2015-07-09

Microenvironment-mediated upregulation of the B-cell receptor (BCR) and nuclear factor-κB (NF-κB) signaling in CLL cells resident in the lymph node and bone marrow promotes apoptosis evasion and clonal expansion. We recently reported that MLN4924 (pevonedistat), an investigational agent that inhibits the NEDD8-activating enzyme (NAE), abrogates stromal-mediated NF-κB pathway activity and CLL cell survival. However, the NAE pathway also assists degradation of multiple other substrates. MLN4924 has been shown to induce DNA damage and cell cycle arrest, but the importance of this mechanism in primary neoplastic B cells has not been studied. Here we mimicked the lymph node microenvironment using CD40 ligand (CD40L)-expressing stroma and interleukin-21 (IL-21) to find that inducing proliferation of the primary CLL cells conferred enhanced sensitivity to NAE inhibition. Treatment of the CD40-stimulated CLL cells with MLN4924 resulted in deregulation of Cdt1, a DNA replication licensing factor, and cell cycle inhibitors p21 and p27. This led to DNA damage, checkpoint activation and G2 arrest. Alkylating agents bendamustine and chlorambucil enhanced MLN4924-mediated DNA damage and apoptosis. These events were more prominent in cells stimulated with IL-21 compared with CD40L alone, indicating that, following NAE inhibition, the culture conditions were able to direct CLL cell fate from an NF-κB inhibition to a Cdt1 induction program. Our data provide insight into the biological consequences of targeting NAE in CLL and serves as further rationale for studying the clinical activity of MLN4924 in CLL, particularly in combination with alkylating agents.

Targeting neddylation induces DNA damage and checkpoint activation and sensitizes chronic lymphocytic leukemia B cells to alkylating agents

PubMed Central

Paiva, C; Godbersen, J C; Berger, A; Brown, J R; Danilov, A V

2015-01-01

Microenvironment-mediated upregulation of the B-cell receptor (BCR) and nuclear factor-κB (NF-κB) signaling in CLL cells resident in the lymph node and bone marrow promotes apoptosis evasion and clonal expansion. We recently reported that MLN4924 (pevonedistat), an investigational agent that inhibits the NEDD8-activating enzyme (NAE), abrogates stromal-mediated NF-κB pathway activity and CLL cell survival. However, the NAE pathway also assists degradation of multiple other substrates. MLN4924 has been shown to induce DNA damage and cell cycle arrest, but the importance of this mechanism in primary neoplastic B cells has not been studied. Here we mimicked the lymph node microenvironment using CD40 ligand (CD40L)-expressing stroma and interleukin-21 (IL-21) to find that inducing proliferation of the primary CLL cells conferred enhanced sensitivity to NAE inhibition. Treatment of the CD40-stimulated CLL cells with MLN4924 resulted in deregulation of Cdt1, a DNA replication licensing factor, and cell cycle inhibitors p21 and p27. This led to DNA damage, checkpoint activation and G2 arrest. Alkylating agents bendamustine and chlorambucil enhanced MLN4924-mediated DNA damage and apoptosis. These events were more prominent in cells stimulated with IL-21 compared with CD40L alone, indicating that, following NAE inhibition, the culture conditions were able to direct CLL cell fate from an NF-κB inhibition to a Cdt1 induction program. Our data provide insight into the biological consequences of targeting NAE in CLL and serves as further rationale for studying the clinical activity of MLN4924 in CLL, particularly in combination with alkylating agents. PMID:26158513

Synthesis and antifungal activities of miltefosine analogs

USDA-ARS?s Scientific Manuscript database

Nine alkylphosphocholine derivatives (3a-3i) were prepared by modifying the choline structural moiety and the alkyl chain length of miltefosine (hexadecylphosphocholine), a broad-spectrum antifungal compound that has shown modest therapeutic efficacy in a mouse model of cryptococcosis. The synthetic...

77 FR 61515 - Alkyl Amines Polyalkoxylates; Exemption From the Requirement of a Tolerance

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-10

... polyoxyethylene polymers and fatty acids; carriers such as clay and diatomaceous earth; thickeners such as carrageenan and modified cellulose; wetting, spreading, and dispersing agents; propellants in aerosol...

Alkylation sensitivity screens reveal a conserved cross-species functionome

PubMed Central

Svilar, David; Dyavaiah, Madhu; Brown, Ashley R.; Tang, Jiang-bo; Li, Jianfeng; McDonald, Peter R.; Shun, Tong Ying; Braganza, Andrea; Wang, Xiao-hong; Maniar, Salony; St Croix, Claudette M.; Lazo, John S.; Pollack, Ian F.; Begley, Thomas J.; Sobol, Robert W.

2013-01-01

To identify genes that contribute to chemotherapy resistance in glioblastoma, we conducted a synthetic lethal screen in a chemotherapy-resistant glioblastoma derived cell line with the clinical alkylator temozolomide (TMZ) and an siRNA library tailored towards “druggable” targets. Select DNA repair genes in the screen were validated independently, confirming the DNA glycosylases UNG and MYH as well as MPG to be involved in the response to high dose TMZ. The involvement of UNG and MYH is likely the result of a TMZ-induced burst of reactive oxygen species. We then compared the human TMZ sensitizing genes identified in our screen with those previously identified from alkylator screens conducted in E. coli and S. cerevisiae. The conserved biological processes across all three species composes an Alkylation Functionome that includes many novel proteins not previously thought to impact alkylator resistance. This high-throughput screen, validation and cross-species analysis was then followed by a mechanistic analysis of two essential nodes: base excision repair (BER) DNA glycosylases (UNG, human and mag1, S. cerevisiae) and protein modification systems, including UBE3B and ICMT in human cells or pby1, lip22, stp22 and aim22 in S. cerevisiae. The conserved processes of BER and protein modification were dual targeted and yielded additive sensitization to alkylators in S. cerevisiae. In contrast, dual targeting of BER and protein modification genes in human cells did not increase sensitivity, suggesting an epistatic relationship. Importantly, these studies provide potential new targets to overcome alkylating agent resistance. PMID:23038810

Advance in Anti-tumor Mechanisms of Shikonin, Alkannin and their Derivatives.

PubMed

Zhang, Xu; Cui, Jia-Hua; Meng, Qing-Qing; Li, Shao-Shun; Zhou, Wen; Xiao, Sui

2018-01-01

Shikonin, alkannin and their derivatives, the main ingredient of Lithospermum erythrorhizon and Arnebia euchroma (Royle) Johnst native to Inner Mongolian and Northwest of China respectively, hold promising potentials for antitumor effects via multiple-target mechanisms. This review will emphasize the importance of their antitumor activity in apoptosis, necroptosis and immunogenic cell death, and expound the relationship of their antitumor activity and naphthoquinone scaffold that could generate ROS and alkylating agent. Meanwhile, the antitumor mechanisms of naturally-occurring shikonin, alkannin and their derivatives, which were divided into the direct interaction involved in alkylating agent, covalently binding the DNA and protein, as well as the indirect interaction mediated by ROS, nonspecifically influencing the mitochondria or multiple signal pathways, will be systematically summarized and discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Risk of Subsequent Leukemia After a Solid Tumor in Childhood: Impact of Bone Marrow Radiation Therapy and Chemotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Allodji, Rodrigue S., E-mail: rodrigue.allodji@gustaveroussy.fr; Gustave Roussy, Villejuif; Paris Sud University, Orsay

Purpose: To investigate the roles of radiation therapy and chemotherapy in the occurrence of subsequent leukemia after childhood cancer. Methods and Materials: We analyzed data from a case-control study with 35 cases and 140 controls. The active bone marrow (ABM) was segmented into 19 compartments, and the radiation dose was estimated in each. The chemotherapy drug doses were also estimated to enable adjustments. Models capable of accounting for radiation dose heterogeneity were implemented for analysis. Results: Univariate analysis showed a significant trend in the increase of secondary leukemia risk with radiation dose, after accounting for dose heterogeneity (P=.046). This trendmore » became nonsignificant after adjustment for doses of epipodophyllotoxins, alkylating agents, and platinum compounds and the first cancer on multivariate analysis (P=.388). The role of the radiation dose appeared to be dwarfed, mostly by the alkylating agents (odds ratio 6.9, 95% confidence interval 1.9-25.0). Among the patients who have received >16 Gy to the ABM, the radiogenic risk of secondary leukemia was about 4 times greater in the subgroup with no alkylating agents than in the subgroup receiving ≥10 g/m{sup 2}. Conclusions: Notwithstanding the limitations resulting from the size of our study population and the quite systematic co-treatment with chemotherapy, the use of detailed information on the radiation dose distribution to ABM enabled consideration of the role of radiation therapy in secondary leukemia induction after childhood cancer.« less

EG-15THE METHYLATION STATUS OF MGMT IN MEDULLOBLASTOMA

PubMed Central

Shimizu, Yuzaburo; Kurimoto, Tomoko; Kondo, Akihide; Arai, Hajime

2014-01-01

BACKGROUND: Medulloblastoma is a highly malignant brain tumor in childhood. Some studies reported that alkylating chemotherapeutic drugs are effective agents in the treatment of patients with medulloblastoma. O6-methylguanine-DNA methyltransferase (MGMT) is one of the DNA repair enzymes and plays a significant role in tumor resistance to alkylating agents. Low MGMT expression or MGMT promoter methylation have been found to be associated with favorable outcomes in malignant glioma patients treated with alkylating agents such as temozolomide. However, impact of MGMT status on clinical outcomes in medulloblastoma patients is not fully evaluated. OBJECTIVE: The objective of this study is to investigate the association between MGMT status and the response for chemotherapy in pediatric patients with medulloblastoma. METHODS: Patients with medulloblastoma treated at our institution between 1995 and 2012 were reviewed retrospectively. Relevant clinical information including current disease status, tumor response to chemotherapy was obtained from the hospital charts. To evaluate the MGMT status, we performed bisulfite sequencing analysis to determine the methylation status of the MGMT promoter. RESULTS: Tumor material and detailed clinical information were available in 22 patients. Of them, 13 patients were alive (11 in CR), seven died of disease and two were lost to follow up. Five patients were with dissemination at diagnosis. We succeeded to evaluate both the MGMT status of tumors and the number of methylation sites in MGMT promoter. CONCLUSIONS: We studied the prognostic value of MGMT promoter methylation in medulloblastoma children.

In vitro testing of drug combinations employing nilotinib and alkylating agents with regard to pretransplant conditioning treatment of advanced-phase chronic myeloid leukemia.

PubMed

Radujkovic, Aleksandar; Luft, Thomas; Dreger, Peter; Ho, Anthony D; Jens Zeller, W; Fruehauf, Stefan; Topaly, Julian

2014-08-01

The prognosis of patients with advanced-phase chronic myeloid leukemia (CML) remains dismal despite the availability of targeted therapies and allogeneic stem cell transplantation (allo-SCT). Increasing the antileukemic efficacy of the pretransplant conditioning regimen may be a strategy to increase remission rates and duration. We therefore investigated the antiproliferative effects of nilotinib in combination with drugs that are usually used for conditioning: the alkylating agents mafosfamide, treosulfan, and busulfan. Drug combinations were tested in vitro in different imatinib-sensitive and imatinib-resistant BCR-ABL-positive cell lines. A tetrazolium-based MTT assay was used for the assessment and quantification of growth inhibition after exposure to alkylating agents alone or to combinations with nilotinib. Drug interaction was analyzed using the median-effect method of Chou and Talalay, and combination index (CI) values were calculated according to the classic isobologram equation. Treatment of imatinib-sensitive, BCR-ABL-positive K562 and LAMA84 cells with nilotinib in combination with mafosfamide, treosulfan, or busulfan resulted in synergistic (CI < 1), additive (CI ~ 1), and predominantly antagonistic (CI > 1) effects, respectively. In imatinib-resistant K562-R and LAMA84-R cells, all applied drug combinations were synergistic (CI < 1) at higher growth inhibition levels. Our in vitro data warrant further investigation and may provide the basis for nilotinib-supplemented conditioning regimens for allo-SCT in advanced-phase CML.

Light of DNA-alkylating agents in castration-resistant prostate cancer cells: a novel mixed EGFR/DNA targeting combi-molecule.

PubMed

Liang, Guan-Can; Zheng, Hao-Feng; Chen, Yan-Xiong; Li, Teng-Cheng; Liu, Wei; Fang, You-Qiang

2017-01-01

The mechanism underlying the therapeutic effects of combi-molecule JDF12 on prostate cancer (PCa) DU145 cells remains still unclear. This study aimed to investigate the proteomic profile after JDF12 treatment in DU145 cells by comparing with that in Iressa treated cells and untreated cells. MTT was used to evaluate drug cytotoxicity, DAPI staining was done to assess apoptosis of cells, and flow cytometry was used to analyze cell cycle. iTRAQ and qPCR were employed to obtain the proteomic profiles of JDF12 treated, Iressa treated, and untreated DU145 cells, and validate the expression of selected differentially expressed proteins, respectively. JDF12 could significantly inhibit the proliferation and increase the apoptosis of DU145 cells when compared with Iressa or blank group. In total, 5071 proteins were obtained, out of which, 42, including 21 up-regulated and 21 down-regulated proteins, were differentially expressed in JDF12 group when compared with Iressa and blank groups. The up-regulated proteins were mainly involved in DNA damage/repair and energy metabolism; while the down-regulated proteins were mainly associated with cell apoptosis. qPCR confirmed the expression of several biologically important proteins in DU145 cells after JDF12 treatment. The molecular mechanisms of DNA alkylating agents on PCa therapy that with the assistant of EGFR-blocker were revealed on proteomic level, which may increase the possible applications of DNA alkylating agents and JDF12 on PCa therapy.

Alkylating chemotherapeutic agents cyclophosphamide and melphalan cause functional injury to human bone marrow-derived mesenchymal stem cells.

PubMed

Kemp, Kevin; Morse, Ruth; Sanders, Kelly; Hows, Jill; Donaldson, Craig

2011-07-01

The adverse effects of melphalan and cyclophosphamide on hematopoietic stem cells are well-known; however, the effects on the mesenchymal stem cells (MSCs) residing in the bone marrow are less well characterised. Examining the effects of chemotherapeutic agents on patient MSCs in vivo is difficult due to variability in patients and differences in the drug combinations used, both of which could have implications on MSC function. As drugs are not commonly used as single agents during high-dose chemotherapy (HDC) regimens, there is a lack of data comparing the short- or long-term effects these drugs have on patients post treatment. To help address these problems, the effects of the alkylating chemotherapeutic agents cyclophosphamide and melphalan on human bone marrow MSCs were evaluated in vitro. Within this study, the exposure of MSCs to the chemotherapeutic agents cyclophosphamide or melphalan had strong negative effects on MSC expansion and CD44 expression. In addition, changes were seen in the ability of MSCs to support hematopoietic cell migration and repopulation. These observations therefore highlight potential disadvantages in the use of autologous MSCs in chemotherapeutically pre-treated patients for future therapeutic strategies. Furthermore, this study suggests that if the damage caused by chemotherapeutic agents to marrow MSCs is substantial, it would be logical to use cultured allogeneic MSCs therapeutically to assist or repair the marrow microenvironment after HDC.

Synthesis of [.sup.13C] and [.sup.2H] substituted methacrylic acid, [.sup.13C] and [.sup.2H] substituted methyl methacrylate and/or related compounds

DOEpatents

Alvarez, Marc A.; Martinez, Rodolfo A.; Unkefer, Clifford J.

2010-02-16

The present invention is directed to labeled compounds of the formulae ##STR00001## wherein Q is selected from the group consisting of --S(.dbd.O)--, and --S(.dbd.O).sub.2--, Z is selected from the group consisting of 1-naphthyl, substituted 1-naphthyl, 2-naphthyl, substituted 2-naphthyl, and phenyl groups with the structure ##STR00002## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are each independently selected from the group consisting of hydrogen, a C.sub.1-C.sub.4 lower alkyl, a halogen, and an amino group selected from the group consisting of NH.sub.2, NHR and NRR' where R and R' are each independently selected from the group consisting of a C.sub.1-C.sub.4 lower alkyl, an aryl, and an alkoxy group, and X is selected from the group consisting of hydrogen, a C.sub.1-C.sub.4 lower alkyl group, and a fully-deuterated C.sub.1-C.sub.4 lower alkyl group.

The photochemical alkylation and reduction of heteroarenes.

PubMed

McCallum, T; Pitre, S P; Morin, M; Scaiano, J C; Barriault, L

2017-11-01

The functionalization of heteroarenes has been integral to the structural diversification of medicinally active molecules such as quinolines, pyridines, and phenanthridines. Electron-deficient heteroarenes are electronically compatible to react with relatively nucleophilic free radicals such as hydroxyalkyl. However, the radical functionalization of such heteroarenes has been marked by the use of transition-metal catalyzed processes that require initiators and stoichiometric oxidants. Herein, we describe the photochemical alkylation of quinolines, pyridines and phenanthridines, where through direct excitation of the protonated heterocycle, alcohols and ethers, such as methanol and THF, can serve as alkylating agents. We also report the discovery of a photochemical reduction of these heteroarenes using only iPrOH and HCl. Mechanistic studies to elucidate the underlying mechanism of these transformations, and preliminary results on catalytic methylations are also reported.

SLURRY SOLVENT EXTRACTION PROCESS FOR THE RECOVERY OF METALS FROM SOLID MATERIALS

DOEpatents

Grinstead, R.R.

1959-01-20

A solvent extraction process is described for recovering uranium from low grade uranium bearing minerals such as carnotit or shale. The finely communited ore is made up as an aqueous slurry containing the necessary amount of acid to solubilize the uranium and simultaneously or subsequently contacted with an organic solvent extractant such as the alkyl ortho-, or pyro phosphoric acids, alkyl phosphites or alkyl phosphonates in combination with a diluent such as kerosene or carbon tetrachlorids. The extractant phase is separated from the slurry and treated by any suitable process to recover the uranium therefrom. One method for recovering the uranium comprises treating the extract with aqueous HF containing a reducing agent such as ferrous sulfate, which reduces the uranium and causes it to be precipitated as uranium tetrafluoride.

Comparative Biochemistry and Metabolism. Part 1. Carcinogenesis

DTIC Science & Technology

1982-08-01

1968), Nitrosamine-induced carcino- genesis. The alkylation of nucleic acids of the rat by N-methvl- N- nitrosourea , dimethylnitrosamine...inorganic reducing agent , hydrazine, is toxic and weakly carcinogenic. In earlier studies it was found that oral administration of a toxic dose of...metabolically activated to a methylatinj agent . Liver DNA from mice and hamsters contained considerably more 7-methyl- guanine and 0 6-methylguanine

One-Step Synthesis of Aliphatic Potassium Acyltrifluoroborates (KATs) from Organocuprates.

PubMed

Liu, Sizhou M; Wu, Dino; Bode, Jeffrey W

2018-04-20

A one-step synthesis of aliphatic KATs from organocuprates is reported. Organolithium and organomagnesium reagents were readily transmetalated onto Cu(I) and coupled with a KAT-forming reagent to yield the respective aliphatic KAT. The protocol is suitable for primary, secondary and-for the first time-tertiary alkyl substrates. These protocols considerably expand the range of KATs that can be readily accessed in one step from commercially available starting materials.

Thiol–ene/oxidation tandem reaction under visible light photocatalysis: synthesis of alkyl sulfoxides† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7cc05672a

PubMed Central

Guerrero-Corella, Andrea; María Martinez-Gualda, Ana; Ahmadi, Fereshteh; Ming, Enrique

2017-01-01

The photocatalyzed synthesis of sulfoxides from alkenes and thiols has been carried out using Eosin Y. This is a metal-free method which uses a low catalyst loading, atmospheric oxygen as the oxidant, and visible light conditions (green light). A mechanism has been proposed that is consistent with the experimental results. PMID:28890975

Ada response – a strategy for repair of alkylated DNA in bacteria

PubMed Central

Mielecki, Damian; Grzesiuk, Elżbieta

2014-01-01

Alkylating agents are widespread in the environment and also occur endogenously. They can be cytotoxic or mutagenic to the cells introducing alkylated bases to DNA or RNA. All organisms have evolved multiple DNA repair mechanisms to counteract the effects of DNA alkylation: the most cytotoxic lesion, N3-methyladenine (3meA), is excised by AlkA glycosylase initiating base excision repair (BER); toxic N1-methyladenine (1meA) and N3-methylcytosine (3meC), induced in DNA and RNA, are removed by AlkB dioxygenase; and mutagenic and cytotoxic O6-methylguanine (O6meG) is repaired by Ada methyltransferase. In Escherichia coli, Ada response involves the expression of four genes, ada, alkA, alkB, and aidB, encoding respective proteins Ada, AlkA, AlkB, and AidB. The Ada response is conserved among many bacterial species; however, it can be organized differently, with diverse substrate specificity of the particular proteins. Here, an overview of the organization of the Ada regulon and function of individual proteins is presented. We put special effort into the characterization of AlkB dioxygenases, their substrate specificity, and function in the repair of alkylation lesions in DNA/RNA. PMID:24810496

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy.

PubMed

Jaffrès, Paul-Alain; Gajate, Consuelo; Bouchet, Ana Maria; Couthon-Gourvès, Hélène; Chantôme, Aurélie; Potier-Cartereau, Marie; Besson, Pierre; Bougnoux, Philippe; Mollinedo, Faustino; Vandier, Christophe

2016-09-01

Synthetic alkyl lipids, such as the ether lipids edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) and ohmline (1-O-hexadecyl-2-O-methyl-rac-glycero-3-β-lactose), are forming a class of antitumor agents that target cell membranes to induce apoptosis and to decrease cell migration/invasion, leading to the inhibition of tumor and metastasis development. In this review, we present the structure-activity relationship of edelfosine and ohmline, and we point out differences and similarities between these two amphiphilic compounds. We also discuss the mechanisms of action of these synthetic alkyl ether lipids (involving, among other structures and molecules, membrane domains, Fas/CD95 death receptor signaling, and ion channels), and highlight a key role for lipid rafts in the underlying process. The reorganization of lipid raft membrane domains induced by these alkyl lipids affects the function of death receptors and ion channels, thus leading to apoptosis and/or inhibition of cancer cell migration. The possible therapeutic use of these alkyl lipids and the clinical perspectives for these lipids in prevention or/and treatment of tumor development and metastasis are also discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Efficient click chemistry towards fatty acids containing 1,2,3-triazole: Design and synthesis as potential antifungal drugs for Candida albicans.

PubMed

Fu, Nina; Wang, Suiliang; Zhang, Yuqian; Zhang, Caixia; Yang, Dongliang; Weng, Lixing; Zhao, Baomin; Wang, Lianhui

2017-08-18

Candida is an important opportunistic human fungal pathogen. The cis-2-dodecenoic acid (BDSF) showing in vitro activity of against C. albicans growth, germ-tube germination and biofilm formation has been a potential inhibitor for Candida and other fungi. In this study, facile synthetic strategies toward a novel family of BDSF analogue, 1-alkyl-1H-1,2,3-triazole-4-carboxylic acids (ATCs) was developed. The straightforward synthetic method including converting the commercial available alkyl bromide to alkyl azide, consequently with a typical click chemistry method, copper(II) sulfate and sodium ascorbate as catalyst in water to furnish ATCs with mild to good yields. According to antifungal assay, 1-decyl-4,5-dihydro-1H-1,2,3-triazole-4-carboxylic acid (5d) showed antifungal capability slightly better than BDSF. The 1,2,3-triazole unit played a crucial role for the bioactivity of ATCs was also confirmed when compared with two alkyl-aromatic carboxylic acids. Given its simplicity, high antifungal activity, and wide availability of compounds with halide atoms on the end part of the alkyl chains, the method can be extended to develop more excellent ATC drugs for accomplishing the challenges in future antifungal applications. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Oxidative coupling of sp 2 and sp 3 carbon-hydrogen bonds to construct dihydrobenzofurans.

PubMed

Shi, Jiang-Ling; Wang, Ding; Zhang, Xi-Sha; Li, Xiao-Lei; Chen, Yu-Qin; Li, Yu-Xue; Shi, Zhang-Jie

2017-08-10

Metal-catalyzed cross-couplings provide powerful, concise, and accurate methods to construct carbon-carbon bonds from organohalides and organometallic reagents. Recent developments extended cross-couplings to reactions where one of the two partners connects with an aryl or alkyl carbon-hydrogen bond. From an economic and environmental point of view, oxidative couplings between two carbon-hydrogen bonds would be ideal. Oxidative coupling between phenyl and "inert" alkyl carbon-hydrogen bonds still awaits realization. It is very difficult to develop successful strategies for oxidative coupling of two carbon-hydrogen bonds owning different chemical properties. This article provides a solution to this challenge in a convenient preparation of dihydrobenzofurans from substituted phenyl alkyl ethers. For the phenyl carbon-hydrogen bond activation, our choice falls on the carboxylic acid fragment to form the palladacycle as a key intermediate. Through careful manipulation of an additional ligand, the second "inert" alkyl carbon-hydrogen bond activation takes place to facilitate the formation of structurally diversified dihydrobenzofurans.Cross-dehydrogenative coupling is finding increasing application in synthesis, but coupling two chemically distinct sites remains a challenge. Here, the authors report an oxidative coupling between sp 2 and sp 3 carbons by sequentially activating the more active aryl site followed by the alkyl position.

Grafting C8-C16 alkyl groups altered the self-assembly and curcumin -loading properties of sodium caseinate in water.

PubMed

Zhang, Yaqiong; Yang, Puyu; Yao, Fangyi; Liu, Jie; Yu, Liangli Lucy

2018-02-01

The data presented here are related to the research article entitled "Synthesis and characterization of alkylated caseinate, and its structure-curcumin loading property relationship in water" (Zhang et al., 2018) [1]. This data article reports the detailed spectra information for 1 H NMR, 13 C NMR and UPLC-Q-TOF MS of the N-succinimidyl fatty acid esters with various alkyl chain lengths (Cn-NHSs, n = 8, 12, 14 and 16). 1 H NMR, 13 C NMR and UPLC-Q-TOF MS spectra for C16-NHS are shown as an example. Then the stacked 1 H NMR spectra of the obtained alkylated caseinates (Cn-caseinates, n = 8, 12, 14 and 16) are provided. The surface hydrophobicity index (S 0 ) of Cn-caseinates with different substitution degrees (SD) of alkyl groups is shown. Additionally, Visual appearances for the formed aqueous dispersions of curcumin-loaded native caseinate (NaCas) and Cn-caseinates self-assemblies are shown. X-ray diffraction patterns of curcumin, C16-caseinate, its physical mixture and curcumin-loaded C16-caseinate self-assemblies are examined. The re-dispersibility and short-term storage stability of the curcumin-loaded NaCas and C16-caseinate self-assemblies are also studied.

Tumor prevalence and biomarkers of genotoxicity in brown bullhead (Ameiurus nebulosus) in Chesapeake Bay tributaries

USGS Publications Warehouse

Pinkney, Alfred E.; Harshbarger, John C.; Karouna-Renier, Natalie K.; Jenko, Kathryn; Balk, Lennart; Skarphéðinsdóttir, Halldora; Liewenborg, Birgitta; Rutter, Michael A.

2011-01-01

We surveyed four Chesapeake Bay tributaries for skin and liver tumors in brown bullhead (Ameiurus nebulosus). We focused on the South River, where the highest skin tumor prevalence (53%) in the Bay watershed had been reported. The objectives were to 1) compare tumor prevalence with nearby rivers (Severn and Rhode) and a more remote river (Choptank); 2) investigate associations between tumor prevalence and polynuclear aromatic hydrocarbons (PAHs) and alkylating agents; and 3) statistically analyze Chesapeake Bay bullhead tumor data from 1992 through 2008. All four South River collections exhibited high skin tumor prevalence (19% to 58%), whereas skin tumor prevalence was 2%, 10%, and 52% in the three Severn collections; 0% and 2% in the Choptank collections; and 5.6% in the Rhode collection. Liver tumor prevalence was 0% to 6% in all but one South River collection (20%) and 0% to 6% in the three other rivers. In a subset of samples, PAH-like biliary metabolites and 32P-DNA adducts were used as biomarkers of exposure and response to polycyclic aromatic compounds (PACs). Adducts from alkylating agents were detected as O6-methyl-2'-deoxyguanosine (O6Me-dG) and O6-ethyl-2'-deoxyguanosine (O6Et-dG) modified DNA. Bullheads from the contaminated Anacostia River were used as a positive control for DNA adducts. 32P-DNA adduct concentrations were significantly higher in Anacostia bullhead livers compared with the other rivers. We identified alkyl DNA adducts in bullhead livers from the South and Anacostia, but not the Choptank. Neither the PAH-like bile metabolite data, sediment PAH data, nor the DNA adduct data suggest an association between liver or skin tumor prevalence and exposure to PACs or alkylating agents in the South, Choptank, Severn, or Rhode rivers. Logistic regression analysis of the Chesapeake Bay database revealed that sex and length were significant covariates for liver tumors and length was a significant covariate for skin tumors.

Influence of promoter/enhancer region haplotypes on MGMT transcriptional regulation: a potential biomarker for human sensitivity to alkylating agents.

PubMed

Xu, Meixiang; Nekhayeva, Ilona; Cross, Courtney E; Rondelli, Catherine M; Wickliffe, Jeffrey K; Abdel-Rahman, Sherif Z

2014-03-01

The O6-methylguanine-DNA methyltransferase gene (MGMT) encodes the direct reversal DNA repair protein that removes alkyl adducts from the O6 position of guanine. Several single-nucleotide polymorphisms (SNPs) exist in the MGMT promoter/enhancer (P/E) region. However, the haplotype structure encompassing these SNPs and their functional/biological significance are currently unknown. We hypothesized that MGMT P/E haplotypes, rather than individual SNPs, alter MGMT transcription and can thus alter human sensitivity to alkylating agents. To identify the haplotype structure encompassing the MGMT P/E region SNPs, we sequenced 104 DNA samples from healthy individuals and inferred the haplotypes using the data generated. We identified eight SNPs in this region, namely T7C (rs180989103), T135G (rs1711646), G290A (rs61859810), C485A (rs1625649), C575A (rs113813075), G666A (rs34180180), C777A (rs34138162) and C1099T (rs16906252). Phylogenetics and Sequence Evolution analysis predicted 21 potential haplotypes that encompass these SNPs ranging in frequencies from 0.000048 to 0.39. Of these, 10 were identified in our study population as 20 paired haplotype combinations. To determine the functional significance of these haplotypes, luciferase reporter constructs representing these haplotypes were transfected into glioblastoma cells and their effect on MGMT promoter activity was determined. Compared with the most common (reference) haplotype 1, seven haplotypes significantly upregulated MGMT promoter activity (18-119% increase; P < 0.05), six significantly downregulated MGMT promoter activity (29-97% decrease; P < 0.05) and one haplotype had no effect. Mechanistic studies conducted support the conclusion that MGMT P/E haplotypes, rather than individual SNPs, differentially regulate MGMT transcription and could thus play a significant role in human sensitivity to environmental and therapeutic alkylating agents.

Peptide/protein-polymer conjugates: synthetic strategies and design concepts.

PubMed

Gauthier, Marc A; Klok, Harm-Anton

2008-06-21

This feature article provides a compilation of tools available for preparing well-defined peptide/protein-polymer conjugates, which are defined as hybrid constructs combining (i) a defined number of peptide/protein segments with uniform chain lengths and defined monomer sequences (primary structure) with (ii) a defined number of synthetic polymer chains. The first section describes methods for post-translational, or direct, introduction of chemoselective handles onto natural or synthetic peptides/proteins. Addressed topics include the residue- and/or site-specific modification of peptides/proteins at Arg, Asp, Cys, Gln, Glu, Gly, His, Lys, Met, Phe, Ser, Thr, Trp, Tyr and Val residues and methods for producing peptides/proteins containing non-canonical amino acids by peptide synthesis and protein engineering. In the second section, methods for introducing chemoselective groups onto the side-chain or chain-end of synthetic polymers produced by radical, anionic, cationic, metathesis and ring-opening polymerization are described. The final section discusses convergent and divergent strategies for covalently assembling polymers and peptides/proteins. An overview of the use of chemoselective reactions such as Heck, Sonogashira and Suzuki coupling, Diels-Alder cycloaddition, Click chemistry, Staudinger ligation, Michael's addition, reductive alkylation and oxime/hydrazone chemistry for the convergent synthesis of peptide/protein-polymer conjugates is given. Divergent approaches for preparing peptide/protein-polymer conjugates which are discussed include peptide synthesis from synthetic polymer supports, polymerization from peptide/protein macroinitiators or chain transfer agents and the polymerization of peptide side-chain monomers.

Verification, Dosimetry, and Biomonitoring of Mustard Gas Exposure via Immunochemical Detection of Mustard Gas Adducts to DNA and Proteins

DTIC Science & Technology

1993-07-01

be a very effective alkylating agent for bases in DNA. Even in blood, with a variety of reactive sites, I out of 124 guanine bases was alkylated to...required for effective competition in the ELISA test, although it contained at least as many adducts as the single-stranded DNA. This difference is...competitor. 203 Figure 92: The effect of the concentration of mustard gas to which single-stranded calf-thymus DNA had been exposed on the 50% inhibition

Synthesis and evaluation of novel marine bromopyrrole alkaloid-based derivatives as potential antidepressant agents.

PubMed

Rane, Rajesh A; Napahde, Shital; Bangalore, Pavan Kumar; Sahu, Niteshkumar U; Shah, Nishant; Kulkarni, Yogesh A; Barve, Kalyani; Lokare, Leena; Karpoormath, Rajshekhar

2014-11-01

Herein, we report synthesis and screening of a series of twenty derivatives of bromopyrrole alkaloids with aroyl hydrazone feature for antidepressant activity by forced swim test (FST), tail suspension test (TST), and actophotometer method. The molecules were further evaluated for in vitro human MAO's inhibitory activities. The tested compounds exhibited moderate to good antidepressant activity compared with standard fluoxetine. Among these, most promising antidepressant derivatives 5b (%DID = 60.48), 5e (%DID = 59), and 5j (%DID = 74.86) reduced immobility duration of 50-70% at 30 mg/kg dose levels in FST. Further, derivative 5b, 5e, and 5j displayed good antidepressant activity with %DID value of 47.50, 46.62, and 52.49, respectively, in TST compared with standard fluoxetine (66.56% DID). Compound 5b showed high in vitro MAO-A potency and selectivity (Ki MAO-A (μM) = 2.4 ± 0.99, SI = 0.06) with promising pharmacological activity recognizing its potential as antidepressant lead candidate for further drug development. Study revealed that the presence of halogen atoms such as chlorine and fluorine at ortho- and/or para-position of phenyl ring and N-alkylation of pyrrole core is favored features for antidepressant activity. © 2014 John Wiley & Sons A/S.

De novo design and synthesis of ultra-short peptidomimetic antibiotics having dual antimicrobial and anti-inflammatory activities.

PubMed

Murugan, Ravichandran N; Jacob, Binu; Ahn, Mija; Hwang, Eunha; Sohn, Hoik; Park, Hyo-Nam; Lee, Eunjung; Seo, Ji-Hyung; Cheong, Chaejoon; Nam, Ky-Youb; Hyun, Jae-Kyung; Jeong, Ki-Woong; Kim, Yangmee; Shin, Song Yub; Bang, Jeong Kyu

2013-01-01

Much attention has been focused on the design and synthesis of potent, cationic antimicrobial peptides (AMPs) that possess both antimicrobial and anti-inflammatory activities. However, their development into therapeutic agents has been limited mainly due to their large size (12 to 50 residues in length) and poor protease stability. In an attempt to overcome the issues described above, a set of ultra-short, His-derived antimicrobial peptides (HDAMPs) has been developed for the first time. Through systematic tuning of pendant hydrophobic alkyl tails at the N(π)- and N(τ)-positions on His, and the positive charge of Arg, much higher prokaryotic selectivity was achieved, compared to human AMP LL-37. Additionally, the most potent HDAMPs showed promising dual antimicrobial and anti-inflammatory activities, as well as anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and proteolytic resistance. Our results from transmission electron microscopy, membrane depolarization, confocal laser-scanning microscopy, and calcein-dye leakage experiments propose that HDAMP-1 kills microbial cells via dissipation of the membrane potential by forming pore/ion channels on bacterial cell membranes. The combination of the ultra-short size, high-prokaryotic selectivity, potent anti-MRSA activity, anti-inflammatory activity, and proteolytic resistance of the designed HDAMP-1, -3, -5, and -6 makes these molecules promising candidates for future antimicrobial therapeutics.

Dopamine D(3) receptor antagonists. 1. Synthesis and structure-activity relationships of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans.

PubMed

Haadsma-Svensson, S R; Cleek, K A; Dinh, D M; Duncan, J N; Haber, C L; Huff, R M; Lajiness, M E; Nichols, N F; Smith, M W; Svensson, K A; Zaya, M J; Carlsson, A; Lin, C H

2001-12-20

5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D(3) receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure-activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D(3) antagonists. Thus, combinations of various alkyl groups were generally inactive at the D(3) receptor. Although substitution with an N-alkylaryl or N-alkylheteroaryl group yields compounds with potent D(3) binding affinity, the D(2) affinity is also enhanced, resulting in a less than 4-fold preference for the D(3) receptor site, and no improvements in metabolic stability were noted. A large-scale synthesis of the D(3) antagonist 3 has been developed that has proven to be reproducible with few purification steps. The improvements include the use of 3,4-dimethoxybenzaldehyde as a low-cost starting material to provide the desired 5,6-dimethoxy-1-indanone 5c in good overall yield (65%) and the formation of a soluble silyl oxime 17 that was reduced efficiently with BH(3).Me(2)S. The resulting amino alcohol was alkylated and then deoxygenated using a Lewis acid and Et(3)SiH to give the desired product 3 in good overall yield of ( approximately 65%) from the indanone 5c.

Synthesis, in vitro and in vivo studies, and molecular modeling of N-alkylated dextromethorphan derivatives as non-competitive inhibitors of α3β4 nicotinic acetylcholine receptor.

PubMed

Jozwiak, Krzysztof; Targowska-Duda, Katarzyna M; Kaczor, Agnieszka A; Kozak, Joanna; Ligeza, Agnieszka; Szacon, Elzbieta; Wrobel, Tomasz M; Budzynska, Barbara; Biala, Grazyna; Fornal, Emilia; Poso, Antti; Wainer, Irving W; Matosiuk, Dariusz

2014-12-15

9 N-alkylated derivatives of dextromethorphan are synthesized and studied as non-competitive inhibitors of α3β4 nicotinic acetylcholine receptors (nAChRs). In vitro activity towards α3β4 nicotinic acetylcholine receptor is determined using a patch-clamp technique and is in the micromolar range. Homology modeling, molecular docking and molecular dynamics of ligand-receptor complexes in POPC membrane are used to find the mode of interactions of N-alkylated dextromethorphan derivatives with α3β4 nAChR. The compounds, similarly as dextromethorphan, interact with the middle portion of α3β4 nAChR ion channel. Finally, behavioral tests confirmed potential application of the studied compounds for the treatment of addiction. Copyright © 2014 Elsevier Ltd. All rights reserved.

Synthesis, characterization, and antifungal activity of novel (Z)-N-(2-cyano-3-phenylprop-2-en-1-yl)-alkyl/aryl-sulfonamides derived from a Morita-Baylis-Hillman adduct

NASA Astrophysics Data System (ADS)

Tavares, Eder C.; Rubinger, Mayura M. M.; Zacchi, Carlos H. C.; Silva, Simone A.; Oliveira, Marcelo R. L.; Guilardi, Silvana; Alcântara, Antônio F. de C.; Piló-Veloso, Dorila; Zambolim, Laércio

2014-06-01

A series of allyl sulfonamides prepared from the reaction of the Morita-Baylis-Hillman adduct 2-[hydroxy(phenyl)methyl]acrylonitrile with primary sulfonamides (RSO2NH2), where R = C6H5 (1), 4-Fsbnd C6H4 (2), 4-Clsbnd C6H4 (3), 4-Brsbnd C6H4 (4), 4-NO2sbnd C6H4 (5), CH3 (6), CH3CH2 (7), CH3(CH2)3 (8), and CH3(CH2)7 (9), were characterized by IR, 1H and 13C NMR spectroscopies, mass spectrometry and elemental analyses. BLYP/6-31G* calculations suggested stereoselective reactions, resulting in the exclusive formation of the thermodynamically more stable Z-products. The Z-configuration of the products was confirmed by NOE difference spectroscopy and single crystal X-ray diffraction measurements. The allyl sulfonamides were active against Colletotrichum gloeosporioides, an important agent of anthracnose in plants.

2-Benzylpiperazine: A new scaffold for potent human carbonic anhydrase inhibitors. Synthesis, enzyme inhibition, enantioselectivity, computational and crystallographic studies and in vivo activity for a new class of intraocular pressure lowering agents.

PubMed

Chiaramonte, Niccolò; Bua, Silvia; Ferraroni, Marta; Nocentini, Alessio; Bonardi, Alessandro; Bartolucci, Gianluca; Durante, Mariaconcetta; Lucarini, Laura; Chiapponi, Donata; Dei, Silvia; Manetti, Dina; Teodori, Elisabetta; Gratteri, Paola; Masini, Emanuela; Supuran, Claudiu T; Romanelli, Maria Novella

2018-05-10

Two series of 2-benzylpiperazines have been prepared and tested for the inhibition of physiologically relevant isoforms of human carbonic anhydrases (hCA, EC 4.2.1.1). The new compounds carry on one nitrogen atom of the piperazine ring a sulfamoylbenzamide group as zinc-binding moiety, and different alkyl/acyl/sulfonyl groups on the other nitrogen. Regio- and stero-isomers are described. The majority of these compounds showed Ki values in the low-medium nanomolar range against hCA I, II and IV, but not IX. In many instances interaction with the enzyme was enantioselective. The binding mode has been studied by means of X-ray crystallography and molecular modelling. Two compounds, evaluated in rabbit models of glaucoma, were able to significantly reduce intraocular pressure, making them interesting candidates for further studies. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Selenoureido-iminosugars: A new family of multitarget drugs.

PubMed

Olsen, Jacob Ingemar; Plata, Gabriela B; Padrón, José M; López, Óscar; Bols, Mikael; Fernández-Bolaños, José G

2016-11-10

Herein we report the synthesis of N-alkylated deoxynojirimycin derivatives decorated with a selenoureido motif at the hydrocarbon tether as an example of unprecedented multitarget agents. Title compounds were designed as dual drugs for tackling simultaneously the Gaucher disease (by selective inhibition of β-glucosidase, Ki = 1.6-5.5 μM, with improved potency and selectivity compared to deoxynojirimycin) and its neurological complications (by inhibiting AChE, Ki up to 5.8 μM). Moreover, an excellent mimicry of the selenoenzyme glutathione peroxidase was also found for the catalytic scavenging of H2O2 (Kcat/Kuncat up to 640) using PhSH as a cofactor, with improved activity compared to known positive controls, like (PhSe)2 and ebselen; therefore, such compounds are also excellent scavengers of peroxides, an example of reactive oxygen species present at high concentrations in patients of Gaucher disease and neurological disorders. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Synthesis of a new series of dithiocarbamates with effective human carbonic anhydrase inhibitory activity and antiglaucoma action.

PubMed

Bozdag, Murat; Carta, Fabrizio; Vullo, Daniela; Akdemir, Atilla; Isik, Semra; Lanzi, Cecilia; Scozzafava, Andrea; Masini, Emanuela; Supuran, Claudiu T

2015-05-15

A new series of dithiocarbamates (DTCs) was prepared from primary/secondary amines incorporating amino/hydroxyl-alkyl, mono- and bicyclic aliphatic ring systems based on the quinuclidine, piperidine, hydroxy-/carboxy-/amino-substituted piperidine, morpholine and piperazine scaffolds, and carbon disulfide. The compounds were investigated for the inhibition of four mammalian α-carbonic anhydrases (CAs, EC 4.2.1.1) of pharmacologic relevance, that is, the human (h) hCA I, II, IX and XII, drug targets for antiglaucoma (hCA II and XII) or antitumor (hCA IX/XII) agents. The compounds were moderate or inefficient hCA I inhibitors (off-target isoform for both applications), efficiently inhibited hCA II, whereas some of them were low nanomolar/subnanomolar hCA IX/XII inhibitors. One DTC showed excellent intraocular pressure (IOP) lowering properties in an animal model of glaucoma, with a two times better efficiency compared to the clinically used sulfonamide dorzolamide. Copyright © 2015 Elsevier Ltd. All rights reserved.

Drilling fluid containing a copolymer filtration control agent

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lucas, J. M.

1985-10-15

The invention relates to an aqueous drilling fluid composition, a filtration control agent for utilization in said aqueous drilling fluid, and a method of forming a filter cake on the wall of a well for the reduction of filtrate from said drilling fluid, by utilization of a copolymer of: a (meth) acrylamido alkyl sulfonic acid or alkali metal salt thereof; and N, N-dialkyl (meth) acrylamide. The copolymer may be cross-linked with N,N'-methylenebisacrylamide or other appropriate cross-linking agent.

Development of polyimide foams with blowing agents

NASA Technical Reports Server (NTRS)

Gagliani, John (Inventor); Sorathia, Usman A. K. (Inventor); Lee, Raymond (Inventor)

1985-01-01

A method of preparing a polyimide foam which includes the steps of: preparing, foaming, and curing a precursor containing at least one alkyl ester of 3,3'4,4'-benzophenonetetracarboxylic acid; a meta- or para-substituted aromatic diamine; a heterocyclic diamine; an aliphatic diamine; and a solid blowing agent. The blowing agent is added to said precursor in a concentration which is sufficient to effect at least one of the following attributes of the foam: cell size, proportion of open cells, cell density, and indentation load deflection.

Translesion synthesis DNA polymerases promote error-free replication through the minor-groove DNA adduct 3-deaza-3-methyladenine.

PubMed

Yoon, Jung-Hoon; Roy Choudhury, Jayati; Park, Jeseong; Prakash, Satya; Prakash, Louise

2017-11-10

N3-Methyladenine (3-MeA) is formed in DNA by reaction with S -adenosylmethionine, the reactive methyl donor, and by reaction with alkylating agents. 3-MeA protrudes into the DNA minor groove and strongly blocks synthesis by replicative DNA polymerases (Pols). However, the mechanisms for replicating through this lesion in human cells remain unidentified. Here we analyzed the roles of translesion synthesis (TLS) Pols in the replication of 3-MeA-damaged DNA in human cells. Because 3-MeA has a short half-life in vitro , we used the stable 3-deaza analog, 3-deaza-3-methyladenine (3-dMeA), which blocks the DNA minor groove similarly to 3-MeA. We found that replication through the 3-dMeA adduct is mediated via three different pathways, dependent upon Polι/Polκ, Polθ, and Polζ. As inferred from biochemical studies, in the Polι/Polκ pathway, Polι inserts a nucleotide (nt) opposite 3-dMeA and Polκ extends synthesis from the inserted nt. In the Polθ pathway, Polθ carries out both the insertion and extension steps of TLS opposite 3-dMeA, and in the Polζ pathway, Polζ extends synthesis following nt insertion by an as yet unidentified Pol. Steady-state kinetic analyses indicated that Polι and Polθ insert the correct nt T opposite 3-dMeA with a much reduced catalytic efficiency and that both Pols exhibit a high propensity for inserting a wrong nt opposite this adduct. However, despite their low fidelity of synthesis opposite 3-dMeA, TLS opposite this lesion replicates DNA in a highly error-free manner in human cells. We discuss the implications of these observations for TLS mechanisms in human cells. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Diversity oriented synthesis of tricyclic compounds from glycals using the Ferrier and the Pauson-Khand reactions.

PubMed

Hotha, Srinivas; Tripathi, Ashish

2005-01-01

Diversity oriented synthesis of tricyclic compounds was achieved using a combination of the Ferrier reaction and the Pauson-Khand reaction. Ferrier reaction was effected using NbCl5, and the Pauson-Khand reaction was carried out using Co2(CO)8, acetonitrile-dimethoxyethane. Michael additions using various alkyl, aryl, and heterocyclic thiols were also performed successfully. The Ferrier, Pauson-Khand, and Michael addition reactions were found to be highly diastereoselective.

The Development of New Protecting/Leaving Groups and Application to the Synthesis of Cage Nitramines

DTIC Science & Technology

1993-01-05

Prepared for: D T I U.S. Office of Naval Research CT Code 1132 E" 7 I 800 N. Quincy Street 1 13 Arlington, VA 22217 S Q Attn: Dr. Richard Miller Contract...Sciences Division • d ’,. . , ,,.L /31- 21 4 CONTENTS LIST OF FIGURES...SAME (INTERNATIONAL PATENT APPLICATION NO. WO 91/19669) ........... B-I C A NEW SYNTHESIS OF ALKYL-N,N-DINITRAMINES BY DIRECT NITRATION OF

Stereoselective synthesis of unsaturated α-amino acids.

PubMed

Fanelli, Roberto; Jeanne-Julien, Louis; René, Adeline; Martinez, Jean; Cavelier, Florine

2015-06-01

Stereoselective synthesis of unsaturated α-amino acids was performed by asymmetric alkylation. Two methods were investigated and their enantiomeric excess measured and compared. The first route consisted of an enantioselective approach induced by the Corey-Lygo catalyst under chiral phase transfer conditions while the second one involved the hydroxypinanone chiral auxiliary, both implicating Schiff bases as substrate. In all cases, the use of a prochiral Schiff base gave higher enantiomeric excess and yield in the final desired amino acid.

Synthesis and Characterization of Polymers for Fuel Cells Application

NASA Technical Reports Server (NTRS)

Tytko, Stephen F.

2003-01-01

The goal of this summer research is to prepare Polymer Exchange Membranes (PEM s) for fuel cell application. Several high temperature polymers such as polybenzimidazoles and polyether ketones were known to possess good high temperature stability and had been investigated by post-sulfonation to yield sulfonated polymers. The research project will involve two approaches: 1. Synthesis of polybenzimidazoles and then react with alkyl sultonse to attach an aliphatic sulfonic groups. 2. Synthesis of monomers containing sulfonic acid units either on a aromatic ring or on an aliphatic chain and then polymerize the monomers to form high molecular weight sulfonate polymers.

Absence of cross-resistance between two alkylating agents: BCNU vs bifunctional galactitol.

PubMed

Institóris, E; Szikla, K; Otvös, L; Gál, F

1989-01-01

Dianhydrogalactitol (DAG) increased the life span of both BCNU-sensitive and -resistant L1210 tumor-bearing mice. However, the BCNU-resistant strain showed slightly lower sensitivity against DAG, which could be overcome by an increase in drug dose of ca. 20%. The somewhat lower sensitivity was proportional to a slightly reduced DNA cross-linking formation induced by DAG in BCNU-resistant cells. The amount of DNA cross-links was determined by measurement of the 1,6-di(guaninyl)-galactitol content of DNA. The slight reduction in cross-links is not attributable to DNA repair but rather to other factors that seem to prevent the formation of DNA-drug adducts. The absence of cross-resistance is explained by different kinds of DNA damage caused by the two alkylating agents and the presumably different defense mechanisms developed by cells against these lesions.

[Multiple organ failure presumably due to alkylating agents used as preconditioning drugs for autologous peripheral blood stem cell transplantation in an acute promyelocytic leukemia].

PubMed

Ida, Tori; Hashimoto, Shigeo; Suzuki, Nobuaki; Ebe, Yusuke; Yano, Toshio; Sato, Naoko; Koike, Tadashi

2016-01-01

A 52-year-old male was diagnosed as having acute promyelocytic leukemia (APL) in 2006. He received induction chemotherapy including all-trans retinoic acid and initially achieved a complete remission (CR). After several courses of consolidation therapy combining anthracyclines and cytarabine, he maintained CR. In 2009, an APL relapse was diagnosed, and he was treated with arsenic trioxide. Since he achieved a second CR, he underwent autologous peripheral blood stem cell transplantation (auto-PBSCT) with a conditioning regimen consisting of busulfan and melphalan. At four months after auto-PBSCT, he developed a pneumothorax and acute respiratory failure. He died despite intensive therapy. Autopsy findings included various atypical and apoptotic cells in his pulmonary tissue. These changes were confirmed in multiple organs throughout the body, suggesting them to be drug-induced. The findings in this case suggested multiple organ failure due to alkylating agents.

Antigenotoxic effects of Citrus aurentium L. fruit peel oil on mutagenicity of two alkylating agents and two metals in the Drosophila wing spot test.

PubMed

Demir, Eşref; Kocaoğlu, Serap; Cetin, Huseyin; Kaya, Bülent

2009-07-01

Antigenotoxic effects of Citrus aurentium L. (Rutaceae) fruit peel oil (CPO) in combination with mutagenic metals and alkylating agents were studied using the wing spot test of D. melanogaster. The four reference mutagens, potassium dichromate (K2Cr2O7), cobalt chloride (CoCl2), ethylmethanesulfonate (EMS), and N-ethyl-N-nitrosourea (ENU) were clearly genotoxic. CPO alone at doses from 0.1 to 0.5% in Tween 80 was not mutagenic and did not enhance the mutagenic effect of the reference mutagens. However, antigenotoxic effects of CPO were clearly demonstrated in chronic cotreatments with mutagens and oil, by a significant decrease in wing spots induced by all four mutagens. The D. melanogaster wing spot test was found to be a suitable assay for detecting antigenotoxic effects in vivo. Copyright 2009 Wiley-Liss, Inc.

Gas chromatography-mass spectrometric studies of O-alkyl O-2-(N,N-dialkylamino) ethyl alkylphosphonites(phosphonates) for chemical weapons convention verification.

PubMed

Saeidian, Hamid; Babri, Mehran; Ramezani, Atefeh; Ashrafi, Davood; Sarabadani, Mansour; Naseri, Mohammad Taghi

2013-01-01

The electron ionization (EI) mass spectra of a series of O-alkyl O-2-(N,N-dialkylaminolethyl alkylphosphonites(phosphonates), which are precursors of nerve agents, were studied for Chemical Weapons Convention (CWC) verification. General El fragmentation pathways were constructed and discussed. Proposed fragment structures were confirmed through analyzing fragment ions of deuterated analogs and density functional theory (DFT) calculations. The observed fragment ions are due to different fragmentation pathways such as hydrogen and McLafferty+1 rearrangements, alkene, amine and alkoxy elimination by alpha- or beta-cleavage process. Fragment ions distinctly allow unequivocal identification of the interested compounds including those of isomeric compounds. The presence and abundance of fragment ions were found to depend on the size and structure of the alkyl group attached to nitrogen, phosphorus and oxygen atoms.

Synthesis of 1,3,3-trinitroazetidine

DOEpatents

Hiskey, Michael A.; Coburn, Michael D.

1994-01-01

A process of preparing 1,3,3-trinitroazetidine including forming a 5-hydroxymethyl-5-nitro-1-alkyltetrahydro-1,3-oxazine, e.g., reacting a 1,3,5-trialkyl hexahydrotriazine and tris(hydroxymethyl)nitromethane, ring opening said 5-hydroxymethyl-5-nitro-1-alkyltetrahydro-1,3-oxazine to form a 3-alkylamino-2-hydroxymethyl-2-nitro-1-propanol salt, ring closing said 3-alkylamino-2-hydroxymethyl-2-nitro-1-propanol salt to form a 3-hydroxymethyl-3-nitro-1-alkylazetidine salt, nitrating said 3-hydroxymethyl-3-nitro-1-alkylazetidine salt to form a 1-alkyl-3,3-dinitroazetidine, and converting said 1-alkyl-3,3-dinitroazetidine into 1,3,3-trinitroazetidine is disclosed.

Synthesis of 1,3,3-trinitroazetidine

DOEpatents

Hiskey, M.A.; Coburn, M.D.

1994-08-09

A process of preparing 1,3,3-trinitroazetidine includes forming a 5-hydroxymethyl-5-nitro-1-alkyltetrahydro-1,3-oxazine, e.g., reacting a 1,3,5-trialkyl hexahydrotriazine and tris(hydroxymethyl)nitromethane, ring opening said 5-hydroxymethyl-5-nitro-1-alkyltetrahydro-1,3-oxazine to form a 3-alkylamino-2-hydroxymethyl-2-nitro-1-propanol salt, ring closing said 3-alkylamino-2-hydroxymethyl-2-nitro-1-propanol salt to form a 3-hydroxymethyl-3-nitro-1-alkylazetidine salt, nitrating said 3-hydroxymethyl-3-nitro-1-alkylazetidine salt to form a 1-alkyl-3,3-dinitroazetidine, and converting said 1-alkyl-3,3-dinitroazetidine into 1,3,3-trinitroazetidine is disclosed. 1 fig.

2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells.

PubMed

Bauer, Matthias R; Joerger, Andreas C; Fersht, Alan R

2016-09-06

The tumor suppressor p53 has the most frequently mutated gene in human cancers. Many of p53's oncogenic mutants are just destabilized and rapidly aggregate, and are targets for stabilization by drugs. We found certain 2-sulfonylpyrimidines, including one named PK11007, to be mild thiol alkylators with anticancer activity in several cell lines, especially those with mutationally compromised p53. PK11007 acted by two routes: p53 dependent and p53 independent. PK11007 stabilized p53 in vitro via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. Unstable p53 was reactivated by PK11007 in some cancer cell lines, leading to up-regulation of p53 target genes such as p21 and PUMA. More generally, there was cell death that was independent of p53 but dependent on glutathione depletion and associated with highly elevated levels of reactive oxygen species and induction of endoplasmic reticulum (ER) stress, as also found for the anticancer agent PRIMA-1(MET)(APR-246). PK11007 may be a lead for anticancer drugs that target cells with nonfunctional p53 or impaired reactive oxygen species (ROS) detoxification in a wide variety of mutant p53 cells.

Subclinical impairment of ovarian reserve in systemic lupus erythematosus patients with normal menstruation not using alkylating therapy.

PubMed

Ma, Wenhong; Zhan, Zhongping; Liang, Xiaoyan; Chen, Jianhui; Huang, Xingfang; Liao, Caiyun

2013-12-01

Disease activity is a major factor in menstrual disorders in systemic lupus erythematosus (SLE) patients not receiving alkylating therapy. However, the ovarian reserve of SLE women with normal menstruation is still unclear. Twenty-three SLE patients naïve to cytotoxic agents (SLE group) and nineteen SLE patients receiving current or previous cyclophosphamide (CTX) therapy (without other cytotoxic agents; SLE-CTX group) were enrolled. Twenty-one age-matched healthy women served as controls. All patients and controls had a regular menstrual cycle. Basal hormone levels, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and anti-Müllerian hormone (AMH), and antral follicle count (AFC) were analyzed in the two study groups and compared with the control group. No significant differences were found between the SLE, SLE-CTX, and control groups in age, body mass index (BMI), and basal FSH and LH levels. The E2 (P=0.023) levels were high and the AMH (P=0.000) values and AFC (P=0.001) were significantly lower in the SLE and SLE-CTX groups compared to control. However, these values were similar between the SLE and SLE-CTX groups. SLE patients not receiving alkylating therapy who had normal menstruation and short illness duration still had an impaired ovarian reserve.

Effects of treatment on fertility in long-term survivors of childhood or adolescent cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Byrne, J.; Mulvihill, J.J.; Myers, M.H.

In a retrospective cohort study of survivors of cancer and of controls, we estimated the risk of infertility after treatment for cancer during childhood or adolescence. We interviewed 2283 long-term survivors of childhood or adolescent cancer diagnosed in the period from 1945 through 1975, who were identified at five cancer centers in the United States. Requirements for admission to the study were diagnosis before the age of 20, survival for at least five years, and attainment of the age of 21. In addition, 3270 controls selected from among the survivors' siblings were interviewed. Cox regression analysis showed that cancer survivorsmore » who married and were presumed to be at risk of pregnancy were less likely than their sibling controls to have ever begun a pregnancy (relative fertility, 0.85; 95 percent confidence interval, 0.78 to 0.92). Radiation therapy directed below the diaphragm depressed fertility in both sexes by about 25 percent. Chemotherapy with alkylating agents, with or without radiation to sites below the diaphragm, was associated with a fertility deficit of about 60 percent in the men. Among the women, there was no apparent effect of alkylating-agent therapy administered alone (relative fertility, 1.02) and only a moderate fertility deficit when alkylating-agent therapy was combined with radiation below the diaphragm (relative fertility, 0.81). Relative fertility in the survivors varied considerably according to sex, site of cancer, and type of treatment; these factors should be taken into consideration in counseling survivors about the long-term consequences of disease.« less

Impact of Radiation and Chemotherapy on Risk of Dental Abnormalities: A Report from the Childhood Cancer Survivor Study

PubMed Central

Kaste, Sue C.; Goodman, Pamela; Leisenring, Wendy; Stovall, Marilyn; Hayashi, Robert; Yeazel, Mark; Beiraghi, Soraya; Hudson, Melissa M.; Sklar, Charles A.; Robison, Leslie L.; Baker, K. Scott

2009-01-01

Purpose Describe frequencies and risk factors of altered oral health and odontogenesis in childhood cancer survivors. Patients and Methods 9308 survivors, diagnosed between 1970–1986, and 2951 siblings from Childhood Cancer Survivor Study completed a survey containing oral-dental health information. We analyzed treatment impact, socioeconomic data and patient demographics on dental outcomes using univariate and multivariate logistic regression models to estimate odds ratios (OR). Results In multivariate analysis, survivors more likely reported microdontia (OR 3.0, 95% confidence interval [CI] 2.4–3.8), hypodontia (OR 1.7, 95% CI 1.4–2.0), root abnormalities (OR 3.0, 95% CI 2.2–4.0), abnormal enamel (OR 2.4, 95% CI 2.0–2.9), teeth loss ≥6 (OR 2.6, 95% CI 1.9–3.6), severe gingivitis (OR 1.2, 95% CI 1.0–1.5), xerostomia (OR 9.7, 95% CI 4.8–19.7). Controlling for chemotherapy and socio-economic factors, radiation exposure of ≥20Gy to dentition was significantly associated with increased risk of ≥1 dental abnormality. Dose-dependent alkylating agent therapy significantly increased risk ≥1 anatomic/developmental dental abnormalities in survivors diagnosed <5 years of age (OR 1.7, 2.7, 3.3 for alkylating agent score of 1, 2, 3, respectively). Conclusion Radiation and chemotherapy are independent risk factors for adverse oral-dental sequelae among childhood cancer survivors. Patients receiving alkylating agents at < 5 years should be closely monitored. PMID:19834960

Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs.

PubMed

Murray, Michael; Hraiki, Adam; Bebawy, Mary; Pazderka, Curtis; Rawling, Tristan

2015-06-01

Lipids have the potential for development as anticancer agents. Endogenous membrane lipids, such as ceramides and certain saturated fatty acids, have been found to modulate the viability of tumor cells. In addition, many tumors over-express cyclooxygenase, lipoxygenase or cytochrome P450 enzymes that mediate the biotransformation of ω-6 polyunsaturated fatty acids (PUFAs) to potent eicosanoid regulators of tumor cell proliferation and cell death. In contrast, several analogous products from the biotransformation of ω-3 PUFAs impair particular tumorigenic pathways. For example, the ω-3 17,18-epoxide of eicosapentaenoic acid activates anti-proliferative and proapoptotic signaling cascades in tumor cells and the lipoxygenase-derived resolvins are effective inhibitors of inflammatory pathways that may drive tumor expansion. However, the development of potential anti-cancer drugs based on these molecules is complex, with in vivo stability a major issue. Nevertheless, recent successes with the antitumor alkyl phospholipids, which are synthetic analogues of naturally-occurring membrane phospholipid esters, have provided the impetus for development of further molecules. The alkyl phospholipids have been tested against a range of cancers and show considerable activity against skin cancers and certain leukemias. Very recently, it has been shown that combination strategies, in which alkyl phospholipids are used in conjunction with established anticancer agents, are promising new therapeutic approaches. In future, the evaluation of new lipid-based molecules in single-agent and combination treatments may also be assessed. This could provide a range of important treatment options in the management of advanced and metastatic cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

Expression in mammalian cells of the Escherichia coli O6 alkylguanine-DNA-alkyltransferase gene ogt reduces the toxicity of alkylnitrosoureas.

PubMed Central

Harris, L. C.; Margison, G. P.

1993-01-01

V79 Chinese hamster cells expressing either the O6-alkylguanine-DNA-alkyltransferase (ATase) encoded by the E. coli ogt gene or a truncated version of the E. coli ada gene have been exposed to various alkylnitrosoureas to investigate the contribution of ATase repairable lesions to the toxicity of these compounds. Both ATases are able to repair O6-alkylguanine (O6-AlkG) and O4-alkylthymine (O4-AlkT) but the ogt ATase is more efficient in the repair of O4-methylthymine (O4-MeT) and higher alkyl derivatives of O6-AlkG than is the ada ATase. Expression of the ogt ATase provided greater protection against the toxic effects of the alkylating agents then the ada ATase particularly with N-ethyl-N-nitrosourea (ENU) and N-butyl-N-nitrosourea (BNU) to which the ada ATase expressing cells were as sensitive as parent vector transfected cells. Although ogt was expressed at slightly higher levels than the truncated ada in the transfected cells, this could not account for the differential protection observed. For-N-methyl-N-nitrosourea (MNU) the increased protection in ogt-transfected cells is consistent with O4-MeT acting as a toxic lesion. For the longer chain alkylating agents and chloroethylating agents, the protection afforded by the ogt protein may be a consequence of the more efficient repair of O6-AlkG, O4-AlkT or both of these lesions in comparison with the ada-encoded ATase. Images Figure 2 Figure 3 PMID:8512805

Exposure to a First World War blistering agent.

PubMed

Le, H Q; Knudsen, S J

2006-04-01

Sulfur mustards act as vesicants and alkylating agents. They have been used as chemical warfare since 1917 during the first world war. This brief report illustrates the progression of injury on a primary exposed patient to a first world war blistering agent. This case documents the rapid timeline and progression of symptoms. It emphasises the importance of appropriate personal protective equipment and immediate medical response plan with rapid decontamination and proper action from military and civilian medical treatment facilities. This case reports the first US active duty military exposure to a blistering agent in the age of global terrorism.

Immunomodulatory therapy for ocular inflammatory disease: a basic manual and review of the literature.

PubMed

Okada, Annabelle A

2005-01-01

Corticosteroids are used as first-line treatment for many ocular inflammatory conditions. The risk of adverse effects, however, necessitates conversion to steroid-sparing immunomodulatory therapy (IMT) for disease that is recurrent, chronic, or poorly responsive to treatment. Combination drug treatments with multiple agent 'recipes' are also considered. Immunomodulatory agents include the broad categories of antimetabolites (azathioprine, methotrexate, mycophenolate mofetil), alkylating agents (cyclophosphamide, chlorambucil), T-cell inhibitors (cyclosporine, tacrolimus), and cytokines (interferon alfa). This article reviews and summarizes the evidence for IMT agent use in the treatment of various forms of ocular inflammation.