64506-98-5Relevant academic research and scientific papers
Design, synthesis and anticancer potential of NSC-319745 hydroxamic acid derivatives as DNMT and HDAC inhibitors
Yuan, Zigao,Sun, Qinsheng,Li, Dan,Miao, Shuangshuang,Chen, Shaopeng,Song, Lu,Gao, Chunmei,Chen, Yuzong,Tan, Chunyan,Jiang, Yuyang
, p. 281 - 292 (2017)
DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) are important epigenetic targets during anticancer drug development. Recent study indicates that DNMT inhibitors and HDAC inhibitors display synergistic effects in certain cancers, therefore, development of molecules targeting both DNMT and HDAC is of therapeutic advantage against these cancers. Based on the structure of DNMT inhibitor NSC-319745 and the pharmacophore characteristics of HDAC inhibitors, a series of hydroxamic acid derivatives of NSC-319745 were designed and synthesized as DNMT and HDAC multifunctional inhibitors. Most compounds displayed potential DNMT inhibitory potency and potent HDAC inhibitory activity, especially compound 15a showed much better DNMT1 inhibitory potency than NSC-319745, and inhibited HDAC1, HDAC6 with IC50 values of 57, 17?nM, respectively. Furthermore, the synthesized compounds exhibited significant cytotoxicity against human cancer cells K562 and U937. Further mechanistic studies demonstrated that 15a treatment in U937 increased histones H3K9 and H4K8 acetylation, prompted P16 CpG islands demethylation and upregulated P16 expression, regulated apoptosis-related protein expression on the cellular level and induced remarkable U937 apoptosis. Moreover, genotoxicity of representative compounds was evaluated. In summary, our study provided a practical drug design strategy targeting multiple enzymes, and 15a represents a novel and promising lead compound for the development of novel epigenetic inhibitors as antitumor agents.
Preparation of phenylethylbenzamide derivatives as modulators of DNMT3 activity
Kabro, Anzhelika,Lachance, Hugo,Marcoux-Archambault, Iris,Perrier, Valerie,Dore, Vicky,Gros, Christina,Masson, Veronique,Gregoire, Jean-Marc,Ausseil, Frederic,Cheishvili, David,Laulan, Nathalie Bibens,St-Pierre, Yves,Szyf, Moshe,Arimondo, Paola B.,Gagnon, Alexandre
, p. 1562 - 1570 (2013/12/04)
DNA-methyltransferases (DNMTs) are a class of epigenetic enzymes that catalyze the transfer of a methyl moiety from the methyl donor S-adenosyl-l-methionine onto the C5 position of cytosine in DNA. This process is dysregulated in cancers and leads to the hypermethylation and silencing of tumor suppressor genes. The development of potent and selective inhibitors of DNMTs is of utmost importance for the discovery of new therapies for the treatment of cancer. We report herein the synthesis and DNMT inhibitory activity of 29 analogues derived from NSC 319745. The effect of selected compounds on the methylation level in the MDA-MB-231 human breast cancer cell line was evaluated using a luminometric methylation assay. Molecular docking studies have been conducted to propose a binding mode for this series.
Hypoglycemically and hypolipidemically active derivatives of phenyl-alkane-carboxylic acids
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, (2008/06/13)
Phenyl-alkane-carboxylic acids of the formula STR1 wherein A is an aryl, aralkyl or arylvinyl radical optionally substituted by hydroxy, halogen, trifluoromethyl, alkyl, alkylthio, alkoxy, alkenyloxy, alkoxyalkoxy, alkyl-substituted amino, aryloxy or alkoxy-substituted aryloxy, or is an aryloxyalkyl or arylthioalkyl radical, or a heterocyclic ring system optionally substituted by halogen, alkyl or alkoxy, Y is a valency bond or an unbranched or branched lower alkylene radical containing up to 3 carbon atoms, X is a straight or branched, saturated or unsaturated divalent aliphatic hydrocarbon radical containing 2 to 8 carbon atoms, there being at least 2 carbon atoms between the benzene ring and the carboxyl group, and R is a hydrogen atom or a lower alkyl radical, as well as physiologically compatible salts, esters and amides thereof, exhibit hypoglycaemic and hypolipidaemic activity.
