188106-90-3Relevant academic research and scientific papers
Discovery of Potent and Novel Dual PARP/BRD4 Inhibitors for Efficient Treatment of Pancreatic Cancer
Gao, Ling-Li,Huang, Lei,Huang, Shi-Hui,Li, Yu,Lin, Qian-Wen,Meng, Liu-Qiong,Sun, Qin,Wang, Shu-Ping,Wu, Shi-Qi,Xu, Yun-Gen,Zhu, Qi-Hua,Zou, Yi
, p. 17413 - 17435 (2021/12/06)
Targeting poly(ADP-ribose) polymerase1/2 (PARP1/2) is a promising strategy for the treatment of pancreatic cancer with breast cancer susceptibility gene (BRCA) mutation. Inducing the deficiency of homologous recombination (HR) repair is an effective way t
Design, synthesis and biological evaluation of 4-amidobenzimidazole acridine derivatives as dual PARP and Topo inhibitors for cancer therapy
Yuan, Zigao,Chen, Shaopeng,Chen, Changjun,Chen, Jiwei,Chen, Chengken,Dai, Qiuzi,Gao, Chunmei,Jiang, Yuyang
, p. 1135 - 1146 (2017/08/02)
PARP-1 could repair the DNA damages induced by Topo inhibitors, therefore inhibiting Topo and PARP-1 simultaneously might be able to overcome resistance and improve outcomes. In this study a series of 4-amidobenzimidazole acridines were designed and synthesized as dual Topo and PARP-1 inhibitors. Compound 11l displayed good inhibitory activities against Topo and PARP-1, as well as significantly inhibited cancer cells proliferation. Further mechanistic evaluations indicated that 11l treatment in MCF-7 cells induced accumulated DNA double-strand breaks, prompted remarkable apoptosis, and caused prominent G0/G1 cell cycle arrest. Moreover, 11l greatly suppressed tumor growth in mice, and displayed favorable metabolic properties in liver microsomes. Our study suggested that single agents inhibiting Topo and PARP concurrently might be an alternative for cancer therapy and 11l represented a potential lead compound for development of antitumor agents.
Substituted 2-Phenylbenzimidazoles and their use as PARP inhibitors
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Page 28, (2010/02/05)
2-Phenyl-benzimidazolecarboxamide derivatives (I) and (II) are new. 2-Phenyl-benzimidazolecarboxamide derivatives of formulae (I) and (II) and their tautomers, enantiomers, diastereomers, prodrugs and salts, are new: [Image] R 1>H or alkyl optionally substituted with OH, alkoxy, amino (optionally mono- or disubstituted) or optionally substituted piperidino, piperazino, pyrrolidino, hexahydroazepino, morpholino or 4,5-dihydropyridino; R 2>H, Cl, Br, I, F, CF 3, NO 2, NHCOR 2> 1>, NR 2> 2>R 2> 3>, OH, alkoxy, alkoxy-Ph, NH 2, or Ph; R 2> 1>, R 2> 2>alkyl; R 2> 3>H, alkyl, or optionally substituted phenyl; x : 0-2; R 3>D-(F 1>) p-(E) q-(F 2>) r-G, E-(D) u-(F 2>) s-(G) v or B; R 4>H, Cl, F, Br, I, alkyl, OH, NO 2, CF 3, CN, NR 4> 4>R 4> 2>, NHCOR 4> 3>, or alkoxy; R 4> 1>, R 4> 2>H or alkyl; R 4> 3>H, alkyl, alkyl-phenyl, or phenyl; D : O or S; E : phenyl, imidazole, pyrrole, thiophene, pyridine, pyrimidine, piperazine, pyrazine, furan, thiazole, isoxazole, pyrrolidine, piperidine or optionally substituted trihydroazepine ring; F 1>, F 2>1-8C chain optionally substituted with OH or alkoxy; p-v : 0 or 1, but p, q and r are not simultaneously 0; G : NR 5> 1>R 52>or optionally substituted pyrrolidinyl, piperidinyl, 1,2,5,6-tetrahydropyridyl, piperizinyl, azepinyl, morpholinyl or 1,4-diazepanyl; R 5> 1>alkyl or (CH 2) t-K; B : optionally substituted pyrrolidinyl, piperidinyl, 1,2,5,6-tetrahydropyridyl, piperizinyl, azepinyl, morpholinyl or 1,4-diazepanyl; t : 0-4; K : optionally substituted phenyl, NR 4> 1>R 4> 2>, phenyl-alkyl-NH, pyrrolidino, piperidino, 1,2,5,6-tetrahydropyridino, morpholino, trihydroazepino, or piperazino or homopiperazino (both optionally substituted with alkyl); R 5>H, alkyl, NR 7>R 9>, or optionally substituted pyrrolidinyl, piperidinyl, 1,2,5,6-tetrahydropyridyl, piperizinyl, azepinyl, morpholinyl or 1,4-diazepanyl; The full definitions are given in the DEFINITIONS (Full Definitions) Field. Independent claims are also included for the following: (i) aminobenzamide intermediates of formulae (III) and (IV) and their salts; (ii) preparation of compounds (III) and (IV); (iii) an in vitro method for the detection of poly(ADP-ribose)polymerase (PARP) inhibitors comprising: (a) incubating a poly-ADP-ribosylable target (optionally bonded to a carrier) with a reaction mixture comprising a PARP, a PARP activator and a PARP inhibitor or an analyte in which one or more PARP inhibitors is presumed to exist; (b) carrying out a poly-ADP-ribosylation reaction; and (c) qualitatively or quantitatively determining the poly-ADP-ribosylation with an anti-poly-(ADP-ribose) antibody. [Image] ACTIVITY : None given. MECHANISM OF ACTION : Poly(ADP-ribose)polymerase (PARP) inhibitor.
Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase
White,Almassy,Calvert,Curtin,Griffin,Hostomsky,Maegley,Newell,Srinivasan,Golding
, p. 4084 - 4097 (2007/10/03)
The nuclear enzyme poly(ADP-ribose) polymerase (PARP) facilitates the repair of DNA strand breaks and is implicated in the resistance of cancer cells to certain DNA-damaging agents. Inhibitors of PARP have clinical potential as resistance-modifying agents capable of potentiating radiotherapy and the cytotoxicity of some forms of cancer chemotherapy. The preclinical development of 2-aryl-1H-benzimidazole-4-carboxamides as resistance-modifying agents in cancer chemotherapy is described. 1H-Benzimidazole-4-carboxamides, particularly 2-aryl derivatives, are identified as a class of potent PARP inhibitors. Derivatives of 2-phenyl-1H-benzimidazole-4-carboxamide (23, K(i) = 15 nM), in which the phenyl ring contains substituents, have been synthesized. Many of these derivatives exhibit K(i) values for PARP inhibition 10 nM, with 2-(4-hydroxymethylphenyl)-1H-benzimidazole-4-carboxamide (78, K(i) = 1.6 nM) being one of the most potent. Insight into structure-activity relationships (SAR) for 2-aryl-1H-benzimidazole-4-carboxamides has been enhanced by studying the complex formed between 2-(3-methoxyphenyl)-1H-benzimidazole-4-carboxamide (44, K(i) = 6 nM) and the catalytic domain of chicken PARP. Important hydrogen-bonding and hydrophobic interactions with the protein have been identified for this inhibitor. 2-(4-Hydroxyphenyl)-1H-benzimidazole-4-carboxamide (45, K(i) = 6 nM) potentiates the cytotoxicity of both temozolomide and topotecan against A2780 cells in vitro (by 2.8- and 2.9-fold, respectively).
