Lookup NU author(s): Alex White,
Professor Alan Calvert,
Professor Nicola Curtin,
Professor Roger Griffin,
Professor Herbie Newell,
Professor Bernard Golding
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
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).
Author(s): White, A.W., Almassy, R., Calvert, A.H., Curtin, N.J., Griffin, R.J., Hostomsky, Z., Maegley, K., Newell, D.R., Srinivasan, S, Golding, B.T.
Publication type: Article
Publication status: Published
Journal: Journal of Medicinal Chemistry
Print publication date: 02/11/2000
ISSN (print): 0022-2623
ISSN (electronic): 1520-4804
PubMed id: 11063605
Altmetrics provided by Altmetric