Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 132, Issue -, Pages 26-41Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.03.013
Keywords
PARP-1 inhibitor; PARP-2 inhibitor; Benzo[d]immidazole-4-carboxamide; Anti-tumor agents
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Funding
- National Natural Science Foundation of China [81673300]
- Special Funds for National Public Benefit Research Institutes [2016ZX350039]
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Novel 1H-benzo[d]immidazole-4-carboxamide derivatives bearing five-membered or six-membered N-heterocyclic moieties at the 2-position were designed and synthesized as PARP-1 inhibitors. Structure activity relationships were conducted and led to a number of potent PARP-1 inhibitors having IC50 values in the single or double digit nanomolar level. Some potent PARP-1 inhibitors also had similar inhibitory activities against PARP-2. Among all the synthesized compounds, compound 10a and 11e displayed strong potentiation effects on temozolomide (TMZ) in MX-1 cells (PF50 = 7.10, PF50 = 4.17). In vivo tumor growth inhibition was investigated using compound 10a in combination with TMZ, and it was demonstrated that compound 10a could strongly potentiate the cytotoxicity of TMZ in MX-1 xenograft tumor model. Two co-crystal structures of compounds 11b and 15e complexed with PARP-1 were achieved and demonstrated a unique binding mode of these benzo-imidazole derivatives. (C) 2017 Elsevier Masson SAS. All rights reserved.
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