Synthesis and biological evaluation of 4′-(6,7-disubstituted-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-biphenyl-4-ol as potent Chk1 inhibitors

Abstract

A new series of potent tricyclic pyrazole-based Chk1 inhibitors are described. Analogues disubstituted on the 6- and 7-positions show improved Chk1 inhibition potency compared with analogues with a single substituent on either the 6- or 7-position. Based on the lead compound 4′-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-biphenyl-4-ol (2), detailed SAR studies on the 6- and 7-positions were performed. 3′-morpholin-4′-yl-propoxy, pyridin-4′-ylmethoxy, pyridin-3′-ylmethoxy, 2′-(5″-ethyl-pyridin-2″-yl)-ethoxy, pyridin-2′-ylethoxy, (6′-methyl-pyridin-2′-yl)-propoxyethoxy, 2′,3′-dihydroxyl-1′-yl-propoxy, and tetrahydro-furan-3′-yloxy have been identified as the best groups on the 6-position when the 7-position is substituted with methoxyl group. Pyridin-2′-ylmethoxy and pyridin-3′-ylmethoxy have been identified as the best substituents at the 7-position while the 6-position bearing methoxyl group. These compounds significantly potentiate the cytotoxicity of DNA-damaging antitumor agents in a cell-based assay and efficiently abrogate the doxorubicin-induced G2/M and the camptothecin-induced S checkpoints, suggesting that their potent biological activities are mechanism-based through Chk1 inhibition.