Cancer is one of the most lethal malignancies worldwide. Although scientists have given the immense efforts, the death rate is still very high. Hepatocellular carcinomas are the second leading cause of cancer death in Asia countries, particular in China. Although several treatment modalities are available, systemic chemotherapy is still considered as an important strategy for improving the survival. However, current available drugs were characterized with low selectivity, high toxicities and acquired resistances. Therefore, several attempts have been made to design and synthesize new drugs. A series of indazole derivatives were synthesized and their antiproliferative activities were evaluated in human MDA-MB-231, PLC/PRF/5, and HCT-116 cell lines. The activity of compounds 1a, 1g, 1h, and 1i was superior or similar to the referenced drug Sorafenib. Several SAR were studied, such as effect of the substituents on indazole ring, effect of the N position in middle benzene ring, and effect of urea moiety replaced by amide or sulfonamide moiety. Compounds with the trifluoromenthyl substituent at the 4 position and with N-(2-(pyrrolidin-1-yl)ethyl)formamide at the position of 3, 5, or 6 on the indazole ring exhibited higher activities than other compounds. Compound 1g with N-(2-(pyrrolidin-1-yl)ethyl)formamide at 3 position of the indazole ring was selected to further evaluate the antiproliferative effect on hepatocellular carcinoma cell lines Bel-7402 and HepG2. Based on the screened results, Compound 1g could be developed as a promising agent for treatment of cancers.

Synthesis of indazole derivatives and evaluation of their antiproliferative activity

251st National Meeting (2016)

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