ABSTRACT
Herein we disclose a series of novel heteroaryl styryl sulfone derivatives as potential anticancer agents. Structure-activity relationships of these newly synthesised compounds were explored with respect to the significance of the position and number of nitrogen atom of the heteroaryl ring for anti-proliferative activity in human cancer cell lines. A lead compound 14f was tested against a panel of cancerous and untransformed cell lines, and found to be highly potent against cancer cells with minimal toxicity in the untransformed cells. Further mechanistic studies uncovered that 14f caused cell-cycle arrest at the G2/M phase and induced apoptosis by targeting CDC25C and Mcl-1 proteins in A2780 ovarian cells.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Sulfones/chemistry , Sulfones/pharmacology , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Humans , Hydrocarbons, Aromatic/chemical synthesis , Hydrocarbons, Aromatic/chemistry , Hydrocarbons, Aromatic/pharmacology , Neoplasms/drug therapy , Structure-Activity Relationship , Sulfones/chemical synthesisABSTRACT
ON01910.Na is a highly effective anticancer agent that induces mitotic arrest and apoptosis. Clinical studies with ON01910 in cancer patients have shown efficacy along with an impressive safety profile. While ON01910 is highly active against cancer cells, it has a low oral availability and requires continuous intravenous infusion or multiple gram doses to ensure sufficient drug exposure for biological activity in patients. We have identified two novel series of styrylsulfonyl-methylpyridines. Lead compounds 8, 9a, 18 and 19a are highly potent mitotic inhibitors and selectively cytotoxic to cancer cells. Impressively, these compounds possess excellent pharmaceutical properties and two lead drug candidates 9a and 18 demonstrated antitumor activities in animal models.
