New Tripentone Analogs with Antiproliferative Activity

Tripentones represent an interesting class of compounds due to their significant cytotoxicityagainst different human tumor cells in the submicro-nanomolar range. New tripentone analogs, inwhich a pyridine moiety replaces the thiophene ring originating the fused azaindole system endowedwith anticancer activity viz 8H-thieno[2,3-b]pyrrolizinones, were efficiently synthesized in four stepswith fair overall yields (34–57%). All tripentone derivatives were tested in the range of 0.1–100 Mfor cytotoxicity against two human tumor cell lines, HCT-116 (human colorectal carcinoma) andMCF-7 (human breast cancer). The most active derivative, with GI50 values of 4.25 µM and 20.73 µMfor HCT-116 and MCF-7 cells, respectively, did not affect the viability of Caco-2 differentiated innormal intestinal-like cells, suggesting tumor cells as the main target of its cytotoxic action. The samecompound was further investigated in order to study its mode of action. Results showed that itdid not exert necrotic effects, while induced a clear shift of viable cells towards early apoptosis.Flow cytometric analysis demonstrated that this compound caused cell cycle alteration, inhibiting itsprogression in S and G2/M phases.