Synthesis, in vitro anticancer activity and in silico study of new disubstituted thiazolidinedione derivatives

Thiazolidinediones are known to have antidiabetic activity, but new activities are being discovered every year; among these, their anticancer activity has received the most attention. In this study, we synthesized three new disubstituted thiazolidinediones and assayed their cytotoxicity against six tumor cell lines, as well as against normal cells. Cytometry studies and molecular modeling were also performed to elucidate the mechanism of cytotoxicity. Of the three new thiazolidinediones synthesized, (5Z)-5-(3-bromo-benzylidene)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione (LPSF/SF-13) exhibited the most promising activity; it was selectively cytotoxic against leukemia, lymphoma, glioblastoma, and hepatocarcinoma cell lines without being toxic to normal cells. Apoptosis was the main cell death process induced by this compound, although it also induced necrosis. Furthermore, molecular modeling studies showed that LPSF/SF-13 had good affinity for peroxisome proliferator-activated receptor γ; binding to the receptor involved hydrogen bonds with Arg288 and Ser342 residues (bond distances of 3.1 and 2.8 A, respectively), as well as a π-bonding interaction with His449. We concluded that LPSF/SF-13 is a promising compound for in vivo and combination therapy studies against cancer.