Synthesis and anti-tumor activities of N′-benzylidene-2-(4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetohydrazone derivatives

A compound with a cyclic thienopyrimidine moiety and an aceto-hydrazone moiety in its chemical structure was discovered in a cell-based screening to have noticeable cytotoxicity on several tumor cell lines. A total of 38 derivatives of this compound were synthesized at five steps with high yields. These compounds were tested in standard MTT assays, and several compounds exhibited improved cytotoxic activities. The most potent compounds have IC50 values of 10–20 μM on A549, HeLa, and MBA-MD-231 tumor cells. Flow cytometry analysis of several active compounds and subsequent examination of caspase activation indicate that they induce caspase-dependent apoptosis in tumor cells. In addition, these compounds do not have obvious effect on a normal cell line HEK-293T, demonstrating the desired selectivity against tumor cells. Results from a fluorescence polarization-based in vitro binding assay indicate that this class of compounds does not significantly interrupt the interactions between Mcl-1 and Bid. Their cytotoxicity is achieved presumably through other mechanisms.

IC50 = 10–20 μM on A549, Hela and MDA-MB-231 tumor cells.Figure optionsDownload as PowerPoint slide