Synthesis, Anticancer Activity, Effect on Cell Cycle Profile, and Apoptosis-Inducing Ability of Novel Hexahydrocyclooctathieno[2,3-d]pyrimidine Derivatives.

A novel series of hexahydrocyclooctathieno[2,3-d]pyrimidines was synthesized. Investigation of the anticancer activity of these derivatives revealed that compounds 2a and b showed broad-spectrum anticancer activity in nanomolar to micromolar concentrations. In particular, compound 2b showed a concentration required for 50% inhibition of cell growth (GI50) value of less than 1 µM against 20 cancer cell lines. Compounds 2a and b induced G2/M- and S-phase cell cycle arrest in human colon adenocarcinoma (HCT116) and human breast adenocarcinoma (MCF7) cell lines with a concomitant increase in the pre-G cell population in a time-dependent manner. Furthermore, compound 2b increased the nuclear expression of the proapoptotic protein cleaved caspase-3, indicating that apoptosis has an important role, at least in part, in the cancer cell death induced by the new compounds.