Synthesis and antitumor activity of isolongifoleno[7,8-d]thiazolo[3,2-a]pyrimidine derivatives via enhancing ROS level.

A series of novel isolongifoleno[7,8-d]thiazolo[3,2-a]pyrimidine derivatives (4a-4x) were synthesized from isolongifolanone according fragment-based design strategy, and their anticancer activity against human aortic smooth muscle cells (HASMC), human breast cancer (MCF-7) cells, human cervical cancer (HeLa) cells, and human liver cancer (HepG2) cells were investigated. Results of the anticancer activity illustrated that most of the compounds showed potent antitumor activity and compound 4i proved to be the most active derivative with IC50 values of 0.33 ± 0.24 (for MCF-7 cells), 0.52 ± 0.13 (for HeLa cells), and 3.09 ± 0.11 μM (for HepG2 cells), respectively. Moreover, we assessed the effects of 4i on cell apoptosis, cell cycle distribution, mitochondrial membrane potential, and reactive oxygen species (ROS) generation. The results indicated that compound 4i altered mitochondrial membrane potential and produced ROS leading to cell apoptosis of MCF-7 cells in a dose-dependent manner, however, without affecting cell cycle progression. These findings suggested that 4i was an effective compound and provided a promising candidate for anticancer drugs.