Synthesis of axially chiral benzochalcogenophene derivatives and their anti-proliferative activities in cancer cells

Axially chiral benzochalcogenophene derivatives bearing sulfur and selenium atoms in their fused cyclic rings were synthesized. Subsequently, their anti-proliferative activity against pancreatic ductal adenocarcinoma and acute myelogenous leukemia cells was evaluated. Optical resolution of these compounds was achieved, and their absolute configurations were determined using X-ray crystallography and CD spectroscopy. Anti-proliferative activity revealed a marked dependence on both axial chirality and the identity of the chalcogen atoms. The benzothiophene derivative (S)-2 potently inhibited the proliferation of all tested cancer cell lines, whereas its enantiomer, (R)-2, displayed weaker activity. In addition, (S)-2 showed stronger anti-proliferative activity than the corresponding selenium analog (S)-1. These results demonstrate that both axial chirality and the nature of the chalcogen atoms affect biological activity. Mechanistic studies demonstrated that (S)-2 induces DNA damage, G2/M-phase arrest, mitotic accumulation, and caspase-dependent apoptosis. These results suggest that (S)-2 is a promising seed compound for the development of novel anticancer agents.