Design and Synthesis of 3,4-diarylpyrrole analogues as Potent Topoisomerase Inhibitors

BACKGROUND: The natural products containing a common 3,4-diarylpyrrole skeleton have attracted considerable attention due to their unique structures and multiplex biological activities. In our previous study, lycogarubin C was synthesized and showed cytotoxicity against MDAMB- 231, A549, PC3 and HeLa cell lines and topoisomerase II inhibitory activities. OBJECTIVE: We present the design, synthesis and antitumor studies of 3,4-diarylprrole derivatives. Their antitumor activities and inhibitory activities against Topo I and Topo IIα of these compounds were assayed. METHODS: A series of 3,4-diarylpyrrole analogues have been designed and synthesized. Their antiproliferation activities were evaluated by sulforhodamine B assay on human breast cancer MDAMB- 231, MDA-MB-435 and human cervical cancer HeLa cells. RESULTS: Four compounds showed modest inhibitory activities against the growth of the three cell lines with IC50 below 50 μM. DNA relaxation assay revealed that compound 19o showed potent inhibitory activity against Topo IIα in vitro. 19o also induced DNA breaks in MDA-MB-435 cells evidenced by comet tails and the accumulation of γ-H2AX foci. The ability of 19o in inducing DNA breaks mediated by Topo IIα resulted in G2/M phase arrest and apoptosis. CONCLUSION: This work indicates that 3,4-diarylpyrrole derivatives represent a novel type of Topo IIα inhibitory scaffold for developing new antitumor chemotherapeutic agents.