Functionalized Benzosuberene Analogues as Potential Vascular Disrupting Agents

Functionalized benzosuberene analogues represent an emerging class of anticancer agents that are inspired, in part, by combretastatin A-4 (CA4), a natural product found in bark extracts from Combretum caffrum, an African bush willow tree. In recent years, these benzosuberenes have become the subject of scientific scrutiny due to their heightened cytotoxicity and ability to inhibit tubulin assembly in the endothelial cells of tumor vasculature, eventually leading to tumor necrosis. Because of this ability, certain benzosuberenes and other similar compounds are more commonly known as vascular disrupting agents (VDAs). This study investigates how the activity of these benzosuberene compounds is affected when altering several moieties in the molecular structure while keeping the [6,7] fused-ring system intact. Specifically, this work seeks to determine whether various molecular substitutions on the benzosuberene core can improve binding to tubulin, leading to enhanced microtubule depolymerization and cytoxicity against human cancer cells. One of the molecules synthesized, featuring an α,β-unsaturated ketone in the final structure, demonstrated cytotoxicity against several human cancer cell lines (GI50 = 23.5 μM against NCI-H460 lung cancer cells; GI50 = 20.1 µM against DU-145 prostate cancer cells; and GI50 = 8.46 μM against SK-OV-3 ovarian cancer cells). Overall, four new benzosuberene analogues were prepared by chemical synthesis. Ultimately, the structures of these new molecules, along with accompanying biochemical and biological studies, were instrumental in extending the structure-activity relationship (SAR) profile for this new class of anticancer agents.