Synthesis of Biologically Active Cortistatin Analogs

Abstract

Cortistatin A, a marine natural product isolated in the mid-2000, was reported as a highly selective and potent anti-angiogenic agent. Based on the known SAR (structure activity relationship) studies of cortistatins and the related synthetic compounds, simplified tricyclic and tetracyclic analogs (3.8, 3.32) resembling cortistatin A were developed and the biological activities were evaluated. Improved cell-growth inhibitory properties were observed after carefully re-designing and synthesizing the analogs with the lessons learned from X-ray crystal structure of cortistatin A bound to the target protein. From the first lead compound 4.65, more than fifty analogs were prepared with different functional groups on the C3 and C17 positions, aided by the readily scalable common intermediate 4.55 from the commercially available estrone in twelve steps with five column purifications. The final lead compound showing both decent potency and stability will be selected in the near future.