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Synthesis of (+)-Cortistatin A
K. C. Nicolaou*, Y.-P. Sun, X.-S. Peng, D. Polet, D. Y.-K. Chen*
Agency for Science, Technology, and Research, Singapore; The Scripps Research Institute, La Jolla and University of California, San Diego, USA
23 March 2009 (online)
(+)-Cortistatin A is a potent anti-angiogenic agent that displays very high antiproliferative activity against human umbilical vein endo-thelial cells (HUVECs, IC50 = 1.8 nM) without showing any toxicity. It also demonstrates an excellent selectivity index (>3000) against HUVECs in comparison to their activity towards normal human dermal fibroplasts (NHDF) and several tumor cells (KB3-1, K562 and Neuro 2A). Based upon a modular strategy, this synthesis features a cascade sequence involving 1,4-addition/aldol condensation to construct dienone I.