Discovery of Potent and Practical Antiangiogenic Agents Inspired by Cortistatin A Barbara Czako ´, † La ´ szlo ´ Ku ¨rti, † Akiko Mammoto, ‡ Donald E. Ingber, ‡ and E. J. Corey* ,† Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford Street, Cambridge, Massachusetts 02138, and Department of Pathology, HarVard Medical School, Vascular Biology Program, Childrens Hospital, 300 Longwood AVenue, Boston, Massachusetts 02115 Received April 1, 2009; E-mail: corey@chemistry.harvard.edu Abstract: The discovery that cortistatins A and J show noteworthy antiangiogenic activity prompted an investigation of the possibility that simpler and much more easily made compounds based on a steroid core might have useful bioactivity. These studies have led to the development of several potent, water- soluble compounds that may be suitable for local application to treat ocular wet macular degeneration, an important cause of blindness, as well as for treatment of various other angiogenesis-dependent diseases. One of these substances was tested in a mouse retinal angiogenesis model and found to inhibit angiogenesis at a locally administered dose of 500 pmol. Comparison of cell migration data for this and two other synthetic compounds with published data on cortistatin A indicate that they inhibit vascular endothelial growth factor- induced cell migration of human umbilical vein endothelial cells more strongly than cortistatin A. Introduction One of the most significant recent developments in cancer therapy is the discovery of a high-affinity antibody that neutralizes the action of the vascular endothelial growth factor (VEGF). 1 That antibody (Avastin, Genentech) now has sales of several billion dollars per annum. A modification of this recombinant DNA-derived antibody is also useful for the treatment of wet macular degeneration. Marketed as Lucentis by Genentech, it has annual sales of about a billion dollars. In cancer therapy, the antibody functions to inhibit the formation of new blood vessels that are required for solid tumor growth. 1,2 In the case of wet macular degeneration, the antibody inhibits the excessive proliferation of blood vessels that leads to the destruction of healthy tissue and consequently compromises vision. 3 Our research was stimulated by the discovery of a potent antiangiogenic natural product, cortistatin A (1, Figure 1), isolated as a trace component from a marine sponge, Corticulum simplex, by Kobayashi in 2006. 4 This complex steroidal natural product was shown to exhibit highly selective antiproliferative activity against human umbilical vein endothelial cells (HUVEC) at nanomolar concentrations. It also was found to inhibit VEGF- induced migration and basic fibroblast growth factor (bFGF)- induced tubular network formation of HUVECs at ca. 200 nM concentrations. 5 In addition to cortistatin A (1), 10 related natural products have been isolated from the same sponge, one of which, cortistatin J (10), also exhibited good antiangiogenic activity (Figure 1). 6,7 To date, the exact cellular target of the cortistatins has not been determined, and in ViVo studies of 1 have not been reported. Initially we were intrigued by the challenge of devising a synthesis of cortistatin A and carried out preliminary studies † Harvard University. ‡ Harvard Medical School. (1) Kim, K. J.; Li, B.; Winer, J.; Armanini, M.; Gillett, N.; Phillips, H. S.; Ferrara, N. Nature 1993, 362, 841–844. (2) Folkman, J. N. Engl. J. Med. 1971, 285, 1182–1186. (3) Ferrara, N.; Damico, L.; Shams, N.; Lowman, H.; Kim, R. Retina 2006, 26, 859–870. (4) Aoki, S.; Watanabe, Y.; Sanagawa, M.; Setiawan, A.; Kotoku, N.; Kobayashi, M. J. Am. Chem. Soc. 2006, 128, 3148–3149. (5) Aoki, S.; Watanabe, Y.; Tanabe, D.; Arai, M.; Suna, H.; Miyamoto, K.; Tsujibo, H.; Tsujikawa, K.; Yamamoto, H.; Kobayashi, M. Bioorg. Med. Chem. 2007, 15, 6758–6762. (6) Aoki, S.; Watanabe, Y.; Tanabe, D.; Setiawan, A.; Arai, M.; Kobayashi, M. Tetrahedron Lett. 2007, 48, 4485–4488. (7) Watanabe, Y.; Aoki, S.; Tanabe, D.; Setiawan, A.; Kobayashi, M. Tetrahedron 2007, 63, 4074–4079. Figure 1. Structures of cortistatin natural products. Published on Web 05/26/2009 10.1021/ja902601e CCC: $40.75  2009 American Chemical Society 9014 9 J. AM. CHEM. SOC. 2009, 131, 9014–9019