Abstract
We have isolated cortistatins, novel steroidal alkaloids having anti-angiogenic property, from the marine sponge Corticium simplex in 2006. Among them, we found that cortistatin A (1) showed highly selective anti-proliferative activity against human umbilical vein endothelial cells (HUVECs). The characteristic structure and intriguing biological activity of 1 attracted synthetic chemists, and many synthetic studies have been reported. We also engaged in synthetic study of 1 for overcoming the scarcity of natural supply. Here we present a new synthetic approach toward 1 using intramolecular Heck cyclization as a key step, and synthesis of some readily accessible analogs of 1. 1. Synthetic study toward total synthesis First, an A-ring fragment 17 was synthesized in 9 steps from 2-cyclohexen- 1 -one. Coupling reaction between the A-ring fragment 17 and a CD-ring fragment 16, which was obtained in 2 steps from readily available (+)-Hajos-Parrish ketone, afforded 21 and subsequent manipulations gave an enol triflate 25. The intramolecular Heck cyclization of 25 proceeded through 7 -endo manner to give compound 26b. After conversion of 26b into an enone 13, oxy-Michael reaction furnished a carbocyclic core structure of 1. Further study toward total synthesis of 1 is now under investigating. 2. Design and synthesis of active lead compounds Although many synthetic reports of cortistatin A (1) have been appeared, there have been no report about the in vivo anti-tumor properties of cortistatins by using the synthesized compounds. Then we are engaging in synthetic study of the structurally simplified and readily available analogs of cortistatins, based on the 3-D structure of 1 and the structure-activity relationship of the isolated eleven minor cortistatins. We found that a synthesized compound 37 having isoquinoline moiety and tetracyclic planar core structure showed potent and selective anti-proliferative activity against HUVECs. The compound 37 also exhibited in vivo anti-tumor activity in a mouse model inoculated sarcoma S180 cells.
