Cortistatins A, B, C, and D, Anti-angiogenic Steroidal Alkaloids, from the Marine Sponge Corticium simplex

Abstract

Four novel steroidal alkaloids named cortistatins A (1), B (2), C (3), and D (4) consisting of a 9(10-19)-abeo-androstane and isoquinoline skeleton have been isolated from the marine sponge Corticium simplex. The absolute stereostructures of 1-4 were elucidated by detailed 2D NMR, CD, and X-ray crystallographic analyses. Cortistatins A-D inhibited proliferation of human umbilical vein endothelial cells (HUVECs) with high selectivity. Among the four substances, cortistatin A (1) showed the strongest anti-proliferative activity (IC50 = 0.0018 muM) against HUVECs, in which the selective index was more than 3000-fold in comparison with that of normal fibroblast or several tumor cell lines.

Search for Anti-angiogenic Substances from Natural Sources

“…Corticium simplex A family of alkaloids named cortistatins A (24) to D (27), with a highly oxidized and rearranged steroidal skeleton, was identified from the Indonesian marine sponge Corticium simplex as HUVEC-selective anti-proliferative substances 30) ( Fig. 5).…”

Synthetic Studies of Cortistatin A Analogue from the CD-Ring Fragment of Vitamin D₂

“…[ 2 (0.7 mg, 3.3 µmol), PPh 3 (1.5 mg, 5.6 µmol), Et 3 N (0.023 mL, 0.162 mmol) and HCOOH (4 µL, 0.108 mmol) were successively added to a solution of 11 (25.4 mg, 0.054 mmol) in THF (1.1 mL) and the whole mixture was stirred for 15 min at 70°C. After cooling to rt, H 2 O was added to the mixture and the whole mixture was extracted with AcOEt.…”

“…Therefore, substances that inhibit angiogenesis have a considerable potential to be novel therapeutic agents for the treatment of cancer. 1) In the course of our study on bioactive substances from marine organisms, we focused on a search for selective inhibitors of proliferation of human umbilical vein endothelial cells (HUVECs) as anti-angiogenic substances and isolated cortistatins, [2][3][4][5] a family of novel abeo-9 (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)-androstanetype steroidal alkaloids, from the Indonesian marine sponge of Corticium simplex. We found that cortistatin A (1, Chart 1), a major constituent, showed remarkably selective antiproliferative activity against HUVECs and also inhibited migration and tubular formation of HUVECs induced by vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF).…”

Synthetic Strategies Directed Towards the Cortistatin Family of Natural Products

“…Upon further experimentation, Hirama and co-workers observed that the diastereomeric ratio was dependent on both temperature and solvent, suggesting an equilibration between 83 and the retro-6π-electrocyclization compound 82. To complete the assembly of the pentacyclic core, a radical cyclization was effected upon treatment of 84 with triethylborane and (TMS) 3 SiH to close the seven-membered ring successfully and to provide the dienone 59 in 78 % yield.…”

“…[2] In 2006, Kobayashi and co-workers reported the structures of four novel steroidal alkaloids, cortistatins A-D (1-4, Figure 1). [3] Milligram quantities of the cortistatins were isolated through bioassay-guided separation of extracts from the Indonesian marine sponge Corticium simplex. Ko- bayashi et al elucidated the pentacyclic structure of the cortistatins through detailed 2D NMR studies and further confirmed their connectivity and absolute configuration through X-ray crystallographic and CD spectroscopic analysis of cortistatin A (1).…”