Synthesis of cortistatins A, J, K and L

Abstract

The cortistatins are a recently identified class of marine natural products characterized by an unusual steroidal skeleton and have been found to inhibit differentially the proliferation of various mammalian cells in culture by an unknown mechanism. We describe a comprehensive route for the synthesis of cortistatins from a common precursor, which in turn is assembled from two fragments of similar structural complexity. Cortistatins A and J, and for the first time, K and L, have been synthesized in parallel processes from like intermediates prepared from a single compound. With the identification of facile laboratory transformations linking intermediates in the cortistatin L synthetic series with corresponding intermediates to cortistatins A and J, we have been led to speculate that somewhat related paths might occur in nature, offering potential sequencing and chemical detail for cortistatin biosynthetic pathways.

Collective Synthesis of Natural Products by Using Metathesis ­Cascade Reactions

“…5 Below, we present a series of representative examples of applications of this strategy, together with a discussion of its use in practice.…”

Search for Anti-angiogenic Substances from Natural Sources

“…The selective index was 7-100-fold in comparison with those for several cancer cell lines. Subsequent chemical modification study revealed that desacyl mixture of senegasaponins (44) and tenuifolin (45) exhibited no anti-proliferative activity against either HUVECs or tumor cells, indicating that the 28-O-glycoside moiety and methoxycinnamoyl group were essential for HUVEC-selective growth inhibition. Senegin III (40) inhibited VEGF-induced in vitro tubular formation of HUVECs and bFGF-induced in vivo neovascularization in the mouse Matrigel plug assay.…”

“…[42][43][44][45][46][47][48][49][50] We also reported the synthetic study of 24, in which the 7-endo-selective intramolecular Heck reaction and oxy-Michael reaction were used for elaborating the B-ring core structure of 24. [51][52][53] On the other hand, only small quantities of the final compound could be obtained in most cases because the many reaction steps were needed for the total synthesis.…”

Hypervalent iodine reagents in the total synthesis of natural products

“…In this one-pot three-step process, an internal hydroxyl group acted as nucleophile (Scheme 32). 112 This strategy has previously been employed in synthetic efforts towards the cortistatin family 28,275 (cf. Scheme 69 for another example).…”