The cortistatins are a recently identified class of marine natural products characterized by an unusual steroidal skeleton, which 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.
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Financial support from the National Institutes of Health (Stimulus grant no. CA047148-22S1) is gratefully acknowledged. A.N.F. acknowledges a scholarship from Eli Lilly and Company. We gratefully acknowledge G. Zou for measuring the GI50 values of cortistatins A, J, K and L and A.W.G. Burgett and M.D. Shair for their assistance with these measurements as well as a gift of the HUVEC. We acknowledge helpful discussions with C. T. Walsh and E. Balskus.
The authors declare no competing financial interests.
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Flyer, A., Si, C. & Myers, A. Synthesis of cortistatins A, J, K and L. Nature Chem 2, 886–892 (2010). https://doi.org/10.1038/nchem.794
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