Total Synthesis of Bioactive Compounds

University Of Colorado At Boulder, Boulder CO

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Abstract

DESCRIPTION (provided by applicant): The principal objectives of this proposal are to develop syntheses of several marine-derived natural products that possess potent pharmacological activity, and that are currently available only in limited amounts. Specific target molecules include cylindramide A, aburatubolactam A, and the C29-C53 subunit of norhalichondrin B, and the C29-C54 subunit of halichondrin B. Cylindramide A and aburatubolactam A are structurally related tetramic acid macrolactams characterized by a substituted bicyclo[3.3.0]octane core and a tetramic acid moiety entrapped within a macrolactam. Both compounds possess potent biological activity - cylindramide inhibits the growth of B16 melanoma cells at low microgram per milliliter IC[50] values, and aburatubolactam A inhibits the growth of P388 murine leukemia cells along with the ability to inhibit superoxide anion generation. As part of synthetic studies on this class of molecules a simple scaffold that can display the tetramic acid macrolactam will be developed as a surrogate for the bicyclo[3.3.0]octane core. Norhalichondrin B and halichondrin B are complex marine-derived polyethers that display remarkably potent in vitro and in vivo anti-cancer activity (GI[50] values of <lnM vs a range of cell lines). Obtaining the halichondrins in reasonable amounts from the natural source seems unlikely, and at present their complex structures seem to preclude synthesis providing a workable solution. Comparably potent biological activity has been observed for truncated halichondrin structures, and concise syntheses of the C29-C53 subunit of norhalichondrin B, and the C29-C54 subunit of halichondrin B will be developed that will provide material for further biological study.