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

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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Lees, Robert G
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University of Colorado at Boulder
Schools of Arts and Sciences
United States
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Hallside, Michal S; Brzozowski, Richard S; Wuest, William M et al. (2014) A concise synthesis of carolacton. Org Lett 16:1148-51
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Griggs, Nolan D; Phillips, Andrew J (2008) A concise and modular synthesis of pyranicin. Org Lett 10:4955-7
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Keaton, Katie A; Phillips, Andrew J (2008) Toward the synthesis of spirastrellolide B: a synthesis of the C1-C23 subunit. Org Lett 10:1083-6
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Henderson, James A; Phillips, Andrew J (2008) Total synthesis of aburatubolactam A. Angew Chem Int Ed Engl 47:8499-501

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