The specific objectives of the proposed research are to establish the relative and absolute configuration and to execute a synthesis of the extremely potent antitumor agent spongistatin 1. Ultimately, perhaps less complex derivatives of this potent antitumor agent with similar or better biological profiles can be prepared. During the course of the investigation, general methodology for the asymmetric synthesis of polyacetate and spiroketal containing natural products will be developed. This methodology can also be applied to the antitumor agents bryostatin 11, leucasandrolide A and mucocin. The asymmetric approaches to polyacetate fragments described herein should also find application in the synthesis of a variety of other biologically important compounds. Spongistatin 1 has been found to be extraordinarily effective against a variety of highly chemoresistant tumor types which comprise the NCI panel of 60 human cancer cell lines. Human melanoma, lung, brain and colon cancers were found to be especially sensitive to spongistatin. The activity of spongistatin correlates well with the class of microtubule interactive antimitotics. Because of the extremely limited availability of spongistatin from natural sources [400 kg wet weight of Spongia sp. provided only 13.8 mg (3.4 x 10-7 percent yield) of spongistatin] synthesis may be essential for providing adequate quantities of the substance for biological studies, structure-activity relationships and even to assist in the elucidation of the complete relative and absolute stereochemistry of this important compound. The bryostatins including bryostatin 11 have also been shown to posess significant antitumor activity including activity against lymphocytic leukemia and carcinosarcoma. Leucasandrolide A displayed significant cytotoxicity (IC50=0.05 and 0.25 mug/ml with KB and P388 cells, respectively) as well as very strong inhibition ofCandida albicans, a pathogenic yeast that attacks AIDS patients.

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 North Carolina Chapel Hill
Schools of Arts and Sciences
Chapel Hill
United States
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Crimmins, Michael T; Christie, Hamish S; Long, Alan et al. (2009) Total synthesis of apoptolidin A. Org Lett 11:831-4
Crimmins, Michael T; Smith, Aaron C (2006) A hetero-Diels-Alder approach to complex pyrones: an improved synthesis of the spongistatin AB spiroketal. Org Lett 8:1003-6
Crimmins, Michael T; DeBaillie, Amy C (2006) Enantioselective total synthesis of bistramide A. J Am Chem Soc 128:4936-7
Crimmins, Michael T; Caussanel, Franck (2006) Enantioselective total synthesis of FD-891. J Am Chem Soc 128:3128-9
Crimmins, Michael T; Long, Alan (2005) Enantioselective synthesis of apoptolidin sugars. Org Lett 7:4157-60
Crimmins, Michael T; Christie, Hamish S; Chaudhary, Kleem et al. (2005) Enantioselective synthesis of apoptolidinone: exploiting the versatility of thiazolidinethione chiral auxiliaries. J Am Chem Soc 127:13810-2
Crimmins, Michael T; Siliphaivanh, Phieng (2003) Enantioselective total synthesis of (+)-leucascandrolide A macrolactone. Org Lett 5:4641-4
Crimmins, Michael T; Katz, Jason D; Washburn, David G et al. (2002) Asymmetric total synthesis of spongistatins 1 and 2. J Am Chem Soc 124:5661-3
Crimmins, Michael T; Stanton, Matthew G; Allwein, Shawn P (2002) Asymmetric total synthesis of (-)-laulimalide: exploiting the asymmetric glycolate alkylation reaction. J Am Chem Soc 124:5958-9
Crimmins, M T; Katz, J D; McAtee, L C et al. (2001) An aldol approach to the synthesis of the EF fragment of spongistatin 1. Org Lett 3:949-52

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