The specific objectives of the proposed research are to execute a synthesis of the potent antitumor agents laulimalide, apoptolidin and leucascandrolide A. Ultimately, perhaps less complex derivatives of these potent antitumor agents with similar or better biological profiles can be prepared. During the course of the investigation, general methodology for the asymmetric synthesis of polyacetate and and polypropionate natural products will be developed. The asymmetric approaches to polyacetate and polypropionate fragments described herein should also find application in the synthesis of a variety of other biologically important compounds. Leucasandrolide A was isolated from the calcareous sponge Leucasandra caveolata. The gross structure and relative stereochemistry was assigned based on extensive two dimensional NMR experiments. The absolute configuration was assigned by Mosher's method using the Mosher's ester of the C5 hydroxyl. Leucasandrolide displayed significant cytotoxicity in vitro (IC50 = 0.05 and 0.25 mug/ml with KB and P388 cells, respectively) as well as very strong inhibition of Candida albicans, a pathogenic yeast that attacks AIDS patients.3 Apoptolidin, from Norcardiopsis sp. induced apoptotic cell death in rat glia cells transformed with the adenovirus E1A oncogene (IC50 11ng/mL) but not in normal glia cells or normal fibroblasts (IC50 greater than 100 mug/mL). Laulimalide is a potent inhibitor of cell growth with low, nanomolar IC50 values which was isolated from an Okinawan sponge Fasciospongia rimosa. Laulimalide shows paclitaxel-like microtubule stabilization, however, in contrast to paclitaxel, laulimalide inhibits proliferation of SKVLB-1 cells, a multidrug resistant cell line. Laulimalide stimulates tubulin polymerization more effectively than paclitaxel. Laulimalide is a representative of a new class of microtubule stabilizing agents with promise for therapeutic potential.

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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