- This research program is broadly directed to investigate fundamental advances for the chemical synthesis of biologically active marine natural products. Part I. Marine Antitumor Macrolides. Section A. A plan for the highly efficient, convergent, and enantiocontrolled synthesis of laulimalide will be executed. Laulimalide displays comparable potency to taxol with IC50 concentrations in the 0.01-0.05 mico/mL range against a broad selection of tumor cell lines. High cytotoxicity was registered toward KB lines (IC50 = 0.015 mico/mL). Significantly laulimalide retains activity in multi-drug resistant SKVLB-1 cultures. Section B. Strategies for the synthesis of peloruside will explore issues of stereoselectivity and efficiency for the assembly of this highly oxygenated hemiketal. With key structural features and macrocyclic rigidity, which address important proposals and research concerning the nature of the antitumor activity of the bryostatins (NCI; phase II trials), peloruside A studies are designed to offer a significant chemical advance for probing the nature of the pharmacophore and the mechanisms of biological activity for this family of molecules. Our chemical studies toward these target molecules will develop asymmetric allylation reactions. Bidirectional, divergent asymmetric allylation strategies are examined. Direct formation of new homochiral allylborane species will be pursued via cross coupling reactions with organozinc reagents. Part II. Zoanthamines. Our investigations of this novel class of marine alkaloids describe challenging issues of chemical synthesis toward densely functionalized, polycyclic systems. Members of this class have exhibited important antitumor and anti-inflammatory activities, and norzoanthamine is considered to be a promising osteoporotic candidate. Part III. Australifungin. This unique natural product is a potent antifungal which is the first nonsphingosine-based inhibitor of sphingolipid biosynthesis. It functions as a selective inhibitor of sphinganine N-acyl transferase, and may have an important role in lipid signal transduction, cell differentiation, and apoptosis. Our plans toward zoanthamines and australifungin will explore asymmetric induction in conjugate addition reactions and intramolecular Michael-based cyclizations. The intramolecular (4+2) cycloadditions of nitroalkene precursors will provide facile construction of trans-decalins. .

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM041560-19
Application #
6400049
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1982-04-01
Project End
2005-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
19
Fiscal Year
2001
Total Cost
$266,615
Indirect Cost
Name
Indiana University Bloomington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
Williams, David R; Claeboe, Christopher D; Liang, Bo et al. (2012) A bidirectional S(E)' strategy for 1,5-syn and 1,5-anti stereocontrol toward the synthesis of complex polyols. Org Lett 14:3866-9
Williams, David R; Klein, J Cullen; Chow, Nicholas S C (2011) Studies of intramolecular Diels-Alder reactions of nitroalkenes for the stereocontrolled synthesis of trans-decalin ring systems. Tetrahedron Lett 52:2120-2123
Williams, David R; Walsh, Martin J; Claeboe, Christopher D et al. (2009) Studies for the synthesis of marine natural products. Pure Appl Chem 81:181
Williams, David R; Nag, Partha P; Zorn, Nicolas (2008) Strategies for the synthesis of the novel antitumor agent peloruside A. Curr Opin Drug Discov Devel 11:251-71
Williams, David R; Reeves, Jonathan T; Nag, Partha P et al. (2006) Studies of the generation and pericyclic behavior of cyclic pentadienyl carbanions. Alkylation reactions as an efficient route to functionalized cis-bicyclo[3.3.0]octenes. J Am Chem Soc 128:12339-48
Williams, David R; Morales-Ramos, Angel I; Williams, Catherine M (2006) Reactivity studies of 3,3-bis(trimethylsilyl)-2-methyl-1-propene in Lewis acid-catalyzed allylation reactions. Org Lett 8:4393-6
Williams, David R; Berliner, Martin A; Stroup, Bryan W et al. (2005) Samarium Barbier reactions of alpha-iodomethyloxazoles and thiazoles with aliphatic aldehydes. Org Lett 7:4099-102
Williams, David R; Kammler, David C; Donnell, Andrew F et al. (2005) Total synthesis of (+)-apiosporamide: assignment of relative and absolute configuration. Angew Chem Int Ed Engl 44:6715-8
Williams, David R; Reeves, Jonathan T (2004) Carbolithiation for the generation of cyclooctadienyl anions and tandem electrocyclization/alkylation to functionalized cis-bicyclo[3.3.0]octenes. J Am Chem Soc 126:3434-5
Williams, David R; Kiryanov, Andre A; Emde, Ulrich et al. (2004) Studies of stereocontrolled allylation reactions for the total synthesis of phorboxazole A. Proc Natl Acad Sci U S A 101:12058-63

Showing the most recent 10 out of 20 publications