(Principal Investigator's) The overall goals of this program are: (i) The development of advances in strategy and the discovery of enabling reactions of value in organic synthesis and (ii) the application of these findings to advance human health. While we continue our long term interest in the synthesis of naturally occurring antiinfectious agents, we also include cytotoxic antitumor agents, particularly where a novel mechanism of action has been inferred. Moreover, in this program we continue our quest to develop and evaluate new vaccine constructs to foster immunity against tumorgenesis and metastasis. Among the specific goal structures that we will attempt to synthesize are (i) class of marine derived natural products which can be classified as the eleuthesides (including eleutherobin, sarcodictyn and valdivone A) (eleutherobin has a demonstrated taxol like effect on the rate of microtubulin depolymerization), (ii) heliquinomycin and related structures such as rubromycin and purpuromycin (heliquinomycin is the first reported inhibitor of DNA helicase), (iii) saframycin B, an antibiotic with potent action against gram positive bacteria, (iv) yaoundamine B which is a potent antimalarial agen and (v) frondosin which is a potent PKC inhibitor and an inhibitor of IL-8 receptors. In addition, (vi) we continue our work on the design, synthesis and evaluation of new second and third generation constructs for evaluation as anticancer vaccines. The scope of this inquiry includes lipid conjugates to replace (or augment) KLH, clustered presentations to mimic antigen as presentations in mucins, and antigen analogs in the hope of triggering more aggressive immune responses.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
Program Officer
Tseng, Christopher K
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Carcache, David A; Cho, Young Shin; Hua, Zihao et al. (2006) Total synthesis of (+/-)-jiadifenin and studies directed to understanding its SAR: probing mechanistic and stereochemical issues in palladium-mediated allylation of enolate-like structures. J Am Chem Soc 128:1016-22
Hua, Zihao; Carcache, David A; Tian, Yuan et al. (2005) The synthesis and preliminary biological evaluation of a novel steroid with neurotrophic activity: NGA0187. J Org Chem 70:9849-56
Keding, Stacy J; Danishefsky, Samuel J (2004) Prospects for total synthesis: a vision for a totally synthetic vaccine targeting epithelial tumors. Proc Natl Acad Sci U S A 101:11937-42
Cho, Young Shin; Carcache, David A; Tian, Yuan et al. (2004) Total synthesis of (+/-)-jiadifenin, a non-peptidyl neurotrophic modulator. J Am Chem Soc 126:14358-9
Dudkin, Vadim Y; Miller, Justin S; Danishefsky, Samuel J (2004) Chemical synthesis of normal and transformed PSA glycopeptides. J Am Chem Soc 126:736-8
Krug, Lee M; Ragupathi, Govind; Hood, Chandra et al. (2004) Vaccination of patients with small-cell lung cancer with synthetic fucosyl GM-1 conjugated to keyhole limpet hemocyanin. Clin Cancer Res 10:6094-100
Warren, J David; Miller, Justin S; Keding, Stacy J et al. (2004) Toward fully synthetic glycoproteins by ultimately convergent routes: a solution to a long-standing problem. J Am Chem Soc 126:6576-8
Miller, Justin S; Dudkin, Vadim Y; Lyon, Gholson J et al. (2003) Toward fully synthetic N-linked glycoproteins. Angew Chem Int Ed Engl 42:431-4
Gaul, Christoph; Njardarson, Jon T; Danishefsky, Samuel J (2003) The total synthesis of (+)-migrastatin. J Am Chem Soc 125:6042-3
Coltart, Don M; Royyuru, Ajay K; Williams, Lawrence J et al. (2002) Principles of mucin architecture: structural studies on synthetic glycopeptides bearing clustered mono-, di-, tri-, and hexasaccharide glycodomains. J Am Chem Soc 124:9833-44

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