Continuing biological evaluation of potential anticancer and antisepsis chemotherapeutic analogues of members of the hydrolyzable tannin family of secondary plant metabolites is proposed. Characterization of the immunomodulatory properties of these species will proceed. Mechanism-of-action investigations at the molecular, cellular, and whole animal levels, coupled with structure/activity studies, are designed to reveal the basis for both up-regulation and down-regulation of cytokine (IL-lb and TNFa) secretion by certain tannins. A novel tumor targeting strategy for tannin delivery will be explored. Appreciation of the molecular-level details responsible for either triggering or suppressing cytokine release may serve as the basis for designing tannin-inspired chemotherapeutic agents for diseases as diverse as cancer and septic shock. Ongoing synthesis studies directed toward the potent marine anticancer principle diazonamide A will be brought to completion. In addition to providing a supply of this scarce material for further biological evaluation, successful execution of the plausibly biomimetic synthesis route will provide insight into the otherwise obscure biosynthesis of this complex peptide-based secondary metabolite. Finally, new studies on the synthesis of the architecturally complex 20S proteosome inhibitor TMC-95A and rationally designed analogues will be pursued. A possibly biomimetic (modified) tryptophan oxidative cyclization forms the centerpiece of the approach, and acquisition of the target and the aforementioned analogues will enable mechanism-of-action studies to move forward. Inhibition of the 20S proteosome can form the basis for chemotherapeutic intervention in a variety of disease states, including cancer, cachexia, and sepsis. The search for selective 20S proteosome inhibitors among the Ntn-type proteases will be advanced by these investigations.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM035727-14
Application #
6914213
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Fabian, Miles
Project Start
1986-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2007-06-30
Support Year
14
Fiscal Year
2005
Total Cost
$307,773
Indirect Cost
Name
Pennsylvania State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Feldman, Ken S; Iyer, Malliga R (2005) Allenyl azide cycloaddition chemistry. synthesis of pyrrolidine-containing bicycles and tricycles via the possible intermediacy of azatrimethylenemethane species. J Am Chem Soc 127:4590-1
Feldman, Ken S; Vidulova, Daniela Boneva; Karatjas, Andrew G (2005) Extending Pummerer reaction chemistry. development of a strategy for the regio- and stereoselective oxidative cyclization of 3-(omega-nucleophile)-tethered indoles. J Org Chem 70:6429-40
Feldman, Ken S; Ngernmeesri, Paiboon (2005) Dragmacidin E synthesis studies. Preparation of a model cycloheptannelated indole fragment. Org Lett 7:5449-52
Feldman, Ken S (2005) Recent progress in ellagitannin chemistry. Phytochemistry 66:1984-2000
Feldman, Ken S; Karatjas, Andrew G (2004) Extending Pummerer reaction chemistry. Application to the oxidative cyclization of tryptophan derivatives. Org Lett 6:2849-52
Feldman, Ken S; Vidulova, Daniela Boneva (2004) Extending Pummerer reaction chemistry. Application to the oxidative cyclization of indole derivatives. Org Lett 6:1869-71
Feldman, Ken S; Iyer, Malliga R; Liu, Yanze (2003) Ellagitannin chemistry. Studies on the stability and reactivity of 2,4-HHDP-containing glucopyranose systems. J Org Chem 68:7433-8
Feldman, Ken S; Wilson, Sarah L; Lawlor, Michael D et al. (2002) In vitro and in vivo inhibition of LPS-induced tumor necrosis factor-alpha production by dimeric gallotannin analogues. Bioorg Med Chem 10:47-55
Feldman, Ken S; Eastman, Kyle J; Lessene, Guillaume (2002) Diazonamide synthesis studies: use of Negishi coupling to fashion diazonamide-related biaryls with defined axial chirality. Org Lett 4:3525-8
Feldman, K S; Sahasrabudhe, K; Lawlor, M D et al. (2001) In vitro and In vivo inhibition of LPS-stimulated tumor necrosis factor-alpha secretion by the gallotannin beta-D-pentagalloylglucose. Bioorg Med Chem Lett 11:1813-5

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