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.
Showing the most recent 10 out of 13 publications
