I. Complex Peptidyl Nucleoside Antibiotics as Novel Antifungal Agents
Streptomyces-derived complex peptidyl nucleoside antibiotics (Figure 1) represent a unique class of natural products with potent antifungal activity against various pathogenic fungi. The demonstrated antifungal activity, fungal cell specificity, potentially novel mechanism of action, and unique structural features of these peptidyl nucleosides have generated considerable interest in their potential utility as new generations of antifungal drugs. To better understand the structural requirements for optimum activity of the antifungal peptidyl nucleosides, the objective of our present research is to develop efficient synthetic routes to these natural products and further application of the methods towards design and synthesis of analogs with more potent activity and improved fungal cell permeability.
II. Amino Acid Chiral Template Assisted Stereoselective Synthesis of Bioactive Compounds
Synthesis of bioactive compounds in enantiopure form, utilizing amino acids as chiral template, has been the major goal of this project. Among the various molecules synthesized so far (Figure 2) are the non-proteinogenic hydroxy amino acids statine, polyoxamic acid, galantinic acid, and 3-hydroxyglutamic acid, the potent antibiotics chloramphenicol, bulgecinine, and preussin, and the all syn-tri substituted piperidine core of the plant alkaloids carpaine and azimine. A novel synthetic route to potent HIV protease inhibitor hydroxyethylamine (HEA) dipeptide isosteres has also been developed.
III. Salinosporamide A : A Proteasome Inhibitor, Cytotoxic Natural Product
The direct relevance of proteasome function in neoplastic processes has resulted in a great deal of interest in exploring the possibility that suitable proteasome inhibitors may prove useful as novel cancer therapeutic agents. Salinosporamide A (Figure 3), a recently isolated a marine bacterium metabolite has showed impressive proteasome inhibition and cytotoxic activity. The present research is focused on the total synthesis, detailed structure-activity relationship investigation and development of more potent analogs based on the natural product lead.
IV. Combinatorial Libraries and Methodology Development (CMLD) : Biomimetics
The main objective of this project is the development of new strategies and approaches for preparing combinatorial libraries of biomimetics – compounds that mimic the building blocks of life (e.g. amino acids, carbohydrates, nucleosides etc.). The research focus is on: (i) investigation of stereocontrolled carbon-carbon and carbon-heteroatom bond forming reactions on a solid support bound chiral template, and, (ii) application of these methods for the combinatorial synthesis of novel nucleosides, azacarbohydrates, and polyfunctionalized pipieridine scaffolds (Figure 4).
For More Information, Please Contact:
Dr. Apurba Dutta
Department of Medicinal Chemistry - KU
1251 Wescoe Hall Dr.
5006 Malott Hall
Lawrence, KS 66045-7582 USA
Phone: (785) 864-4117
Fax: (785) 864-5329
Email:
adutta@ku.edu
