Director of Chemistry
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The central focus of my work is the development of efficient approaches to the synthesis of novel small molecule and macrocyclic compounds. All of the libraries prepared are being made available to the scientific community through the Institute Biological Outreach Program for the identification of new hits as first steps of an optimal “design and selection” process for lead optimization for the development of new pain management, cancer, tuberculosis and antimicrobial drugs.
Considering the large number of biologically active cyclic peptides in nature and their potential as drugs in vivo, the synthesis of cyclic peptides and analogues remains an important goal for both academic and pharmaceutical laboratories. Numerous strategies to synthesize cyclic peptides have been reported, but a general, high-yielding route to small cyclic peptides has yet to be developed. We will continue with our work toward the development of innovative approaches for the generation of unique macrocyclic peptides. Examples of new strategies will include Hantzsch based macrocyclization approach for the synthesis of thaizole containing cyclopeptides.
The last decade has witnessed major breakthroughs in the identification of genes, gene products, metabolic pathways, and signaling pathways, as well as progress in miniaturization and robotics, enabling the development of high-throughput mechanism-based biological assays. One of the central objectives of organic and medicinal chemistry is the design, synthesis, and production of molecules having value as human therapeutic agents. Nitrogen heterocycles of different ring sizes, with different substitution patterns and embedded in various molecular frameworks constitute important structure classes in the search for bioactivity. We will continue with our work on the diversity-oriented synthesis of structurally unique fused and tethered biologically relevant heterocyclic libraries that will enrich and increase the diversity and uniqueness of the collection of compounds in the chemical space. Parallel solid phase synthesis and solution phase synthesis will be used to generate fused and/or tethered heterocyclic compounds. The compounds will be designed to follow known drug-likeness rules including “Lipinski’s Rule of Five”. We will work closely with computational chemists to use cheminformatic tools to refine and enhance our selection of building blocks to ensure a better distribution of the synthesized compounds in chemical space.
Despite the recognized biological significance of cell-surface oligosaccharides as targets for bacterial, toxin, and viral attachment, and in mammalian cell-cell adhesion, approaches for the chemical assembly of sugar-containing libraries have not been extensively explored. Starting from resin-bound peptide and peptidomimetic libraries, and commercially available functional 2,3,4,6-tetra-O-acetyl-ß-D-glucopyranosyl compounds, we will perform the parallel synthesis of a variety of polyaminoglycoside libraries.
All small molecule, macrocyclic and glycopeptide libraries are natural product-like compounds that promise a high potential of generating biologically active molecules. All libraries will be screened in a series of assays representing a variety of fundamental biological functions. The diversity of the chemical structures of the final compounds, as well as the large number of compounds making up each class of structures greatly increases the ultimate probability of identifying compounds with desirable properties.
Our work will have a significant societal impact in by contributing to efforts to develop new chemistries for the synthesis of unique structurally complex compounds that can open up avenues for the development of novel therapeutics.