It is undeniable that a majority of small molecule medicinal agents are natural products or are inspired by natural product scaffolds. Total synthesis greatly contributes to this arena via the procurement of natural products (and analogs) and the creation of new methodologies to enable future syntheses. The pyrrole-imidazole class of natural products possesses a wealth of bioactivities including antitumor, antibiotic, antihistaminic, antiviral, immunosuppressant and cell-motility inhibition. Additionally, the complex architectures of the polycyclic members of this natural product family instigate the creation of new chemical methods. This proposal encompasses the chemical syntheses of the remaining members of this class, the elaboration of a novel silver(II)- oxidation methodology, and numerous collaborative efforts to extensively investigate the biogenesis and structural intricacies of these molecules. Research will also be conducted on a new class of dimeric marine natural products: the indole-imidazole alkaloids. This class possesses interesting architectural parallels to the pyrrole-imidazole alkaloids, and can serve as a similar platform for the invention of chemical methods and investigation of biological properties. The breadth of research proposed herein is enabled by an extensive collaboration network that includes Pfizer, Professor Donna Blackmond (Imperial College London), Professor Matthias Kvck (Alfred-Wegener-Institut f|r Polar- und Meeresforschung), Professor Philip Williams (University of Hawaii at Manoa), Professor Paul Hergenrother (University of Illinois), and Professor Angel Cipres (Burnham Institute for Medical Research).
Project Narrative This proposal aims at using chemical synthesis to prepare several natural products (and analogs thereof) of the pyrrole-imidazole and indole-imidazole alkaloid families. Innovations in chemistry are anticipated and substantial contributions to medicine may result through several strategic collaborative efforts with a variety of experts in related fields.
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