The proposed research program combines three research topics: 1) development and application of methods for efficient asymmetric synthesis using readily available chiral lithium amides as recoverable stereodirecting reagents, 2) total synthesis of complex bioactive molecules, and 3) investigating effects of Cyclic Imine (CI) toxins on various aspects cholinergic transmission by defining their interaction with nicotinic acetylcholine receptors (nAChRs). Total synthesis of complex natural products, in particular CI toxins, has served as a unifying platform for our diverse research interests. Within the first two areas, we will extend the utility of chiral lithium reagents for asymmetric alkylation reactions with momoanionic and dianionic intermediates. This methodology forms the basis of synthesis strategies directed at the enantioselective preparation of duocarmycin alkaloids and a morphine and related alkaloids by a shortest synthetic sequence to date. In the third area, we bring in our expertise in scalable synthesis of CI toxins to produce subtype-selective probes and radiotracers for the study of nAChRs. CI toxins are an emerging group of marine toxins with global distribution and uncertain human health risks. We will carry out comprehensive functional studies on the interaction of CI toxins with selected subtypes of individual nAChRs using electrophysiology, radioligand-displacement, and other functional studies. Using radiolabeled CI toxins produced by total synthesis, we will investigate in vivo biodistribution of these marine toxins and their effect of developmental biology using chick embryo as a model. In this sense, synthetic CI toxins will serve as unique tools that promise to enrich our knowledge of this important class of ionotropic receptors, including, in long term, additional insight into metabolic turnover and broader impact of nAChRs on neurodegenerative disorders.
Complex molecules derived from nature continue to be important lead compounds for drug development in many therapeutic areas, especially in cancer, infectious diseases, and neurological disorders. Our goals are the development of methods and strategies to enable rapid and economical access to such compounds. Another specific goal is to use a novel class of marine toxins as probes to study the biology associated with nicotinic acetylcholine receptors and their effect on cholinergic signal transmission, which is implicated in a number of physiologically important processes.
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