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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Yang, Jiong
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University of California Santa Barbara
Schools of Arts and Sciences
Santa Barbara
United States
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Reid, Bradley T; Mailyan, Artur K; Zakarian, Armen (2018) Total Synthesis of (+)-Guadinomic Acid via Hydroxyl-Directed Guanidylation. J Org Chem 83:9492-9496
Mailyan, Artur K; Chen, Joanna L; Li, Weiwei et al. (2018) Short Total Synthesis of [15N5]-Cylindrospermopsins from 15NH4Cl Enables Precise Quantification of Freshwater Cyanobacterial Contamination. J Am Chem Soc 140:6027-6032
Yu, Kai; Lu, Ping; Jackson, Jeffrey J et al. (2017) Lithium Enolates in the Enantioselective Construction of Tetrasubstituted Carbon Centers with Chiral Lithium Amides as Noncovalent Stereodirecting Auxiliaries. J Am Chem Soc 139:527-533
Molgó, Jordi; Marchot, Pascale; Aráoz, Rómulo et al. (2017) Cyclic imine toxins from dinoflagellates: a growing family of potent antagonists of the nicotinic acetylcholine receptors. J Neurochem 142 Suppl 2:41-51
Cano, Rafael; Zakarian, Armen; McGlacken, Gerard P (2017) Direct Asymmetric Alkylation of Ketones: Still Unconquered. Angew Chem Int Ed Engl 56:9278-9290
Martinez, Juliana A; Xiao, Qing; Zakarian, Armen et al. (2017) Antidiabetic Disruptors of the Glucokinase-Glucokinase Regulatory Protein Complex Reorganize a Coulombic Interface. Biochemistry 56:3150-3157
Burns, Alexander S; Wagner, Alexander J; Fulton, Jennifer L et al. (2017) Determination of the Absolute Configuration of ?-Chiral Primary Alcohols Using the Competing Enantioselective Conversion Method. Org Lett 19:2953-2956
Lacharity, Jacob J; Fournier, Jeremy; Lu, Ping et al. (2017) Total Synthesis of Unsymmetrically Oxidized Nuphar Thioalkaloids via Copper-Catalyzed Thiolane Assembly. J Am Chem Soc 139:13272-13275
Ma, Yun; Mack, Kyle A; Liang, Jun et al. (2016) Mixed Aggregates of the Dilithiated Koga Tetraamine: NMR Spectroscopic and Computational Studies. Angew Chem Int Ed Engl 55:10093-7
Alvarado, Joseph; Fournier, Jeremy; Zakarian, Armen (2016) Synthesis of Functionalized Dihydrobenzofurans by Direct Aryl C-O Bond Formation under Mild Conditions. Angew Chem Int Ed Engl 55:11625-11628

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