Bioassay-guided fractionation of cells often uncovers small molecules that bind macromolecular targets in new and unexpected ways. Exploration of the chemical reactivity and target selectivity of these metabolites has laid the chemical foundation for the development of new biological tools and therapeutics. The molecular architecture of secondary metabolites is challenging and different than the chemical space explored by most medicinal chemistry campaigns: there is recognized `natural product-like' space and we lack the tools to explore it with the same depth as `drug-like' space. Our lab has developed new tools to more easily access natural products, and has focused our efforts on secondary metabolite families that appear to covalently modify their targets as the basis for their phenotypic effects. Our chemical syntheses are deliberately concise and easily-scaled to enable subsequent investigation into reactivity and biological activity. The current application significantly advances these efforts, provides compelling preliminary data as a foundation for the proposed work, and delves into new areas of chemistry. In this proposal, two areas of research are described: 1. the identification and investigation of covalently-reactive pharmacophores associated with the asmarine alkaloids, Nuphar dimers and isocyanoterpenes; and 2. the development of cross-coupling technology to access `natural product-space' more generally. In the first area, we disclose a preliminary cellular target of the unusual N-hydroxydiazepine purine (HAP) pharmacophore of the asmarine alkaloids and address unsolved problems posed by this motif. As part of a theme that runs throughout our work, we show how the aims of chemistry and biology intersect in the study of covalently reactive secondary metabolites. We also investigate the sulfur-electrophilicity of the Nuphar dimers, a property recently demonstrated by our lab to operate in organic solvent and cellular environments. We propose solutions to the challenging stereochemical problems posed by the monohydroxy dimers and show how chemistry developed in our lab can generate a combinatorial library of sulfur electrophiles. In a third area, we investigate the challenging architecture and reactivity of the isocyanoterpenes, which we recently demonstrated can kill Plasmodia by an alternative mechanism to the heme detoxification pathway often suggested. We also propose a novel caging strategy to render the isonitriles systemically-viable. In part two, we investigate a bimetallic catalytic cycle capable of solving long-standing problems in chemical synthesis. The proposed methodology is supported by proof-of-principle examples and provides chemists the reaction vehicles necessary to `escape from flatland.'
Natural product synthesis, chemical reactivity and biology intersect at the study of covalent inhibitors. This proposal describes the invention of new chemical reactions to access poorly understood, covalently reactive natural products that target heretofore unidentified biological targets. These studies lay the foundation for the development of new tools to study human disease and new therapeutics to alleviate it.
| Green, Samantha A; Vásquez-Céspedes, Suhelen; Shenvi, Ryan A (2018) Iron-Nickel Dual-Catalysis: A New Engine for Olefin Functionalization and the Formation of Quaternary Centers. J Am Chem Soc 140:11317-11324 |
| Witkin, Jeffrey M; Shenvi, Ryan A; Li, Xia et al. (2018) Pharmacological characterization of the neurotrophic sesquiterpene jiadifenolide reveals a non-convulsant signature and potential for progression in neurodegenerative disease studies. Biochem Pharmacol 155:61-70 |
| Roach, Jeremy J; Shenvi, Ryan A (2018) A review of salvinorin analogs and their kappa-opioid receptor activity. Bioorg Med Chem Lett 28:1436-1445 |
| Matos, Jeishla L M; Vásquez-Céspedes, Suhelen; Gu, Jieyu et al. (2018) Branch-Selective Addition of Unactivated Olefins into Imines and Aldehydes. J Am Chem Soc : |
| Hirasawa, Shun; Cho, Min; Brust, Tarsis F et al. (2018) O6C-20-nor-salvinorin A is a stable and potent KOR agonist. Bioorg Med Chem Lett 28:2770-2772 |
| Green, Samantha A; Crossley, Steven W M; Matos, Jeishla L M et al. (2018) The High Chemofidelity of Metal-Catalyzed Hydrogen Atom Transfer. Acc Chem Res 51:2628-2640 |
| Shevick, Sophia L; Obradors, Carla; Shenvi, Ryan A (2018) Mechanistic Interrogation of Co/Ni-Dual Catalyzed Hydroarylation. J Am Chem Soc 140:12056-12068 |
| Lambrecht, Michael J; Kelly, Jeffery W; Shenvi, Ryan A (2018) Mechanism of Action of the Cytotoxic Asmarine Alkaloids. ACS Chem Biol 13:1299-1306 |
| Roach, Jeremy J; Sasano, Yusuke; Schmid, Cullen L et al. (2017) Dynamic Strategic Bond Analysis Yields a Ten-Step Synthesis of 20-nor-Salvinorin A, a Potent ?-OR Agonist. ACS Cent Sci 3:1329-1336 |
