Natural product synthesis through the lens of informatics Ryan Shenvi Scripps Research, USA Natural products (NPs) often populate areas of chemical space that are remote from commercial compounds and thus challenging to access, study and modify. Therefore, our group develops new chemistry to accelerateaccess to nodes in NP space. These syntheses can be leveraged to assign mechanism of action, remove structural liabilities and perturb target selectivity. Recently, we developed new cross-coupling methods toaccess two alkaloids from Galbulimima . These syntheses led to the identification of potent ligands for the κ- and μ-opioid receptors, and optimization of their pharmacology. 1,2 This work extended our research in naturally occurring psychotropics, 3 including salvinorin A (SalA). 4 Here, we identified two scaffold mutations that were predicted to stabilize the SalA scaffold, maintain target affinity, maintain gross physicochemical properties yet increase our ability to diversify and optimize the natural product, 4 recently delivering analogs with increased potency, selectivity, stability and functional bias for G protein signaling. 5 An identical workflow led to 5-methyl-picrotoxinin, a more complex analog of picrotoxinin (PXN)that simplified synthetic access, stabilized the scaffold and allowed diversification to probe selectivity among ligand-gated ion channels (LGICs). 6 References 1. Woo, S.; Shenvi, R. A. "Synthesis and target annotation of GB18" Nature, 2022 , 606 , 917–921. 2. Landwehr, E. M.; Baker, M. A.; Oguma, T.; Burdge, H. E.; Kawajiri, T.; Shenvi, R. A. “Concise syntheses of GB22, GB13 and himgaline by cross-coupling and complete reduction” Science , 2022 , 375 , 1270–1274 . 3. Shevick, S. L.; Freeman, S.; Tong, G.; Russo, R. J.; Bohn, L. M.; Shenvi, R. A. “Asymmetric syntheses of (+)- and (–)-collybolide enable re-evaluation of kappa -opioid receptor agonism” ACS Cent. Sci. 2022 , 8 , 948–954. 4. Roach, J. J.; Sasano, Y.; Schmid, C. L.; Zaidi, S.; Katrich, V.; Stevens, R. C.; Bohn, L. M.; Shenvi, R. A. “Dynamic Strategic Bond Analysis Yields a 10-step Synthesis of 20-nor-SalA, a Potent Κ-OR Agonist” ACS Central Science, 2017 , 3 , 1329–1336 5. Hill, S. J.†, Dao, N.;† Dang, V. Q.; Stahl, E.; Bohn, L. M.; Shenvi R. A. "A route to potent, selective and biased salvinorin chemical space" 2023 Chemrxiv-2023-h7h38 6. Tong, G.; Griffin, S.; Sader, A.; Crowell, A. B.; Beavers, K.; Watson, J.; Buchan, Z.; Chen, S.; Shenvi, R. A. “C5 Methylation Confers Accessibility, Stability and Selectivity to Picrotoxinin” 2022, Chemrxiv-2022-0l4nt
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