C5 methylation confers accessibility, stability and selectivity to picrotoxinin

Guanghu Tong, Samantha Griffin, Avery Sader, Anna B. Crowell, Ken Beavers, Jerry Watson, Zachary Buchan, Shuming Chen () and Ryan A. Shenvi ()
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Guanghu Tong: Scripps Research
Samantha Griffin: Corteva Agriscience
Avery Sader: Corteva Agriscience
Anna B. Crowell: Department of Chemistry and Biochemistry, Oberlin College
Ken Beavers: Corteva Agriscience
Jerry Watson: Corteva Agriscience
Zachary Buchan: Corteva Agriscience
Shuming Chen: Department of Chemistry and Biochemistry, Oberlin College
Ryan A. Shenvi: Scripps Research

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract Minor changes to complex structures can exert major influences on synthesis strategy and functional properties. Here we explore two parallel series of picrotoxinin (PXN, 1) analogs and identify leads with selectivity between mammalian and insect ion channels. These are the first SAR studies of PXN despite its >100-year history and are made possible by advances in total synthesis. We observe a remarkable stabilizing effect of a C5 methyl, which completely blocks C15 alcoholysis via destabilization of an intermediate twist-boat conformer; suppression of this secondary hydrolysis pathway increases half-life in plasma. C5 methylation also decreases potency against vertebrate ion channels (γ-Aminobutyric acid type A (GABAA) receptors) but maintains or increases antagonism of homologous invertebrate GABA-gated chloride channels (resistance to dieldrin (RDL) receptors). Optimal 5MePXN analogs appear to change the PXN binding pose within GABAARs by disruption of a hydrogen bond network. These discoveries were made possible by the lower synthetic burden of 5MePXN (2) and were illuminated by the parallel analog series, which allowed characterization of the role of the synthetically simplifying C5 methyl in channel selectivity. These are the first SAR studies to identify changes to PXN that increase the GABAA-RDL selectivity index.

Date: 2023
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DOI: 10.1038/s41467-023-44030-3

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