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Bridgehead Modifications of Englerin A Reduce TRPC4 Activity and Intravenous Toxicity but not Cell Growth Inhibition.

ABSTRACT: Modifications at the bridgehead position of englerin A were made to explore the effects of variation at this site on the molecule for biological activity, as judged by the NCI 60 screen, in which englerin A is highly potent and selective for renal cancer cells. Replacement of the isopropyl group by other, larger substituents yielded compounds which displayed excellent selectivity and potency comparable to the natural product. Selected compounds were also evaluated for their effect on the ion channel TRPC4 as well as for intravenous toxicity in mice, and these had lower potency in both assays compared to englerin A.

SUBMITTER: Wu Z

PROVIDER: S-EPMC7488277 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Bridgehead Modifications of Englerin A Reduce TRPC4 Activity and Intravenous Toxicity but not Cell Growth Inhibition.

Wu Zhenhua Z Suppo Jean-Simon JS Tumova Sarka S Strope Jonathan J Bravo Fernando F Moy Melody M Weinstein Ethan S ES Peer Cody J CJ Figg William D WD Chain William J WJ Echavarren Antonio M AM Beech David J DJ Beutler John A JA

ACS medicinal chemistry letters 20200803 9

Modifications at the bridgehead position of englerin A were made to explore the effects of variation at this site on the molecule for biological activity, as judged by the NCI 60 screen, in which englerin A is highly potent and selective for renal cancer cells. Replacement of the isopropyl group by other, larger substituents yielded compounds which displayed excellent selectivity and potency comparable to the natural product. Selected compounds were also evaluated for their effect on the ion cha ...[more]

PMID: 32944138

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(-)-Englerin-A Has Analgesic and Anti-Inflammatory Effects Independent of TRPC4 and 5.

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| S-EPMC5512125 | biostudies-literature

Englerin A, a selective inhibitor of renal cancer cell growth, from Phyllanthus engleri.

Project description:An extract from Phyllanthus engleri was identified in a bioinformatic analysis of NCI 60-cell natural product extract screening data that selectively inhibited the growth of renal cancer cell lines. Bioassay-guided fractionation yielded two new guaiane sesquiterpenes, englerins A (1) and B (2). Englerin A showed 1000-fold selectivity against six of eight renal cancer cell lines with GI(50) values ranging from 1-87 nM. The structures of 1 and 2 and their relative stereochemistry were established by spectroscopic methods.

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Physical activity and checkpoint inhibition: association with toxicity and survival.

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| S-EPMC10995850 | biostudies-literature

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