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

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

  • ACS Med Chem Lett. 2020 Aug 3;11(9):1711-1716. doi: 10.1021/acsmedchemlett.0c00186.
Zhenhua Wu 1,  Jean-Simon Suppo 2,  Sarka Tumova 3,  Jonathan Strope 4,  Fernando Bravo 2,  Melody Moy 1,  Ethan S Weinstein 1,  Cody J Peer 4,  William D Figg 4,  William J Chain 1,  Antonio M Echavarren 2,  David J Beech 3,  John A Beutler 5
Affiliations

Affiliations

  • 1 Department of Chemistry & Biochemistry, University of Delaware, 163 The Green, Newark, Delaware 19716, United States.
  • 2 Institute of Chemical Research of Catalonia (ICIQ), 43007 Tarragona, Spain.
  • 3 School of Medicine, University of Leeds, Leeds LS2 9JT, U.K.
  • 4 Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, United States.
  • 5 Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.
PMID: 32944138 DOI: 10.1021/acsmedchemlett.0c00186
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.

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