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

Zhenhua Wu; Jean Simon Suppo; Sarka Tumova; Jonathan Strope; Fernando Bravo; Melody Moy; Ethan S. Weinstein; Cody J. Peer; William D. Figg; William J. Chain; Antonio M. Echavarren; David J. Beech; John A. Beutler

doi:10.1021/acsmedchemlett.0c00186

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

Zhenhua Wu, Jean Simon Suppo, Sarka Tumova, Jonathan Strope, Fernando Bravo, Melody Moy, Ethan S. Weinstein, Cody J. Peer, William D. Figg, William J. Chain, Antonio M. Echavarren, David J. Beech, John A. Beutler^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English
Pages (from-to)	1711-1716
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	9
DOIs	https://doi.org/10.1021/acsmedchemlett.0c00186
State	Published - 10 Sep 2020
Externally published	Yes

Keywords

Englerin
TRPC4
ion channels
kidney cancer
mice

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10.1021/acsmedchemlett.0c00186

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Wu, Z., Suppo, J. S., Tumova, S., Strope, J., Bravo, F., Moy, M., Weinstein, E. S., Peer, C. J., Figg, W. D., Chain, W. J., Echavarren, A. M., Beech, D. J., & Beutler, J. A. (2020). Bridgehead Modifications of Englerin A Reduce TRPC4 Activity and Intravenous Toxicity but not Cell Growth Inhibition. ACS Medicinal Chemistry Letters, 11(9), 1711-1716. https://doi.org/10.1021/acsmedchemlett.0c00186

@article{2b0abc8a11c549f3a2dba47bd169c471,

title = "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.",

keywords = "Englerin, TRPC4, ion channels, kidney cancer, mice",

author = "Zhenhua Wu and Suppo, {Jean Simon} and Sarka Tumova and Jonathan Strope and Fernando Bravo and Melody Moy and Weinstein, {Ethan S.} and Peer, {Cody J.} and Figg, {William D.} and Chain, {William J.} and Echavarren, {Antonio M.} and Beech, {David J.} and Beutler, {John A.}",

note = "Funding Information: Thanks are extended to Jason Evans for the COMPARE analysis. This research was supported in part by the Intramural Program of the Center for Cancer Research, National Cancer Institute, under 1Z1A BC011470-07 (J.A.B.) and 1ZIABC010547-17 (W.D.F.). Support for the Echavarren lab was from MINECO/FEDER, UE (CTQ2016-75960-), and AGAUR (2017 SGR 1257). S.T. was funded by a Medical Research Council Confidence in Concept Award to D.J.B. W.J.C. gratefully acknowledges financial support from the University of Delaware and the National Institutes of Health (R01CA163287 and P20GM104316). Spectral data at UD was acquired on instruments obtained with the assistance of NSF and NIH funding (NSF CHE0421224, CHE0840401, CHE1229234, CHE1048367; NIH S10 OD016267-01, S10 RR026962-01, P20GM104316, P30GM110758). Publisher Copyright: Copyright {\textcopyright} 2020 American Chemical Society.",

year = "2020",

month = sep,

day = "10",

doi = "10.1021/acsmedchemlett.0c00186",

language = "English",

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Wu, Z, Suppo, JS, Tumova, S, Strope, J, Bravo, F, Moy, M, Weinstein, ES, Peer, CJ, Figg, WD, Chain, WJ, Echavarren, AM, Beech, DJ & Beutler, JA 2020, 'Bridgehead Modifications of Englerin A Reduce TRPC4 Activity and Intravenous Toxicity but not Cell Growth Inhibition', ACS Medicinal Chemistry Letters, vol. 11, no. 9, pp. 1711-1716. https://doi.org/10.1021/acsmedchemlett.0c00186

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T1 - Bridgehead Modifications of Englerin A Reduce TRPC4 Activity and Intravenous Toxicity but not Cell Growth Inhibition

AU - Wu, Zhenhua

AU - Suppo, Jean Simon

AU - Tumova, Sarka

AU - Strope, Jonathan

AU - Bravo, Fernando

AU - Moy, Melody

AU - Weinstein, Ethan S.

AU - Peer, Cody J.

AU - Figg, William D.

AU - Chain, William J.

AU - Echavarren, Antonio M.

AU - Beech, David J.

AU - Beutler, John A.

N1 - Funding Information: Thanks are extended to Jason Evans for the COMPARE analysis. This research was supported in part by the Intramural Program of the Center for Cancer Research, National Cancer Institute, under 1Z1A BC011470-07 (J.A.B.) and 1ZIABC010547-17 (W.D.F.). Support for the Echavarren lab was from MINECO/FEDER, UE (CTQ2016-75960-), and AGAUR (2017 SGR 1257). S.T. was funded by a Medical Research Council Confidence in Concept Award to D.J.B. W.J.C. gratefully acknowledges financial support from the University of Delaware and the National Institutes of Health (R01CA163287 and P20GM104316). Spectral data at UD was acquired on instruments obtained with the assistance of NSF and NIH funding (NSF CHE0421224, CHE0840401, CHE1229234, CHE1048367; NIH S10 OD016267-01, S10 RR026962-01, P20GM104316, P30GM110758). Publisher Copyright: Copyright © 2020 American Chemical Society.

PY - 2020/9/10

Y1 - 2020/9/10

N2 - 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.

AB - 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.

KW - Englerin

KW - TRPC4

KW - ion channels

KW - kidney cancer

KW - mice

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JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 9

ER -

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

Abstract

Keywords

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