Design, synthesis and pharmacological characterization of analogs of 2-aminoethyl diphenylborinate (2-APB), a known store-operated calcium channel blocker, for inhibition of TRPV6-mediated calcium transport

Hofer, Alexandre; Kovacs, Gergely; Zappatini, Anna; Leuenberger, Michele; Hediger, Matthias A.; Lochner, Martin (2013). Design, synthesis and pharmacological characterization of analogs of 2-aminoethyl diphenylborinate (2-APB), a known store-operated calcium channel blocker, for inhibition of TRPV6-mediated calcium transport. Bioorganic & medicinal chemistry, 21(11), pp. 3202-3213. Elsevier 10.1016/j.bmc.2013.03.037

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2-Aminoethyl diphenylborinate (2-APB) is a known modulator of the IP3 receptor, the calcium ATPase SERCA, the calcium release-activated calcium channel Orai and TRP channels. More recently, it was shown that 2-APB is an efficient inhibitor of the epithelial calcium channel TRPV6 which is overexpressed in prostate cancer. We have conducted a structure-activity relationship study of 2-APB congeners to understand their inhibitory mode of action on TRPV6. Whereas modifying the aminoethyl moiety did not significantly change TRPV6 inhibition, substitution of the phenyl rings of 2-APB did. Our data show that the diaryl borinate moiety is required for biological activity and that the substitution pattern of the aryl rings can influence TRPV6 versus SOCE inhibition. We have also discovered that 2-APB is hydrolyzed and transesterified within minutes in solution.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Kovacs, Gergely; Leuenberger, Michele; Hediger, Matthias and Lochner, Martin

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
500 Science > 540 Chemistry

ISSN:

0968-0896

Publisher:

Elsevier

Funders:

[UNSPECIFIED] Swiss National Science Foundation
[UNSPECIFIED] NCCR TransCure

Language:

English

Submitter:

Martin Lochner

Date Deposited:

31 Mar 2014 11:43

Last Modified:

24 Aug 2015 15:14

Publisher DOI:

10.1016/j.bmc.2013.03.037

PubMed ID:

23602525

BORIS DOI:

10.7892/boris.44484

URI:

https://boris.unibe.ch/id/eprint/44484

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