Title

Development of Flavonoid-Based Inverse Agonists of the Key Signaling Receptor US28 of Human Cytomegalovirus

Authors

Authors

A. Kralj; M. T. Nguyen; N. Tschammer; N. Ocampo; Q. Gesiotto; M. R. Heinrich;O. Phanstiel

Comments

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Abbreviated Journal Title

J. Med. Chem.

Keywords

PROTEIN-COUPLED-RECEPTOR; CHEMOKINE RECEPTOR; INHIBITORY-ACTIVITY; ANTIVIRAL ACTIVITY; IDENTIFICATION; CHALCONES; 5-LIPOXYGENASE; ANTAGONISTS; EXPRESSION; MODULATORS; Chemistry, Medicinal

Abstract

A series of 31 chalcone- and flavonoid-based derivatives were synthesized in good overall yields and screened for their inverse agonist activity on the US28 receptor of human cytomegalovirus (HCMV). With one exception (e.g., 2-(5-bromo-2-methoxyphenyl)-3-hydroxy-4H-chromen-4-one), halogen-substituted flavonoids were, typically more potent inverse agonists than their related hydro derivatives. While toxicity could be used to partially explain the inverse agonist activity of some members of the series, 5-(benzyloxy)-2-(5-bromo-2-methoxyphenyl)-4H-chromen-4-one (11b) acted on the US28 receptor as a nontoxic, inverse agonist. The full inverse agonism (efficacy, -89%) and potency (EC50 = 3.5 mu M) observed with flavonoid lib is especially important as it provides both a new tool to study US28 signaling and a potential platform for the future development of HCMV-targeting drugs.

Journal Title

Journal of Medicinal Chemistry

Volume

56

Issue/Number

12

Publication Date

1-1-2013

Document Type

Article

Language

English

First Page

5019

Last Page

5032

WOS Identifier

WOS:000321237100016

ISSN

0022-2623

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