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

    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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