Adamantyl Arotinoids That Inhibit IκB Kinase α and IκB Kinase β

Authors

  • Dr. Paula Lorenzo,

    1. Departamento de Química Orgánica e Instituto de Investigaciones Biomédicas de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo (Spain)
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  • Dr. María A. Ortiz,

    1. Torrey Pines Institute for Molecular Studies, 3550 General Stomics Ct., San Diego, CA 92121 (USA)
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  • Prof. Dr. Rosana Álvarez,

    Corresponding author
    1. Departamento de Química Orgánica e Instituto de Investigaciones Biomédicas de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo (Spain)
    • Departamento de Química Orgánica e Instituto de Investigaciones Biomédicas de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo (Spain)
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  • Dr.  F. Javier Piedrafita,

    Corresponding author
    1. Torrey Pines Institute for Molecular Studies, 3550 General Stomics Ct., San Diego, CA 92121 (USA)
    • Torrey Pines Institute for Molecular Studies, 3550 General Stomics Ct., San Diego, CA 92121 (USA)
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  • Prof. Dr. Ángel R. de Lera

    Corresponding author
    1. Departamento de Química Orgánica e Instituto de Investigaciones Biomédicas de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo (Spain)
    • Departamento de Química Orgánica e Instituto de Investigaciones Biomédicas de Vigo (IBIV), Universidade de Vigo, Lagoas-Marcosende, 36310 Vigo (Spain)
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Abstract

A series of analogues of the adamantyl arotinoid (AdAr) chalcone MX781 with halogenated benzyloxy substituents at C2′ and heterocyclic derivatives replacing the chalcone group were found to inhibit IκBα kinase α (IKKα) and IκBα kinase β (IKKβ) activities. The growth inhibitory capacity of some analogues against Jurkat T cells as well as prostate carcinoma (PC-3) and chronic myelogenous leukemia (K562) cells, which contain elevated basal IKK activity, correlates with the induction of apoptosis and increased inhibition of recombinant IKKα and IKKβ in vitro, pointing toward inhibition of IKK/NFκB signaling as the most likely target of the anticancer activities of these AdArs. While the chalcone functional group present in many dietary compounds has been shown to mediate interactions with IKKβ via Michael addition with cysteine residues, AdArs containing a five-membered heterocyclic ring (isoxazoles and pyrazoles) in place of the chalcone of the parent system are potent inhibitors of IKKs as well, which suggests that other mechanisms for inhibition exist that do not depend on the presence of a reactive α,β-unsaturated ketone.

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