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Discovery of a Fluorinated Enigmol Analog with Enhanced in Vivo Pharmacokinetic and Anti-Tumor Properties

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Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Med. Chem. Lett. 2016, 7, 5, 537-542
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    Discovery of a Fluorinated Enigmol Analog with Enhanced in Vivo Pharmacokinetic and Anti-Tumor Properties
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    † Department of Chemistry, Emory University, 1521 Dickey Drive NE, Atlanta, Georgia 30322, United States
    ‡ Emory University School of Medicine, Department of Urology, 1365 Clifton Road NE, Atlanta, Georgia 30322, United States
    § Emory University School of Medicine, Department of Pathology and Laboratory Medicine, 1364 Clifton Road NE, Atlanta, Georgia 30322, United States
    ∥ Emory Institute for Drug Development (EIDD), 954 Gatewood Road NE, Atlanta, Georgia 30329, United States
    ⊥ Yerkes National Primate Research Center, Biomarkers Core Laboratory, Emory University, 954 Gatewood Road NE, Atlanta, Georgia 30329, United States
    # Winship Cancer Institute, Emory University, 1365 Clifton Road NE, Atlanta, Georgia 30322, United States
    ∇ Atlanta Veterans Affairs Medical Center, Atlanta, Georgia 30033, United States
    *E-mail: [email protected]
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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2016, 7, 5, 537–542
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    https://doi.org/10.1021/acsmedchemlett.6b00113
    Published March 21, 2016
    Copyright © 2016 American Chemical Society
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    Abstract

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    The orally bioavailable 1-deoxy-sphingosine analog, Enigmol, has demonstrated anticancer activity in numerous in vivo settings. However, as no Enigmol analog with enhanced potency in vitro has been identified, a new strategy to improve efficacy in vivo by increasing tumor uptake was adopted. Herein, synthesis and biological evaluation of two novel fluorinated Enigmol analogs, CF3-Enigmol and CF2-Enigmol, are reported. Each analog was equipotent to Enigmol in vitro, but achieved higher plasma and tissue levels than Enigmol in vivo. Although plasma and tissue exposures were anticipated to trend with fluorine content, CF2-Enigmol absorbed into tissue at strikingly higher concentrations than CF3-Enigmol. Using mouse xenograft models of prostate cancer, we also show that CF3-Enigmol underperformed Enigmol-mediated inhibition of tumor growth and elicited systemic toxicity. By contrast, CF2-Enigmol was not systemically toxic and demonstrated significantly enhanced antitumor activity as compared to Enigmol.

    Copyright © 2016 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.6b00113.

    • Synthetic procedures utilized for the preparation of CF3-Enigmol and CF2-Enigmol, concentration–response curves of Enigmol, CF2-Enigmol, and CF3-Enigmol, and experimental methods and raw data from pharmacokinetic and xenograft experiments. (PDF)

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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2016, 7, 5, 537–542
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsmedchemlett.6b00113
    Published March 21, 2016
    Copyright © 2016 American Chemical Society
    Request reuse permissions

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