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

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• 作者：Eric J. Miller ; Suzanne G. Mays ; Mark T. Baillie ; Randy B. Howard ; Deborah G. Culver ; Manohar Saindane ; Sarah T. Pruett ; Jason J. Holt ; David S. Menaldino ; Taylor J. Evers ; G. Prabhakar Reddy ; Richard F. Arrendale ; Michael G. Natchus ; John A. Petros ; Dennis C. Liotta
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：May 12, 2016
• 年：2016
• 卷：7
• 期：5
• 页码：537-542
• 全文大小：456K
• 年卷期：0
• ISSN：1948-5875

文摘

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.