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

The orally bioavailable 1-deoxy-sphingosine analog, Enigmol, has demonstrated anticancer activity in numerous <i>in vivo</i> settings. However, as no Enigmol analog with enhanced potency <i>in vitro</i> has been identified, a new strategy to improve efficacy <i>in vivo</i> 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 <i>in vitro</i>, but achieved higher plasma and tissue levels than Enigmol <i>in vivo</i>. 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