- Design, synthesis and analysis of novel sphingosine kinase-1 inhibitors to improve oral bioavailability
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The sphingomyelin pathway is important in cell regulation and determining cellular fate. Inhibition of sphingosine kinase isoform 1 (SK1) within this pathway, leads to a buildup of sphingosine and ceramide, two molecules directly linked to cell apoptosis, while decreasing the intracellular concentration of sphingosine-1-phosphate (S1P), a molecule linked to cellular proliferation. Recently, an inhibitor capable of inhibiting SK1 in vitro was identified, but also shown to be ineffective in vivo. A set of compounds designed to assess the impact of synthetic modifications to the hydroxynaphthalene ring region of the template inhibitor with SK1 to obtain a compound with increased efficacy in vivo. Of these fifteen compounds, 4A was shown to have an IC50 = 6.55 μM with improved solubility and in vivo potential.
- Butler, Kendarius J.,Castro, Angel A.,Dwyer, Tiffany S.,Hardwick, Louise M.,Iacino, Melody C.,Manore, Sara G.,Mays, Kevin M.,McGlade, Caylie A.,Hair, Lisa N.,Parker, Erin W.,Smith, Mikala R.,Turnow, Morgan T.,Wilson, Matthew R.,Woodson, Stephanie R.,Cotham, William E.,Walla, Michael D.,Hurlbert, Jason C.,Christian Grattan
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supporting information
(2021/08/24)
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- Synthesis and bioactivity of sphingosine kinase inhibitors and their novel aspirinyl conjugated analogs
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Sphingosine kinase (SphK) is a lipid kinase with oncogenic activity, and SphK inhibitors (SKIs) are known for their anti-cancer activity. Here, we report highly efficient syntheses of SKIs and their aspirinyl (Asp) analogs. Both SKIs and their Asp analogs were highly cytotoxic towards multiple human cancer cell lines; in several cases the Asp analogs were up to three times more effective. Furthermore, they were equally potent inhibitors of SphK. The pharmacokinetic study indicated that SKI-I-Asp cleaved efficiently to form SKI-I and the half-life of SKI-I was increased from ~7 h in SKI-I to ~10 h in SKI-I-Asp injected mice, thereby prolonging its effect. In summary, the Asp-conjugated SKIs seem to be promising prodrugs of SKIs where delivery in vivo remains a problem.
- Sharma, Arun K.,Sk, Ugir Hossain,Gimbor, Melissa A.,Hengst, Jeremy A.,Wang, Xujun,Yun, Jong,Amin, Shantu
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experimental part
p. 4149 - 4156
(2010/10/02)
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- SPHINGOSINE KINASE INHIBITORS
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The invention relates to compounds, compositions and methods for inhibiting sphingosine kinase and for treating or preventing hyperproliferative disease, autoimmune disease, inflammatory disease, or allergy.
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