Design, synthesis and analysis of novel sphingosine kinase-1 inhibitors to improve oral bioavailability. (15th October 2021)

• Record Type: Journal Article
• Authors: 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, T.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 50(2021)
• Publication Date: 2021-10-15
• Subjects: Sphingosine kinase -- Kinase inhibition -- Bioorganic synthesis -- Microwave synthesis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128329
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.