Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that regulates the growth, survival, and migration of several cell types. S1P is a ligand for five transmembranes G-protein –coupled receptors, S1P1-5, and for several intracellular targets such as histone deacetylases 1 and 2. Cellular biosynthesis of S1P occurs through phosphorylation of Sphingosine (Sph) catalyzed by Sphingosine Kinases. Sphingosine, a bioeffector molecule is biosynthesized by Ceramidase activity on central lipid Ceramide. Sphingosine kinases exist in two isoforms SphK1 and SphK2 encoded by unlinked genes. Pharmacologically, ceramide and sphingosine are associated with growth arrest and apoptosis. On Contrary, S1P is associated with pro-survival roles. Sphingosine kinases exist in two isoforms, SphK1 and SphK2, encoded by unlinked genes. SphKs & S1P have been implicated in a variety of disease states including cancer, sickle cell disease, atherosclerosis, asthma, diabetes, and fibrosis, among others. Although SphK1 and SphK2 share a high degree of homology, they differ in size, localization, distribution, and intracellular roles. SphKs are the sole source of S1P. Based on Structure-Activity Relationship (SAR) studies, our lab synthesized 5-alkylated phthalimide analogs to mimic the structural features of SphK inhibitor SLM6031434. The synthesized analogs included alkyl, cyclic alkyl, phenyl & substituted phenyl group in the 5th position of the phthalimide core. After preliminary screening, the analogs exhibited little inhibition and selectivity. Our new efforts involve replacing the phthalimide core with isoindoline. The design of these analogs constitutes a polar head group, linker, and lipophilic tail mimic. Towards synthesis of these analogs, palladium-catalyzed C-coupling chemistry is utilized for the addition of lipophilic functionalities to the linker. Mitsunobu or nucleophilic displacement strategies are employed towards the incorporation of the polar head group. A representative scheme is shown below. Successful analogs invitro screening for SphKs selectivity and potency will be presented.

Strategy towards the design, synthesis & structure: Activity relationship of γ-lactam linker-based sphingosine kinase inhibitors

ACS Fall 2021

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