In Silico Studies, Synthesis and Biological Evaluation of 4,5-Dehydrospisulosine Butyrate Ceramides as Potential Sphingosine Kinase I Inhibitors

Abstract

In the present work, synthesis of 4,5-dehydrospiulosine and its chain analogues (1-3) as potential Sphingosine Kinase I inhibitors has been achieved via the diasteroselective Grignard reaction, stereoselective cross metathesis reaction followed by N-acylation with p-nitrophenyl butyrate to give the corresponding butyrate ceramides (4-6). All compounds were obtained in high yield and purity followed by molecular docking simulation studies using AutoDock which indicated their varying binding affinities with Sphingosine Kinase 1 protein was done. Further, the biological evaluation studies, as potential anti-prostate cancer agents by inhibiting the sphingosine kinase 1 protien of all synthesized compounds (1-6) on PC-3 cell lines by SRB method was done. Compound N-((2S,3S,E)-3 hydroxyheptadec-4-en-2-yl) butyramide (4) exhibited remarkable cytotoxicity with an IC50 value of 6.06 µM.