In Silico Studies, Synthesis and Biological Evaluation of 4,5-Dehydrospisulosine Butyrate Ceramides as Potential Anticancer Agents

In the present work, synthesis of 4,5-dehydrospiulosine and its chain analogues (7-9) as potential Sphingosine Kinase I inhibitors has been achieved via the diastereoselective Grignard reaction and stereoselective cross-metathesis reaction followed by N-acylation with p-nitrophenyl butyrate to give the corresponding butyrate ceramides (10-12). All compounds were obtained in high yield and purity. Molecular docking simulation studies were performed for the synthesized compounds that indicated their varying binding affinities with the Sphingosine Kinase 1 (SPHK1) protein. Following, molecular dynamics simulations were performed for the SPHK1-compound (10) complex that indicated compound (10) to be structurally and energetically stable within the binding pocket of SPHK1. Further, the biological evaluation studies, as potential anti-prostate cancer agents and as anti-colon cancer agents by inhibiting the SPHK1 of all synthesized compounds (7-12) on PC-3 cell lines and HCT-116 cell lines by the SRB method were done. Compound N-((2S,3S,E)-3-hydroxyheptadec-4-en-2-yl) butyramide (10) exhibited remarkable cytotoxicity with an IC₅₀ value of 0.018 μM against PC-3 cell lines and 0.076 μM against HCT-116 cell lines, whereas compound (11) showed best cytotoxicity with an IC₅₀ value of 0.062 μM against HCT-116 cell lines.