(476) Total synthesis and anticancer potential of sphingoid natural products targeting mitochondrial membrane potential.

Objective : Ceramide is an apoptotic sphingolipid. The strategies aimed at increasing cellular ceramide induced apoptosis in several cancer cells. Jaspine B and Spisulosine have structural resemblances to ceramide and have the potential to interfere with the function of ceramide-derived membranes. Our objective is to develop a robust total synthesis of spisulosine and its analogs, gram scale synthesis of jaspine B and its analogs. Perform in vitro and in vivo studies for anticancer potential.

Methods: Enatioselective total syntheses of jaspine B and Spisulosine were performed utilizing a chiral pool strategy starting from L-aminoacids. Strategy involved enantioselective methodologies, chelation-controlled reduction, C-C bond formation, and protection-deprotection strategies. It is a robust synthetic scheme to afford gram quantities for studying anticancer potential involving ceramide flux. The biophysical characterization of spisulosine, jaspine B, resulted in micelle formation.

Results: Developed a robust enantioselective total syntheses of spisulosine, jaspine B. Both natural products exhibited anticancer potential in in vitro studies involving NCI-60 cell lines. jaspine B and its liposomal formulation exhibited anticancer potential in a synovial sarcoma mouse model.

Conclusions: Ceramide mimics have the potential to interfere with sphingolipid biochemistry and perturb ceramide flux. Spisulosine, jaspine B, and their analogs exhibited anticancer potential as evidenced by in vitro and in vivo studies. jaspine B treated synovial cells showed cytochrome c release suggesting mitochondrial membrane depolarization. The asymmetric polarity of spisulosine, and jaspine B resulted in the development of liposomal formulation.