Synthesis and Biological Evaluation of Carbocyclic Analogues of Pachastrissamine

摘要

A series of carbocyclic analogues of naturally-occurring marine sphingolipid pachastrissamine were prepared and biologically evaluated. The analogues were efficiently synthesized via a tandem enyne/diene-ene metathesis reaction as a key step. We found that the analogue >4b exhibited comparable cytotoxicity and more potent inhibitory activity against sphingosine kinases, compared to pachastrissamine. Molecular modeling studies were conducted to provide more detailed insight into the binding mode of >4b in sphingosine kinase. In our docking model, pachastrissamine and >4b were able to effectively bind to the binding pocket of sphingosine kinase 1 as co-crystalized sphingosine. However, >4b showed a hydrophobic interaction with Phe192, which suggests that it contributes to its increased inhibitory activity against sphingosine kinase 1.