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Synthesis and biological evaluation of carbocyclic analogues of pachastrissamine.

ABSTRACT: 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.

SUBMITTER: Kwon Y

PROVIDER: S-EPMC4344604 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Synthesis and biological evaluation of carbocyclic analogues of pachastrissamine.

Kwon Yongseok Y Song Jayoung J Bae Hoon H Kim Woo-Jung WJ Lee Joo-Youn JY Han Geun-Hee GH Lee Sang Kook SK Kim Sanghee S

Marine drugs 20150203 2

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 o ...[more]

PMID: 25654428

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