title: 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.
authors: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. chemys@snu.ac.kr.
authors: Yongseok
authors: Y
authors: Kwon
authors: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. poppy27@snu.ac.kr.
authors: Jayoung
authors: J
authors: Song
authors: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. hoonbae1234@gmail.com.
authors: Hoon
authors: H
authors: Bae
authors: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. lwjkim@snu.ac.kr.
authors: Woo-Jung
authors: WJ
authors: Kim
authors: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. leejooyoun@snu.ac.kr.
authors: Joo-Youn
authors: JY
authors: Lee
authors: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. thariel@snu.ac.kr.
authors: Geun-Hee
authors: GH
authors: Han
authors: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. sklee61@snu.ac.kr.
authors: Sang Kook
authors: SK
authors: Lee
authors: College of Pharmacy, Seoul National University, Seoul 151-742, Korea. pennkim@snu.ac.kr.
authors: Sanghee
authors: S
authors: Kim
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D012235:Rhodamines; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000099157:Sphingosine Kinase
chemical_list: D004396:Coloring Agents; D004791:Enzyme Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D012235:Rhodamines; D013110:Sphingosine; D000099157:Sphingosine Kinase; C468594:pachastrissamine; C022027:lissamine rhodamine B
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