title: Synthesis and bioactivity of sphingosine kinase inhibitors and their novel aspirinyl conjugated analogs.
abstract: Sphingosine kinase (SphK) is a lipid kinase with oncogenic activity, and SphK inhibitors (SKIs) are known for their anti-cancer activity. Here, we report highly efficient syntheses of SKIs and their aspirinyl (Asp) analogs. Both SKIs and their Asp analogs were highly cytotoxic towards multiple human cancer cell lines; in several cases the Asp analogs were up to three times more effective. Furthermore, they were equally potent inhibitors of SphK. The pharmacokinetic study indicated that SKI-I-Asp cleaved efficiently to form SKI-I and the half-life of SKI-I was increased from approximately 7 h in SKI-I to approximately 10 h in SKI-I-Asp injected mice, thereby prolonging its effect. In summary, the Asp-conjugated SKIs seem to be promising prodrugs of SKIs where delivery in vivo remains a problem.
authors.affiliation: Department of Pharmacology, Penn State Hershey College of Medicine, Penn State Hershey Cancer Institute, CH72, 500 University Drive, Hershey, PA 17033, USA. aks14@psu.edu
authors.forename: Arun K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Ugir Hossain
authors.initials: UH
authors.lastname: Sk
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Gimbor
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Hengst
authors.forename: Xujun
authors.initials: X
authors.lastname: Wang
authors.forename: Jong
authors.initials: J
authors.lastname: Yun
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
mesh_terms: D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D001241:Aspirin; D004791:Enzyme Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D011355:Prodrugs; D000099157:Sphingosine Kinase