title: Structure-activity relationships and molecular modeling of sphingosine kinase inhibitors.
abstract: The design, synthesis, and evaluation of the potency of new isoform-selective inhibitors of sphingosine kinases 1 and 2 (SK1 and SK2), the enzyme that catalyzes the phosphorylation of d-erythro-sphingosine to produce the key signaling lipid, sphingosine 1-phosphate, are described. Recently, we reported that 1-(4-octylphenethyl)piperidin-4-ol (RB-005) is a selective inhibitor of SK1. Here we report the synthesis of 43 new analogues of RB-005, in which the lipophilic tail, polar headgroup, and linker region were modified to extend the structure-activity relationship profile for this lead compound, which we explain using modeling studies with the recently published crystal structure of SK1. We provide a basis for the key residues targeted by our profiled series and provide further evidence for the ability to discriminate between the two isoforms using pharmacological intervention.
authors.affiliation: Department of Chemistry and Biochemistry, Queens College, The City University of New York , Flushing, New York 11367-1597, United States.
authors.forename: Dong Jae
authors.initials: DJ
authors.lastname: Baek
authors.forename: Neil
authors.initials: N
authors.lastname: MacRitchie
authors.forename: Nahoum G
authors.initials: NG
authors.lastname: Anthony
authors.forename: Simon P
authors.initials: SP
authors.lastname: Mackay
authors.forename: Susan
authors.initials: S
authors.lastname: Pyne
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pyne
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
mesh_terms: D001549:Benzamides / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry; D000099157:Sphingosine Kinase
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D010880:Piperidines; D000644:Quaternary Ammonium Compounds; D014230:Triazoles; D000099157:Sphingosine Kinase; C583391:1-(4-octylphenethyl)piperidin-4-ol; C037689:benzamide