title: Total synthesis of two novel subpicomolar sarco/endoplasmatic reticulum Ca2+-ATPase inhibitors designed by an analysis of the binding site of thapsigargin.
abstract: Analysis of molecular interaction fields based on the published crystal structure of thapsigargin bound to the sarco/endoplasmatic reticulum Ca(2+)-ATPase and analysis of the volume and shape of the ligand binding site and of the SERCA-thapsigargin interactions have enabled design of two new compounds inhibiting SERCA in the subpicomolar range. The two inhibitors were synthesized using (S)-carvone as starting material and found to be 3 and 10 times more potent than thapsigargin.
authors.affiliation: Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Helmer
authors.initials: H
authors.lastname: Søhoel
authors.forename: Tommy
authors.initials: T
authors.lastname: Liljefors
authors.forename: Steven V
authors.initials: SV
authors.lastname: Ley
authors.forename: Steven F
authors.initials: SF
authors.lastname: Oliver
authors.forename: Alessandra
authors.initials: A
authors.lastname: Antonello
authors.forename: Martin D
authors.initials: MD
authors.lastname: Smith
authors.forename: Carl Erik
authors.initials: CE
authors.lastname: Olsen
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
authors.forename: S Brøgger
authors.initials: SB
authors.lastname: Christensen
mesh_terms: D052176:Azulenes / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D013237:Stereoisomerism; D019284:Thapsigargin / Q000737:chemistry*
chemical_list: C506292:2-methylbut-2-enoic acid 4-butyryloxy-6-ethoxy-3,3a-dihydroxy-3,6,9-trimethyl-2-oxododecahydroazuleno(4,5-b)furan-8-yl ester; C506293:2-methylbut-2-enoic acid 6-acetoxy-4-butyryloxy-3,3a-dihydroxy-3,6,9-trimethyl-2-oxododecahydroazuleno(4,5-b)furan-8-yl ester; D052176:Azulenes; D004791:Enzyme Inhibitors; D008024:Ligands; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases