Total synthesis of two novel subpicomolar sarco/endoplasmatic reticulum Ca2+-ATPase inhibitors designed by an analysis of the binding site of thapsigargin.
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.
Søhoel
Helmer
H
Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
Liljefors
Tommy
T
Ley
Steven V
SV
Oliver
Steven F
SF
Antonello
Alessandra
A
Smith
Martin D
MD
Olsen
Carl Erik
CE
Isaacs
John T
JT
Christensen
S Brøgger
SB
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*
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