Natural products as starting materials for development of second-generation SERCA inhibitors targeted towards prostate cancer cells.
An analysis of the binding of the 8-O-N-tert-butoxycarbonyl-12-aminododecanoyl derivative of 8-O-debutanoylthapsigargin to the target molecule, the SERCA pump, has revealed the importance of the length and flexibility of the side chain attached to O-8. Based on the analysis a series of analogues to the 2-unsubstituted analogue trilobolide has been constructed and shown to be equipotent with thapsigargin as SERCA inhibitors. Only the 12-Boc-aminododecaonoyl derivative, however, was found to be apoptotic.
Søhoel
Helmer
H
Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Jensen
Anne-Marie Lund
AM
Møller
Jesper V
JV
Nissen
Poul
P
Denmeade
Samuel R
SR
Isaacs
John T
JT
Olsen
Carl Erik
CE
Christensen
S Brøgger
SB
D000818:Animals; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008958:Models, Molecular; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D011817:Rabbits; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases