Design, synthesis, and biological evaluation of hydroquinone derivatives as novel inhibitors of the sarco/endoplasmic reticulum calcium ATPase.
Analogues of the compound 2,5-di-tert-butylhydroquinone (BHQ) are capable of inhibiting the enzyme sarco/endoplasmic reticulum ATPase (SERCA) in the low micromolar and submicromolar concentration ranges. Not only are SERCA inhibitors valuable research tools, but they also have potential medicinal value as agents against prostate cancer. This study describes the synthesis of 13 compounds representing several classes of BHQ analogues, such as hydroquinones with a single aromatic substituent, symmetrically and unsymmetrically disubstituted hydroquinones, and hydroquinones with omega-amino acid tethers attached to their hydroxyl groups. Structure-activity relationships were established by measuring the inhibitory potencies of all synthesized compounds in bioassays. The assays were complemented by computational ligand docking for an analysis of the relevant ligand/receptor interactions.
Paula
Stefan
S
Department of Chemistry, Natural Sciences Center, Northern Kentucky University, Highland Heights, KY 41099-1905, United States. paulas1@nku.edu
Abell
Josh
J
Deye
Joel
J
Elam
Christopher
C
Lape
Michael
M
Purnell
Justin
J
Ratliff
Robert
R
Sebastian
Kelly
K
Zultowsky
Jodie
J
Kempton
Robert J
RJ
D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D003198:Computer Simulation; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D006873:Hydroquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D006873:Hydroquinones; D000252:Calcium-Transporting ATPases
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