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 v...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2009-09, Vol.17 (18), p.6613-6619
Main Authors: Paula, Stefan, Abell, Josh, Deye, Joel, Elam, Christopher, Lape, Michael, Purnell, Justin, Ratliff, Robert, Sebastian, Kelly, Zultowsky, Jodie, Kempton, Robert J.
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Calcium pump
Calcium-Transporting ATPases - antagonists & inhibitors
Calcium-Transporting ATPases - chemistry
Calcium-Transporting ATPases - metabolism
Computer Simulation
Endoplasmic Reticulum - enzymology
Enzyme inhibition
General aspects
gold
Hydroquinones - chemical synthesis
Hydroquinones - chemistry
Hydroquinones - pharmacology
Ligand docking
Medical sciences
Medicinal chemistry
Models, Molecular
Organic synthesis
Pharmacology. Drug treatments
Prostate cancer
Protein Binding
Protein Conformation
SERCA
Structure-Activity Relationship
Urinary system
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Summary: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 ω-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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2009.07.075