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Structure–Activity Relationship Refinement and Further Assessment of 4-phenylquinazoline-2-carboxamide Translocator Protein (TSPO) Ligands as Antiproliferative Agents in Human Glioblastoma Tumors
- Publication Year :
- 2014
-
Abstract
- Structure-activity relationships (SARs) within the 4-phenylquinazoline-2- carboxamide series of translocator protein (TSPO) ligands have been explored further by the synthesis and TSPO binding affinity evaluation of N-benzyl-N-ethyl/methyl derivatives variously decorated at the 6-, 2′-, 4′-, and 4″-positions. Most of the compounds showed high affinity with Ki values in the nanomolar/subnanomolar range. A pharmacophore model was developed and employed to better address SAR data presented by the new TSPO ligands. A subset of the new compounds (5, 8, 12, and 19) were tested for their ability to inhibit the viability of human glioblastoma cell line U343. The observed antiproliferative effect was demonstrated to be specific for compound 19, endowed with the best combination of binding affinity and efficacy. Furthermore, the ability of 19 to induce mitochondrial membrane dissipation (Δψm) substantiated the intracellular pro-apoptotic mechanism activated by the binding of this class of ligands to TSPO. © 2014 American Chemical Society.
- Subjects :
- Models, Molecular
18 KDA
Molecular Conformation
Carboxamide
Plasma protein binding
translocator protein (TSPO), steroidogenesis, 4-phenylquinazoline-2-carboxamide derivatives, structure-activity relationships, pharmacophore model
Kidney
COLORECTAL-CANCER
Drug Discovery
PERIPHERAL BENZODIAZEPINE-RECEPTOR
Inner mitochondrial membrane
Membrane Potential, Mitochondrial
biology
Chemistry
DERIVATIVES
Brain Neoplasms
glioblastoma tumor
BINDING-SITES
BIOLOGICAL EVALUATION
TSPO EXPRESSION
BREAST-CANCER
CELLS
APOPTOSIS
Biochemistry
Molecular Medicine
Pharmacophore
Intracellular
Protein Binding
medicine.drug_class
Cell Survival
Antineoplastic Agents
Structure-Activity Relationship
antiproliferative agents
Receptors, GABA
Cell Line, Tumor
medicine
Translocator protein
TRANSLOCATOR PROTEIN
Structure–activity relationship
Animals
Humans
Binding site
Dose-Response Relationship, Drug
Computational Biology
Rats
Kinetics
biology.protein
Glioblastoma
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....dd2cabb7f486fdb1e427d03ad8eacfd0