title: Structure-activity relationship refinement and further assessment of 4-phenylquinazoline-2-carboxamide translocator protein ligands as antiproliferative agents in human glioblastoma tumors.
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 K(i) 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 (Δψ(m)) substantiated the intracellular pro-apoptotic mechanism activated by the binding of this class of ligands to TSPO.
authors.affiliation: Dipartimento di Farmacia, Universitá di Salerno , Via Giovanni Paolo II 132, 84084 Fisciano, Salerno, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Castellano
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.forename: Monica
authors.initials: M
authors.lastname: Viviano
authors.forename: Ciro
authors.initials: C
authors.lastname: Milite
authors.forename: Eleonora
authors.initials: E
authors.lastname: Da Pozzo
authors.forename: Barbara
authors.initials: B
authors.lastname: Costa
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barresi
authors.forename: Agostino
authors.initials: A
authors.lastname: Bruno
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Greco
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sbardella
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019295:Computational Biology; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D018079:Receptors, GABA; C499229:TSPO protein, human