Structure鈥揂ctivity Relationship Refinement and Further Assessment of 4-Phenylquinazoline-2-carboxamide Translocator Protein Ligands as Antiproliferative Agents in Human Glioblastoma Tumors
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- 作者：Sabrina Castellano ; Sabrina Taliani ; Monica Viviano ; Ciro Milite ; Eleonora Da Pozzo ; Barbara Costa ; Elisabetta Barresi ; Agostino Bruno ; Sandro Cosconati ; Luciana Marinelli ; Giovanni Greco ; Ettore Novellino ; Gianluca Sbardella ; Federico Da Settimo ; Claudia Martini
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：March 27, 2014
- 年：2014
- 卷：57
- 期：6
- 页码：2413-2428
- 全文大小：606K
- 年卷期：v.57,no.6(March 27, 2014)
- ISSN：1520-4804
文摘
Structure鈥揳ctivity 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鈥?, 4鈥?, and 4鈥?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 (螖蠄m) substantiated the intracellular pro-apoptotic mechanism activated by the binding of this class of ligands to TSPO.