title: Lead Optimization of 2-Phenylindolylglyoxylyldipeptide Murine Double Minute (MDM)2/Translocator Protein (TSPO) Dual Inhibitors for the Treatment of Gliomas.
abstract: In glioblastoma multiforme (GBM), translocator protein (TSPO) and murine double minute (MDM)2/p53 complex represent two druggable targets. We recently reported the first dual binder 3 possessing a higher anticancer effect in GBM cells than the standards PK11195 1 or Nutlin-3 2 singularly applied. Herein, through a structure-activity relationship study, we developed derivatives 4-10 with improved potencies toward both TSPO and MDM2. As a result, compound 9: (i) reactivated the p53 functionality; (ii) inhibited the viability of two human GBM cells; (iii) impaired the proliferation of glioma cancer stem cells (CSCs), more resistant to chemotherapeutics and responsible of GBM recurrence; (iv) sensitized GBM cells and CSCs to the activity of temozolomide; (v) directed its effects preferentially toward tumor cells with respect to healthy ones. Thus, 9 may represent a promising cytotoxic agent, which is worthy of being further developed for a therapeutic approach against GBM, where the downstream p53 signaling is intact and TSPO is overexpressed.
authors.affiliation: Department of Pharmacy, University of Pisa , Pisa 56126, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.affiliation: Department of Pharmacy, University of Naples Federico II , Via Montesano 49, Naples 80131, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.affiliation: Department of Pharmacy, University of Pisa , Pisa 56126, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barresi
authors.affiliation: DiSTABiF, Seconda Università di Napoli , Caserta 81100, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Di Maro
authors.affiliation: Department of Pharmacy, University of Pisa , Pisa 56126, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Da Pozzo
authors.affiliation: Department of Pharmacy, University of Pisa , Pisa 56126, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Robello
authors.affiliation: Department of Pharmacy, University of Pisa , Pisa 56126, Italy.
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.affiliation: DiSTABiF, Seconda Università di Napoli , Caserta 81100, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.affiliation: Department of Pharmacy, University of Pisa , Pisa 56126, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.affiliation: Department of Pharmacy, University of Naples Federico II , Via Montesano 49, Naples 80131, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.affiliation: Department of Pharmacy, University of Naples Federico II , Via Montesano 49, Naples 80131, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Pharmacy, University of Pisa , Pisa 56126, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.affiliation: Department of Pharmacy, University of Pisa , Pisa 56126, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018079:Receptors, GABA / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C000619423:2-(phenylindol-3-yl)glyoxylyl-phenylalanyl-leucine methyl ester; D000970:Antineoplastic Agents; D004151:Dipeptides; D018079:Receptors, GABA; C499229:TSPO protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2