title: Platinum(II) complexes with bioactive carrier ligands having high affinity for the translocator protein.
abstract: Peripheral benzodiazepine receptors (PBRs, also named TSPO) are overexpressed in many tumor types, with the grade of TSPO overexpression correlating with the malignancy of the tumor. For this reason, TSPO-binding ligands have been widely explored as carriers for receptor-mediated drug delivery. In this paper we have selected a ligand with nanomolar affinity for TSPO, [2-(4-chlorophenyl)-8-aminoimidazo[1,2-a]pyridin-3-yl]-N,N-di-n-propylacetamide (3), for preparing platinum adducts that are structural analogues to picoplatin, cis-[PtCl(2)(NH(3))(2-picoline)] (AMD0473, 6), a platinum analogue currently in advanced clinical investigation. In vitro studies assessing receptor binding and cytotoxicity against human and rat glioma cells have shown that the new compounds cis-[PtX(2)(NH(3)){[2-(4-chlorophenyl)-8-aminoimidazo[1,2-a]pyridin-3-yl]-N,N-di-n-propylacetamide}] (X = I, 4; X = Cl, 5) keep high affinity and selectivity for TSPO (nanomolar concentration) and are as cytotoxic as cisplatin. Moreover, they appear to be equally active against sensitive and cisplatin-resistant A2780 cells. Similar to cisplatin, these compounds induce apoptosis but show a favorable 10- to 100-fold enhanced accumulation in the glioma cells.
authors.affiliation: Pharmaco-Chemistry Department, Bioinorganic Division, University "A. Moro" of Bari, Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Margiotta
authors.forename: Nunzio
authors.initials: N
authors.lastname: Denora
authors.forename: Rosa
authors.initials: R
authors.lastname: Ostuni
authors.forename: Valentino
authors.initials: V
authors.lastname: Laquintana
authors.forename: Amy
authors.initials: A
authors.lastname: Anderson
authors.forename: Steven W
authors.initials: SW
authors.lastname: Johnson
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Trapani
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018079:Receptors, GABA / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C463819:Bzrp protein, mouse; D008024:Ligands; D009944:Organoplatinum Compounds; D018079:Receptors, GABA; C499229:TSPO protein, human