Platinum(II) complexes with bioactive carrier ligands having high affinity for the translocator protein.
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.
Margiotta
Nicola
N
Pharmaco-Chemistry Department, Bioinorganic Division, University "A. Moro" of Bari, Via E. Orabona 4, 70125 Bari, Italy.
Denora
Nunzio
N
Ostuni
Rosa
R
Laquintana
Valentino
V
Anderson
Amy
A
Johnson
Steven W
SW
Trapani
Giuseppe
G
Natile
Giovanni
G
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
D000970:Antineoplastic Agents; C463819:Bzrp protein, mouse; D008024:Ligands; D009944:Organoplatinum Compounds; D018079:Receptors, GABA; C499229:TSPO protein, human