Pharmaco-Chemistry Department, Bioinorganic Division, University "A. Moro" of Bari, Via E. Orabona 4, 70125 Bari, Italy.
J Med Chem. 2010 Jul 22;53(14):5144-54. doi: 10.1021/jm100429r.
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.
外周苯二氮䓬受体（PBRs，也称为 TSPO）在许多肿瘤类型中过度表达，TSPO 的过度表达程度与肿瘤的恶性程度相关。出于这个原因，TSPO 结合配体已被广泛探索作为受体介导的药物递送的载体。在本文中，我们选择了一种对 TSPO 具有纳摩尔亲和力的配体，[2-(4-氯苯基)-8-氨基咪唑并[1,2-a]吡啶-3-基]-N,N-二正丙基乙酰胺（3），用于制备结构类似顺铂的铂加合物，顺-[PtCl2(NH3)2(picoline)]（AMD0473，6），这是一种目前正在进行临床研究的铂类似物。评估受体结合和对人胶质瘤细胞和大鼠胶质瘤细胞的细胞毒性的体外研究表明，新化合物顺-[PtX2(NH3){[2-(4-氯苯基)-8-氨基咪唑并[1,2-a]吡啶-3-基]-N,N-二正丙基乙酰胺}]（X = I，4；X = Cl，5）对 TSPO 保持高亲和力和选择性（纳摩尔浓度），并且与顺铂一样具有细胞毒性。此外，它们似乎对敏感和顺铂耐药的 A2780 细胞同样有效。与顺铂类似，这些化合物诱导细胞凋亡，但在神经胶质瘤细胞中的积累增加了 10 到 100 倍。
