Synthesis, characterization, and cytotoxicity of dinuclear platinum-bisphosphonate complexes to be used as prodrugs in the local treatment of bone tumours
作者:Nicola Margiotta、Rosa Ostuni、Valentina Gandin、Cristina Marzano、Sara Piccinonna、Giovanni Natile
DOI:10.1039/b919721d
日期:——
For over 30 years cisplatin has been one of the most active antitumour agents in clinical use, nevertheless research for overcoming cisplatin toxicity and resistance or for improving its efficacy has never ceased. In this context we have recently proposed dinuclear Pt complexes with bridging geminal bisphosphonates as novel Pt-prodrugs with potential activity at the bone surface after embedment in inorganic matrices and implantation at the tumour site. In the present paper we report the synthesis and full characterization of four new platinum complexes having a dinuclear structure with a bisphosphonate (2-ammonium-1-hydroxyethane-1,1-diyl-bisphosphonate or 3-ammonium-1-hydroxypropane-1,1-diyl-bisphosphonate, AHBP-H and PAM-H, respectively) acting as a bridging ligand between two platinum moieties (cis-[Pt(NH3)2]2+, directly related to cisplatin, and [Pt(cis-1,4-DACH)]2+, known to be able to overcome the cisplatin resistance). Moreover, as a preliminary investigation, the in vitro cytotoxicity of the new complexes has been evaluated on a panel of 13 human tumour cell lines including cisplatin- and multidrug-resistant sublines.
超过30年来,顺铂一直是临床使用中活性最强的抗肿瘤药物之一。然而,关于克服顺铂毒性和耐药性或提高其疗效的研究从未停止。在此背景下,我们最近提出了桥接双膦酸盐的双核铂络合物,作为新型铂前药,具有在无机基质嵌入后及在肿瘤部位植入时在骨表面潜在活性的可能性。在本论文中,我们报告了四种新的铂络合物的合成及其完全表征,这些络合物具有双核结构,双膦酸盐(2-铵基-1-羟基乙烷-1,1-双膦酸盐或3-铵基-1-羟基丙烷-1,1-双膦酸盐,分别为AHBP-H和PAM-H)充当连接两种铂部分的桥接配体(顺-[Pt(NH3)2]2+,与顺铂直接相关,以及[Pt(cis-1,4-DACH)]2+,已知能够克服顺铂耐药性)。此外,作为初步研究,新络合物的体外细胞毒性已在包括顺铂和多药耐药亚系在内的13个人肿瘤细胞株上进行评估。