cis-(trans-1,2-双(氨甲基)环丁烷)(3-羟基-1,1-环丁烷二羧酸根)合铂(Ⅱ)的合成和抗癌活性

摘要

通过对洛铂和卡铂的结构进行重组和优化,合成了一种新型洛铂衍生物c is-[trans-1,2-双(氨甲基)环丁烷)(3-羟基-1,1-环丁烷二羧酸根)合铂(Ⅱ)],采用元素分析、红外光谱、质谱和核磁共振表征了其化学结构,并考察了此化合物的水溶性和稳定性.应用标准SRB法测试了目标化合物对人肺癌细胞株(NCI-H460、A549)、人乳腺癌细胞株(DU4475)、人白血病细胞株(Sup-B15)生长的抑制活性,评价了它对人肺癌细胞NCI-H460裸鼠移植瘤的治疗作用.结果表明:目标化合物水溶性好、稳定,对多种癌细胞的生长有明显的抑制活性,IC50均小于10 μmol· L-1.更重要的是,其体内对人肺癌细胞NCI-H460裸鼠移植瘤的治疗效果明显,与洛铂相当.%A new water-soluble and more water-stable analogue of lobaplatin,cis-[Pt(Ⅱ)(trans-1,2-bis(methylamino) cyclobutane)(3-hydroxyl-1,1-cyclobutanedicarboxylate)],was designed,with an attempt to improve the water-stability of lobaplatin while retaining its excellent anticancer profile,via the structural recombination and optimization of lobaplatin and carboplatin.The analogue was synthesized by the direct reaction between cis-[Pt(Ⅱ)(trans-1,2-bis (methylamino))I2] as an intermediate and the silver salt of 3-hydroxyl-1,1-cyclobutanedicarboxylic acid,and characterized by elemental analysis,ESI-MS,IR and 1H,13C NMR.The anticancer activity was evaluated by both in vitro cyotoxicity against four human cancer cell lines and in vivo antitumor efficiency in human lung carcinoma NCI-H460 xenografts in nude mice.The biological tests revealed that the analogue produced significant inhibition of the tumor growth,resulting in an inhibitory rate of 54％ at the dose of 60 mg·kg-1 and more importantly,it had in vivo anticancer activity comparable to that of lobaplatin.