Synthesis and Anticancer Activity of cis-[Pt(Ⅱ)(trans-1, 2-bis(methylamino)cyclobutane) (3-hydroxyl-1, 1-cyclobutanedicarboxylate)]
高安丽 昆明贵金属研究所, 稀贵金属综合利用新技术国家重点实验室, 昆明 650106  
邱洁 临沧市妇幼保健中心, 临沧 677000  
侯树谦 昆明贵金属研究所, 稀贵金属综合利用新技术国家重点实验室, 昆明 650106  
姜婧 昆明贵金属研究所, 稀贵金属综合利用新技术国家重点实验室, 昆明 650106 
楼丽广 中国科学院上海药物研究所肿瘤药理研究室, 上海 201203  
刘伟平 昆明贵金属研究所, 稀贵金属综合利用新技术国家重点实验室, 昆明 650106 
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)],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。
关键词: 铂类配合物  合成  表征  抗癌活性
基金项目: 国家自然科学基金(NO.21661018)和云南省科技计划项目(No.2014BC010,2016BC021)资助。
Abstract: 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.
Keywords: platinum complexes  synthesis  characterization  anticancer activity
投稿时间:2016-12-01 修订日期:2017-03-14
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