目的 设计并合成高水溶性铂类抗肿瘤化合物,通过体外抗肿瘤细胞毒性研究证明其抗肿瘤药效。方法 以氯亚铂酸钾为起始原料制备络合氨(胺)基二碘合铂,并与Ag2SO4反应得中间体Ⅰ,中间体Ⅱ为2-氨基或N-取代氨基烷基丙二酸二钠,两者按1∶1在酸性条件下反应得到目标化合物Ⅲ。结果 成功合成了一类新型结构的铂类化合物,其水溶性明显优于现有的三代铂类化合物。新化合物对多种肿瘤细胞株显示了抗肿瘤药效,作用强于卡铂;其中Ⅲg在一些肿瘤细胞株的作用与顺铂相当;而且一些化合物对顺铂耐药株有效。结论 目标化合物Ⅲg作为进入临床研究的高水溶性铂类抗肿瘤候选药,体外实验证明其具有良好的抗肿瘤药效,小鼠体内半数致死量实验显示毒性小于顺铂和卡铂。
Abstract
OBJECTIVE To design and synthesize a new kind of highly water-soluble platinum antitumor compounds, and then evaluate their cytotoxicity in order to confirm their antitumor efficacy. METHODS Diamide-diiodide platinum was firstly synthesized from potassium chloroplatinate, which was then reacted with Ag2SO4 to obtain intermediate Ⅰ. Using disodium 2-amino-alkyl malonate or N-substituted amino alkyl malonate as the intermediate Ⅱ, the two intermediates reacted at 1∶1 molar ratio to obtain the target compound Ⅲ in the presence of acid. RESULTS A new class of platinum compounds were synthesized, which had much better water solubility than that of the existing three-generation platinum compounds. Their antitumor efficacy was confirmed against a variety of tumor cell lines which was higher than that of carboplatin. Ⅲg was similar to cisplatin in antitumor efficacy on some tumor cell lines. Some target compounds were effective against cisplatin-resistant cell lines. CONCLUSION Currently in the clinical trial, the target compound Ⅲg is a new platinum-base antitumor candidate, which exhibits good water solubility and antitumor efficacy in vitro, and the LD50 based on mice shows its lower toxicity than that of cisplatin and carboplatin in vivo.
关键词
Pt(0506)101 /
顺铂 /
卡铂 /
奥沙利铂 /
药物合成 /
溶解度 /
体外抗肿瘤药效 /
半数致死量
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Key words
Pt(0506)101 /
cisplatin /
carboplatin /
oxaliplatin /
drug synthesis /
solubility /
in vitro antitumor efficacy /
LD50
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中图分类号：
R944
R95
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参考文献
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脚注
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基金
科技部“十一五”科技重大专项课题资助(2009ZX09103-114);北京市首都市民健康项目资助(111102058511008);北京G20工程医药产业创新研发资助(Z18100002218021)
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