水溶性铂类抗肿瘤药的合成与体外抗肿瘤活性评价

Preparation of Highly Water-soluble Platinum Antitumor Drugs and Evaluation of Antitumor Efficacy on Tumor Cell Lines

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。

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 Ag2 SO4 to obtain intermediateⅠ.Using disodium 2-amino-alkyl malonate or N-substituted amino alkyl malonate as the intermediateⅡ,the two intermediates reacted at 1∶1 molar ratio to obtain the target compoundⅢin 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.Ⅲgwas 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 compoundⅢgis 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.