以磷酸二氢根为轴向配体的铂(Ⅳ)前药的设计、合成和抗癌活性测试

Design, Syntheses and Anticancer Activities of Platinum(Ⅳ) Prodrugs with Dihydrogen Phosphate as an Axial Ligand

以顺铂和奥沙利铂为原药,合成了2种以磷酸二氢根为配体的铂(Ⅳ)前药(代号:CPL-1501和CPL-1504),采用元素分析、红外光谱和核磁共振表征了其化学结构,通过循环伏安法测定了它们的还原电位。应用标准MTT法,测试了这2种铂(Ⅳ)前药对多种人癌细胞株生长的抑制活性。结果表明:CPL-1501作为顺铂的前药,水溶性好(10 mg·mL^(-1))、稳定,E_p值分别为0.16和-0.52V,为不可逆的双电子还原过程,在癌细胞缺氧的微环境中易被还原激活。CPL-1501对多种癌细胞株的生长均有明显的抑制作用,抗癌活性与顺铂相当、明显高于水溶性Pt(Ⅱ)抗癌药物-卡铂。CPL-1504虽然水溶性(50 mg·mL^(-1))高于奥沙利铂,却未表现出明显的抗癌活性,这可能与其较低的还原电位(E_p值分别为-0.51和-0.76 V)有关。

CPL-1501 and CPL-1504,two platinum(Ⅳ)prodrugs with dihydrogen phosphate as one axial ligand,were synthesized from cisplatin and oxaliplatin,respectively,as the starting material,and characterized by elemental analysis,IR as well as 13C and 31P NMR.Their reduction potential was measured via the cyclic voltammetry.The standard MTT was used to evaluate anticancer activity of the two prodrugs against several human cancer cell lines.CPL-1501 has a good water-solubility(10 mg·mL^-1)and water-stability.With the favorable Ep values,it can be readily reduced to an active prototype cisplatin in the oxygen-deprived micro-environment of cancer cells.The biological tests reveal that CPL-1501 is able to inhibit the growth of cancer cells and its anticancer activity is comparable to that of cisplatin but much greater than that of carboplatin,whereas CPL-1504 does not show significant activity,probably due to its lower Ep values.