1,1-环戊二羧酸环己二胺合铂(Ⅱ)的合成与抗肿瘤活性研究

Synthesis and antitumor activity of(1,1-cyclopentane-dicarboxylato)(cyclohexane-1,2-diamine)platinum(Ⅱ)

目的合成一种新的抗肿瘤铂络合物(QLNC-801)——1,1-环戊二羧酸环己二胺合铂(Ⅱ)。方法以左旋-反式-1,2-环己二胺和四氯亚铂酸钾为原料,水为溶剂,在室温下反应合成左旋-反式-1,2-环己二胺-顺式二氯合铂(2);以四丁基溴化铵为相转移催化剂,丙二酸二乙酯与1,4-二溴丁烷在碱性条件下反应生成1,1-环戊二羧酸二乙酯,再经水解生成1,1-环戊二羧酸(3),3在弱碱性条件下与硝酸银反应生成1,1-环戊二羧酸银(4);2和4在水中,于40～50℃反应生成目标化合物QLNC-801。以卡铂和奥沙利铂为阳性对照药,对目标化合物进行体外细胞毒活性和体内抗肿瘤活性评价。结果与结论目标化合物的合成总收率为36%,其结构经元素分析、质谱和核磁共振氢谱等确证;体外对人胃癌SGC7901、人结肠癌HT29和人肺癌A549细胞株的IC50值分别为7.8、31、25μmol.L-1;体内实验以13、26、52 mg.kg-1剂量给药后对小鼠Lewis肺癌移植瘤的抑瘤率分别为52.7%、69.5%和86.7%,对小鼠结肠癌C38的抑瘤率为44.3%、70.6%和75.7%,体外细胞毒活性和体内抗肿瘤活性与奥沙利铂相当,毒副作用相对较低。目标化合物的合成工艺稳定、操作简便。

Much effort has been dedicated to discover new platinum-based anticancer agents and most structural modifications were based on changing one or both of the ligand types coordinated to platinum. Based on the stucture of carboplatin or oxaliplatin, QLNC-801, chemical name cis-（ 1,1-cyclopentanedicarboxylato ） （1R,2R-cyclohexane-1,2-diamine） platinum（ II ）, was designed and synthesized as a potential cancer drug candidate. The title compound was prepared through four-step synthesis, starting with diethyl malonate, which reacted with 1,4-dibromobutane using tetrabutyl ammonium bromide as phase transfer catalyst and followed by the hydrolysis with KOH to form cyclopentane-1,1-dicarboxylic acid（3）. The acid 3 was converted to the corresponding silver salt（4） as a key intermediate. The target compound was obtained by substitution reaction between the salt 4 and cis- （ 1 R, 2R-cylohexane-1,2-diamine） dichloroplatinum （Ⅱ ） （ 2 ）, which was obtained from K2PtC14. QLNC-801was prepared in a total yield 36% from diethyl malonate with a high purity 99.89 %. Its structure was characterized by element analysis, MS and 1^H-NMR. The compound QLNC-801 showed significiant inhibition activity to gastric SCJ^901, colon HT29 and lung A549 cancer cells with ICs0 of 7.8,31 ,and 25μmol·L^-1respectively in vitro,and also possessed great antitumor potent to Lewis lung and C38 colon cancer homograft in mouse,which indicated that QLNC-801 could be functionly equivalent as but lower toxic than oxaliplatin.