Kim J C, Lee M H, Choi S K
Department of Chemistry, College of Natural Science, Pusan National University, Korea.
Arch Pharm Res. 1998 Aug;21(4):465-9. doi: 10.1007/BF02974644.
The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diaminedichloroplatinum (II) complexes linked to uracil and uridine. Six heretofore unreported uracil and uridine-platinum (II) complexes are; [N-(uracil-5-yl-methyl)ethane-1,2-di-amine]dichloroplatinum (II) (3a), [N-(uracil-6-yl-methyl)ethane-1,2-diamine] dichloroplatinum (II) (3b), ¿[N-(2', 3',5'-tri-O-acetyl)uridine-5-yl-methyl] ethane-1,2-diamine¿dichloroplatinum (II) (6a), ¿[N-(2',3', 5'-tri-O-acetyl) uridine-6-yl-methyl)ethane-1,2-diamine¿dichloroplatinum (II) (6b), [N-(uridine-5-yl-methyl)ethane-1,2-diamine]dichloroplatinum (II) (7a), [N-(uridine-6-yl-methyl)ethane-1,2-diamine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-chloromethyluracil (1a) and 6-chloromethyluracil (1b) which were reacted with ethylenediamine to afford the respective 5-[(2-aminoethyl)amino] methyluracil (2a) and 6-[(2-aminoethyl)amino]methyluracil (2b). The cis-platin complexes 3a and 3b were obtained through the reaction of the respective 2a and 2b with potassium tetrachloroplatinate (II). The heterocyclic nucleic acid bases 1a and 1b were efficiently introduced on the beta-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannic chloride under anhydrous acetonitrile to yield the stereospecific beta-anomeric 5-chloromethyl-2',3',5'-tri-O-acetyluridine (4a) and 6-chloromethyl-2',3',5'-tri-O-acetyluridine (4b), respectively. The nucleosides 4a and 4b were coupled with ethylenediamine to provide the respective 5-[(amino-ethyl)amino]methyl-2',3',5'-tri-O-acetyluridine (5a) and 6-[(aminoethyl)amino] methyl-2',3',5'-tri-O-acetyluridine (5b). The diamino-uridines 5a and 5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes, 6a and 6b, respectively which were deacetylated into the free nucleosides, 7a and 7b by the treatment with CH3ONa. The cytotoxic activities were evaluated against three cell lines (FM-3A, P-388 and J-82) and none of the synthesized compounds showed any significant activity.
为了寻找具有更好治疗特性的铂（II）基化合物，人们设计并合成了一个新的水溶性第三代顺式二氨基二氯铂（II）配合物家族，这些配合物与尿嘧啶和尿苷相连。六个此前未报道的尿嘧啶和尿苷 - 铂（II）配合物分别是：[N -（尿嘧啶 - 5 - 基 - 甲基）乙烷 - 1,2 - 二胺]二氯铂（II）（3a）、[N -（尿嘧啶 - 6 - 基 - 甲基）乙烷 - 1,2 - 二胺]二氯铂（II）（3b）、[N -（2',3',5' - 三 - O - 乙酰基）尿苷 - 5 - 基 - 甲基]乙烷 - 1,2 - 二胺二氯铂（II）（6a）、[N -（2',3',5' - 三 - O - 乙酰基）尿苷 - 6 - 基 - 甲基]乙烷 - 1,2 - 二胺二氯铂（II）（6b）、[N -（尿苷 - 5 - 基 - 甲基）乙烷 - 1,2 - 二胺]二氯铂（II）（7a）、[N -（尿苷 - 6 - 基 - 甲基）乙烷 - 1,2 - 二胺]二氯铂（II）（7b）。这些类似物由关键起始原料5 - 氯甲基尿嘧啶（1a）和6 - 氯甲基尿嘧啶（1b）制备，它们与乙二胺反应分别得到相应的5 - [（2 - 氨基乙基）氨基]甲基尿嘧啶（2a）和6 - [（2 - 氨基乙基）氨基]甲基尿嘧啶（2b）。顺铂配合物3a和3b通过相应的2a和2b与四氯铂酸钾（II）反应得到。杂环核酸碱基1a和1b通过在无水乙腈中与六甲基二硅氮烷、三甲基氯硅烷和氯化锡进行Vorbruggen型核苷偶联反应，有效地引入到β - D - 核糖环上，分别得到立体特异性的β - 异头物5 - 氯甲基 - 2',3',5' - 三 - O - 乙酰基尿苷（4a）和6 - 氯甲基 - 2',3',5' - 三 - O - 乙酰基尿苷（4b）。核苷4a和4b与乙二胺偶联，分别得到相应的5 - [（氨基 - 乙基）氨基]甲基 - 2',3',5' - 三 - O - 乙酰基尿苷（5a）和6 - [（氨基乙基）氨基]甲基 - 2',3',5' - 三 - O - 乙酰基尿苷（5b）。二氨基尿苷5a和5b与四氯铂酸钾（II）反应，分别得到新型核苷配合物6a和6b，通过用CH3ONa处理将其脱乙酰化为游离核苷7a和7b。针对三种细胞系（FM - 3A、P - 388和J - 82）评估了细胞毒性活性，合成的化合物均未显示出任何显著活性。
