Synthesis and antitumor evaluation of cis-(1,2-diaminoethane)dichloroplatinum(II) complexes linked to 5- and 6-methyleneuracil and -uridine analogues

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-diamine-dichloroplatinum (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-l,2-diamine}dichloroplatinum (II) (Gb),[N-(uridine-5-yl-methyl)ethane-l,2-diamine]dichloroplatinum (If) (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 la 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-[(aminoethyl)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.