ATTEMPTS ON DECREASE IN TOXICITY OF THE CIS-PLATIN BY USING POLYMER MODIFICATION THROUGH DERIVATIZATION OF OLIGOAMINES

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Aimed on decreasing the severe toxicity of cis-Platin, chemical modifications of cis-Pt complex were attempted. The principal approach of our modification is the use of oligoethylenimine-containing polymeric or oligomeric ligands and syntheses of their cis-type water-soluble Pt(II)Cl_2 complexes. First of all, triethylentetramine (N4-amine) and pentaethylenhexamine (N6-amine) were protected by formaldehyde and acetaldehyde to terminally bi-functionalize these multi-functional amines. The protection methods were established to obtain high-purity bis- and tris-imidazolidyl derivatives. The protected terminally bi-functionalized N6-amine were reacted with adipoyl dichloride or succinoyl dichloride to give water-soluble linear (without crosslinking) polyamides. This procedures for the condensation polymerization were shown to applicable to ternary copolymerization using the second diamines as exemplified with hexamethylene diamine. Thus, hydrophilicity and hydrophobicity of the polyamides … More can be delicately adjusted. Deprotection gave highly water-soluble polyamides with proper degree of polymerization for the physiological applications. Similarly, the acetaldehyde-protected N4- amine was used to polyaddition reaction with a diepoxide, and showed that the oligoethylenimine segments can be incorporated in the linear polyether polyamine chains. Although the polymer itself was water-insoluble, it could be converted readily to water-soluble polymer when its salts were formed. Again, terpolymers can be prepared in the presence of the second diamines. Activated amino acids were reacted with the formaldehyde-protected N6-amine to produce diamides of N6-amine carrying bis-terminally amino acid substituents. From the water- soluble deprotected poly-or oligo-amides, water-soluble platinum(II) complexes with cisconfiguration were prepared in reasonable yields. The Pt complexes were found to be non-toxic, and showed even an indication of extension effect for the lifetime of gastronome-cancered mice. Hence, further systematic chemical modifications of cis-Pt(II) complexes with the ligands having oligoamine segments should be continued as a quite important method. Less