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

尝试通过低聚胺衍生化进行聚合物改性来降低顺铂的毒性

基本信息

批准号：
03640448
负责人：
ARAKI Takeo
金额：
$ 1.22万
依托单位：
KYOTO INSTITUTE OF TECHNOLOGY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

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

为了降低顺铂的严重毒性，尝试了顺铂配合物的化学修饰。我们的修饰的主要方法是使用含寡乙烯亚胺的聚合或寡聚配体并合成其顺式水溶性Pt(II)Cl_2配合物。首先，用甲醛和乙醛保护三亚乙基四胺（N4-胺）和五亚乙基六胺（N6-胺），以对这些多官能胺进行末端双官能化。建立了保护方法以获得高纯度的双和三咪唑烷基衍生物。受保护的末端双官能化N6-胺与己二酰二氯或琥珀酰二氯反应，得到水溶性线性（无交联）聚酰胺。该缩聚程序被证明适用于使用第二二胺的三元共聚，如以六亚甲基二胺为例。因此，聚酰胺的亲水性和疏水性可以进行精细调节。脱保护得到高度水溶性的聚酰胺，其具有适合生理应用的适当聚合度。类似地，乙醛保护的N4-胺用于与双环氧化物进行加聚反应，结果表明低聚乙烯亚胺链段可以掺入线性聚醚多胺链中。尽管聚合物本身不溶于水，但当形成盐时，它可以很容易地转化为水溶性聚合物。同样，三元共聚物可以在第二二胺存在下制备。活化的氨基酸与甲醛保护的N6-胺反应生成带有双末端氨基酸取代基的N6-胺的二酰胺。由水溶性脱保护的聚酰胺或低聚酰胺，以合理的产率制备了具有顺式构型的水溶性铂(II)配合物。人们发现铂复合物是无毒的，甚至显示出对患有胃癌的小鼠的寿命有延长作用的迹象。因此，用具有寡胺片段的配体对顺式Pt(II)配合物进行进一步系统的化学修饰应该继续作为一种非常重要的方法。较少的