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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-03640448/
• 关键词: Modification of cis-Platin; Non-toxic Pt complexes; Oligoamine segment; Water-soluble polyamides; Bi-functionalization of oligoamines; Polyether polyamines; Condensation polymerization; Anti-cancer drug; 高分子・オリゴマ-医薬; ポリエ-テルポリアミン

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

旨在降低顺铂的严重毒性，尝试对CIS-PT复合物进行化学修饰。我们修改的主要方法是使用含寡乙基的聚合物或寡聚物配体以及其顺式水溶性PT（II）CL_2复合物的合成。首先，三甲基甲胺（N4-胺）和甲状腺己胺（N6-胺）受到甲醛和乙醛保护，以终止双实施这些多功能胺。建立了保护方法以获得高纯度的双二唑啶基衍生物。将受保护的终末双官能化的N6-胺与二磷脂或二氯二氯化物反应，从而产生水溶性线性（无交联）聚酰胺。这种用于凝结聚合的方法可用于使用己二胺二氨酸的第二氨基氨酸来适用于三​​元共聚。这是聚酰胺的亲水性和疏水性……可以清楚地调节更多。脱保护给出了高度水溶性的聚酰胺，并为物理应用提供了适当程度的聚合。类似地，使用乙醛保护的N4-胺与二氧化胺一起多化反应，并表明可以将寡乙基苯基的片段掺入线性多胺链中。尽管聚合物本身是不溶的，但在形成沙拉时，可以轻松地将其转换为水溶性聚合物。同样，可以在第二次二胺的情况下制备特里聚合物。活化的氨基酸与甲醛保护的N6-胺反应，以产生携带双末端氨基酸亚物质的N6胺的二胺。从水溶性的脱旋转聚或寡酰胺中，水溶性铂（II）配合物具有Cisconfiguration，它们以合理的收率制备。发现PT复合物是无毒的，甚至显示出胃组癌症小鼠寿命的延伸效应的指示。因此，应继续作为具有寡胺片段的配体的顺式-PT（II）复合物进行进一步的系统化学修饰，作为一种非常重要的方法。较少的

项目成果

T.Fujiki: "Block Modification of Nylon-66 with Oligoethylenimine Segments and Their Platinum Complexes" IUPAC International Symposium on New Polymers. 53-54 (1991)

T.Fujiki：“用寡乙烯亚胺片段及其铂配合物对尼龙 66 进行嵌段改性”IUPAC 国际新型聚合物研讨会。

藤木 徹: "鎖状オリゴエチレンイミン単位を高分子主鎖に導入する方法とポリマー白金錯体形成" Polymer Preprints,Jpn.40. 2576-2578 (1991)

Toru Fujiki：“将线性低聚乙烯亚胺单元引入聚合物主链和形成聚合物铂络合物的方法”Polymer Preprints，Jpn. 40. 2576-2578 (1991)

T.Fujiki: "Introduction of Linear Oligoethylene Units in the Polymer Backbone and cis-Pt Complexes" Polymer Preprints,Jpn.(English Edition). 40. E-854-E-854 (1991)

T.Fujiki：“聚合物主链和顺铂复合物中线性低聚乙烯单元的介绍”Polymer Preprints，Jpn.（英文版）。

宮西 浩伸: "ペンタエチレンヘキサミンとコハク酸クロリドによる水溶性ポリアミドの合成と白金錯体形成" 日本化学会第63春季年会. (1993)

Hironobu Miyanishi：“使用五乙烯六胺和琥珀酰氯合成水溶性聚酰胺和铂络合物形成”，第 63 届日本化学会春季年会（1993 年）。

T.Fujiki: "Introduction of Linear Oligoethylene Units in the Polymer Backbone and cisーPt Complexes" Polymer Preprints,Japan(English Edition). 40. E-854-E-854 (1991)

T.Fujiki：“聚合物主链和顺铂复合物中线性寡乙烯单元的介绍”聚合物预印本，日本（英文版）40. E-854-E-854（1991）。