NEW APPROACHES TO ANTIFOLATE CHEMOTHERAPY

抗叶酸化疗的新方法

基本信息

批准号：
3166859
负责人：
ANDRE ROSOWSKY
金额：
$ 21.81万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-04-01 至 1995-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3166859
关键词：
aminopterin diaminoacid dihydrofolate reductase drug adverse effect drug design /synthesis /production drug metabolism drug resistance drug screening /evaluation enzyme inhibitors folate antagonist homocysteine laboratory mouse methotrexate analog neoplasm /cancer chemotherapy neoplasm /cancer pharmacology pharmacokinetics prodrugs thymidylate synthase

项目摘要

This laboratory has been engaged for some time in the design, synthesis, and biological evaluation of derivatives and structural analogues of methotrexate (MTX), aminopterin (AMT), and other classical antifolates with the aim of producing new agents with improved pharmacological and therapeutic properties or a qualitatively altered spectrum of antitumor activity. The research is part of an ongoing collaborative effort with other groups sharing an interest in innovative approaches to antifolate drug development. An urgent goal of the work is to find compounds with an increased ability to accumulate in tumor cells which are MTX resistant because of a defect in their uptake mechanism for this drug. It is anticipated that cross-resistance between such compounds and MTX will be low, and that there will be the potential for clinical use against tumors with natural or acquired resistance to MTX. Since another important form of MTX resistance is known to involve structural alteration of the target enzyme dihydrofolate reductase (DHFR) resulting in decreased inhibition by MTX, a further goal of the work is to find compounds that will bind more tightly than MTX to this altered enzyme. Finally, since it increasingly recognized that inhibition of folate pathway enzymes other than DHFR offers a major approach to the selective killing of tumor cells, a third goal of the research is to generate compounds that will inhibit these other enzymes, in place of or in addition to DHFR. Specific aims to be pursued include the synthesis and testing of the following compounds of the diaminopteridine type: (1) lipophilic MTX analogues with alkyl groups on the beta or gamma-carbon of glutamate; (2) chain-lengthened lipophilic analogues in which glutamate is replaced by S-carboxyalkyl-L-cysteine or S- carboxyalkyl-L-homocysteine; (3) "stretched" MTX analogues than can inhibit both DHFR an thymidylate synthase; (4) AMT analogues containing a delta- or epsilon-modified ornithine side- chain as potential dual inhibitors of DHFR and folylpolyglutamate synthetase; and (5) MTX analogues in which the gamma-carboxyl is joined to an aminoboronic acid so as to give a product that forms a strong tetrahedral boronate complex to polar active-site residues in DHFR. In addition, we plan to synthesize and test a series of heretofore unstudied class of compounds consisting of 5,8,10-trideaza- and 6-aza-5,8,10-trideazatetrahydroaminopterin analogues and 5,8,10-trideaza- and 6-aza-5,8,10- trideazatetrahydrofolate analogues with H, Me, or Et substitution at position 10.

这个实验室已经从事了一段时间的设计，衍生物和结构的合成和生物学评价甲氨蝶呤 (MTX)、氨基蝶呤 (AMT) 等类似物经典抗叶酸剂，旨在生产具有改善药理和治疗特性或抗肿瘤活性谱发生了质的改变。这研究是与其他机构持续合作的一部分对抗叶酸创新方法有共同兴趣的团体药物开发。这项工作的一个紧迫目标是找到在肿瘤细胞中积累能力增强的化合物由于摄取缺陷而对 MTX 产生耐药性这种药物的作用机制。预计交叉耐药性此类化合物与 MTX 之间的差异会很低，并且会存在具有天然或可用于临床对抗肿瘤的潜力获得了对 MTX 的耐药性。由于另一种重要形式已知 MTX 耐药性涉及 MTX 的结构改变靶酶二氢叶酸还原酶 (DHFR) 导致 MTX 的抑制作用降低，该工作的进一步目标是找到比 MTX 与这种改变的结合更紧密的化合物酶。最后，由于人们越来越认识到抑制除 DHFR 之外的叶酸途径酶提供了主要的选择性杀死肿瘤细胞的方法是该研究的第三个目标研究的目的是产生能够抑制这些其他物质的化合物酶，代替 DHFR 或作为 DHFR 的补充。具体目标是所追求的包括以下内容的合成和测试二氨基蝶啶类化合物： (1) 亲脂性 MTX β或γ-碳上带有烷基的类似物谷氨酸； (2) 链延长的亲脂性类似物，其中谷氨酸被S-羧烷基-L-半胱氨酸或S-取代羧烷基-L-高半胱氨酸； (3)“拉伸”MTX类似物可以抑制 DHFR 和胸苷酸合酶； (4) 主动管理技术含有δ-或ε-修饰的鸟氨酸侧的类似物链作为 DHFR 和叶酰聚谷氨酸的潜在双重抑制剂合成酶； (5) MTX类似物，其中γ-羧基与氨基硼酸连接以得到如下产物：与极性活性位点形成强四面体硼酸盐络合物 DHFR 中的残留物。此外，我们计划合成并测试一系列迄今为止未经研究的化合物，包括 5,8,10-三氮杂-和6-氮杂-5,8,10-三氮杂四氢氨基蝶呤类似物和 5,8,10-trideaza- 和 6-aza-5,8,10- 带 H、Me 或 Et 取代的三脱氮四氢叶酸类似物在位置 10。