NEW APPROACHES TO ANTIFOLATE CHEMOTHERAPY

这个实验室已经从事设计一段时间了， 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）和其它类似物 经典的抗叶酸剂，目的是生产新的药物， 改善的药理学和治疗性质或 定性改变的抗肿瘤活性谱。 的 研究是正在进行的合作努力的一部分， 对抗叶酸剂的创新方法感兴趣的团体 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加的化合物 因为它们的吸收缺陷， 这种药物的机制。 预计交叉耐药性 这种化合物和MTX之间的关系将是低的， 具有临床应用的潜力， 对MTX产生耐药性。 由于另一种重要的 已知MTX耐药性涉及细胞膜的结构改变， 靶向酶二氢叶酸还原酶（DHFR）， 减少MTX的抑制，工作的进一步目标是找到 比MTX更紧密地结合到这种改变的 酵素 最后，由于它越来越认识到， 叶酸途径的酶比DHFR提供了一个主要的 选择性杀死肿瘤细胞的方法， 研究的目的是生产能够抑制这些其他的化合物， 酶，代替DHFR或除了DHFR之外。 具体目标是 所追求的包括综合和测试以下内容 二氨基蝶啶型化合物：（1）亲脂性MTX 在β或γ-碳上具有烷基的类似物 （2）链延长的亲脂性类似物，其中 谷氨酸被S-羧基烷基-L-半胱氨酸或S-羧基烷基-L-半胱氨酸替代。 羧烷基-L-高半胱氨酸;（3）“拉伸”MTX类似物， 能抑制DHFR和胸苷酸合成酶;（4）AMT 含有δ-或ε-修饰的鸟氨酸侧的类似物， 链作为DHFR和Folylpolyglutamate的潜在双重抑制剂 合成酶;和（5）MTX类似物，其中γ-羧基 与氨基硼酸连接以得到产物， 形成一个强的四面体硼酸盐配合物的极性活性位点 DHFR中的残留物。 此外，我们计划合成和测试一种 一系列迄今未被研究的化合物，由 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5，8，10-三脱氮-和6-氮杂-5，8，10- 具有H、Me或Et取代的三脱氮四氢叶酸类似物 在位置10处。

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.