NEW APPROACHES TO ANTIFOLATE CHEMOTHERAPY

这个实验室参与设计已经有一段时间了， 衍生物和结构的合成、生物活性评价 氨甲喋呤(MTX)、氨基喋呤(AMT)等类似物 经典的抗叶酸，目的是生产新的药物 改善的药理和治疗特性或 定性改变了抗肿瘤活性的光谱。这个 研究是与其他人持续合作努力的一部分 对抗叶酸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 在肿瘤细胞中积聚能力增强的化合物 它们对甲氨蝶呤具有抗药性，因为它们的吸收存在缺陷 这种药物的作用机理。预计交叉抗性 这类化合物和甲氨蝶呤之间的关系将是低的，并且将有 是否有可能在临床上用于治疗具有天然或特殊性质的肿瘤 对甲氨蝶呤产生获得性耐药。因为另一种重要的形式 已知的甲氨蝶呤耐药性涉及甲氨蝶呤的结构性改变 靶酶二氢叶酸还原酶(DHFR)导致 减少MTX的抑制作用，这项工作的另一个目标是找到 会比甲氨蝶呤更紧密地结合到这种改变的化合物 酵素。最后，由于它越来越认识到抑制 除DHFR以外的叶酸途径酶提供了主要的 选择性杀伤肿瘤细胞的方法，第三个目标是 研究是产生一种化合物来抑制这些其他的 酶，取代或补充DHFR。具体目标是 所追求的包括以下方面的综合和测试 二氨基蝶啶类化合物：(1)亲脂性MTX β或γ-碳上含有烷基的类似物 谷氨酸；(2)链加长的亲脂类似物，其中 谷氨酸被S-羧基-L-半胱氨酸或S-取代- 羧烷基-L-同型半胱氨酸； 能抑制DHFR和胸苷合成酶；(4)AMT 含有三角洲或epsilon修饰的鸟氨酸侧边的类似物- 链作为DHFR和叶基聚谷氨酸的潜在双重抑制剂 合成酶；和(5)MTX类似物，其中伽玛-羧基 与一种氨基硼酸连接，从而得到一种 与极性活性中心形成强烈的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种 一系列迄今未被研究过的化合物，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5，8，10-三氮杂-和6-氮杂-5，8，10- H、Me或Et取代的三氮杂四氢叶酸类似物 在10号位。

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.