NOVEL APPROACHES TO ANTIFOLATE CHEMOTHERAPY

该项目的总体目标仍然是设计和合成用于癌症化疗的新的抗叶酸盐，特别强调导致二氢叶酸还原酶(DHFR)抑制剂的创新方法，其作用模式旨在使它们有别于氨蝶呤(AMT)、甲氨蝶呤(MTX)和依替曲克星(EDX)等经典的抑制剂。具体目的1：为了扩展和完成目前正在进行的紧密结合DHFR和高效转运但非多谷氨酸类似物的工作，其中先导化合物N-α-(4-氨基-4-脱氧蝶酰)-N-三角洲-半邻苯二甲酰基-L-鸟氨酸(PT523，NSC 633713)最近被国家癌症研究所选为加速临床前开发和I期测试的新的RAID计划的一部分。特异性目的2：合成一系列DHFR抑制剂，它们是良好的FPOS底物，但仅限于加成一个谷氨基残基。这将通过使用桥来阻止侧链酰胺键的自由旋转来实现，就像在有效的胸苷合成酶抑制剂GW1843的情况下所做的那样。这些化合物将代表介于代谢为长链多谷氨酸(例如MTX、EDX)的DHFR抑制剂和那些根本不是多谷氨酸的(例如PT523)之间的中间类。特异性目的3：合成2-去氨基-2-甲基氨基蝶呤(PT557，dmAMT)的第二代类似物，它是一种弱的单谷氨酸脱氢酶受体(DHFR)抑制剂，但一旦它在细胞内代谢为多谷氨酸，则是一种强大的“多靶点抗叶酸”。因为只有多聚谷氨酸盐，而不是母体药物，才能有效地抑制靶标酶，所以这些化合物将比AMT更真实地代表“前体药物”，因此相对于剂量限制的宿主组织，它们对具有高FPGS活性的肿瘤表现出更好的选择性。重点将放在通过修饰B-环和/或PABA部分来增强先导化合物dmAMT的聚谷氨酸化。

The overall goal of this project continues to be the design and synthesis of new antifolates for cancer chemotherapy, with particular emphasis on innovative approaches leading to dihydrofolate reductase (DHFR) inhibitors whose mode of action is designed to set them favorably apart from 'classical' inhibitors such as aminopterin (AMT), methotrexate (MTX), and edatrexate (EDX). SPECIFIC AIM 1: To extend and complete the currently ongoing work on tightly DHFR bound and efficiently transported but nonpolyglutamated analogs, of which the lead compound, N-alpha-(4-amino-4deoxypteroyl)- N-delta-hemiphthaloyl-L-ornithine (PT523, NSC 633713), was recently selected by the National Cancer Institute for accelerated preclinical development and Phase I testing as part of its new RAID program. SPECIFIC AIM 2: To synthesize a series of DHFR inhibitors which are good FPOS substrates but are limited to the addition of only one glutamyl residue. This will be accomplished by blocking free rotation of the side chain amide bond via the use of a bridge as has been done in the case of the potent thymidylate synthase inhibitor GW1843. These compounds will represent an intermediate class of DHFR inhibitors between those which are metabolized to longchain polyglutamates (e.g., MTX, EDX) and those which are not polyglutamated at all (e.g., PT523). SPECIFIC AIM 3: To synthesize a series of second generation analogs of 2-desamino-2-methylaminopterin (PT557, dmAMT), which was previously shown to be a weak DHFR inhibitor as the monoglutamate but a potent 'multitargeted antifolate' once it is metabolized intracellularly to polyglutamates. Because only the polyglutamates, and not the parent drug, will potently inhibit the target enzyme these compounds will more truly represent 'prodrugs' than AMT, and should therefore display improved selectivity against tumors with high FPGS activity relative to dose limiting host tissues. The focus will be on enhancing polyglutamation of the lead compound dmAMT by modification of the B-ring and/or pABA moiety.