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抗叶酸剂，特别强调创新方法，从而产生二氢叶酸还原酶（DHFR）抑制剂，其作用模式旨在将其与“经典”抑制剂（如氨基蝶呤（AMT），甲氨蝶呤（MTX）和edatrexate（EDX））区分开来。具体目标1：为了扩展和完成目前正在进行的关于DHFR紧密结合和有效转运但非多聚谷氨酸类似物的工作，其中先导化合物N-α-（4-氨基-4-脱氧蝶酰基）-N-δ-半邻苯二甲酰-L-鸟氨酸（PT 523，NSC 633713）最近被国家癌症研究所选择用于加速临床前开发和I期测试，作为其新RAID计划的一部分。具体目的2：合成一系列DHFR抑制剂，它们是良好的FPOS底物，但仅限于添加一个谷氨酰残基。这将通过使用桥阻断侧链酰胺键的自由旋转来实现，如在有效胸苷酸合酶抑制剂GW 1843的情况下所做的那样。这些化合物将代表在代谢为长链聚谷氨酸盐（例如，MTX、EDX）和根本不是多谷氨酸化的那些（例如，PT523）。具体目标3：合成一系列2-脱氨基-2-甲基氨基蝶呤（PT 557，dmAMT）的第二代类似物，其先前被证明是一种弱DHFR抑制剂，作为单谷氨酸盐，但一旦其在细胞内代谢为多谷氨酸盐，则是一种有效的“多靶向抗叶酸剂”。因为只有聚谷氨酸盐而不是母体药物将有效地抑制靶酶，所以这些化合物将比AMT更真实地代表“前药”，并且因此相对于剂量限制性宿主组织，应该显示出针对具有高FPGS活性的肿瘤的改善的选择性。重点将是通过B环和/或pABA部分的修饰来增强先导化合物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.