NOVEL APPROACHES TO ANTIFOLATE CHEMOTHERAPY

抗叶酸化疗的新方法

• 批准号: 6512545
• 负责人: ANDRE ROSOWSKY
• 金额: $ 53.59万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6512545
• 关键词: aminopterin; antineoplastics; chemical synthesis; dihydrofolate reductase; drug adverse effect; drug design /synthesis /production; drug metabolism; drug resistance; enzyme inhibitors; folate antagonist; homocysteine; ligands; membrane transport proteins; methotrexate analog; neoplasm /cancer pharmacology; pharmacokinetics; polyglutamates; prodrugs

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.

该项目的总体目标仍然是设计和合成用于癌症化疗的新型抗叶酸药物，特别强调二氢叶酸还原酶（DHFR）抑制剂的创新方法，其作用方式旨在使其与“经典”抑制剂有明显区别例如氨基蝶呤 (AMT)、甲氨蝶呤 (MTX) 和依达曲沙 (EDX)。具体目标 1：扩展和完成目前正在进行的有关 DHFR 紧密结合和有效转运但非多谷氨酸类似物的工作，其中的先导化合物 N-α-(4-氨基-4 脱氧蝶酰基)-N-δ-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择用于加速临床前开发和 I 期测试，作为其新 RAID 的一部分 程序。具体目标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，就像在有效的胸苷酸合酶抑制剂 GW1843 的情况下所做的那样。这些化合物将代表 DHFR 抑制剂的中间类别，介于代谢为长链聚谷氨酸盐的化合物（例如 MTX、EDX）和根本不聚谷氨酸盐的化合物（例如 PT523）之间。具体目标 3：合成一系列 2-脱氨基-2-甲基氨基蝶呤 (PT557, dmAMT) 的第二代类似物，该类似物之前被证明是与单谷氨酸一样弱的 DHFR 抑制剂，但一旦被代谢，它就是一种有效的“多靶点抗叶酸剂”细胞内形成聚谷氨酸盐。因为只有聚谷氨酸盐而不是母体药物会有效地抑制靶酶，所以这些化合物将比 AMT 更真正地代表“前药”，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 活性的肿瘤的改进的选择性。重点是通过修饰 B 环和/或 pABA 部分来增强先导化合物 dmAMT 的多谷氨酸化。