NOVEL APPROACHES TO ANTIFOLATE CHEMOTHERAPY

抗叶酸化疗的新方法

• 批准号: 6632963
• 负责人: ANDRE ROSOWSKY
• 金额: $ 55.13万
• 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 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6632963
• 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.

该项目的总体目标继续是对癌症化学疗法的新抗基因疗法的设计和合成，特别着重于导致二氢叶酸还原酶（DHFR）抑制剂的创新方法，其作用方式的设计旨在使它们与诸如Aminopterin（Amt）的“经典”侵害者（如Amt）（AMT），甲基甲氧酸酯（METREXARX）（METREX）和MTEREXERXERTERE（MMTREX）和MTEREXERTERE（MMTREX）（MMTREX）（MMTREX）（and）。具体目的1：扩展并完成当前正在进行的工作，对紧密的DHFR绑定，有效地运输但非聚谷氨酸的类似物，其中铅化合物N-α-（4-氨基-4-二氧基翅目） - N-delta-Hemiphthaloyl-l--l- ornithine（pt523，pt523，nsc 6sc 63333333333333313）临床前开发和I期测试是其新RAID计划的一部分。具体目标2：合成一系列DHFR抑制剂，这些DHFR抑制剂是良好的FPOS底物，但仅限于仅添加一个谷氨酸残基。这将通过使用桥梁的使用来阻止侧链酰胺键的自由旋转，就像在有效的胸腺丙酸甲酯合酶抑制剂GW1843的情况下所做的那样。这些化合物将代表中间类的DHFR抑制剂，这些DHFR抑制剂被代谢为长链聚谷氨酸盐（例如MTX，EDX），而那些完全没有聚谷氨酸的抑制剂（例如，PT523）。具体目的3：合成一系列的第二代类似物的2-脱甲米诺-2-甲基胺（PT557，DMAMT），以前被证明是一种弱DHFR抑制剂，是单谷氨酸氨酸氨酸氨基氨基氨酸盐，但曾经是一种有效的“多核抗酸盐”，曾经是内肠内内植入室内的polyglutlutally tollacemize''。因为只有多谷氨酸而不是母体药物，这些化合物将有效抑制靶酶，而与AMT相比，这些化合物将更真正地代表“前药”，因此应提高针对与剂量限制宿主组织的较高FPG活性的肿瘤的选择性。重点将是通过修改B环和/或Paba部分来增强铅化合物DMAMT的多谷氨酸。

项目成果

Methotrexate analogues-27. Dual inhibition of dihydrofolate reductase and folylpolyglutamate synthetase by methotrexate and aminopterin analogues with a gamma-phosphonate group in the side chain.

甲氨蝶呤类似物-27。

• DOI: 10.1016/0006-2952(86)90431-4
• 发表时间: 1986
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: Rosowsky,A;Moran,RC;Forsch,RA;Radike-Smith,M;Colman,PD;Wick,MM;Freisheim,JH
• 通讯作者: Freisheim,JH

Methotrexate analogues. 16. Importance of the side-chain amide carbonyl group as a structural determinant of biological activity.

甲氨蝶呤类似物。

• DOI: 10.1021/jm00354a013
• 发表时间: 1982
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Rosowsky,A;Forsch,R
• 通讯作者: Forsch,R

A mechanism for the addition of multiple moles of glutamate by folylpolyglutamate synthetase.

通过叶酰聚谷氨酸合成酶添加多摩尔谷氨酸的机制。

• DOI: 10.1021/jm00376a005
• 发表时间: 1984
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Moran,RG;Colman,PD;Forsch,RA;Rosowsky,A
• 通讯作者: Rosowsky,A

Synthesis and biologic activity of new side-chain-altered methotrexate and aminopterin analogs with dual inhibitory action against dihydrofolate reductase and folylpolyglutamate synthetase.

对二氢叶酸还原酶和叶酰聚谷氨酸合成酶具有双重抑制作用的新型侧链改变的甲氨蝶呤和氨基蝶呤类似物的合成和生物活性。

• 发表时间: 1987
• 期刊: NCI monographs : a publication of the National Cancer Institute
• 作者: Rosowsky,A;Moran,RG;Freisheim,JH;Bader,H;Forsch,RA;Solan,VC
• 通讯作者: Solan,VC

Biochemical and biological studies on 2-desamino-2-methylaminopterin, an antifolate the polyglutamates of which are more potent than the monoglutamate against three key enzymes of folate metabolism.

对 2-脱氨基-2-甲基氨基蝶呤的生化和生物学研究，这是一种抗叶酸剂，其多谷氨酸盐比单谷氨酸盐对抗叶酸代谢的三种关键酶更有效。

• 发表时间: 1992
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Rosowsky,A;Galivan,J;Beardsley,GP;Bader,H;O'Connor,BM;Russello,O;Moroson,BA;DeYarman,MT;Kerwar,SS;Freisheim,JH
• 通讯作者: Freisheim,JH