The effect of side-chain, para-aminobenzoyl region, and B-ring modifications on dihydrofolate reductase binding, influx via the reduced folate carrier, and cytotoxicity of the potent nonpolyglutamatable antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta
The effect of side-chain, para-aminobenzoyl region, and B-ring modifications on dihydrofolate reductase binding, influx via the reduced folate carrier, and cytotoxicity of the potent nonpolyglutamatable antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta
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侧链、对氨基苯甲酰区和 B 环修饰对二氢叶酸还原酶结合、通过还原叶酸载体流入以及强效非聚谷氨酸抗叶酸 N(α)-(4-氨基-4-脱氧蝶酰) 的细胞毒性的影响
DOI：
10.1016/s0163-7258(99)00055-8
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发表时间：
2000
影响因子：
13.5
通讯作者：
Forsch,RA
中科院分区：
文献类型：
--
作者：
Rosowsky,A;Wright,JE;Vaidya,CM;Forsch,RA
Nα-（4-氨基-4-脱氧蝶酰基）-Nδ-半邻苯二甲酰-l-鸟氨酸（PT 523）是一种异常紧密结合的二氢叶酸还原酶（DHFR）抑制剂，并通过还原叶酸载体（RFC）被有效地吸收到细胞中。与具有谷氨酸侧链的经典DHFR抑制剂如甲氨蝶呤和氨基蝶呤不同，PT 523不能形成聚谷氨酸。因此，它类似于亲脂性抗叶酸剂，如曲美蝶呤，不需要通过叶酰聚谷氨酸合成酶代谢活化，以产生其抗叶酸作用。然而，与曲美蝶呤相反，PT 523在具有多药耐药表型的细胞中保留了生长抑制活性。作为该药物临床前开发的一部分，我们对PT 523分子的几个区域进行了系统性修饰，目的是定义DHFR结合的最佳结构特征，通过RFC流入细胞，以及抑制细胞生长的能力。本文讨论了半邻苯二甲酰鸟氨酸侧链的最佳长度、芳香族羧基的最佳位置、半邻苯二甲酰鸟氨酸侧链的最佳长度、芳香族羧基的最佳位置、半邻苯二甲酰鸟氨酸侧链的最佳长度、芳香族羧基的最佳位置、半邻苯二甲酰鸟氨酸侧链的最佳长度、芳香族羧基的最佳位置、芳香族羧基的最佳位置、半邻苯二甲酰鸟氨酸侧链的最佳长度、芳香族羧基的最佳位置和芳香族羧基的最佳位置。和（3）用萘取代对氨基苯甲酸部分的苯环，用碳取代桥10位的氮，以及B环的5-和/或8-位上的氮被碳取代都是良好耐受的。PT 523的几种第二代类似物是比PT 523本身更有效的DHFR抑制剂和更好的RFC底物，并且是培养物中肿瘤细胞生长的更有效抑制剂。
Nα-(4-Amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-l-ornithine (PT523) is an unusually tight-binding dihydrofolate reductase (DHFR) inhibitor and is efficiently taken up into cells via the reduced folate carrier (RFC). Unlike classical DHFR inhibitors with a glutamate side chain, such as methotrexate and aminopterin, PT523 cannot form polyglutamates. Thus, it resembles lipophilic antifolates such as trimetrexate in not requiring metabolic activation by folylpolyglutamate synthetase in order to produce its antifolate effect. However, in contrast to trimetrexate, PT523 retains growth inhibitory activity in cells with the multidrug resistance phenotype. As part of the preclinical development of this drug, we have performed systematic modification of several regions of the PT523 molecule, with the aim of defining the optimal structural features for DHFR binding, influx into cells via the RFC, and the ability to inhibit cell growth. The following structure-activity correlations have emerged from this ongoing investigation, and are discussed: (1) the hemiphthaloylornithine side chain has the optimal length; (2) the preferred location of the aromatic carboxyl group is the ortho position; and (3) replacement of the phenyl ring of the para-aminobenzoic acid moiety by naphthalene, of nitrogen at the 10-position of the bridge by carbon, and of nitrogen at the 5- and/or 8-position of the B-ring by carbon are all well tolerated. Several of the second generation analogs of PT523 are more potent DHFR inhibitors and better RFC substrates than PT523 itself, and are more potent inhibitors of tumor cell growth in culture.