Synthesis and in vitro antitumor activity of new deaza analogues of the nonpolyglutamatable antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (PT523).
Synthesis and in vitro antitumor activity of new deaza analogues of the nonpolyglutamatable antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (PT523).
复制标题
非聚谷氨酸抗叶酸剂 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) 的新型脱氮类似物的合成和体外抗肿瘤活性。
DOI：
10.1021/jm010518t
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发表时间：
2002
影响因子：
7.3
通讯作者：
Rosowsky,Andre
中科院分区：
文献类型：
--
作者：
Vaidya,ChitraM;Wright,JoelE;Rosowsky,Andre
本发明公开了N α-[4-[2-（2-甲氧基苯基）-2-甲基-3-氧代-4-甲基-2-氧代-3-氧代-4-（2，4-二氨基喹唑啉-6-基）乙基]苯甲酰基]-Nδ-半邻苯二甲酰-L-鸟氨酸（2）和N α-[4-[5-（2-氨基喹唑啉-6-基）乙基]苯甲酰基]-Nδ-半邻苯二甲酰-L-鸟氨酸（2，4-二氨基蝶啶-6-基）[[（2，4-二氨基蝶啶-1-炔-4-基]苯甲酰基]-Nδ-半邻苯二甲酰基-1-鸟氨酸（6）作为N α-（4-氨基-4-脱氧蝶酰基）-Nδ-半邻苯二甲酰-L-鸟氨酸（1，PT 523），一种非多聚谷氨酸抗叶酸剂，目前处于临床前开发阶段。在针对CCRF-CEM人白血病淋巴母细胞培养物的72小时生长抑制试验中，2和6的IC 50分别为0.69 ± 0.044 nM和1.3 ± 0.35 nM，而先前报道的氨基蝶呤（AMT）和PT 523的IC 50值分别为4.4 ± 0.10 nM和1.5 ± 0.39 nM。在以二氢叶酸和NADPH为共底物的二氢叶酸还原酶（DHFR）抑制的分光光度测定中，以前未报道的化合物2和6的混合10 R和10 S非对映体的Ki值分别为0.21 ± 0.05 pM和0.60 ± 0.02 pM，与先前报道的AMT为3.70 ± 0.35 pM和PT 523为0.33 ± 0.04 pM的值相比。因此，虽然它们与1及其先前研究的几种类似物结合DHFR并抑制CCRF-CEM细胞生长的能力相当，但2和6的混合非对映体的活性比AMT高出数倍，尽管它们不能形成AMT和其他具有谷氨酸侧链的经典抗叶酸剂在细胞中形成的γ-聚谷氨酰化代谢物。
Details are disclosed for the synthesis ofNα-[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]-Nδ-hemiphthaloyl-l-ornithine (2) andNα-[4-[5-(2,4-diaminoteridin-6-yl)pent-1-yn-4-yl]benzoyl]-Nδ-hemiphthaloyl-l-ornithine (6) as analogues ofNα-(4-amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-l-ornithine (1, PT523), a nonpolyglutamatable antifolate currently in advanced preclinical development. In a 72 h growth inhibition assay against cultures of CCRF-CEM human leukemic lymphoblasts, the IC50of2and6was 0.69 ± 0.044 nM and 1.3 ± 0.35 nM, respectively, as compared with previously reported values 4.4 ± 0.10 nM for aminopterin (AMT) and 1.5 ± 0.39 nM for PT523. In a spectrophotometric assay of dihydrofolate reductase (DHFR) inhibition using dihydrofolate and NADPH as the cosubstrates, the previously unreported compounds2and the mixed 10Rand 10Sdiastereomers of6hadKivalues of 0.21 ± 0.05 pM and 0.60 ± 0.02 pM, respectively, as compared with previously reported values of 3.70 ± 0.35 pM for AMT and 0.33 ± 0.04 pM for PT523. Thus, while they were comparable to1and several of its previously studied analogues in their ability to bind to DHFR and inhibit the growth of CCRF-CEM cells,2and the mixed diastereomers of6were several times more active than AMT despite the fact that they cannot form γ-polyglutamylated metabolites of the type formed in cells from AMT and other classical antifolates with a glutamate side chain.