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首页> 外文期刊>Journal of Medicinal Chemistry >Analogues of the potent nonpolyglutamatable antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, p-aminobenzoyl moiety, or 9,10-bridge: synthesis and in vitro antitumor activity
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Analogues of the potent nonpolyglutamatable antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, p-aminobenzoyl moiety, or 9,10-bridge: synthesis and in vitro antitumor activity

机译：强大的不可聚谷氨酸抗叶酸剂Nα-（4-氨基-4-脱氧蝶酰基）-Nδ-半邻苯二甲酰基-L-鸟氨酸（PT523）的类似物，其侧链，对氨基苯甲酰基部分或9,10有所修饰桥：合成和体外抗肿瘤活性

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Seven N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L-o rnithine (2, PT523) analogues were synthesized by modifications of the literature synthesis of the corresponding AMT (1) analogues and were tested as inhibitors of tumor cell growth. In growth assays against cultured CCRF-CEM human leukemic cells exposed to drug for 72 h, the IC(50) values of analogues in which N(10) was replaced by CH(2) and CHMe were found to be 0.55 +/- 0.07 and 0.63 +/- 0.08 nM, and thus these analogues are more potent than 1 (IC(50) = 4.4 +/- 1.0 nM) or 2 (IC(50) = 1.5 +/- 0.39 nM). The 10-ethyl-10-deaza analogue of 2 (IC(50) = 1.2 +/- 0.25 nM) was not statistically different from 2 but was more potent than edatrexate, the 10-ethyl-10-deaza analogue of 1, which had an IC(50) of 3.3 +/- 0.36 nM. In contrast, the analogue of 2 with both an ethyl and a CO(2)Me group at the 10-position had an IC(50) of 54 +/- 4.9 nM, showing this modification to be unfavorable. The 4-amino-1-naphthoic acid analogue of 2 had an IC(50) of 1.2 +/- 0.22 nM, indicating that replacement of the p-aminobenzoic acid (pABA) moiety does not diminish cytotoxicity. The analogues in which the (CH(2))(3) side chain was replaced by slightly longer CH(2)SCH(2) and (CH(2))(2)SCH(2) groups gave IC(50) values of 4.4 +/- 1.1 and 5.0 +/- 0.56 nM and thus were somewhat less potent than the parent molecule. However the analogues in which the aromatic COOH group was at the meta and para positions of the phthaloyl ring had IC(50) values of 7.5 +/- 0.47 and 55 +/- 0.07 nM, confirming the low potency we had previously observed with these compounds against other cell lines. Overall, the results in this study support the conclusion that, while the position of the phthaloyl COOH group and the length of the amino acid side chain in 2 are important determinants of cytotoxic potency, changes in the pABA region and 9, 10-bridge are well-tolerated and can even increase potency.
机译：通过修改相应AMT（1）类似物的文献合成方法合成了七个Nα-（4-氨基-4-脱氧蝶酰基）-N（δ）-半邻苯二甲酰-L鸟氨酸（2，PT523）类似物。作为肿瘤细胞生长的抑制剂。在针对暴露于药物72小时的培养的CCRF-CEM人类白血病细胞的生长测定中，发现其中N（10）被CH（2）和CHMe取代的类似物的IC（50）值为0.55 +/- 0.07和0.63 +/- 0.08 nM，因此这些类似物比1（IC（50）= 4.4 +/- 1.0 nM）或2（IC（50）= 1.5 +/- 0.39 nM）更有效。 2的10-乙基-10-deaza类似物（IC（50）= 1.2 +/- 0.25 nM）在统计学上与2无差异，但比edatrexate（1的10-乙基-10-deaza类似物）更有效。 IC（50）为3.3 +/- 0.36 nM。相反，在10位上带有乙基和CO（2）Me基团的2的类似物的IC（50）为54 +/- 4.9 nM，表明这种修饰是不利的。 2的4-氨基-1-萘甲酸类似物的IC（50）为1.2 +/- 0.22 nM，这表明对氨基苯甲酸（pABA）部分的取代不会降低细胞毒性。其中（CH（2））（3）侧链被稍长的CH（2）SCH（2）和（CH（2））（2）SCH（2）组取代的类似物给出IC（50）值分子量为4.4 +/- 1.1和5.0 +/- 0.56 nM，因此效力略低于母体分子。但是，其中芳族COOH基位于邻苯二甲酰基环的间位和对位的类似物的IC（50）值为7.5 +/- 0.47和55 +/- 0.07 nM，这证实了我们以前在这些化合物上观察到的低效价化合物对抗其他细胞系。总体而言，本研究结果支持以下结论：尽管邻苯二甲酰基COOH基团的位置和2个氨基酸侧链的长度是细胞毒性潜能的重要决定因素，但pABA区和9、10-桥的变化却是重要的。耐受性好，甚至可以提高效力。

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