Quinazoline antifolates inhibiting thymidylate synthase: 2-desamino derivatives with enhanced solubility and potency.
Quinazoline antifolates inhibiting thymidylate synthase: 2-desamino derivatives with enhanced solubility and potency.
复制标题
喹唑啉抗叶酸药抑制胸苷酸合酶：2-脱氨基衍生物，具有增强的溶解度和效力。
DOI：
10.1021/jm00124a018
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发表时间：
1989
影响因子：
7.3
通讯作者：
A. Calvert
中科院分区：
文献类型：
--
作者：
T. Jones;T. J. Thornton;A. Flinn;A. Jackman;D. Newell;A. Calvert
胸苷合成酶(TS)抑制抗叶酸10-丙叉基-5，8-二氮杂环酸的溶解性差，给其临床应用带来了困难，可能是其肾毒性的原因之一。不溶是由于药物中的2-氨基-3，4-二氢-4-氧代嘧啶部分通过分子间氢键稳定了固体状态。在研究这一部分时，我们去掉了2-氨基，现在报告了2-去氨基-10-丙叉基-5，8-二氮杂甲醛酸(8E)和四个在N10处与H、Me、Et和烯丙基的类似物。3，4-二氢-4-氧代-6-甲基喹唑啉通过内酰胺氮与氯甲酸甲酯的烷基化反应得到增溶产物。与N-溴代丁二亚胺反应得到相应的6-溴甲基化合物，再与N-(4-氨基苯甲酰基)-L-谷氨酸二乙酯或其适当的N-取代衍生物偶联。最后用冷碱同时脱保护产物中的喹唑啉、N3、氮和羧基，得到所需的五种抗叶酸。这些化合物被用来对抗L1210 TS，结果发现，去除2-氨基会导致TS抑制作用轻微(3-9倍)丧失。8E的TS抑制剂仅为母药的8倍。三种化合物对大鼠肝脏二氢叶酸还原酶的抑制作用均降低了1个数量级以上。所有五个类似物在培养中对L1210细胞的细胞毒作用都比它们的2-氨基类似物强；8E的活性是它们的8.5倍，ID_(50)为0.4微米。这一显着的结果可能要归功于细胞渗透率的提高。8E在pH 5.0时的溶解度是1的5倍，在pH 7.4时是1的340倍以上。
The poor solubility of the thymidylate synthase (TS) inhibiting antifolate 10-propargyl-5,8-dideazafolic acid has posed problems for its clinical use and is probably responsible for its renal toxicity. The insolubility is caused by the 2-amino-3,4-dihydro-4-oxopyrimidine moiety of the drug which stabilizes the solid state by intermolecular hydrogen bonding. In examining this moiety we have removed the 2-amino group and now report on 2-desamino-10-propargyl-5,8-dideazafolic acid (8e) and four analogues with H, Me, Et, and allyl at N10. 3,4-Dihydro-4-oxo-6-methylquinazoline was solubilized by alkylating the lactam nitrogen with chloromethyl pivalate. Reaction with N-bromosuccinimide gave the corresponding 6-bromomethyl compound, which was coupled with diethyl N-(4-aminobenzoyl)-L-glutamate or the appropriate N-substituted derivative thereof. The quinazoline N3 nitrogen and carboxyl groups in the product were simultaneously deprotected by cold alkali in the final step to give the desired five antifolates. These were tested against L1210 TS and it was found that removal of the 2-amino group caused a slight (3-9-fold) loss of TS inhibition. 8e was only 8-fold a lesser TS inhibitor than the parent drug. Inhibition of rat liver dihydrofolate reductase was reduced by over 1 order of magnitude for three compounds tested. All five analogues were more cytotoxic to L1210 cells in culture than their 2-amino counterparts; 8e was 8.5-fold more active with an ID50 of 0.4 microM. This remarkable result probably owes to increased cellular penetration. 8e was 5-fold more soluble than 1 at pH 5.0 and greater than 340-fold more soluble at pH 7.4.