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新型吡咯并[2,3-d]嘧啶抗叶酸剂：合成与抗肿瘤活性

Novel pyrrolo[2,3-d]pyrimidine antifolates: synthesis and antitumor activities.

作者信息

Miwa T, Hitaka T, Akimoto H, Nomura H

机构信息

Research & Development Division, Takeda Chemical Industries, Ltd., Osaka, Japan.

出版信息

J Med Chem. 1991 Feb;34(2):555-60. doi: 10.1021/jm00106a012.

DOI:10.1021/jm00106a012
PMID:1847428
Abstract

New antifolates, characterized by a 6-5 fused ring system, a pyrrolo[2,3-d]pyrimidine ring, and a trimethylene bridge at position 5 (12a,b and 13a,b) were designed and efficiently synthesized. The synthetic method included (1) construction of the key intermediary acyclic skeleton, 5-[4-(tert-butoxycarbonyl)phenyl]- 2-(dicyanomethyl)pentanoates (6a,b), (2) cyclization with guanidine, followed by reduction to the pyrrolo[2,3-d]pyrimidine derivatives (8a,b and 9a,b), and (3) subsequent glutamate coupling and saponification. These antifolates were more growth-inhibitory by about 1 order of magnitude than methotrexate (MTX) against KB human epidermoid carcinoma cells and A549 human nonsmall cell lung carcinoma cells in in vitro culture. Growth inhibitory IC50 values for N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5- yl)propyl]benzoyl]-L-glutamic acid (12a) against KB and A549 were 0.27 and 4.5 ng/mL, while those for MTX were 5.0 and 35 ng/mL, respectively. Other members of this class of antifolates, 12b and 13a,b, showed good activities nearly equal to that of 12a.

摘要

设计并高效合成了新型抗叶酸剂，其特征为具有一个6-5稠环系统、一个吡咯并[2,3-d]嘧啶环以及在5位（12a,b和13a,b）的一个三亚甲基桥。合成方法包括：(1)构建关键的非环状中间体骨架，即5-[4-(叔丁氧羰基)phenyl]-2-(二氰基甲基)戊酸酯(6a,b)；(2)与胍环化，随后还原为吡咯并[2,3-d]嘧啶衍生物(8a,b和9a,b)；以及(3)后续的谷氨酸偶联和皂化反应。在体外培养中，这些抗叶酸剂对KB人表皮样癌细胞和A549人非小细胞肺癌细胞的生长抑制作用比甲氨蝶呤(MTX)强约1个数量级。N-[4-[3-(2,4-二氨基-7H-吡咯并[2,3-d]嘧啶-5-基)丙基]苯甲酰基]-L-谷氨酸(12a)对KB和A549的生长抑制IC50值分别为0.27和4.5 ng/mL，而MTX的IC50值分别为5.0和35 ng/mL。这类抗叶酸剂的其他成员，12b和13a,b，显示出与12a几乎相当的良好活性。

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