Synthesis and evaluation of a classical 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine as antifolates
Synthesis and evaluation of a classical 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine as antifolates
复制标题
DOI：
10.1016/j.bmc.2006.08.029
复制
发表时间：
2006-12-15
影响因子：
3.5
通讯作者：
Kisliuk, Roy L.
中科院分区：
文献类型：
--
作者：
Gangjee, Aleem;Yang, Jie;Kisliuk, Roy L.
合成了两种典型的叶酸抑制剂，一种是2，4-二氨基-5-取代呋喃并[2，3-d]嘧啶，另一种是2-氨基-4-氧代-6-取代吡咯并[2，3-d]嘧啶，它们是二氢叶酸还原酶（DHFR）和胸苷酸合成酶（TS）的潜在抑制剂。通过2，6-二氨基-3（H）-4-氧代-嘧啶与α-氯酮21缩合得到两个关键中间体23和24，然后水解，与L-谷氨酸二乙酯偶联，二乙酯皂化得到经典的抗叶酸剂13和14。具有单碳原子桥的化合物13和14都是叶酰聚γ-谷氨酸合成酶（FPGS）的底物，FPGS是负责形成具有增加的效力和/或增加的细胞保留的关键聚-γ-谷氨酸抗叶酸代谢物的酶。化合物14是一种高效的FPGS底物，证明2，4-二氨基-5-取代的呋喃并[2，3-d]嘧啶是设计具有FPGS底物活性的抗叶酸剂的重要先导结构。与两个原子桥连的类似物5相比，它保留了对DHFR和TS的抑制效力。化合物13是纯化的DHFR和TS的不良抑制剂，并且13和14都是培养物中CCRF-CEM人白血病细胞生长的不良抑制剂，这表明这些系列中的单碳桥连化合物虽然有助于FPGS底物活性，但不是有效的抑制剂。(c)2006爱思唯尔有限公司保留所有权利。
Two classical antifolates, a 2,4-diamino-5-substituted furo[2,3-d]pyrimidine and a 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine, were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS). The syntheses were accomplished by condensation of 2,6-diamino-3(H)-4-oxo-pyrimidine with alpha-chloro-ketone 21 to afford two key intermediates 23 and 24, followed by hydrolysis, coupling with L-glutamate diethyl ester and saponification of the diethyl ester to afford the classical antifolates 13 and 14. Compounds 13 and 14 with a single carbon atom bridge are both substrates for folylpoly,gamma-glutamate synthetase (FPGS), the enzyme responsible for forming critical poly-gamma-glutamate antifolate metabolites with increased potency and/or increased cell retention. Compound 14 is a highly efficient FPGS substrate demonstrating that 2,4-diamino-5-substituted furo[2,3-d]pyrimidines are important lead structures for the design of antifolates with FPGS substrate activity. It retains inhibitory potency for DHFR and TS compared to the two atom bridged analog 5. Compound 13 is a poor inhibitor of purified DHFR and TS, and both 13 and 14 are poor inhibitors of the growth of CCRF-CEM human leukemia cells in culture, indicating that single carbon bridged compounds in these series though conducive to FPGS substrate activity were not potent inhibitors. (c) 2006 Elsevier Ltd. All rights reserved.