Synthesis of classical, four-carbon bridged 5-substituted furo [2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates
Synthesis of classical, four-carbon bridged 5-substituted furo [2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates
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DOI：
10.1021/jm058213s
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发表时间：
2005-08-11
影响因子：
7.3
通讯作者：
Kisliuk, RL
中科院分区：
文献类型：
--
作者：
Gangjee, A;Zeng, YB;Kisliuk, RL
我们首次报道了四碳原子桥接的经典抗叶酸药对二氢叶酸还原酶（DHFR）、胸苷酸合成酶（TS）和叶酸聚谷氨酸合成酶（FPGS）的生物学活性以及抗肿瘤活性。对经典的二碳桥接抗叶酸盐(5-取代2,4-二氨基呋喃[2,3d]嘧啶（1)和6-取代2-氨基-4-氧吡喃[2,3d]嘧啶(2)）的桥接同源性研究的延伸，提供了两种四碳桥接抗叶酸盐，类似物5和6，具有增强的FPGS底物活性和对肿瘤细胞的抑制活性（EC50）
We report, for the first time, the biological activities of four-carbon-atom bridged classical antifolates on dihydrofolate reductase (DHFR), thymidylate synthase (TS), and folylpolyglutamate synthetase (FPGS) as well as antitumor activity. Extension of the bridge homologation studies of classical two-carbon bridged antifolates, a 5-substituted 2,4-diaminofuro[2,3d]pyrimidine (1) and a 6-subsituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine (2), afforded two four-carbon bridged antifolates, analogues 5 and 6, with enhanced FPGS substrate activity and inhibitory activity against tumor cells in culture (EC50