Inhibition of mammalian dihydrofolate reductase by selected 2,4-diaminiquinazolines and related compounds.
Inhibition of mammalian dihydrofolate reductase by selected 2,4-diaminiquinazolines and related compounds.
复制标题
选定的 2,4-二氨基喹唑啉和相关化合物对哺乳动物二氢叶酸还原酶的抑制作用。
DOI：
10.1021/jm00255a007
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发表时间：
1974
影响因子：
7.3
通讯作者：
J. McCormack
中科院分区：
文献类型：
--
作者：
Richter We;J. McCormack
从大鼠肝脏和L1210小鼠白血病细胞中获得多种喹唑啉类、吡啶类[2,3 -d]嘧啶类和翼啶类化合物，并对其作为二氢叶酸还原酶抑制剂进行了评价。某些2,4 -二氨基喹唑啉在6位上含有苯胺或苯胺甲基取代基，从两种来源证明能够抑制酶活性，其程度（id50 -10 ~ 8-10-9 M）可与抗肿瘤剂甲氨蝶呤相比较。在喹唑啉系列中，2位和4位的一级氨基的存在是高抑制效力所必需的。在2,4 -二氨基-6-苄基氨基喹唑啉的苯基环上引入卤素、甲基或羟基取代基(1)，或用杂芳香官能团（吡啶基、呋喃基、噻吩基）取代苯基取代基，都不会显著影响抑制效力。另一方面，1的第5位氯取代基的存在与抑制效力的显着增加有关。有趣的是，2,4 -二氨基-6-哌啶喹唑啉被发现具有适度的活性（IDso= 2 × 10”8 M），作为所研究的两种酶系统的抑制剂，在该化合物的哌啶环上插入2-乙基功能可以产生大约50倍的抑制效力。所研究的2,4 -二氨基吡啶[2,3 -d]嘧啶作为二氢叶酸还原酶活性的抑制剂与类似的喹唑啉一样有效。一系列2,4 -二氨基蝶啶，其特征是与蝶啶核的6和7位融合的脂环的大小逐渐增加，对两种酶系统进行了评估。随着环尺寸的增加，抑制效力呈一致的增加趋势，其中12元环（IDso= 2.1 X 10-7 M）的抑制效力低于6元环（IDso= 1.9 X 10”4M）的抑制效力。许多含有2,4 -二氨基嘧啶核的化合物，包括多种翼啶类化合物，可以作为二氢叶酸还原酶[5,6,7,8 -四氢叶酸盐：NAD (P)氧化还原酶ec1.5]的抑制剂。1.3.从细菌，1'3原生动物，4'7和哺乳动物来源。8”10已被合成为该酶系统潜在抑制剂的化合物类型包括喹唑啉和吡啶[2,3 -d]嘧啶，它们与翼啶的不同之处在于，它们与嘧啶核融合的环中分别缺少两个和一个氮原子。
A variety of quinazolines, pyrido [2, 3-d] pyrimidines, and pteridines were evaluated as inhibitors of dihydrofolate re-ductase obtained from rat liver and L1210 mouse leukemia cells. Certain of the 2, 4-diaminoquinazolines bearing benzylamino or anilinomethyl substituents at position 6 proved to be capable of inhibiting enzyme activity, from both sources, to a degree (ID5o 10~ 8-10-9 M) comparable to that observed for the antineoplastic agent methotrex-ate. In the quinazoline series, the presence of primary amino groups at positions 2 and 4 was essential for high in-hibitory potency. Neither introduction of halogen, methyl, or hydroxyl substituents anywhere into the phenyl ring of 2, 4-diamino-6-benzylaminoquinazoline (1) nor replacement of the phenyl substituent with heteroaromatic func-tions (pyridyl, furyl, thienyl) markedly affected inhibitory potency. On the other hand, the presence of a chloro substituent at position 5 of 1 was associated with a pronounced increase in inhibitory potency. Interestingly, 2, 4-diamino-6-piperidinoquinazoline was found to possess modest activity (IDso= 2 x 10 “8 M) as an inhibitor ofboth enzyme systems studied, and insertionof a 2-ethyl function into the piperidine ring of this compound produced an approximately 50-fold increase in inhibitory potency. 2, 4-Diaminopyrido [2, 3-d] pyrimidines investigated were as po-tent as the analogous quinazolines as inhibitors of dihydrofolate reductase activity from both sources. A series of 2, 4-diaminopteridines characterized by a progressive increase in the size of an alicyclic ring fused to positions 6 and 7 of the pteridine nucleus was evaluated against both enzyme systems. A consistent trend of increased inhibitory potency with increasing ring size was observed and is exemplified by the lower IDso observed for the compound bearing a 12-membered ring (IDso= 2.1 X 10-7 M) compared with that for the compound bearing a six-membered ring (IDso= 1.9 x 10" 4M).Many compounds possessing the 2, 4-diaminopyrimidine nucleus, including a variety of pteridines, can function as inhibitors of dihydrofolatereductase [5, 6, 7, 8-tetrahydrofo-late: NAD (P) oxidoreductase EC 1.5. 1.3.] from bacteri-al, 1'3 protozoal, 4'7 and mammalian sources. 8" 10 The types of compounds which have been synthesized as potential inhibitors of this enzyme system include quinazolines and pyrido [2, 3-d] pyrimidines, which differ from pteridine by, respectively, the absence of two and one nitrogen atoms in the ring fused to the pyrimidine nucleus.