Tricyclic 2,4-diaminopyrimidines with broad antifolate activity and the ability to inhibit Pneumocystis carinii growth in cultured human lung fibroblasts in the presence of leucovorin.
Tricyclic 2,4-diaminopyrimidines with broad antifolate activity and the ability to inhibit Pneumocystis carinii growth in cultured human lung fibroblasts in the presence of leucovorin.
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三环 2,4-二氨基嘧啶，具有广泛的抗叶酸活性，并且能够在亚叶酸存在的情况下抑制培养的人肺成纤维细胞中卡氏肺囊虫的生长。
DOI：
10.1016/0006-2952(89)90554-6
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发表时间：
1989
影响因子：
5.8
通讯作者：
Modest,EJ
中科院分区：
文献类型：
--
作者：
Rosowsky,A;Freisheim,JH;Hynes,JB;Queener,SF;Bartlett,M;Smith,JW;Lazarus,H;Modest,EJ
1，3-二氨基苯并[f]喹唑并[f]和1，3-二氨基-5，6-二氢苯并[f]喹唑并[f]可被视为脂溶性抗叶酸类化合物乙胺胺(PM)、美托品(DDMP)和依托泊碱(DDEP)的三环类似物，它们分别作为纯化的二氢叶酸还原酶(DHFR)的抑制剂和粪链球菌ATCC 8043和L1210小鼠白血病细胞的生长抑制物。此外，还测试了这些三环化合物对伯氏疟原虫小鼠的抗疟活性，以及在亚叶酸钙(LV)存在下，在WI-38人肺成纤维细胞培养上抑制卡氏肺孢子虫亚硝化体生长的能力。最有效的类似物是那些在2，4-二氨基嘧啶部分远端环上有氯取代的类似物。全芳香族化合物往往比5，6-键被还原的化合物更具活性，这表明平面性有利于与DHFR活性部位的结合，可能有利于细胞摄取。一些2，4-二氨基嘧啶类似物显示出比PM、DDMP或DDEP更强的效力，并且更接近于已知的选择性毒性TOP的双环2，4-二氨基嘧啶抗叶酸三甲氧胺(TMQ)或吡替曲辛(BW301U)。在LV存在的情况下，Carinii。其中两个三环化合物1，3-二氨基-8-氯苯并[f]喹唑啉和1，3-二氨基-9-氯苯并[f]喹唑啉在该体系中具有与TMQ和BW301U相似的活性。
A selected number of 1,3-diaminobenzo[f]quinazolines and 1,3-diamino-5,6-dihydrobenzo[f]quinazolines, which may be viewed as tricyclic analogues of the lipid-soluble antifolates pyrimethamine (PM), metoprine (DDMP), and etoprine (DDEP), were tested as inhibitors of purified dihydrofolate reductase (DHFR) from WI-L2 lymphoblasts, and as inhibitors of the growth ofStreptococcus faeciumATCC 8043 and L1210 murine leukemia cells in culture. In addition, these tricyclic compounds were tested for antimalarial activity againstPlasmodium bergheiin mice, and for the ability to inhibit the growth ofPneumocystis cariniitrophozoites in WI-38 human lung fibroblast cultures in the presence of leucovorin (LV). The most potent analogues were those with chlorine substitution in the ring distal to the 2,4-diaminopyrimidine moiety. Fully aromatic compounds tended to be more active than those in which the 5,6-bond was reduced, suggesting that planarity favors binding to the DHFR active site and may be favorable for cellular uptake. Several of the 2,4-diaminopyrimidine analogues showed greater potency than PM, DDMP or DDEP, and were more nearly comparable to the bicyclic 2,4-diaminopyrimidine antifolates trimetrexate (TMQ) or piritrexim (BW301U), which are known to be selectively toxic toP. cariniiin the presence of LV. Two of the tricyclic compounds, 1,3-diamino-8- chlorobenzo[f]quinazoline and 1,3-diamino-9-chlorobenzo[f]quinazoline, proved to have activity similar to TMQ and BW301U in this system.