2,4-diamino-5-deaza-6-substituted pyrido [2, 3 - d]嘧啶抗强而有力且选择性模二氢叶酸还原酶的抑制剂。

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Gangjee, Vasudevan女王科幻,Kisliuk RL

2,4-diamino-5-deaza-6-substituted pyrido [2, 3 - d]嘧啶抗强而有力且选择性模二氢叶酸还原酶的抑制剂。

J地中海化学。1996年3月29日,39(7):1438 - 46所示。

PubMed ID

8691474 (在PubMed

]

文摘

4-diamino-6十五小说模和两个经典2——(benzylamino) pyrido [2, 3 - d]嘧啶抗卡氏肺孢子虫的合成作为潜在的抑制剂,(pc)刚地弓形虫(tg)大鼠肝脏(rl),和人类(h)重组二氢叶酸还原酶(DHFR)。这些类似物缺乏5-methyl替换已被证明是重要的增加hDHFR抑制活动。此外,它们包含的逆转C9-N10桥在叶酸最抗。合成化合物参与反应的2,4,6-triaminopyrimidine nitromalonaldehyde买得起的钠盐的关键中间体2,4-diamino-6-nitropyrido [2, 3 - d]嘧啶(7),在一个单一的步骤。减少7 - 2,4,6-triaminopyrido [2, 3 - d]嘧啶(8),其次是适当的苯甲醛、苯乙醛还原胺化提供目标化合物。N9的甲基化这些类似物进行了使用甲醛和cyanoborohydride钠。类似物显示显著抑制pcDHFR tgDHFR。N9 DHFR抑制甲基化显著提高效能。化合物11日3 ' 4 ' 5 ' -trimethoxy-substituted模拟的选择性比9.4 tgDHFR (rlDHFR相比)的选择性模拟模系列。N9甲基化合物22日2 ' 5 ' -dimethoxy-substituted模拟是最强有力的模拟对tgDHFR (IC 50 = 6.3海里),第二个最选择性模拟tgDHFR (rlDHFR相比)模系列。 The naphthyl-substituted analogues 23-25 were generally more potent against rlDHFR than against pcDHFR and tgDHFR. Selected analogues were also evaluated against Streptococcus faecium (sf) DHFR, Escherichia coli (ec) DHFR, Lactobacillus casei (lc) DHFR and tgDHFR with hDHFR as the mammalian reference, under slightly different assay conditions than those employed for rlDHFR. Analogues 11 and 22 had selectivity ratios of greater than 100 for tgDHFR (compared to hDHFR). Analogue 22 in particular, was the most selective analogue of the nonclassical series against tgDHFR (selectivity ratio = 303.5) with excellent potency (28 nM). Analogue 11, also displayed significant selectivity for sfDHFR (selectivity ratio = 4902). Compound 22 was evaluated in vivo for the inhibition of the growth of T.gondii trophozoites in mice, where at 50 mg/kg orally, it demonstrated distinct prolongation of survival without toxicity. Compounds 11, 12 and 21-23 were evaluated as antitumor agents in the National Cancer Institutes preclinical in vitro screening program. Compounds 12, 22, and 23 showed GI50s for tumor growth inhibition in the 10 -6 - 10 -7 M range.

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绑定属性

药物	目标	财产	测量	pH值	温度(°C)
2,4-Diamino-6 - [N - (3 ', 5 ' -Dimethoxybenzyl) -N-Methylamino] Pyrido [2, 3 - d]嘧啶	二氢叶酸还原酶	集成电路50 (nM)	2900年	N /一个	N /一个	细节
甲氨蝶呤	二氢叶酸还原酶	集成电路50 (nM)	38	N /一个	N /一个	细节
(N6) - 2, 5-Dimethoxy-Benzyl -N6-Methyl-Pyrido [2, 3 - d] Pyrimidine-2, 4, 6-Triamine	二氢叶酸还原酶	集成电路50 (nM)	8500年	N /一个	N /一个	细节