2,4-Diamino-5-methyl-6-substituted arylthio-furo(2,3-d)pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and dihydrofolate reductase inhibitors.

Gangjee A; Jain HD; Phan

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2,4-Diamino-5-methyl-6-substituted arylthio-furo(2,3-d)pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and dihydrofolate reductase inhibitors.

机译：2,4-二氨基-5-甲基-6-取代的芳硫基-呋喃（2,3-d）嘧啶类化合物是新型的经典和非经典抗叶酸药，它们是潜在的双重胸苷酸合酶和二氢叶酸还原酶抑制剂。

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A novel classical antifolate N-{4-[(2,4-diamino-5-methyl-furo[2,3-d]pyrimidin-6-yl)thio]-benzoyl}-l-glutamic acid 5 and 11 nonclassical antifolates 6-16 were designed, synthesized, and evaluated as inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS). The nonclassical compounds 6-16 were synthesized from 20 via oxidative addition of substituted thiophenols using iodine. Peptide coupling of the intermediate acid 21 followed by saponification gave the classical analog 5. Compound 5 is the first example, to our knowledge, of a 2,4-diamino furo[2,3-d]pyrimidine classical antifolate that has inhibitory activity against both human DHFR and human TS. The classical analog 5 was a nanomolar inhibitor and remarkably selective inhibitor of Pneumocystis carinii DHFR and Mycobacterium avium DHFR at 263-fold and 2107-fold, respectively, compared to mammalian DHFR. The nonclassical analogs 6-16 were moderately potent against pathogen DHFR or TS. This study shows that the furo[2,3-d]pyrimidine scaffold is conducive to dual human DHFR-TS inhibitory activity and to high potency and selectivity for pathogen DHFR.

机译：新型经典抗叶酸剂N- {4-[（2,4-二氨基-5-甲基-呋喃[2,3-d]嘧啶-6-基）硫代]-苯甲酰基} -1-谷氨酸5和11种非经典抗叶酸剂设计，合成和评估了6-16，作为二氢叶酸还原酶（DHFR）和胸苷酸合酶（TS）的抑制剂。通过使用碘氧化取代的苯硫酚由20合成非经典化合物6-16。中间体酸21的肽偶联，然后进行皂化，得到了经典的类似物5。据我们所知，化合物5是2,4-二氨基呋喃[2,3-d]嘧啶经典抗叶酸的第一个实例，该化合物具有针对人类DHFR和人类TS。与哺乳动物DHFR相比，经典类似物5是卡纳氏肺孢子虫DHFR和鸟分枝杆菌DHFR的纳摩尔抑制剂和显着选择性抑制剂，分别为263倍和2107倍。非经典类似物6-16对病原体DHFR或TS具有中等效力。这项研究表明，呋喃并[2,3-d]嘧啶骨架有利于双重人DHFR-TS抑制活性，并具有较高的效价和对病原体DHFR的选择性。

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《Bioorganic and medicinal chemistry》 |2010年第2期|共9页
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Gangjee A; Jain HD; Phan;
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中图分类药学;生物化学;
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1. 2,4-Diamino-5-methyl-6-substituted arylthio-furo(2,3-d)pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and dihydrofolate reductase inhibitors. [J] . Gangjee A, Jain HD, Phan Bioorganic and medicinal chemistry . 2010,第2期

机译：2,4-二氨基-5-甲基-6-取代的芳硫基-呋喃（2,3-d）嘧啶类化合物是新型的经典和非经典抗叶酸药，它们是潜在的双重胸苷酸合酶和二氢叶酸还原酶抑制剂。
2. 2,4-Diamino-5-methyl-6-substituted arylthio-furo(2,3-d)pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and dihydrofolate reductase inhibitors. [J] . Gangjee A, Jain HD, Phan Bioorganic and medicinal chemistry . 2010,第2期

机译：2,4-二氨基-5-甲基-6-取代的芳硫基 - 呋喃（2,3-D）嘧啶作为新型经典和非生物化防雾，作为潜在的双胸苷合酶和二氢醇还原酶抑制剂。
3. 2,4-Diamino-5-methyl-6-substituted arylthio-furo(2,3-d)pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and dihydrofolate reductase inhibitors. [J] . Gangjee A, Jain HD, Phan Bioorganic and medicinal chemistry . 2010,第2期

机译：2,4-二氨基-5-甲基-6-取代的芳硫基 - 呋喃（2,3-D）嘧啶作为新型经典和非生物化防雾，作为潜在的双胸苷合酶和二氢醇还原酶抑制剂。
4. Mechanistic and structure-function analysis of thymidylate synthase-dihydrofolate reductase from protozoal parasites: Implications for the development of non-active site inhibitors. [D] . Atreya, Chloe E. 2004

机译：原生动物寄生虫胸苷酸合酶-二氢叶酸还原酶的机制和结构功能分析：对非活性位点抑制剂的发展的影响。
5. 24-Diamino-5-methyl-6-substituted Arylthio-furo23-dpyrimidines as Novel Classical and Nonclassical Antifolates as Potential Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors [O] . Aleem Gangjee, Hiteshkumar D. Jain, Jaclyn Phan, -1

机译：24-二氨基-5-甲基-6-取代的芳硫基-6-呋喃23-D嘧啶作为新型古典和非生物化防雾作为潜在的双胸苷合酶和二氢酚酸还原酶抑制剂
6. Potent Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors: Classical and Nonclassical 2-Amino-4-oxo-5-arylthio-substituted-6-methylthieno2,3-dpyrimidine Antifolates [O] . Aleem Gangjee, Yibin Qiu, Wei Li, 2008

机译：有效的双胸腺酯合酶和二氢氢醇还原酶抑制剂：经典和无菌2-氨基-4-氧代-5-芳硫基取代 - 6-甲基硫磺酸盐2,3-D嘧啶

2,4-Diamino-5-methyl-6-substituted arylthio-furo(2,3-d)pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and dihydrofolate reductase inhibitors.

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