Synthesis of N-{4-[(2,4-Diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic Acid and N-{4-[(2-Amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic Acid as Dual Inhibitors of Dihyd

Aleem Gangjee; Xin Lin; Roy L.Kisliuk; John J.McGuire

首页> 外文期刊>Journal of Medicinal Chemistry >Synthesis of N-{4-[(2,4-Diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic Acid and N-{4-[(2-Amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic Acid as Dual Inhibitors of Dihyd

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Synthesis of N-{4-[(2,4-Diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic Acid and N-{4-[(2-Amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic Acid as Dual Inhibitors of Dihyd

机译：N- {4-[（2,4-二氨基-5-甲基-4,7-二氢-3H-吡咯并[2,3-d]嘧啶-6-基）硫代]苯甲酰基} -L-谷氨酸的合成和N- {4-[（2-氨基-4-氧代-5-甲基-4,7-二氢-3H-吡咯并[2,3-d]嘧啶-6-基）硫代]苯甲酰基} -L-谷氨酸酸作为二醛的双重抑制剂

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Two novel classical antifolates N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 3 and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 4 were designed,synthesized,and evaluated as antitumor agents.Compounds 3 and 4 were obtained from 2,4-diamino-5-meth-ylpyrrolo[2,3-d]pyrimidine 7 and 2-amino-4-oxo-5-methylpyrrolo[2,3-d]pyrimidine 12,respectively,in a concise three-step sequence.Compound 3 is the first example,to our knowledge,of a 2,4-diamino classical antifolate that has potent inhibitory activity against both human dihydrofolate reductase(DHFR)and human thymidylate synthase(TS).Compound 4 was a dual DHFR-TS inhibitor against the bifunctional enzyme derived from Toxoplasma gondii(tg).Further evaluation of the mechanism of action of 3 implicated DHFR as its primary intracellular target.Both 3 and 4 were folylpolyglutamate synthetase(FPGS)substrates.Compound 3 also inhibited the growth of several human tumor cell lines in culture with GI_(50)< 10~(-8)M.This study shows that the pyrrolo[2,3-d]pyrimidine scaffold is conducive to dual DHFR-TS and tumor inhibitory activity,and the potency is determined by the 4-position substituent.

机译：两种新型经典抗叶酸剂N- {4-[（2,4-二氨基-5-甲基-4,7-二氢-3H-吡咯并[2,3-d]-嘧啶-6-基）硫代]苯甲酰基} -L -谷氨酸3和N- {4-[（2-氨基-4-氧代-5-甲基-4,7-二氢-3H-吡咯并[2,3-d]嘧啶-6-基）硫代]苯甲酰基}设计，合成并评价了-L-谷氨酸4作为抗肿瘤剂。由2,4-二氨基-5-甲基-吡咯并[2,3-d]嘧啶7和2-氨基-4获得化合物3和4。 -oxo-5-methylpyrrolo [2,3-d] pyrimidine 12分别以简洁的三步顺序进行。据我们所知，化合物3是具有有效抑制作用的2,4-二氨基经典抗叶酸药物的第一个实例。化合物4是针对弓形虫（tg）衍生的双功能酶的双重DHFR-TS抑制剂。化合物4是一种双重DHFR-TS抑制剂，可对抗弓形虫（tg）的双功能酶。它的主要细胞内靶标。3和4均为叶酰聚谷氨酸合成酶（FPGS）底物。化合物3也抑制了GI_（50）<10〜（-8）M培养的几种人类肿瘤细胞系的生长。本研究表明吡咯并[2,3-d]嘧啶支架有助于双重DHFR-TS和抑癌活性，效力由4位取代基决定。

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《Journal of Medicinal Chemistry》 |2005年第23期|共8页
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Aleem Gangjee; Xin Lin; Roy L.Kisliuk; John J.McGuire;
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1. Synthesis of N-{4-[(2,4-Diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic Acid and N-{4-[(2-Amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic Acid as Dual Inhibitors of Dihyd [J] . Aleem Gangjee, Xin Lin, Roy L.Kisliuk, Journal of Medicinal Chemistry . 2005,第23期

机译：N- {4-[（2,4-二氨基-5-甲基-4,7-二氢-3H-吡咯并[2,3-d]嘧啶-6-基）硫代]苯甲酰基} -L-谷氨酸的合成和N- {4-[（2-氨基-4-氧代-5-甲基-4,7-二氢-3H-吡咯并[2,3-d]嘧啶-6-基）硫代]苯甲酰基} -L-谷氨酸酸作为二醛的双重抑制剂
2. SYNTHESIS OF PYRROLO[2,3-d]PYRIMIDINE ANALOGUES OF THE POTENT ANTITUMOR AGENT N-{4-[3-(2,4-DIAMINO-7H-PYRROLO-[2,3-d]PYRIMIDIN-5-YL)PROPYL]BENZOYL}-L-GLUTAMIC ACID(TNP-351) [J] . Gaojun Zhu, Zenglu Liu, Yun Xu Heterocycles: An International Journal for Reviews and Communications in Heterocyclic Chemistry . 2008,第7期

机译：潜在反作用剂N- {4- [3-（2-，3-DIAMINO-7H-PYROROLO- [2,3-d] PYRIMIDIN-5-YL）丙基的吡咯并[2,3-d]嘧啶类似物的合成]苯甲酰} -L-谷氨酸（TNP-351）
3. Synthesis of N-[4-[1-Ethyl-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid as an Antifolate [J] . Aleem Gangjee, Yibin Zeng, John J. McGuire, Journal of Medicinal Chemistry . 2002,第9期

机译：N- [4- [1-乙基-2-（2,4-二氨基呋喃[2,3-d]嘧啶-5-基）乙基]苯甲酰基] -L-谷氨酸的合成作为抗叶酸剂
4. Synthesis of N-{4-(2, 4-Diamino-5-methyl-4, 7-dihydro-3H-pyrrolo2, 3-dpyrimidin-6-yl)thiobenzoyl}-l-glutamic Acid and N-{4-(2-Amino-4-oxo-5-methyl-4, 7-dihydro-3H-pyrrolo2, 3-dpyrimidin-6-yl)thiobenzoyl}-l-glutamic Acid as Dual Inhibitors of Dihydrofolate Reductase and Thymidylate Synthase and as Potential Antitumor Agents [O] . -1

机译：N- {4 - （2,4-二氨基-5-甲基-4,7-二氢-3H-吡咯并2,3-D嘧啶-6-基）苯甲酰} -L-谷氨酸的合成和N- {4 - （2-氨基-4-氧代-5-甲基-4,7-二氢-3H-吡咯，2,3-D嘧啶-6-基）苯甲酰基-L-谷氨酸酸作为二氢酚酸还原酶和胸苷合酶的双抑制剂和潜在的抗肿瘤剂

Synthesis of N-{4-[(2,4-Diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic Acid and N-{4-[(2-Amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic Acid as Dual Inhibitors of Dihyd

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