设计、合成和x射线晶体结构的一个强有力的双重抑制剂thymidylate合酶和二氢叶酸还原酶作为抗肿瘤剂。
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Gangjee, Yu J, McGuire JJ,科迪V, Galitsky N, Kisliuk RL,女王科幻
设计、合成和x射线晶体结构的一个强有力的双重抑制剂thymidylate合酶和二氢叶酸还原酶作为抗肿瘤剂。
J地中海化学。2000年10月19日,43 (21):3837 - 51。
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11052789 (在PubMed]
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小说N -反向问题mark2-amino-4-methyl [(pyrrolo [2, 3 - d] pyrimidin-5-yl)乙基)苯甲酰反向问题mark-L-glutamic酸(3)设计并合成作为一个强有力的双重抑制剂thymidylate合成酶(TS)和二氢叶酸还原酶(DHFR)和作为抗肿瘤剂。化合物3 b, N7-benzylated模拟3,也是合成作为抗肿瘤剂。3的合成是通过12步序列完成涉及的合成2-amino-4-methylpyrrolo [2, 3 - d]嘧啶(10)从2-acetylbutyrolactone 5步骤。保护2-amino群10和特定选择的碘化在5-position其次是钯催化的交叉偶联提供中间14转换为3的减少和皂化。类似的合成方法被用于3 b。3 x射线晶体结构的三元复杂,DHFR,和NADPH表明pyrrolo [2, 3 - d]嘧啶环结合在“2 4-diamino模式”的吡咯氮模拟4-amino一半的4-diaminopyrimidines。这是第一个例子的一个经典pyrrolo [2, 3 - d]嘧啶antifolate证明DHFR这个备用模式绑定。化合物3和3 b抑制比LY231514对TS干酪乳杆菌和大肠杆菌。模拟3对DHFR也更抑制人类,刚地弓形虫,卡氏肺孢子虫。评价3对甲氨蝶呤(MTX)防细胞系与定义的机制表明,抗力移转3 MTX的比这低得多。 Metabolite protection studies and folylpoly-gamma-glutamate synthetase studies suggest that the antitumor activity of 3a against the growth of tumor cells in culture is a result of dual inhibition of TS and DHFR. Compound 3a inhibited the growth of CCRF-CEM and FaDu cells in culture at ED(50) values of 12.5 and 7.0 nM, respectively, and was more active against FaDu cells than MTX. In contrast, compound 3b was inactive against both cell lines. Compound 3a was evaluated in the National Cancer Institute in vitro preclinical antitumor screening program and afforded IG(50) values in the nanomolar range against a number of tumor cell lines.