古典和模furo [2, 3 - d]嘧啶作为新型抗:合成和生物活性。
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Gangjee, Devraj R, McGuire JJ, Kisliuk RL,女王科幻,巴罗斯LR
古典和模furo [2, 3 - d]嘧啶作为新型抗:合成和生物活性。
J地中海化学。1994年4月15日,37 (8):1169 - 76。
- PubMed ID
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8164259 (在PubMed]
- 文摘
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古典antifolate类似物包含小说furo [2, 3 - d]嘧啶环系统包括N - [4 - (N - [(2, 4-diaminofuro [2, 3 - d] pyrimidin-5 - yl)甲基)氨基)苯甲酰)-L-glutamic酸(1)及其N - 9甲基模拟2合成作为潜在的双重抑制剂thymidylate合成酶(TS)和二氢叶酸还原酶(DHFR)和作为抗肿瘤剂。四模抗2 4-diamino-5 (anilinomethyl) furo [2, 3 - d]嘧啶3 - 6和3、4,5-trimethoxy, 3, 4, 5-trichloro, 3, 4-dichloro,和2,5-dimethoxy取代基,分别在苯基环,也合成的潜在抑制剂DHFRs包括卡氏肺孢子虫、刚地弓形虫的生物负责艾滋病患者机会性感染。古典和模得到了类似物通过亲核位移的关键中间体2,4-diamino-5——(chloromethyl) furo [2, 3 - d]嘧啶与适当的(p-aminobenzoyl) -L-glutamate或取代苯胺。关键中间体的合成2,3-dichloroacetone 4-diamino-6-hydroxypyrimidine和1。最后的化合物进行体外对大鼠肝、人类(重组),p .囊虫,弓形虫,干酪乳杆菌DHFRs。经典的类似物显示中度至良好DHFR抑制活动(IC50 10 (6) -10 (8) M)与N-CH3模拟2对1的两倍。beplayapp模类似物是不活跃的IC50S > 3 x 10 (5) m . TS的古典类似物也被评为抑制剂(l .干酪乳杆菌(重组)人类和人类CCRF-CEM),甘氨酰胺核苷酸formyltransferase,和5-aminoimidazole-4-carboxamide核苷酸formyltransferase并针对这些酶被发现是不活跃的。经典的类似物(尤其是2)明显细胞毒性对多种肿瘤细胞系的文化。模类似物是稍微活跃。经典的化合物都是好人类folylpolyglutamate合成酶的底物。 Further evaluation of the cytotoxicity of 1 and 2 in CCRF-CEM cells and its sublines, having defined mechanisms of methotrexate (MTX) resistance, demonstrated that the analogues utilize the reduced folate/MTX-transport system and primarily inhibit DHFR and that poly-gamma-glutamylation was crucial to their mechanism of action. Protection studies in the FaDu squamous cell carcinoma cell line indicated that inhibition was completely reversed by leucovorin or the combination of thymidine plus hypoxanthine. Furthermore, for compounds 1 and 2, in contrast to MTX, the FaDu cells were better protected by thymidine alone than hypoxanthine alone, suggesting a predominantly antithymidylate effect.