合成5-methyl-5-deaza模抗作为二氢叶酸还原酶抑制剂和潜在antipneumocystis antitoxoplasma和抗肿瘤药物。
文章的细节
-
引用
复制到剪贴板 -
施Gangjee, J,女王科幻,巴罗斯LR, Kisliuk RL
合成5-methyl-5-deaza模抗作为二氢叶酸还原酶抑制剂和潜在antipneumocystis antitoxoplasma和抗肿瘤药物。
J地中海化学。1993年10月29日,36 (22):3437 - 43。
- PubMed ID
-
8230134 (在PubMed]
- 文摘
-
(一系列的2,4-diamino-5-methyl-6) - anilinomethyl pyrido [2, 3 - d]嘧啶合成为4 - 9日5-deaza模包含trimethoxy抗,二氯-,或trichlorophenyl替换和h, N-CH3或N-CHO 10-position。化合物被评为二氢叶酸还原酶抑制剂(DHFR)卡氏肺孢子虫(p .囊虫),刚地弓形虫(弓形虫),大鼠肝脏(RL)和干酪乳杆菌(l .干酪乳杆菌);弓形虫的抑制剂和p .囊虫细胞生长在文化;作为抗肿瘤剂。化合物是由古典5-deaza叶酸的修改程序。2,4-Diamino-5-methyl-6 - [(3 ', 4 ', 5 ' -trimethoxy-N - methylanilino)甲基]pyrido [2, 3 - d]嘧啶(5)表现出高效力以及选择性(RL DHFR相比)p囊虫和弓形虫DHFR。化合物5是其中一个最强大的和选择性模叶酸弓形虫DHFR已知的抑制剂。的N-10甲酰模拟2,4-diamino-5-methyl-6 - [(N-formyl-3 ', 4 ', 5 ' -trimethoxyanilino)甲基]pyrido - [2, 3 - d]嘧啶(6)效力下降,但它为弓形虫DHFR保持高选择性。相应的chloro-substituted类似物保持效力或降低了力量;N-10替换没有增加力量或选择性的程度上观察到的3 ',4 ',5 ' -trimethoxy系列。 Partial reduction of the B ring to afford the dihydro analogue 2,4-diamino-5-methyl-6-[(N-formyl-3',4',5'-trimethoxyanilino) methyl]-5,8-dihydropyrido[2,3-d]pyrimidine (7), its 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine analogue 8, and 2,4-diamino-5-methyl-6-[(3',4',5'-trimethoxyanilino)methyl]-5,6,7, 8- tetrahydropyrido[2,3-d]pyrimidine (9) resulted in a significant decrease in potency. In T. gondii cell culture inhibitory studies, 2,4-diamino-5-methyl-6-[(3',4',5'- trimethoxyanilino)methyl]pyrido[2,3-d]pyrimidine (4a), 5a, and 6a were less potent compared to their DHFR inhibitory potencies. Against P. carinii cells in culture, 4a and 5a at 10 micrograms/mL were as effective as the clinically used combination of trimethoprim/sulfamethoxazole (50/250 micrograms/mL). With the exception of the B ring reduced analogues 7-9, all of the compounds were significantly cytotoxic to leukemia CCRF-CEM cells in culture. The chloro-substituted analogues, in general, were more potent against a variety of other tumor cells in culture than the trimethoxy analogues. These results were corroborated by the preclinical tumor screening program at the National Cancer Institute where the most potent compound 2,4-diamino-5-methyl-6-[(3',4'-dichloroanilino)methyl]pyrido[2,3- d]pyrimidine (4b) was found to inhibit the growth of 26 tumor cell lines at an IG50 < 1.00 x 10(-8) M.