合成和b环的有力antifolate活动和细胞毒性deaza nonpolyglutamatable的类似物二氢叶酸还原酶抑制剂Nalpha - (4-amino-4-deoxypteroyl) -Ndelta-hemiphthaloyl L-ornithine (PT523)。
文章的细节
-
引用
复制到剪贴板 -
Rosowsky,赖特我,Vaidya厘米,巴德H, Forsch RA,莫塔CE、Pardo J,陈CS,陈YN
合成和b环的有力antifolate活动和细胞毒性deaza nonpolyglutamatable的类似物二氢叶酸还原酶抑制剂Nalpha - (4-amino-4-deoxypteroyl) -Ndelta-hemiphthaloyl L-ornithine (PT523)。
J地中海化学。1998年12月17日,41 (26):5310 - 9。
- PubMed ID
-
9857098 (在PubMed]
- 文摘
-
6个新的b环的类似物nonpolyglutamatable antifolate Nalpha——(4-amino-4-deoxypteroyl) -Ndelta-hemiphthaloy l-L-ornithine (PT523 3)合成的影响以确定修改5 -和/或8-position的二氢叶酸还原酶(DHFR)绑定和肿瘤细胞生长抑制。5 -和8-deaza类似物都准备从甲基2-L-amino-5-phthalimidopentanoate 4-amino-4-deoxy-N10-formyl-5-deaza 8-deazapteroic酸,分别。5,8-dideaza类似物是由甲基2 l - [(4-aminobenzoyl)氨基]5-phthalimidopentanoate和2,4-diaminoquinazoline-6-carbonitriles。抑制人类的Ki DHFR 5-deaza和5-methyl-5-deaza类似物是一样3(0.35点),11-fold低于氨喋呤(AMT) 1),和15倍低于甲氨蝶呤(MTX, 2)。然而,Ki 8-deaza模拟的27倍低于1和5,8-dideaza, 5-methyl-5, 8-dideaza,和5-chloro-5 8-dideaza类似物低大约是50倍。这种趋势符合文献发表相应的DHFR抑制剂谷氨酸侧链。集落形成试验中对人体头颈部鳞状细胞癌细胞系SCC25 72 h后治疗,大约5 -和8-deaza类似物一样的3,而5 8-dideaza模拟强是3倍。5-Methyl 5-chloro替换也有利,5-methyl-5-deaza模拟2。5倍比5-deaza模拟更有效。然而5-methyl替换的效果没那么明显,比5-deaza 8-dideaza类似物类似物。5-chloro-5, 8-dideaza模拟3系列的最活跃的成员,以IC50 = 0.33和1.8 nM 3和15 nM MTX。 The 5-methyl-5-deaza analogue of 3 was also tested at the National Cancer Institute against a panel of 50 human tumor cell lines in culture and was consistently more potent than 3, with IC50 values in the low-nanomolar to subnanomolar range against most of the tumors. Leukemia and colorectal carcinoma cell lines were generally most sensitive, though good activity was also observed against CNS tumors and carcinomas of the breast and prostate. The results of this study demonstrate that B-ring analogues of 3 inhibit DHFR activity and tumor cell colony formation as well as, or better than, the parent compound. In view of the fact that 3 and its B-ring analogues cannot form polyglutamates, their high cytotoxicity relative to the corresponding B-ring analogues of AMT is noteworthy.