腺苷和肌苷类似物对腺苷脱氨酶的抑制作用，这些类似物含有共同的杂环碱基4(7)-氨基-6(5)H-咪唑并[4,5-d]哒嗪-7(4)酮。

Inhibition of adenosine deaminase by analogues of adenosine and inosine, incorporating a common heterocyclic base, 4(7)-amino-6(5)H-imidazo[4,5-d]pyridazin-7(4)one.

作者信息

Ujjinamatada Ravi K, Phatak Pornima, Burger Angelika M, Hosmane Ramachandra S

机构信息

Laboratory for Drug Design and Synthesis, Department of Chemistry and Biochemistry, University of Maryland Baltimore County, Baltimore, MD 21250, USA.

出版信息

J Med Chem. 2008 Feb 14;51(3):694-8. doi: 10.1021/jm700931t. Epub 2008 Jan 4.

DOI:10.1021/jm700931t

PMID:18173230

Abstract

Four nucleoside analogues ( 1- 4) containing a common heterocyclic base, 4(7)-amino-6(5) H-imidazo[4,5- d]pyridazin-7(4)one, were screened against calf-intestine adenosine deaminase. Compounds 1 and 3 with K(i) values of 10-12 microM are more than four times as potent inhibitors of ADA compared with 2 and 4, with K(i) values of 51-52 microM. Also, 3 is not a substrate of ADA. Nucleosides 3 and 4 also exhibit moderate in vitro activity against breast cancer cell lines, while all four are only minimally or nontoxic to the normal cells.

摘要

针对小牛肠腺苷脱氨酶筛选了四种含有常见杂环碱基4(7)-氨基-6(5)H-咪唑并[4,5-d]哒嗪-7(4)酮的核苷类似物(1 - 4)。化合物1和3的抑制常数(Ki)值为10 - 12微摩尔，与抑制常数(Ki)值为51 - 52微摩尔的化合物2和4相比，它们作为腺苷脱氨酶(ADA)抑制剂的效力要强四倍多。此外，化合物3不是ADA的底物。核苷3和4对乳腺癌细胞系也表现出中等程度的体外活性，而所有四种对正常细胞的毒性都很小或无毒性。