硝基芳基磷酰胺作为酶前药疗法中用于激活大肠杆菌硝基还原酶的新型前药。

Nitroaryl phosphoramides as novel prodrugs for E. coli nitroreductase activation in enzyme prodrug therapy.

作者信息

Hu Longqin, Yu Chengzhi, Jiang Yongying, Han Jiye, Li Zhuorong, Browne Patrick, Race Paul R, Knox Richard J, Searle Peter F, Hyde Eva I

机构信息

Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey 08854, USA.

出版信息

J Med Chem. 2003 Nov 6;46(23):4818-21. doi: 10.1021/jm034133h.

DOI:10.1021/jm034133h

PMID:14584930

Abstract

Cyclic and acyclic nitroaryl phosphoramide mustard analogues were activated by E. coli nitroreductase, an enzyme explored in GDEPT. The more active acyclic 4-nitrobenzyl phosphoramide mustard (7) showed 167 500x selective cytotoxicity toward nitroreductase-expressing V79 cells with an IC(50) as low as 0.4 nM. This is about 100x more active and 27x more selective than CB1954 (1). The superior activity was attributed to its better substrate activity (k(cat)/K(m) 19x better than 1) and/or excellent cytotoxicity of phosphoramide mustard released.

摘要

环状和非环状硝基芳基磷酰胺芥类似物可被大肠杆菌硝基还原酶激活，该酶是基因导向酶解药物前体疗法（GDEPT）中所研究的一种酶。活性更高的非环状4-硝基苄基磷酰胺芥（7）对表达硝基还原酶的V79细胞表现出167500倍的选择性细胞毒性，其半数抑制浓度（IC50）低至0.4 nM。这比CB1954（1）的活性高约100倍，选择性高27倍。其卓越的活性归因于其更好的底物活性（催化常数与米氏常数的比值比1高19倍）和/或释放出的磷酰胺芥具有出色的细胞毒性。