Nitroaryl phosphoramides as novel prodrugs for E. coli nitroreductase activation in enzyme prodrug therapy.
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.
Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey 08854, USA.
Longqin
L
Hu
Chengzhi
C
Yu
Yongying
Y
Jiang
Jiye
J
Han
Zhuorong
Z
Li
Patrick
P
Browne
Paul R
PR
Race
Richard J
RJ
Knox
Peter F
PF
Searle
Eva I
EI
Hyde
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D009601:Nitroreductases / Q000378:metabolism*; D010084:Oxidation-Reduction; D010752:Phosphoramide Mustards / Q000138:chemical synthesis* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D018906:Antineoplastic Agents, Alkylating; D020536:Enzyme Activators; D009574:Nitro Compounds; D010752:Phosphoramide Mustards; D011355:Prodrugs; D003520:Cyclophosphamide; D009601:Nitroreductases