Mustard prodrugs for activation by Escherichia coli nitroreductase in gene-directed enzyme prodrug therapy.
Twenty nitrogen mustard analogues derived from 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954, 1) were evaluated as candidate prodrugs for gene-directed enzyme prodrug therapy (GDEPT) in Chinese hamster V79 cell lines engineered to express Escherichia coli nitroreductase (NR). Structural variations within the series included the use of N-dihydroxypropyl and (N-dimethylamino)ethyl carboxamide side chains, the use of chloro, bromo, mesyl, and iodo leaving groups on the mustards, and regioisomeric changes. The compounds were assayed for cytotoxicity (IC50) with the NR-expressing and controls of non-NR-expressing cell lines. The proportion of NR-expressing cells required in a mixture for nonexpressing cells to experience 50% of their cytotoxicity (termed the TE50) was used to assess the compounds' ability to induce a bystander effect. This study suggests that 5-[N,N-bis(2-bromoethyl)amino]-2,4-dinitrobenzamide (8), 5-[N,N-bis(2-iodoethyl)amino]-2,4-dinitrobenzamide (9), 2-[N,N-bis(2-bromoethyl)-amino]-3,5-dinitrobenzamide (13), and 2-[N,N-bis(2-iodoethyl)amino]-3,5-dinitrobenzamide (14) showed considerable improvements over 1, exhibiting greater potency, higher IC50 ratios, and lower TE50s, and are thus superior prodrugs to 1 for GDEPT.
Friedlos
F
F
Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, U.K.
Denny
W A
WA
Palmer
B D
BD
Springer
C J
CJ
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D004789:Enzyme Activation; D004926:Escherichia coli; D005818:Genetic Engineering; D008466:Mechlorethamine / Q000031:analogs & derivatives*; D009601:Nitroreductases / Q000378:metabolism*; D011355:Prodrugs / Q000138:chemical synthesis / Q000627:therapeutic use*
D011355:Prodrugs; D008466:Mechlorethamine; D009601:Nitroreductases