Nitrobenzylcarbamate prodrugs of cytotoxic acridines for potential use with nitroreductase gene-directed enzyme prodrug therapy.
The synthesis, solvolytic behaviour and cytotoxicity of novel 4-nitrobenzyl carbamates and carbonates derived from 3-amino-4-hydroxymethylacridine 1 are described. Compounds 2 and 6 are both substrates for Escherichia coli nitroreductase and the highly active lead structure 1 is liberated upon incubation of the two compounds in the presence of NTR and its cofactor NADH. Additionally, the cytostatic activity of 2 and 6 against human HT29 colon carcinoma cell lines is decreased 80-fold and 360-fold, respectively, indicating their suitability and potency as prodrugs for either gene-directed enzyme prodrug therapy or antibody-directed enzyme prodrug therapy.
Asche
Christian
C
CNRS UMR 5616 and ICMG-FR260, Université Joseph Fourier, BP53, 38041 Grenoble Cédex 9, France.
Dumy
Pascal
P
Carrez
Danièle
D
Croisy
Alain
A
Demeunynck
Martine
M
D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D015316:Genetic Therapy; D019073:HT29 Cells; D006801:Humans; D009601:Nitroreductases / Q000235:genetics*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*
D000166:Acridines; D002219:Carbamates; D011355:Prodrugs; D009601:Nitroreductases