Triazene metabolism. VI. 3-Azidomethyl-3-alkyl-1-aryltriazenes, a new class of anti-tumour triazene with potential pro-drug applications.
The synthesis of a new series of 3-azidomethyl-3-methyl-1-aryltriazenes is described. 3-Acetoxymethyl-3-methyl-1-aryltriazenes react with a large molar excess of sodium azide in aqueous acetone to afford the 3-azidomethyltriazenes in high yield. The rate of formation of the azidomethyltriazene increasing azide concentration, suggesting either an SN2 mechanism or a significant ionic strength effect on an SN1 reaction. In the absence of azide ion, the acetoxymethyltriazene undergoes a slow hydrolysis to give a bis-anilinomethane, which presumably arises via hydrolysis of the triazene to the aniline followed by condensation with formaldehyde released during the hydrolysis. The azidomethyltriazenes undergo facile hydrolysis in aqueous buffer solution with identical kinetic parameters to those of the hydrolysis of hydroxymethyltriazenes, suggesting that the azides may be good pro-drugs for the cytotoxic monomethyltriazene, the hydrolysis product derived from the hydroxymethyltriazene. Indeed, the azidomethyltriazenes have comparable anti-tumour activity against the P388 and PC6 tumours to other triazenes in this series. Furthermore, the azidomethyltriazenes display selective toxicity towards a human tumour cell line (the BE cell line) which is deficient in the repair of O6-methylguanine lesions, suggesting that these triazenes are capable of generating the monomethyltriazene without the need for metabolic activation.
Vaughan
K
K
Department of Chemistry, St Mary's University, Halifax, Nova Scotia, Canada.
Nicholas
G
G
Singer
R D
RD
Roy
M
M
Gibson
N W
NW
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006868:Hydrolysis; D007700:Kinetics; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D014226:Triazenes / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004364:Pharmaceutical Preparations; D011355:Prodrugs; D014226:Triazenes