Triazene drug metabolites: part 15. Synthesis and plasma hydrolysis of anticancer triazenes containing amino acid carriers.
OBJECTIVE
The synthesis of chemically stable triazene prodrugs capable of hydrolysing under physiological conditions to liberate cytotoxic monomethyltriazene alkylating agents.


METHODS
A series of 3-aminoacyl-1-aryl-3-methyltriazenes was synthesised through reaction of 1-aryl-3-methyltriazenes with N-BOC protected amino acids using the DCC method of activation, followed by deprotection of the amino function using HCl in nitromethane. Half-lives for the hydrolysis of these compounds to the corresponding monomethyltriazenes at 37 degrees C in isotonic phosphate buffer and in 80% human plasma containing 20% phosphate buffer were determined by HPLC.


RESULTS
The aminoacyltriazene prodrugs hydrolyse in isotonic phosphate buffer with t1/2 values ranging from 26 to 619 minutes. In human plasma, several decompose at the same rate as in phosphate buffer whereas those containing more lipophilic groups decompose more slowly. A beta-alanyl derivative was found to be more stable in phosphate buffer (t1/2 = 180 minutes) than in plasma (t1/2 = 53 minutes). An N-acetylated alpha-alanyl derivative was found to be chemically stable in phosphate buffer (t1/2 = 10 hours) but liberated the cytotoxic drug in t1/2 = 41 minutes in plasma, demonstrating its ability to act as a substrate for plasma enzymes.


CONCLUSIONS
Aminoacyltriazenes are prodrugs of the antitumour monomethyltriazenes hydrolysing in human plasma with a range of reactivities. The acylation of the alpha-amino group seems to be an effective and simple means of reducing the chemical reactivity of the alpha-aminoacyl derivatives while retaining a rapid rate of enzymatic hydrolysis.
Carvalho
E
E
CECF, Faculdade de Farmácia Universidade de Lisboa, Portugal.
Iley
J
J
Perry
M J
MJ
Rosa
E
E
D000596:Amino Acids / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry; D004337:Drug Carriers; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D014226:Triazenes / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry
D000596:Amino Acids; D000970:Antineoplastic Agents; D004337:Drug Carriers; D014226:Triazenes