PURPOSE: 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.
PURPOSE: 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.
Authors: A S Clark; B Deans; M F Stevens; M J Tisdale; R T Wheelhouse; B J Denny; J A Hartley Journal: J Med Chem Date: 1995-04-28 Impact factor: 7.446