title: Triazene drug metabolites: part 15. Synthesis and plasma hydrolysis of anticancer triazenes containing amino acid carriers.
abstract: 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.
authors.affiliation: CECF, Faculdade de Farmácia Universidade de Lisboa, Portugal.
authors.forename: E
authors.initials: E
authors.lastname: Carvalho
authors.forename: J
authors.initials: J
authors.lastname: Iley
authors.forename: M J
authors.initials: MJ
authors.lastname: Perry
authors.forename: E
authors.initials: E
authors.lastname: Rosa
mesh_terms: 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
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D004337:Drug Carriers; D014226:Triazenes