Studies of the mode of action of antitumor triazenes and triazines. 6. 1-Aryl-3-(hydroxymethyl)-3-methyltriazenes: Synthesis, chemistry, and antitumor properties

Article abstract of DOI:10.1021/jm00369a020

1-Aryl-3-(hydroxymethyl)-3-alkyltriazenes [ArN=NN(CH₃)CH₂OH] have been synthesized by diazonium coupling to the carbinolamine (RNHCH₂OH), generated in situ from the alkylamine and formaldehyde mixtures. The (hydroxymethyl)triazene structure has been confirmed by IR, NMR, and mass spectral analysis and also by the preparation of a crystalline benzoate derivative. The mass spectra of the (hydroxymethyl)triazenes suggest that they fragment by loss of formaldehyde to give the methyltriazene, which is also the product of hydrolysis in solution. The degradation of the (hydroxymethyl)triazenes in solution has been followed by UV spectroscopy and by HPLC analysis, and the half-lives were determined under a variety of conditions. The half-lives of the corresponding methyl- and (hydroxymethyl)triazenes are very similar. Both methyl- and (hydroxymethyl)triazenes decompose on silica plates during TLC analysis to give products consistent with known diazo-migration reactions. The (hydroxymethyl)triazenes have pronounced antitumor activity against the TLX5 tumor in vivo; in vivo-in vitro bioassay experiments suggest that the (hydroxymethyl)triazenes exert their in vivo antitumor activity via the degradation product, the alkyltriazene.