Structure/activity investigations in eight arylalkyltriazenes comparison of chemical stability, mode of decomposition, and SCE induction in Chinese hamster V79-E cells

Abstract

A series of seven 1-aryl-3.3-dialkyltriazenes, including 1-phenyl-3.3-dimethyltriazene (DMPT), 1-phenyl-3.3-di-(trideuteromethyl)-triazene (DMPT-ds), 1-p-methylphenyl-3.3-dimethyltriazene (DMpMPT), 1-p-nitrophenyl-3.3-dimethyltriazene (DMpNPT), 1-phenyl-3.3-diethyltriazene (DEPT), 1-phenyl-3.3-di-n-propyltriazene (DnPrPT) and 1-phenyl-3.3-diisopropyltriazene (DiPrPT) and 1.3-diphenyl-3-methyltriazene (DPMT), was synthesized and characterized by UV/VIS, IR and 1H-NMR spectroscopy. Chemical half-life was determined in phosphate buffer at 37 degrees using UV/VIS spectroscopy. With the exception of DMpNPT, which was stable, the triazenes underwent pH-dependent hydrolytic decomposition (acid catalysis). By means of UV/VIS spectra, TLC and HPLC, phenol, aniline and secondary azocoupling products were identified after complete hydrolytic cleavage of the parent compounds. Pathways of spontaneous hydrolysis are proposed and discussed. Genotoxic activity of the triazenes was assayed by measurement of sister chromatid exchanges (SCE) in V79-E cells without and with rat liver S9 mix as an exogenous metabolizing system. In the direct SCE assay (without S9 mix), all triazenes except DMpNPT exerted a toxic action (cell cycle delay) in a narrow concentration range between no effect and overt cytotoxicity. This non-specific toxicity depended on the pH of the incubation system and was inversely proportional to chemical half-life. The toxicity of these agents is most likely due to the arenediazonium cation which is a relatively stable intermediate. In a sublethal concentration range most triazeness induced significant increases of SCE rates. These are interpreted as an indirect consequence of cytotoxicity. Upon metabolic activation, the compounds were genotoxic in a dose-dependent fashion. Their SCE-inducing capacity depended on the nature of the alkylating species generated, i.e., the alkyldiazonium cation, and on chemical stability. Surprisingly, no deuterium isotope effect was observed in DMPT-d6. The order of genotoxic activity among the aryldialkyltriazenes was DMpNPT much greater than DMPT = DMPT-ds greater than DMpMPT much greater than DEPT greater than DnPrPT greater than or equal to DiPrPT. DPMT was a marginal SCE inducer but very toxic upon metabolic activation. As monooxygenation of DPMT, like spontaneous hydrolysis, should generate a phenyldiazonium cation, the results suggest that arylation of DNA causes a very low SCE induction, if any.

Six-Membered Aromatic Polyazides: Synthesis and Application

“…All three azido groups of 1 react with Grignard reagents to give tris -triazenes 9a – d in 47%–70% yield (Scheme 3) [68]. Triazenes are of considerable interest as anticancer drugs and powerful carcinogens [69,70,71].…”

1‐Aryl‐3,3‐diisopropyltriazenes: An Easily Accessible and Particularly Stable Class of Triazenes Towards Strong Basic and Lewis Acid Conditions

“…Most importantly, to avoid this deprotonation is of course the choice of suitable alkyl substituents on N‐3. The aryl substituent on N‐1 on the other hand, should also have its significance as it is also known to influence the acid‐catalyzed cleavage of triazenes 12…”

Ortho‐Trifluormethylierung funktionalisierter aromatischer Triazene

“…[9] Die Toxizität von Triazenen kann hierbei durch Verwendung von diisopropylsubstituierten Triazenen signifikant reduziert werden. [10] Bei der Suche nach einer neuen Spaltungsmethode für Triazene konnten wir durch den Einsatz von Ag 2 CO 3 , KF und TMS-CF 3 in 31 % Ausbeute das ortho-substituierte Triazen 2 a isolieren. Die hier beobachtete Substitution geschieht wahrscheinlich durch in situ erzeugtes AgCF 3 .…”