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

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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° 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 consequences 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 ≫ DMPT = DMPT- ds > DMpMPT ≫ DEPT > DnPrPT ≥ DiPrPT. DMPT 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.

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Abbreviations

BUdR:

5-bromodeoxyuridine

CP:

cyclophosphamide

DEPT:

1-phenyl-3.3-diethyltriazene

DiPrPT:

1-phenyl-3.3-diisopropyltriazene

DMPT:

1-phenyl-3.3-dimethyltriazene

DMPT-d6 :

1-phenyl-3.3-di(trideuteromethyl)triazene

DMpMPT:

1-p-methylphenyl-3.3-dimethyltriazene

DMpNPT:

1-p-nitrophenyl-3.3-dimethyltriazene

DnPrPT:

1-phenyl-3.3-di-n-propyltriazene

DPMT:

1.3-diphenyl-3-methyltriazene

SCE:

sister chromatid exchange

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  1. Institute of Pathological Anatomy, Medical Academy of Erfurt, Federal Republic of Germany

    Rudolf Thust, Martin Schneider, Ursula Wagner & Dieter Schreiber

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  1. Rudolf Thust
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  2. Martin Schneider
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  4. Dieter Schreiber
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Thust, R., Schneider, M., Wagner, U. et al. Structure/activity investigations in eight arylalkyltriazenes comparison of chemical stability, mode of decomposition, and SCE induction in Chinese hamster V79-E cells. Cell Biol Toxicol 7, 145–165 (1991). https://doi.org/10.1007/BF00122828

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  • DOI: https://doi.org/10.1007/BF00122828

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