Urinary metabolites of 3,3-dimethyl-1-phenyltriazene

Kolar, G.F.; Schlesiger, J.

doi:10.1016/0009-2797(76)90109-5

Cited by 28 publications

(7 citation statements)

References 20 publications

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“…The origin of arenediazonium ions by hydrolysis of triazenes (pathways A and B1) has been repeatedly reported (Kolar & Preussmann, 1971, Preussmann et al, 1974, Kolar et al, 1974, Malaveille et al, 1976, Kolar, 1984, Gescher & Threadgill, 1987. Kolar & Preussmann, (1971) determined the half-life of a series of 1-aryl-3.3-dimethyltriazenes at pH 7.0 and 37 ° and found values of 210 min for DMPT, 35 min for DMpMPT and 232 000 min for DMpNPT which roughly corresponds to our data.…”

Section: Sister Chromatid Exchange Rates and Cell Cycle Delay Inducedsupporting

confidence: 66%

“…In Neurospora crassa and Saccharomyces cerevisiae, DMPT induced forward mutations (Ong & de Serres, 1973) and mitotic gene conversion (Fahrig, 1971;Vogel et al, 1973), but it could not be clarified whether or not the genetic activity was due to either the direct action of the substance, to its hydrolysis products or to metabolic activation. DMPT was found to be a potent inducer of dominant and recessive lethals in Drosophila, but less active with respect to translocation induction and X-chromosome loss (Vogel et al, 1973;Kolar et al, 1974). In the clastogenicity test in human leukocytes, DMPT was marginally effective (Vogel et al, 1973).…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 1991

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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 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.

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Section: Sister Chromatid Exchange Rates and Cell Cycle Delay Inducedsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

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

et al. 1991

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“…Using the A431 carcinoma of the vulva cell line that coexpresses EGFR and its ligand TGFR and aggressively proliferates by autocrine induction, we found that the aminoquinazolines (4-8) and dimethyltriazenes (12)(13)(14)22, and 24), whose activities were solely dependent on their ability to block EGFR-mediated cell signaling, were in the 50-100 µM range in a basal growth assay. In contrast, all monoalkyltriazenes were more potent than their blocked counterpart ( Table 1).…”

Section: Resultsmentioning

confidence: 98%

“…The primary models focused on 3-monoalkyltriazenes, since 3,3-dialkyltriazenes, despite their superior stability and clinical activity, require metabolic activation to ultimately generate the cytotoxic alkyldiazonium. [10][11][12] This type of compound (12)(13)(14) will be used in this study as examples of non-DNA-damaging combi-molecules.…”

Section: Introductionmentioning

confidence: 99%

“…As depicted in Scheme , in these models the TZ − I represents the triazenoquinazoline, TZ the released methyldiazonium, and the I the released aminoquinazolines. The primary models focused on 3-monoalkyltriazenes, since 3,3-dialkyltriazenes, despite their superior stability and clinical activity, require metabolic activation to ultimately generate the cytotoxic alkyldiazonium. − This type of compound ( 12 − 14 ) will be used in this study as examples of non-DNA-damaging combi-molecules.

2 …”

Section: Introductionmentioning

confidence: 99%

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The Combi-Targeting Concept: Chemical Dissection of the Dual Targeting Properties of a Series of “Combi-Triazenes”

et al. 2003

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The combi-targeting concept postulates that a molecule termed a "combi-molecule" designed to interact with an oncoreceptor on its own and allowed to further degrade to another more stable inhibitor of the latter receptor + a DNA-damaging species should be more potent than the individual combination of the same inhibitor with a DNA-damaging agent in cells expressing the targeted receptor. Recently, using the epidermal growth factor receptor (EGFR) as a target, we demonstrated the feasibility of combi-molecules with dual EGFR/DNA-targeting properties and with the ability to degrade to another potent inhibitor of EGFR. However, despite a clear demonstration of their superior potency when compared with classical combinations in EGFR-expressing cells, the true contribution of each fragment of the combi-molecules to their overall antiproliferative activity remained elusive. Here, we report a structure-function approach whereby a series of quinazoline-based "combi-triazenes" were altered to either abrogate the affinity of the EGFR-targeting quinazoline head or to suppress the DNA-damaging property of the triazene tail. The results showed that (a) inactivation of the quinazoline head by appending an N-methylaniline group to its 4-position reduced EGFR tyrosine kinase (TK) inhibitory activity by ca. 200-fold and decreased the ability of the combi-molecule to block serum-induced growth stimulation in c-erbB2 transfected NIH3T3 cells by ca. 10-fold, (b) abrogation of the alkylating activity or the DNA-damaging potential of the triazene tail by forming 3,3-dimethyltriazenes did not suppress EGFR TK inhibitory affinity but decreased the antiproliferative activity in basal growth assays, and (c) the antiproliferative activities of the monoalkyltriazenes that possessed binary EGFR TK inhibitory and alkylating activities were superior to those of their monotargeted counterparts. The results in toto suggest that each component of the dual targeting property of combi-triazenes plays a critical role in their overall antiproliferative activity.

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Teratogenicity of 3,3‐dimethyl‐1‐phenyltriazene in the rat: Gross malformations including micrognathism

Frank

Thompson²,

Kazacos

1989

Teratology

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3,3-Dimethyl-1-phenyltriazene (DMPT), an alkylating agent, has been reported to be teratogenic in chickens, mice, and rats. One of the most commonly affected structures is the mandible; however, a complete description and incidence rates of all malformations produced have not been published. Rats were treated on day 12 of gestation (day 0 = sperm in vaginal smear) with a single intraperitoneal injection of 30 mg DMPT/kg. Fetuses were examined on each subsequent day of gestation for external and skeletal abnormalities. Standard soft tissue examinations were performed on day-20 fetuses. A high percentage (greater than or equal to 80%) of treated litters contained numerous fetuses with micrognathism, cleft palates, syndactyly, adactyly, and misshapen digits and limbs. Lordosis, cerebellar and cerebral hypoplasia, decreased fetal size, and generalized delayed ossification were also observed. Dams exposed to DMPT had decreased food consumption and weight gains, although clinicopathologic and histopathologic evaluations failed to indicate other evidence of maternal toxicity. DMPT caused numerous permanent structural alterations that were not attributed to maternal toxicity.

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Urinary metabolites of 3,3-dimethyl-1-phenyltriazene

Cited by 28 publications

References 20 publications

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

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

The Combi-Targeting Concept: Chemical Dissection of the Dual Targeting Properties of a Series of “Combi-Triazenes”

Teratogenicity of 3,3‐dimethyl‐1‐phenyltriazene in the rat: Gross malformations including micrognathism

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