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1.
Some effects of 4(5)-(3,3-dimethyl-1-triazeno)imidazole-5(4)-carboxamide (DIC) on normal proliferating tissues in rats were described. DIC caused marked but transient inhibition of labeled thymidine incorporation into DNA and presumably DNA synthesis of thymus, regenerating liver, spleen and small intestine. The inhibition was reversible and its duration dose dependent. When incorporation of precursors into DNA was markedly inhibited, no consistent concomitant effect on incorporation of precursors into RNA or protein was observed. Karyorrhectic cells appeared in the intestinal crypts as well as signs of necrosis in the thymus after administration of 125 mg/kg of DIC, but no significant pathologic changes were found in the spleen or regenerating liver. The relationship between selective inhibition of DNA synthesis and cytotoxic effect was observed.  相似文献   

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From the reaction of silylated 4-(3,3-dimethyl-1-triazeno)imidazole-5-carboxamide (DTIC, 5) and 3-(3,3-dimethyl-1-triazeno)pyrazole-4-carboxamide (DTPC, 9) with 2-chlorotetrahydrofuran, we have isolated in both cases a single tetrahydrofuran-2-yl derivative. However, when silylated DTPC was reacted with 2-chlorotetrahydropyran, two tetrahydropyran-2-yl compounds were obtained, and these were shown to be positional isomers on the basis of 1H NMR and UV data. These furanyl and pyranyl derivatives were tested for antileukemic activity (L-1210, in vivo) and the results were compared with the results obtained for the corresponding ribosyl derivatives of DTIC and DTPC.  相似文献   

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All experiments were performed in the absence of light. A 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MIC) concentration of less than 10?4 M had no effect on cell growth of L cells. At higher concentrations, the cells were inhibited to levels which were similar to those obtained with equimolar doses of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DIC). MIC inhibited the incorporation of 3H-thymidine by DNA more than that of 3H-uridine by RNA. Uptake of 3H from 3H-methyl-MIC by DNA was not influenced by the stage of the cell cycle. The greatest binding took place with DNA of the euchromatin fraction. MIC-treated DNA exhibited impaired template activity in vitro in the RNA polymerase s ystem but not with that of DNA polymerase. Chromatography of DNA hydrolysate from 3H-methyl-MIC-treated cells showed three major radioactive peaks, which corresponded to adenine, guanine and 7-methylguanine. Hydroxyurea markedly reduced the uptake of 3H by adenine and guanine but had relatively little effect on the 3H content of 7-methylguanine. Similarity of cytotoxic reactions of MIC to those of DIC supports the thesis that in the animal system DIC is metabolically converted to MIC, a potential methylating agent. Many of the effects of DIC can be accounted for by the action of MIC.  相似文献   

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The cytostatic drug dacarbazine [DTIC, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide] is strongly carcinogenic in rats. Bioactivation of DTIC yields a methylating intermediate but the extent of interaction with cellular macromolecules has not previously been reported. Following a single i.p. injection of [14C-methyl]DTIC, exhalation of 14CO2 occurred with a t1/2 max of approximately 2 hr (0.95 mg/kg) and 2.5 hr (95 mg/kg). Of the total radioactivity administered, 8.5% was exhaled as 14CO2; 54% was excreted via the urine, predominantly as unchanged DTIC. In liver, kidney and lung, formation of 7-[14C]methylguanine in DNA and RNA was directly proportional with dose. DNA methylation by a single dose of DTIC (9.8 mg/kg; 5 hr survival time) was highest in liver (35 mumoles 7-methylguanine/mole guanine), followed by kidney (25 mumoles) and lung (20 mumoles). The remainder tissues showed 7-methylguanine concentrations approximately 50% of those in liver DNA, with the exception of the brain which had a very low extent of DNA modification (approximately 1 mumole/mole guanine). At the specific radioactivity used (48 mCi/mmole), the promutagenic base O6-methylguanine was only detectable in liver, kidney, lung, and stomach DNA (0.6-0.8 mumoles/mole guanine). Autoradiographic studies revealed a diffuse distribution of reaction products in rat liver. In contrast, N-nitrosodimethylamine and related carcinogens known to be bioactivated by the hepatic cytochrome P-450 system show a predominantly centrilobular distribution. This difference may be due to the greater stability of proximate carcinogens generated by alpha-C hydroxylation at one of the methyl groups of DTIC.  相似文献   

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Halogenated 4-(3,3-dimethyl-1-triazeno)quinolines were synthesized as potential antitumor agents on the basis of the biochemical pharmacological properties of existing triazenes, their structural-activity relationships, and the high melanin binding of chloroquine and iodoquine in vivo and in vitro. They were synthesized by diazotization of appropriate halogen-substituted 4-aminoquinolines in fluoboric acid at -5 degrees C followed by coupling with dimethylamine. Among these new compounds, 8-chloro-4-(3,3-dimethyl-1-triazeno)quinoline produces significant antitumor activity against both P-388 and L1210 murine leukemias. Although only marginally active or inactive against P-388, the other chloro, bromo, or iodo analogues show activity against L1210 comparable to that of dacarbazine (DIC). However, none of these compounds is active against B-16 melanoma. Compared with DIC these new agents demonstrate a higher in vitro affinity for melanin; however, this affinity is apparently not correlated with their antitumor activity.  相似文献   

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Addition of the cytostatic agent 5-(3,3-dimethyl-1-triazeno)-imidazole-carboxamide (DTIC, dacarbazin) to MH1C1 hepatoma cells, alone or in combination with adrenaline, was shown to elevate intracellular cyclic AMP. The cyclic AMP level was increased from basal values of about 0.40 to about 0.75 pmol/mg protein 10 min. after DTIC addition. Accumulation of cyclic AMP in response to a supramaximal concentration of adrenaline is amplified in a dose-dependent way by 0.1-2 mM DTIC. The effect is apparently due to inhibition of cyclic AMP breakdown, since DTIC inhibits the low-Km form of the cyclic AMP phosphodiesterase without significantly affecting the adenylate cyclase activity of MH1C1 homogenates.  相似文献   

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1-Glycosyl derivatives of 5-aminoimidazole-4-carboxamide   总被引:1,自引:0,他引:1  
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5-氨基咪唑-4-甲酰胺盐酸盐(C4H6N4O·HCI,5-aminoimidazole-4-carboxamide hydrochloride,1),为治疗肝炎类药物阿卡明(aicamin)的组分,其含量测定多采用重氮化反应,以KI淀粉溶液为指示剂,该法不够灵敏.本文采用电位滴定法,准确度略高,能满足药物质控的要求.  相似文献   

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