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At least 19 recordsLinked to original sources
PubMed1994

TcO(PnA.O-1-(2-nitroimidazole)) [BMS-181321], a new technetium-containing nitroimidazole complex for imaging hypoxia: synthesis, characterization, and xanthine oxidase-catalyzed reduction.

A technetium(V)oxo nitroimidazole complex that shows promise for imaging regional hypoxia in vivo, [BMS-181321, TcO(PnAO-1-(2-nitroimidazole))] (1) was prepared from 3,3,9,9-tetramethyl-1-(2-nitro-1H-imidazol-1-yl)-4,8-diazaundecane -2,10-dione dioxime, a 2-nitroimidazole-containing derivative of propyleneamine oxime (PnAO). The 99Tc complex [99Tc]Oxo[[3,3,9,9-tetramethyl-1-(2-nitro-1H-imidazol-1-yl)-4,8- diazaundecane-2,10-dione dioximato]-(3-)-N,N',N'',N''']technetium (V) was synthesized both from pertechnetate and [TcO(Eg)2]- (Eg = ethylene glycol). A new synthetic route to TcO(PnAO) (2) is also described. 99TcO(PnAO-1-(2-nitroimidazole)) was characterized by 1H NMR, IR, and UV/vis spectroscopy, HPLC, FAB mass spectrometry, and X-ray crystallography. Electrochemistry of 1 reveals that the nitro redox chemistry found in the ligand is maintained upon coordination to technetium but shifts to a slightly more positive potential. Using chiral HPLC (Chiracel OD), 99mTc (1) was resolved into its two enantiomers. However, the two isomers were found to racemize quickly (t1/2 < 2 min) in the presence of water. Localization of 1 is believed to be mediated by enzymatically catalyzed reduction of the nitroimidazole group, so the in vitro reaction of 99Tc(1) with the nitroreductase enzyme xanthine oxidase (XOD) was studied. XOD catalyzed the quantitative reduction of the nitroimidazole group on the molecule under anaerobic conditions in the presence of hypoxanthine. No reaction was noted using a non-nitro-containing complex (2). The rate of reduction of the Tc-nitroimidazole complex (1.5 +/- 0.16 nmol/min per unit XOD) was faster than that observed previously for the nitroimidazole BATOs (BATO = boronic acid adduct of technetium dioxime) and was about two-thirds that of fluoromisonidazole, a compound that has proven useful for imaging hypoxia in humans when labeled with 18F. These data suggest that BMS-181321 (1) has the potential to be recognized by nitroreductase enzymes in vivo, thus satisfying one of the criteria required for this potential hypoxia imaging agent.

Chromatography, High Pressure Liquid↗
PubMed2002

DNA-targeted 2-nitroimidazoles: studies of the influence of the phenanthridine-linked nitroimidazoles, 2-NLP-3 and 2-NLP-4, on DNA damage induced by ionizing radiation.

The nitroimidazole-linked phenanthridines 2-NLP-3 (5-[3-(2-nitro-1-imidazoyl)-propyl]-phenanthridinium bromide) and 2-NLP-4 (5-[3-(2-nitro-1-imidazoyl)-butyl]-phenanthridinium bromide) are composed of the radiosensitizer, 2-nitroimidazole, attached to the DNA intercalator phenanthridine by a 3- and 4-carbon linker, respectively. Previous in vitro assays showed both compounds to be 10-100 times more efficient as hypoxic cell radiosensitizers (based on external drug concentrations) than the untargeted 2-nitroimidazole radiosensitizer, misonidazole (Cowan et al., Radiat. Res. 127, 81-89, 1991). Here we have used a (32)P postlabeling assay and 5'-end-labeled oligonucleotide assay to compare the radiation-induced DNA damage generated in the presence of 2-NLP-3, 2-NLP-4, phenanthridine and misonidazole. After irradiation of the DNA under anoxic conditions, we observed a significantly greater level of 3'-phosphoglycolate DNA damage in the presence of 2-NLP-3 or 2-NLP-4 compared to irradiation of the DNA in the presence of misonidazole. This may account at least in part for the greater cellular radiosensitization shown by the nitroimidazole-linked phenanthridines over misonidazole. Of the two nitroimidazole-linked phenanthridines, the better in vitro radiosensitizer, 2-NLP-4, generated more 3'-phosphoglycolate in DNA than did 2-NLP-3. At all concentrations, phenanthridine had little effect on the levels of DNA damage, suggesting that the enhanced radiosensitization displayed by 2-NLP-3 and 2-NLP-4 is due to the localization of the 2-nitroimidazole to the DNA by the phenanthridine substituent and not to radiosensitization by the phenanthridine moiety itself.

Animals↗
PubMed1990

Enhancement of melphalan (L-PAM) toxicity by reductive metabolites of 1-methyl-2-nitroimidazole, a model nitroimidazole chemosensitizing agent.

Chemosensitization of bifunctional alkylators by misonidazole (MISO) and related nitroimidazoles in vitro has been shown to require hypoxic exposures. Presumably, reductive metabolism of the nitroimidazole under hypoxic conditions results in generation of a chemosensitizing intermediate(s) in a manner analogous to that described for the hypoxic toxicity of these compounds. In an attempt to identify these intermediates, we examined the ability of reductive metabolites of a model 2-nitroimidazole compound, 1-methyl-2-nitroimidazole (INO2), to enhance the toxicity of melphalan (t-PAM) in HT-29 human colon cancer cells. INO2 was a modest chemosensitizing agent, enhancing L-PAM only under hypoxic conditions. The 2-electron reduction product, 1-methyl-2-nitrosoimidazole (INO), was a potent chemosensitizer, enhancing L-PAM toxicity at micromolar concentrations under either aerobic or hypoxic conditions. In contrast, the 4- and 6-electron reduction products, 1-methyl-2-[hydroxylamino]imidazole and 1-methyl-2-aminoimidazole, respectively, failed to modify cell kill by L-PAM even at millimolar concentration. These results suggest that nitrosoimidazoles may be the active chemosensitizing species generated upon the reductive metabolism of nitroimidazoles.

Buthionine Sulfoximine↗
PubMed1989

Chemosensitization at reduced nitroimidazole concentrations by mixed-function compounds combining 2-nitroimidazole and chloroethylnitrosourea.

A mixed-function compound (I-278) combining 2-nitroimidazole and chloroethylnitrosourea has been shown to be greater than 2-fold more toxic to hypoxic HeLa-MR cells than to cells similarly exposed under aerobic conditions, consistent with chemosensitization of nitrosourea toxicity by the 2-nitroimidazole Misonidazole (MISO). However, in the case of I-278, the enhancement resulted from micromolar concentrations of 2-nitroimidazole as opposed to the millimolar quantities required for a similar enhancement by MISO. These experiments provide evidence (1) that the enhanced hypoxic toxicity of I-278 is not attributable to additional, independent hypoxic cell killing by the nitroimidazole group and (2) that the interaction between the two functions under hypoxic conditions results in increased crosslink formation typical of chemosensitization. The data strongly suggest that the chemosensitizing efficiency of nitroimidazoles can be dramatically improved by covalent linkage to a chloroethylating species.

Cell Survival↗
PubMed1983

Studies on the action of nitroimidazole drugs. The products of nitroimidazole reduction.

The electron requirements for the electrolytic reduction of misonidazole, metronidazole and 4(5)-nitroimidazole have been measured using high-resolution coulometry. Eleven of the labelled final reduction products of metronidazole (a 5-nitroimidazole) have been separated by high-performance liquid chromatography and identified. These appear to be formed without the prior generation of a stable intermediate. In contrast, the reduction products of misonidazole (a 2-nitroimidazole) show little similarity to those of metronidazole but are likely to be formed via the four-electron hydroxylamine derivative. None of the final reduction products show toxicity towards Clostridium bifermentans or Escherichia coli suggesting that the short-lived cytotoxic agent of nitroimidazoles is a reduction product formed by the addition of not more than three electrons.

Chemical Phenomena↗
PubMed1975

The mutagenic action of nitroimidazoles. II. Effects of 2-nitroimidazoles.

The 2-nitroimidazoles Ro-71051 (N-benzyl-2-nitro-1-imidazole-acetamide) and Ro-5-9963 (3(2-nitro-1-imidazolyl)-1,2-propanediol) increased the mutation rate of a Klebsiella pneumoniae mutant to streptomycin-resistance including streptomycin-dependence in Luria and Delbruck's fluctuation test in concentrations of 0.05-1 mM and 0.02-0.2 mM respectively. The 2-nitroimidazole, azomycin, (Ro-5-9129/001) failed to increase the mutation rate. The results are compared to those obtained with the 5-nitroimidazoles methronidazoles metronidazole, nimorazole and dimetridazole, which caused a degree of increase similar to Ro-7-1051 and Ro-59963.

Acetamides↗
PubMed1979

The mutagenic action of nitroimidazoles. IV. A comparison of the mutagenic action of several nitroimidazoles and some imidazoles.

The mutagenic action of 51 imidazoles was investigated. The fluctuation test of Luria and Delbrück was used, with Klebsiella pneumoniae as test organism. 8 compounds, including 5 with a weak mutagenic action in the fluctuation test, were also investigated by the Ames test in which Salmonella typhimurium TA100 was used. Of the 51 imidazoles examined, 33 were nitroimidazoles. 31 of the latter appeared to be mutagenic, whereas out of the 18 other imidazoles without a nitro group only 2 were mutagenic. Several of the substances tested for mutagenicity showed an antimicrobial activity. No direct relationship between antimicrobial action, growth inhibition and mutagenicity was established. With methyl-nitroimidazoles a relationship was found between the chemical structure and mutagenic action. However, when the nitroimidazoles had a more complex chemical structure, a relationship between this structure and mutagenicity could not be established.

Drug Evaluation, Preclinical↗
PubMed1999

The influence of in vitro nitroimidazole resistance on the efficacy of nitroimidazole-containing anti-Helicobacter pylori regimens: a meta-analysis.

OBJECTIVE: The aim of this study was to determine the influence of nitroimidazole resistance (NIR) on the efficacy of treatment for Helicobacter pylori (H. pylori) infections by meta-analysis of the world literature. METHODS: A MEDLINE search, a manual search of all major gastroenterological journals from 1993 to 1997, and abstracts of gastroenterological and H. pylori meetings from 1993 to 1997 were performed. All treatment studies using a nitroimidazole and providing data about the medication used, dose frequency, total daily dose, duration of treatment, and eradication results in relation to NIR were included. Eradication had to be assessed by two biopsy-based tests or a urea breath test > or = 4 wk after treatment. Individual studies were pooled into groups according to the medication used and the duration of treatment. The pooled estimate of the odds ratio (OR) of NIR for treatment failure and its 95% confidence interval (95% CI) were calculated for each group using the logit method. To detect any possible bias, funnel plots (plots of effect estimates against sample size) were constructed. RESULTS: A total of 91 treatment arms, including a total of 4823 patients, were evaluated. The pooled ORs of NIR for treatment failure (95% CI) of proton pump inhibitors, bismuth, and quadruple regimens were 5.2 (3.8-7.1), 5.9 (4.1-8.3), and 7.0 (3.1-16.0), respectively. Eradication rates were 90% in susceptible strains but <75% in resistant strains. In susceptible strains, neither treatment duration nor the choice of the second antibiotic influenced efficacy. In resistant strains, tetracycline was more effective than amoxicillin (bismuth regimens), and the longer the duration of regimens (bismuth-amoxicillin regimens) the more effective they were. Only quadruple regimens given for > or = 1 wk were effective in resistant strains. CONCLUSIONS: NIR decreases treatment efficacy. Treatment duration and choice of other drugs influence the impact of NIR on treatment efficacy. If NIR is present, a nitroimidazole-containing regimen should be avoided or a quadruple regimen should be given for > 1 wk.

Drug Resistance, Microbial↗
PubMed1986

Effect of 1-methyl-5-sulfonamide-4-nitroimidazole and 1-methyl-5-bromide-4-nitroimidazole on the radiosensitivity of EMT6 tumor cells.

The compounds 1-methyl-5-sulfonamide-4-nitroimidazole and 1-methyl-5-bromide-4-nitroimidazole are extremely effective radiosensitizers of hypoxic cells in vitro. Preincubation of hypoxic cells with these and related drugs produces greater sensitization than is obtained with short incubations or is expected from the electron affinities of the compounds. The experiments reported here were undertaken to determine whether these agents were effective in sensitizing the naturally occurring hypoxic cells of solid tumors in mice. Neither of the 4-nitroimidazoles produced significant radiosensitization of the hypoxic cells of EMT6 mouse mammary tumors in vivo with any of the single- or multiple-injection regimens tested.

Animals↗
PubMed1992

Nitroimidazoles, XIV: Synthesis of 4-nitroimidazoles with 1-substituents containing acid, ester or phenol functions, and radiosensitizing efficiency of some of these compounds.

1,4-Dinitroimidazole and 1,4-dinitro-2-methylimidazole were reacted with aminocarboxylic acids and their esters, aminosulfonic acids, and aminophenol to obtain the corresponding 1-substituted-4-nitroimidazoles. The radiosensitizing efficiency of some esters of 2-(4-nitro-1-imidazolyl)alkanecarboxylic acids was tested.

Animals↗
PubMed2006

Nitroimidazoles, part 2: Synthesis, antiviral and antitumor activity of new 4-nitroimidazoles.

A series of 5-alkylamino and 5-alkylsulfanyl derivatives of 1-aryl-2-alkyl-4-nitro-1H-imidazoles 12-21, 31, and 34 were synthesized by a simple method with the aim to develop novel HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs). All the new compounds were tested against HIV-1 and HIV-2 in MT-4 cells. Compound 21, with an arylsulfanyl group at C(5) of the 4-nitro-1H-imidazole backbone showed an EC(50) value of 0.22 microg/ml against HIV-1 with a therapeutic index of 13. This means that compound 21 was cytotoxic to MT-4 cells at a CC(50) value of 2.57 microg/ml; also compounds 8, 22-25, 28, and 29 were cytotoxic to MT-4 cells within the 0.4-4 microg/ml concentration range. Compounds 8, and 12-21 were evaluated, as a rule, but found inactive at non-toxic concentrations against hepatitis C virus, herpes simplex type 1 and 2, cytomegalovirus (CMV), varicella-zoster virus (VZV), vaccinia virus, and vesicular stomatitis virus, and a number of other viruses. Yet, the therapeutic index of compounds 17 and 21 for CMV and VZV approached the tenfold cut-off point. Compounds 8 and 21 exhibited some cytostatic activity against leukemia and melanoma cell lines.

Antineoplastic Agents↗
PubMed1985

Pre-clinical toxicity studies on the new nitroimidazole 1-methylsulphonyl-3-(1-methyl-5-nitroimidazole-2-yl)-2- imidazolidinone.

Administration of 1-methylsulphonyl-3-(1-methyl-5-nitro-2-imidazole-yl)-2-imidazolidinone (Go 10213) at a dose of 5000 mg/kg to rat, mouse, guinea pig and rabbit and 3000 mg/kg to dog did not induce any toxic symptoms or mortality. Repeated daily gavaging with doses ranging from 50-3000 mg/kg/day were tolerated by rats for 2 weeks. No mortality was noticed in treated animals. Reduction in weight gain was observed in male rats on 2000 mg/kg per day and females on 1000 mg/kg per day. No toxic changes were noticed in dogs treated with 200 mg/kg per day for 2 weeks. One monkey treated with 75 mg/kg per day for 4 weeks tolerated the compound without exhibiting any toxic effects. No drug induced alterations were noticed in rats gavaged with 60 and 200 mg/kg per day for 4 weeks. Rats treated with a daily dose of 600 mg/kg showed reduction in body weight gain and atrophy of testes and these changes were reversible after stopping of medication. Dogs medicated with 30 and 100 mg/kg per day tolerated the drug for 4 weeks. Except slight ataxia in a few dogs treated with 100 mg/kg per day, no other drug induced toxic effects were noticed. Neurological symptoms were noticed in all dogs on high dose of 200 mg/kg. Three animals out of six were sacrificed in extremis in this dose. After discontinuation of Go 10213 all dogs on 100 and 200 mg/kg per day recovered normal gait in about a week. No definitive drug induced changes were noticed in laboratory investigations, gross and histopathological examinations.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗