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At least 217 records · Page 12Linked to original sources
PubMed2006

New azasterols against Trypanosoma brucei: role of 24-sterol methyltransferase in inhibitor action.

A series of azasterol derivatives, designed as potential inhibitors of the Delta(24)-sterol methyltransferase enzyme (24-SMT), were synthesized and evaluated for their activities against parasitic protozoa. Values in the nanomolar range were obtained for 50% effective dose against the Trypanosoma brucei subsp. rhodesiense bloodstream form cultured in vitro. In order to investigate the mode of action, Trypanosoma brucei subsp. brucei 24-SMT was cloned and overexpressed and compounds were assayed for inhibitory activity. None of the inhibitors tested appeared to be active against the enzyme. Sterol composition analysis showed that only cholestane type sterols are present in membranes of bloodstream forms while ergosterol is a major component of procyclic sterol extracts. Interestingly, Northern blot analysis showed the presence of 24-SMT mRNA in both the procyclic and the bloodstream forms of the parasite, although levels of mRNA were threefold lower in the latter. Likewise, Western blot analysis and activity determinations evidenced the existence of active enzyme in both forms of the parasite. We conclude that the designed compounds act at sites other than 24-SMT in Trypanosoma brucei.

Animals↗
PubMed1975

Carcinogenicity of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, and its metabolites in rats.

Chronic oral administration of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (NSC-45388, DTIC), induced predominantly thymic and mammary tumors as demonstrated previously. Male and female Sprague-Dawley and female Buffalo rats were susceptible to the carcinogenicity of DTIC. A 50% incidence of mammary adenocarcinomas was induced in males within 18 weeks. Type of tumor and tumor incidence were dose dependent. Single and multiple intraperitoneal injections of DTIC did not alter organ specificity. DTIC-induced thymic lymphosarcomas and mammary adenocarcinomas were transplantable. Tissue distribution studies revealed no correlation between uptake of DTIC by a given tissue and its susceptibility to carcinogenicity. Metabolites of DTIC were tested for carcinogenic activity. Animals administered 5-diazoimidazole-4-carboxamide orally, intraperitoneally, or intragastrically developed low incidences of thymic, stomach, bladder, or mammary tumors. A low incidence of mammary tumors developed in rats fed 2-azahypoxanthine. A variety of tumors, including several ependymoblastomas, were induced in rats that received 5-aminoimidazole-4-carboxamide orally. 5-(3-Methyl-1-triazeno)imidazole-4-carboxamide (MTIC), when fed or given in single or multiple intraperitoneal injections, induced a high incidence of mammary adenofibromas and a low incidence of uterine leiomyosarcomas. Control rats had low incidences of mammary adenocarcinomas and adenofibromas after 52 weeks. These data show that the carcinogenic properties of DTIC resemble those of carcinogenic N-nitroso compounds, hydrazine, azo, and azoxy-alkanes and aryltriazenes and thus suggest similar mechanism(s) of action. These data also indicate that MTIC is involved in the induction of mammary adenofibromas and uterine leiomyosarcomas by DTIC.

Adenofibroma↗
PubMed2004

Design, synthesis, and biological evaluation of novel 7-azaindolyl-heteroaryl-maleimides as potent and selective glycogen synthase kinase-3beta (GSK-3beta) inhibitors.

Two approaches were developed to synthesize the novel 7-azaindolyl-heteroarylmaleimides. The first approach was based upon the palladium-catalyzed Suzuki cross-coupling or Stille cross-coupling of 2-chloro-maleimide 5 with various arylboronic acids or arylstannanes. The second approach was based upon the condensation of ethyl 7-azaindolyl-3-glyoxylate 12 with various acetamides. The hydroxypropyl-substituted 7-azaindolylmaleimide template was first used to screen different heteroaryls attached to the maleimide. Replacement of hydroxypropyl with different chain lengths and different functional groups were studied next. Many compounds synthesized were demonstrated to have high potency at GSK-3beta, good GS activity in HEK293 cells and good to excellent metabolic stability in human liver microsomes. Three representative compounds (21, 33, and 34) were demonstrated to have good selectivity against a panel of 80 kinase assays. Among them, compound 33 exhibited very weak inhibitions at the other 79 kinase assays, and behaved as a highly selective GSK-3beta inhibitor.

Animals↗
PubMed2004

Preparation of 4-azaindole and 7-azaindole dimers with a bisalkoxyalkyl spacer in order to preferentially target melatonin MT1 receptors over melatonin MT2 receptors.

Several 4-azaindole and 7-azaindole dimer analogues of melatonin with a bisalkoxyalkyl spacer between the position 5 of each heterocycle were synthetized. Our aim was to investigate the influence of the spacers length on the selectivity of such compounds for the MT(1) receptors over the MT(2) receptors. Our results suggest the distance between indole ring seems to be an important parameter in determining the potency of binding with melatonin receptor site.

Aza Compounds↗
PubMed2004

Construction of azacycles based on endo-mode cyclization of allenes.

A new procedure for constructing monocyclic five- and six-membered azacycles by the endo-mode ring-closing reaction of allenylazido derivatives under neutral conditions has been developed. The azabicyclo[m.n.0] compounds were prepared by applying this newly developed procedure. The seven-membered azacycle was prepared when the allene possessing an unsubstituted carboxyl amido functionality was submitted to the basic conditions. In addition, indole and quinoline skeletons were synthesized using this procedure.

Alkadienes↗
PubMed2006

7-Functionalized 7-deazapurine ribonucleosides related to 2-aminoadenosine, guanosine, and xanthosine: glycosylation of pyrrolo[2,3-d]pyrimidines with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose.

[reaction: see text] The Silyl-Hilbert-Johnson reaction as well as the nucleobase-anion glycosylation of a series of 7-deazapurines has been investigated, and the 7-functionalized 7-deazapurine ribonucleosides were prepared. Glycosylation of the 7-halogenated 6-chloro-2-pivaloylamino-7-deazapurines 9b-d with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (5) gave the beta-D-nucleosides 11b-d (73-75% yield), which were transformed to a number of novel 7-halogenated 7-deazapurine ribonucleosides (2b-d, 3b-d, and 4b-d) related to guanosine, 2-aminoadenosine, and xanthosine. 7-Alkynyl derivatives (2e-i, 3e-h, or 4g) have been prepared from the corresponding 7-iodonucleosides 2d, 3d, or 4d employing the palladium-catalyzed Sonogashira cross-coupling reaction. The 7-halogenated 2-amino-7-deazapurine ribonucleosides with a reactive 6-chloro substituent (18b-d) were synthesized in an alternative way using nucleobase-anion glycosylation performed on the 7-halogenated 2-amino-6-chloro-7-deazapurines 13b-d with 5-O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-alpha-D-ribofuranosyl chloride (17). Compounds 18b-d have been converted to the nucleosides 19b-d carrying reactive substituents in the pyrimidine moiety. Conformational analysis of selected nucleosides on the basis of proton coupling constants and using the program PSEUROT showed that these ribonucleosides exist in a preferred S conformation in solution.

Adenosine↗
PubMed1975

New azasteroidal antifungal antibotics from Geotrichum flavo-brunneum. I. Discovery and fermentation studies.

Although Geotrichum species occur ubiquitously, antibiotic production by members of this genus has not previously been reported. The antibiotic complex designated A25822, consisting of one major and six minor structurally-related components active primarily against Candida and Trichophyton, represents a new family of naturally-occurring compounds. Approximately 90% of the antibiotic activity synthesized remained associated with the fungal cell mass, from which it was recovered by multiple methanolic extractions for quantitation. Antibiotic production was enhanced by tryptophan, iron, zinc, and high levels of dextrin.

Antifungal Agents↗
PubMed1993

Investigation of possible metabolism of pigment yellow 17, a 3,3'-dichlorobenzidine-based pigment, after inhalation exposure in rats.

Rats were exposed by inhalation to the technically highest administrable concentration of 230 mg Pigment Yellow 17/m3 air for 4 h. Inhalability of the dust was guaranteed by a mass-median aerodynamic diameter of 1.0-1.1 microns. For 14 days after exposure, urine and serum samples were analysed for 3,3'-dichlorobenzidine, the parent carcinogenic amine of the test compound. No 3,3'-dichlorobenzidine could be detected either in urine or blood, the detection limit being 5 ng/ml for both media. Based on the results of this study there is no evidence for metabolic cleavage of Pigment Yellow 17 to 3,3'-dichlorobenzidine in the rat.

3,3'-Dichlorobenzidine↗
PubMed2006

PRIMA-1(MET) induces nucleolar accumulation of mutant p53 and PML nuclear body-associated proteins.

We have previously identified PRIMA-1, a low molecular weight compound that restores the transcriptional transactivation function to mutant p53 and induction of apoptosis. To explore the molecular mechanism for PRIMA-1-induced mutant p53-dependent apoptosis, we examined the intracellular distribution of mutant p53 upon treatment with PRIMA-1(MET) by immunofluorescence staining. We found that PRIMA-1(MET) induced nucleolar translocation of mutant p53 and the promyelocytic leukemia (PML) nuclear body-associated proteins PML, CBP and Hsp70. Levels of Hsp70 were significantly enhanced by PRIMA-1(MET) treatment. PRIMA-Dead, a compound structurally related to PRIMA-1 but unable to induce mutant p53-dependent apoptosis, failed to induce nucleolar translocation of mutant p53. Our results suggest that redistribution of mutant p53 to nucleoli plays a role in PRIMA-1-induced apoptosis.

Active Transport, Cell Nucleus↗
PubMed1998

A 2-alkyl substituted 2,3,1-benzodiazaborine.

The structure of the fourth member of a family of structurally related 2,3,1-benzodiheteroborines has been solved by crystallographic means, providing data for proper direct comparison with the others. The title compound, 1,2-dihydro-1-hydroxy-2-methyl-2,3,1-benzodiazaborine (C8H9BN2O) is obtained via condensation of 2-formylbenzeneboronic acid and methylhydrazine, and is similar in most respects to its 2-unsubstituted parent, in internal geometry and intramolecular association topography, but has some subtle oxazaborine-like characteristics.

Aza Compounds↗
PubMed2004

Urinary concentrations and bactericidal activities of newer fluoroquinolones in healthy volunteers.

Eleven healthy male subjects participated in a crossover study to compare the urine concentrations and bactericidal activities of newer fluoroquinolones against common uropathogens. Each volunteer received a single oral dose of gatifloxacin (400 mg), levofloxacin (250 mg), moxifloxacin (400 mg) and trovafloxacin (200 mg), and a urine sample was obtained at 2, 6, 12 and 24 h after the dose. Urine concentrations were highest with gatifloxacin and levofloxacin and lowest with trovafloxacin. Each drug concentration was studied against a levofloxacin susceptible and moderately-susceptible strain of Escherichia coli (minimal inhibitory concentration, MICs: 0.125 and 4 mg/l), K. pneumoniae (MICs: 0.125 and 4 mg/l), Pseudomonas aeruginosa (MICs: 0.5 and 4 mg/l) and Enterococcus faecalis (MICs: 0.25 and 4 mg/l). The duration of urine bactericidal activity (UBA) was based upon the median bactericidal titre at each time period. Both gatifloxacin and levofloxacin exhibited prolonged (> or = 6 h) UBA against all of the study isolates. Moxifloxacin exhibited prolonged UBA against both isolates of E. coli, K. pneumoniae and E. faecalis but not against either strain of P. aeruginosa. Prolonged UBA was not observed for trovafloxacin against the moderately-susceptible strains with the exception of E. faecalis. Furthermore, UBA was not observed for trovafloxacin against the susceptible strain of P. aeruginosa. Although these newer fluoroquinolones exhibited similar in vitro activity against these uropathogens, only those compounds with the highest urinary concentrations (gatifloxacin and levofloxacin) produced prolonged UBA against both strains of P. aeruginosa. The findings from this study suggest that both microbiological activity and urinary concentrations are important parameters to consider when choosing a fluoroquinolone for empirical treatment of urinary tract infections (UTIs).

Adult↗
PubMed1975

Benzopyranopyridine derivatives. 1. Aminoalkyl derivatives of the azaxanthenes as bronchodilating agents.

The preparation of the four isomeric azaxanthones 3 and a number of their aromatic ring substituted derivatives is described. These ketones were converted into the title compounds which were examined for their biological properties. The most interesting compound in this series, the 1-methyl-4-piperidylidene derivative of 1-azaxanthene, shows the profile of an orally effective potent bronchodilating agent as well as a moderate antihistamine. Biological properties of this compound were compared to a number of antihistamines as well as known bronchodilating agents. Structure-activity relationships are also discussed.

Airway Resistance↗
PubMed2005

Photoreaction of [Ru(hat)2phen]2+ with guanosine-5'-monophosphate and DNA: formation of new types of photoadducts.

[Ru(hat)2phen]2+ (HAT=1,4,5,8,9,12-hexaazatriphenylene, phen=1,10-phenanthroline) interacts with a good affinity with polynucleotides and DNA by intercalation, despite the presence of a second voluminous ancillary HAT ligand. It photoreacts with guanosine-5'-monophosphate (GMP). From HPLC, ESMS and NMR analyses, it can be concluded that this complex forms photoadducts with GMP. In contrast to the photoadducts isolated with Ru-TAP complexes (TAP=1,4,5,8-tetraazaphenanthrene), the photoadducts with [Ru(hat)2phen]2+ contain a covalent link between the oxygen atom of the guanine unit and a HAT ligand. Formation of oxidised photoadducts and compounds resulting from the addition of two GMP entities to the complex are also detected as side products. In the presence of oligo- and polynucleotides, [Ru(hat)2phen]2+ yields photoadducts when guanine bases are present.

Aza Compounds↗
PubMed2003

Structure elucidation of Sch 538415, a novel acyl carrier protein synthase inhibitor from a microorganism.

A novel acyl carrier protein synthase inhibitor, Sch 538415 (1), was isolated from an unidentified bacterial microbe. Structure elucidation of 1 was accomplished based on analysis of spectroscopic data including UV, MS and 2D-NMR spectra. Compound 1 exhibited inhibitory activity in the acyl carrier protein synthase (AcpS) assay with an IC(50) value of 4.19 microM and showed antibacterial activity against Staphylococcus aureus in the agar diffusion assay.

Aza Compounds↗
PubMed2006

The identification of pyrimidine-diazabicyclo[3.3.0]octane derivatives as 5-HT2C receptor agonists.

The 5-HT2C receptor has been implicated in the regulation of appetite. As such, small molecule agonists to this receptor may serve as novel therapies to combat obesity. We describe here the identification, synthesis, and SAR of a 5-HT2C agonist from a unique pyrimidine-diazabicyclo[3.3.0]octane series. This compound displayed good potency at the 5-HT2C receptor, modest selectivity relative to other 5-HT2 receptors, and was efficacious in an acute feeding study in rats.

Amines↗
PubMed1999

Synthesis and activity of gamma-(L-gamma-azaglutamyl)-S-(p-bromobenzyl)-L-cysteinylglycine: a metabolically stable inhibitor of glyoxalase I.

The inhibition of glyoxalase I enzyme to increase cellular levels of methylglyoxal has been developed as a rationale for the production of anticancer agents. Synthesis of a peptidomimetic analog of the previously prepared potent glyoxalase inhibitor, S-(p-bromobenzyl)glutathione (PBBG), was accomplished by inserting a urea linkage, NH-CO-NH, to replace the gamma-glutamyl peptide bond. Thus, the target compound, gamma-(L-gamma-azaglutamyl)-S-(p-bromobenzyl)-L-cysteinylglycine 6, was a potent inhibitor of glyoxalase I with almost no loss of activity when compared to PBBG. However, unlike PBBG, 6 was completely resistant to enzymatic degradation by kidney homogenate or by purified gamma-glutamyltranspeptidase enzyme.

Animals↗
PubMed2006

Mechanism of pH-dependent decomposition of monoalkylamine diazeniumdiolates to form HNO and NO, deduced from the model compound methylamine diazeniumdiolate, density functional theory, and CBS-QB3 calculations.

Isopropylamine diazeniumdiolate, IPA/NO, the product of the reaction of isopropylamine and nitric oxide, NO, decomposes in a pH-dependent manner to afford nitroxyl, HNO, in the pH range of 13 to above 5, and NO below pH 7. Theoretical studies using B3LYP/6-311+G(d) density functional theory, the polarizable continuum and conductor-like polarizable continuum solvation models, and the high-accuracy CBS-QB3 method on the simplified model compound methylamine diazeniumdiolate predict a mechanism involving HNO production via decomposition of the unstable tautomer MeNN+(O-)NHO-. The production of NO at lower pH is predicted to result from fragmentation of the amide/NO adduct upon protonation of the amine nitrogen.

Aza Compounds↗