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At least 937 records · Page 52Linked to original sources
PubMed1994

Synthesis and iron(III) binding properties of 3-hydroxypyrid-4-ones derived from kojic acid.

In an attempt to reduce the toxicity of the 3-hydroxypyrid-4-ones, the more hydrophilic derivatives of kojic acid were explored and compared to the standard, 1,2-dimethyl-3-hydroxypyrid-4-one, L1. The synthesis and iron(III) binding properties of these chelators are described. Neither these compounds nor the clinically effective 1,2-dimethyl-3-hydroxypyrid-4 one is able to completely remove all of the iron(III) from the Fe(III)EDTA complex in sodium acetate buffered solutions, when the 3-hydroxypyrid-4-one: Fe(III) ratio is 6:1. The ability of these compounds to enhance the urinary excretion of iron in rats indicates that the behavior of the 3-hydroxypyrid-4-ones derived from kojic acid is comparable to the analogous derivatives of maltol and ethyl maltol. The structure of the iron(III) complex of 3-hydroxy-6-hydroxymethyl-1-methylpyrid-4-one was determined by x-ray diffraction and found to be similar to the previously reported structure of the iron(III) complex of L1.

Animals↗
PubMed1994

Organomercury(II) complexes of kojic acid and maltol: synthesis, characterization, and biological studies.

A number of organomercury(II) complexes of kojic acid (HL1, I) and maltol (HL2, II) of the type p-XC6H4HgL1 (III) and p-XC6H4HgL2 (IV) [X = Me, MeO, NO2] have been synthesized and characterized. [formula: see text] Conductance measurements indicate the nonelectrolyte behavior of the complexes. From IR and UV studies, the bonding modes of the ligands to the organomercury(II) moieties have been elucidated. The 1H and 13C NMR spectra support the stoichiometry of the complexes. The fragmentation pattern has been analyzed on the basis of mass spectra. From thermal studies (TG and DTA), various kinetic and thermodynamic parameters for thermal degradation have been enumerated. The complexes have been screened against some pathogenic bacterial strains. The bactericidal activity has been correlated with the thermal data.

Anti-Bacterial Agents↗
PubMed1994

Antiviral activity of natural and semi-synthetic chromone alkaloids.

The activity against human immunodeficiency virus (HIV) and herpes simplex virus (HSV), of the non-polar fraction of a methanolic extract of the rootbark of Schumanniophyton magnificum was found to be present in a fraction containing the chromone secondary amine schumannificine 1. Other chromone alkaloids present in the plant were isolated and tested for inhibition of HIV and HSV infections in C8166 and Vero cells, respectively. Acyl and methyl derivatives were prepared and tested. Of all the compounds tested, schumannificine 1 displayed the greatest activity against HIV, whereas potent anti-HSV activity was observed for a number of its derivatives. The presence of a piperidine ring and unsubstituted hydroxy groups on the molecules seems to favour the anti-HIV activity. The anti-HIV activity is considered to be due to irreversible binding to gp120 rather than inhibition of reverse transcriptase or protease.

Alkaloids↗
PubMed1985

Partial transition-state inhibitors of glyoxalase I from human erythrocytes, yeast and rat liver.

Glyoxalase I (lactoylglutathione lyase, EC 4.4.1.5) converts the hemithiolacetal of glutathione and an alpha-ketoaldehyde to S-D-lactoylglutathione which is hydrolysed under the catalytic influence of glyoxalase II to produce D-lactate and regenerate glutathione. There is much evidence that glyoxalase I operates via an enediol intermediate, and in this study a number of inhibitors are described which were designed based on the enediol moiety of this reactive intermediate. These enediol and paene-enediol moieties were combined with groups designed to make use of an adjacent hydrophobic site and can be described as partial transition-state analogues. Derivatives of lapachol and kojic acid were good competitive inhibitors of glyoxalase I from various sources unless the free hydroxy group was blocked or replaced. Flavones with strong inhibitors of glyoxalase I and gallocyanine (a dye) showed spectral changes on binding to glyoxalase I indicative of binding to a metal-ion site (probably Zn2+ or Mg2+). The use of the enediol-binding determinant to produce glyoxalase I inhibitors is discussed as a route to potential antitumour derivatives.

Animals↗
PubMed1994

Inhibition of the G1-S transition of the cell cycle by inhibitors of deoxyhypusine hydroxylation.

The formation of the unusual amino-acid hypusine in eIF-5A (eukaryotic initiation factor 5A) is associated with cellular proliferation. We used a panel of compounds, including mimosine, to probe the relationship between the exit from the G1 phase of the cell cycle, i.e., the onset of DNA replication, and the formation of hypusine by the enzyme deoxyhypusyl hydroxylase (DOHH). These two parameters displayed the same dose dependency and structure-activity relationship. Only compounds that inhibited DOHH also suppressed proliferation. This effect was observed: (i) in spontaneously proliferating, virally transformed, and mitogen-stimulated cells; (ii) for both anchorage-dependent and anchorage-independent proliferation; and (iii) with normal and malignant cell lines. DOHH reactivation occurred rapidly after inhibitor withdrawal and correlated with synchronized entry into S. The changes in the expression of specific genes during the G1-to-S transition mimicked the physiological pattern. These findings suggest that hypusine formation in eIF-5A which occurs in a specific, invariant sequence motif acquired early in evolution, may be involved in the G1-to-S transition in the eukaryotic cells tested.

Alanine↗
PubMed1990

Preclinical toxicological evaluation of fostriecin, a novel anticancer antibiotic, in rats.

Fostriecin, a novel anticancer antibiotic produced by Streptomyces pulveraecus, is believed to act via inhibition of topoisomerase II. Single-dose intravenous administration to rats at dose levels of 8.8 to 48 mg/kg resulted in lethality at dose levels of 35 mg/kg and higher. Major toxic effects were observed primarily at 17.5 mg/kg and higher, were reversible, and consisted of bone marrow hypocellularity, leukopenia, neutropenia, thrombocytopenia, and diffuse necrosis of various lymphoid tissues. The kidney was also identified as a target organ. Renal effects were observed primarily at 20 mg/kg, were reversible, and included increases in serum BUN, creatinine, and 24-hr glucose excretion. Twenty-four-hour excretion of Na+, K+ and urine osmolality were decreased postdosing at 10 and 20 mg/kg. Renal lesions, observed primarily at 20 mg/kg, consisted of vacuolization and necrosis of proximal and distal tubular epithelium at the corticomedullary junction extending into the medulla. Repeated daily intravenous administration of fostriecin for 5 days to rats at dose levels of 2.5 to 26.5 mg/kg resulted in death at 10 mg/kg and above and similar hematologic, bone marrow, lymphoid tissue, and renal changes as observed in the single-dose study. Hematological, bone marrow, lymphoid, and renal changes observed in rats were consistent with the cytotoxic mechanism of action of the compound.

Alkenes↗
PubMed1991

The toxicity of a fluorinated-biphenyl HMG-CoA reductase inhibitor in beagle dogs.

L-645, 164, a potent inhibitor of hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase, is a structurally unique, synthetic monofluorinated-biphenyl that was administered to beagle dogs at dosages of 2, 10, or 50 mg/kg/day for 14 weeks to evaluate its toxic potential. Previously tested HMG-CoA reductase inhibitors from this laboratory have either been semisynthetic or fermentation-derived products containing a hexahydronaphthalene ring structure (i.e., lovastatin and simvastatin). Administration of L-645, 164 produced a significant spectrum of lesions, some of which have been previously associated with compounds of this pharmacological class, while others were unique to this monofluorinated-biphenyl inhibitor. Subcapsular lenticular opacities were produced in six of eight of the dogs receiving 50 mg/kg/day of L-645, 164 within 8 weeks of dosing. One dog receiving this dosage level experienced increases in serum alanine aminotransferase activity to levels 10 times those in concurrent control dogs. Light and electron microscopy of a wedge biopsy obtained within 3 days of this transaminase elevation failed to reveal any significant changes and the elevation resolved spontaneously despite continued drug administration. Lesions of the optic nerve and acoustic-vestibular tract and trapezoid decussation were observed in several dogs receiving 50 mg/kg/day. In addition, similar changes were observed in the optic tract in several of the dogs receiving 50 mg/kg/day and in one dog receiving 2 mg/kg/day of L-645,164. These were unique to L-645,164 and have not been observed after the administration of other HMG-CoA reductase inhibitors in this laboratory. Optic tract changes were generally mild, consisting of small to medium vacuoles without apparent myelin loss. Lesions in the other areas ranged from very slight to prominent vacuolation. No clinical signs were observed. Peak plasma drug levels of L-645,164 at 50 mg/kg were greater than 5 micrograms/ml, about one order of magnitude greater than those attained after administration of pharmacologically equipotent doses of lovastatin and simvastatin. These findings support previous observations that HMG-CoA reductase inhibitors producing high plasma drug levels are associated with a significant degree of systemic toxicity. In addition, the drug-induced CNS lesions attributed to L-645,164 appear also to be related to its chemical structure since similar lesions have not been observed after the administration of other structurally unrelated HMG-CoA reductase inhibitors that produce high plasma drug concentrations and comparable degrees of serum cholesterol lowering.

Animals↗
PubMed1986

In vitro activity of the novel antitumor antibiotic fostriecin (CI-920) in a human tumor cloning assay.

A human tumor cloning assay was utilized to evaluate the antineoplastic activity of the novel antitumor antibiotic fostriecin (CI-920). Initial screening with 10.0 mcg/ml continuous exposure against a variety of histologic tumor types resulted in 14/51 (27%) in vitro responses (defined as greater than 50% decrease in TCFUs). Further investigation of the compound was performed in 1-hr preincubation experiments. The in vitro response rate at a concentration of 1.0 mcg/ml (which was considered to correspond to a clinically achievable concentration) was 15/43 (35%). Response rates for specific tumor types included: 5/15 in ovarian cancer, 5/12 in breast, and 4/11 in human lung cancer. The impression of significant antitumor activity of the compound at this dose was further substantiated by comparing its in vitro activity with a variety of simultaneously tested standard anticancer agents. In addition, these data indicated the possibility of non-cross resistance of CI-920 to several established cytostatics. CI-920 is a compound with good in vitro activity which should be further developed for clinical trials.

Alkenes↗
PubMed1989

Comparison of the effects of flavone acetic acid, fostriecin, homoharringtonine and tumour necrosis factor alpha on colon 38 tumours in mice.

Advanced subcutaneous Colon 38 tumours in mice were used for the assessment of activity of a number of anticancer drugs. Activity was measured by histological examination of tumours 24 h after a single dose of the drug and in some cases by tumour growth delay. Agents thought to exert their cytotoxic effect by damaging DNA, including Adriamycin, amsacrine and its analogue CI-921, cyclophosphamide, 5-fluorouracil and methotrexate produced no gross histological changes after 24 h, even though some delayed the growth of subcutaneous tumours. In contrast, flavone acetic acid, fostriecin and homoharringtonine caused extensive necrosis of tumours after 24 h, and each delayed the growth of advanced subcutaneous tumours by at least 10 days when administered as a single dose. The histological effects of flavone acetic acid and fostriecin were indistinguishable from those of recombinant human tumour necrosis factor alpha. It is proposed that histological assay of advanced tumours may provide a useful adjunct to existing methods in screening for antitumour agents with novel mechanisms of action.

Alkaloids↗
PubMed1988

Micronucleus tests in mice on 39 food additives and eight miscellaneous chemicals.

A total of 47 chemical substances including 32 synthetic food additives, seven additives from natural sources, three trihalogenated methanes, two fluoro-compounds for dental use, one insecticide, and two other compounds were subjected to the micronucleus test in mice. Five compounds, i.e. chlorine dioxide, maltol, potassium bromate, sodium chlorite and sodium dehydroacetate, were found to induce micronuclei after a single ip injection. Potassium bromate, sodium chlorite and sodium dehydroacetate were tested further by oral administration, and potassium bromate showed a clearly positive result. Almost all the compounds which were negative with the single treatment were additionally tested by four or five multiple treatments, but none showed any indication of micronucleus induction.

Animals↗
PubMed1988

Tissue distribution of gallium following administration of the gallium-maltol complex in the rat: a model for an aluminium-maltol complex of neurotoxicological interest.

The intestinal absorption and subsequent tissue distribution of aluminium-maltol, a potentially neurotoxic complex found in foods, was investigated using gallium as a marker for aluminium. Gallium or gallium-maltol labelled with 67Ga was administered orally to rats. The amount of gallium in 'blood-free' tissues was measured by correcting for gallium in residual blood and an estimate of intestinal absorption was then made by summing the values for all tissues examined. In both the test (gallium-maltol dosed) and control (gallium only dosed) experiments absorption of gallium was significantly increased in the fasted state when compared with that of the fed animals. In fasted but not in fed animals, administration of gallium-maltol doubled the amount of gallium absorbed when compared with administration of gallium alone.

Aluminum↗
PubMed1986

Development of sensitive bacterial tests, exemplified by two mycotoxins.

For a sensitive bacterial test for mycotoxins the cup plate assay, based on growth inhibition, was optimised with Bacillus thuringiensis as test strain. Bacillus thuringiensis allowed the detection of 1.25 microgram kojic acid. A minimal amount of 12.5 micrograms kojic acid or 1.25 micrograms patulin was detectable by means of pigment suppression with isolated mutants of Serratia marcescens, whereas the wild type of this strain was insensitive.

Bacillus thuringiensis↗
PubMed1991

Effect of allixin, a phytoalexin produced by garlic, on mutagenesis, DNA-binding and metabolism of aflatoxin B1.

Allixin, a phytoalexin isolated from garlic, was examined for its effects on aflatoxin B1(AFB1)-induced mutagenesis using Salmonella typhimurium TA100 as the bacterial tester strain and rat liver S9 fraction as the metabolic activation system. The effects of allixin on the binding of [3H]AFB1 to calf thymus DNA and on the formation of metabolites of [3H]AFB1 were also determined. Allixin showed a dose-related inhibition of Histidine+ revertants induced by AFB1. Allixin at 75 micrograms/ml inhibited [3H]AFB1 binding to calf thymus DNA and reduced formation of AFB1-DNA adducts. In addition, allixin exhibited a concentration-dependent inhibition of the formation of organosoluble metabolites and the glutathione conjugates of [3H]AFB1. The data indicate that the effect of allixin on AFB1-induced mutagenesis and binding of metabolites to DNA may be mediated through an inhibition of microsomal P-450 enzymes. Allixin may thus be useful in the chemoprevention of cancer.

Aflatoxin B1↗
PubMed1981

Further evidence for a GABA-like action on kojic amine.

Data are reported to support the hypothesis that kojic amine is a GABA agonist in an in vivo model of GABAergic activity. The unilateral intranigral microinjection of kojic amine elicited dose-related turning contraversive from the injection site. The direction of the turning is identical to that observed after the intranigral administration of muscimol or other GABA agonists. Furthermore, the numbers of turns elicited by kojic amine was significantly reduced following pretreatment with the GABA antagonist, bicuculline. The results suggest that kojic amine is a GABA agonist.

Animals↗
PubMed1985

Inhibition of mitochondrial respiration by asteltoxin, a respiratory toxin from Emericella variecolor.

Asteltoxin, a respiratory toxin from Emericella variecolor, was examined for an inhibitory effect on mitochondrial function. Asteltoxin strongly inhibited state 3 respiration, which was released by an uncoupling agent, 2,4-dinitrophenol (DNP), indicating that the action site of asteltoxin is localized in the energy transfer system of mitochondria. Asteltoxin strongly depressed Mg2+-ATPase activity in mitochondria and only slightly affected Na+, K+-activated ATPase in microsomes at the concentration range for inhibition of mitochondrial respiration.

Animals↗
PubMed1991

Mutagenicity studies of kojic acid.

Kojic acid, a fungal metabolite produced by some species of Aspergillus and Penicillium, was found to induce sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of the rat liver S9 mix. Furthermore, this compound was demonstrated to induce mutations in Salmonella typhimurium strains TA98 and TA100 using both plate-incorporation and preincubation methods.

Animals↗