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J L Bernier

Publications and source records attributed to J L Bernier.

At least 37 records · Page 2Linked to original sources
PubMed1992

Redox chemistry of complexes of nickel(II) with some biologically important peptides in the presence of reduced oxygen species: an ESR study.

The reactions between some Ni(II) oligopeptides (Gly-His-Lys, (Gly)4, Asp-Ala-His-Lys, Gly-Gly-His, beta Ala-His, and serum albumin) and reduced oxygen species have been characterized by spin-trapping experiments using DMPO and Me2SO. Most of the peptides possessed superoxide dismutase- and catalase-like activities leading to the formation of either oxene [NiO]2+ or, in the case of beta Ala-His, hydroxyl radicals. Both these species may affect DNA integrity through distinct mechanisms.

Amino Acid Sequence↗
PubMed1992

Scavenger and antioxidant properties of ten synthetic flavones.

To study the effect of the hydroxyl groups on biological activities of flavones, we synthesized 10 polyhydroxyflavones with varied substitution patterns. The abilities of the 10 compounds to act as radical scavengers were investigated using chemiluminescence in two biological models: the xanthine/xanthine oxidase system and the oxidative burst of rat alveolar macrophages. Stable radical formation was observed by electron spin resonance (ESR) spectroscopy. We found that the presence of the pyrogallol moiety in the B component of flavones gave rise to radical scavenger activity and that C-6 substituted hydroxyl group may also provide the basis for biological activity. Furthermore, compounds with a hydroxyl at C-7 position appeared to be xanthine oxidase inhibitors. One particular compound exhibited radical scavenger activity and xanthine oxidase inhibition. This type of compound should prove to be useful in the treatment of ischemia, for which both properties were required.

Animals↗
PubMed1992

Electron microscopic observations of the effects of anthraquinone derivatives on plasmid DNA.

Electron microscopy was used to analyse the precipitation of DNA observed when mixed with two tripeptide derivatives of mitoxantrone, with or without a 5,8-dihydroxy group (DHQ-GHK and Q-GHK, respectively) on the anthraquinonic ring. This precipitation was compared to that obtained with the basic drugs, mitoxantrone (DHAQ) and ametantrone (AQ). The effects of these compounds on the supercoiling of form I and the lengthening of form II of pBR322 DNA molecules, respectively, were evaluated. A strong lengthening of the DNA molecules was observed for ametantrone (max: 57%), but only 32% for Q-GHK, both at r (drug/base pari) = 250. With the dihydroxy derivative DHQ-GHK, it was not possible to show more than a 10% increase in length because DNA molecules were not measurable at r greater than 100. Only Q-GHK relaxed supercoiled molecules at the low r values of 10. Complex phenomena of condensation-precipitation were observed with these two tripeptide derivatives. In addition to a strong lengthening of form II DNA molecules, AQ induced specifically the formation of toruses, and DHAQ that of large organized DNA condensation. The variety of the aggregations is described and discussed with regard to the antitumor properties of these derivatives, and the literature concerning the various descriptions of DNA aggregation.

Anthraquinones↗
PubMed1991

Antioxidant properties of natural hydroquinones from the marine colonial tunicate Aplidium californicum.

Antioxidant prenylated hydroquinones and non active chromene or chroman extracted from the marine colonial tunicate Aplidium californicum have been studied in order to throw some light on their biological activity. It has been found that the active compounds inhibit superoxide anion production in rat alveolar macrophages and in the xanthine/xanthine oxidase system. The antioxidant activity may be ascribed rather to a direct reaction of the superoxide anion with the hydroquinones than to an enzymatic inhibition or a membrane signal transfer. A physiological activity close to that of alpha tocopherol can be considered.

Animals↗
PubMed1990

Plasma membrane perturbations of KB3 cells induced by the bleomycin-iron complex.

The effect of the anticancer drug bleomycin on acyl chain order of KB cell membranes was examined by electron paramagnetic resonance and fluorescence polarization spectroscopies using respectively, the 5-doxyl stearic acid spin probe and the 1,6-diphenyl-1,3,5-hexatriene and the 1-[4-(trimethylammonio)phenyl]-6-phenyl-1,3,5-hexatriene fluorescent probes. Measurements of the order parameter, S, by the two techniques showed a perturbation of the plasma membrane fluidity with bleomycin-iron, while no effect was observed with bleomycin or iron alone. A kinetic study of the location of the 1,6-diphenyl-1,3,5-hexatriene fluorescent probe into the cell was followed by fluorescence microscopy. Lipid peroxidation measurements were also performed using isolated unsaturated lipids, intact cells, or isolated plasma membranes whose purity was checked by electronic microscopy. These membrane perturbation effects not observed with bleomycin-iron in the presence of a hydroxyl radical scavenger, dimethyl thiourea, or a chelating agent, desferrioxamine, were correlated with the ability of the complex to generate highly reactive oxygen species.

Bleomycin↗
PubMed1990

Free radical production and DNA cleavage by copper chelating peptide-anthraquinones.

Two pseudopeptides incorporating a peptide metal-chelating moiety (Gly-His-Lys) and a polyhydroxy anthraquinone ring related to the nuclei of anti-tumor drugs such as mitoxantrone and ametantrone, have been synthesized. The goal was to conjugate the redox effects of a quinone ring with the iron-chelating properties of the peptide in order to generate free radical species capable of damaging DNA. Indeed quinone-containing drugs undergo, in vivo, one-electron reduction to the corresponding semiquinone radicals which, in the presence of molecular oxygen, produce a superoxide anion radical, hydrogen peroxide and ultimately, in the presence of metal, hydroxyl radical (Fenton reaction). Hydroxyl radicals (OH.) are short-lived and extremely reactive with their bioenvironment. The interaction of both drugs with DNA has been studied by fluorescence quenching and DNA melting experiments. Spectroscopic and e.s.r. studies demonstrated that several types of Cu-complex are formed depending on the copper-drug ratio. The production of free radicals, as evidenced by spin-trapping, is optimum with a Cu/drug ratio of 0.1; in this case the metal ion is chelated by the peptide moiety. This latter complex is able to induce DNA breakage at a high level. Thus, it appears that the proposed concept works but that care must be taken in the choice of the relative concentration of copper.

Animals↗
PubMed1989

2,3-bis(2-pyridyl)-5,8-quinoxalinediones with metal chelating properties: synthesis and biological evaluation.

The synthesis of 2,3-bis(2-pyridyl)-5,8-quinoxalinediones has been carried out in order to provide new antitumor drugs related to streptonigrin. Some derivatives have been found to possess significant cytotoxic properties and their mechanism of action has been studied. They were found to induce single-strand cleavage of covalently closed circular DNA (ccc-DNA). This biological activity requires an apparent in situ reduction (NADH activation) of the quinone to a hydroquinone or semiquinone radical, is facilitated by the presence of Cu(II), and involves activation of molecular oxygen to highly reactive radical species. Thus, although less active than the parent drugs, these molecules provide an attractive rationale for the observed cytotoxic and antitumor potency, as well as the cell-free single strand DNA cleavage efficacy of that family of drugs.

Animals↗
PubMed1989

Effect of combination of m-AMSA and doxorubicin on their redox properties and on DNA cleavage.

In vitro studies with the drug combination m-AMSA and doxorubicin were carried out in order to point out whether they can form a redox-system. Indeed, while doxorubicin is known to be bioactivated by NADPH cytochrome P-450 reductase, m-AMSA is readily and reversibly oxidized either chemically or microsomally, to give a quinone diimine with electrophile properties. This redox chemistry has been shown to play a major role in the antineoplastic properties of both drugs. The oxidation of m-AMSA was followed by absorption spectroscopy and the reduction of doxorubicin was observed by circular dichroism. It has been found that both drugs may form a redox-couple and that their association enhances their ability to cut DNA in the absence of cupric ions. Indeed, doxorubicin catalyses the oxidation of m-AMSA in sodium borate buffer (pH 9.25) and conversely the chemical reduction of doxorubicin by m-AMSA induces single and double strand breaks in pBR 322 DNA. This chemical activation may be of importance in vivo, and perhaps the combination of both drugs may lead to a therapeutic advantage.

Amsacrine↗
PubMed1989

Synthesis, biological activity and DNA interaction of anilinoacridine and bithiazole peptide derivatives related to the anti-tumor drugs m-AMSA and bleomycin.

The synthesis of two depsipeptides including a peptide metal-chelating moiety (Gly-His-Lys) and a moiety with DNA affinity, namely either glycyl-anilino-9-aminoacridine 1 or 2'-(2-aminoethyl)-4-methoxycarbonyl-2",4'-bithiazole 2, has been carried out. The goal was to introduce separately on the same molecule the two factors contributing to the biological activity of many anti-tumor drugs. The interaction of both drugs with DNA has been studied and the acridine ring of 1 was found to intercalate in the double helix. The production of free radicals has been evidenced by spin-trapping for 1 although both compounds were revealed to be good copper-chelating agents. In vitro cytostatic activity and inhibition of [3H]-thymidine incorporation were obtained for 1 while 2 exhibited no activity in both tests. In view of these results, it can be pointed out that the anti-tumor properties of such drugs rely (1) on their ability to reach and to bind DNA and (2) on redox mechanisms involving interactions between the drugs, metals and molecular oxygen. The latter phenomenon leads to the formation of active radical species, able to degrade the DNA.

Aminoacridines↗
PubMed1988

The role of the gulose-mannose part of bleomycin in activation of iron-molecular oxygen complexes.

A comparison of the complexing properties of metal ions and O2 activation by bleomycin-A2 (BLM-A2) and deglyco-BLM-A2 is presented. Deglyco-BLM-A2 is obtained from the parent derivative by HF cleavage of the sugar moiety followed by h.p.l.c. purification. Complexing of Cu(II) and Fe(III) is studied by using c.d. and e.s.r. spectroscopy. Spin-trapping experiments in the presence of phenyl N-t-butylnitrone indicated lower production of free radicals by deglyco-BLM-A2. Finally, a proposal is made to explain this discrepancy, focusing on the probable role of the gulose-mannose moiety acting as a protecting pocket, comparable with the pocket and picket-fence porphyrins described for haemoproteins.

Bleomycin↗
PubMed1988

DNA-binding and DNA-cleaving properties of a synthetic model AGAGLU related to the antitumour drugs AMSA and bleomycin.

We have previously described two synthetic models gathering a simplified model of the complexing part of Bleomycin (Blm) and the intercalating moiety of m-AMSA. These molecules, namely AGGA and AGAMGA, do not seem able to cleave DNA as Blm does. The present work is devoted to the study of a new derivative, AGAGLU, which includes in its structure a judiciously chosen connector between the two parts of the molecule. This compound, the chelating and DNA-binding properties of which are described here, has been shown to induce single-strand breakage of duplex DNA in a high level.

Aminoacridines↗
PubMed1987

Complexation of copper(II) by a peptide hybrid of bleomycin and amsacrine. Circular dichroism and electron spin resonance studies.

A model incorporating the metal chelating moiety of bleomycin and an anilinoacridine ring able to intercalate in DNA has been synthesized. The copper(II) complex of that molecule has been studied using circular dichroism and electron spin resonance by comparison with bleomycin. The introduction of the anilinoacridine ring involves a modification in the geometry of the complex. A distortion of the square-pyramidal form (type II complex) gives rise to a type I complex in which the metallic atom is drawn out of the plane of the four square-planar ligands and displaced slightly towards the fifth ligand.

Bleomycin↗
PubMed1987

Chelating, DNA-binding and DNA-cleaving properties of a synthetic model for bleomycin.

We have previously described a simplified model of the complexing part of bleomycin, namely methyl 2-(2-aminoethyl)-aminomethyl-pyridine-6-carboxyl-histidinate (AMPHIS), and disubstituted bithiazoles structurally related to the 'tripeptide S' moiety of bleomycin. The present work is devoted to the study of a new derivative, [3-[2-[2-(2-aminoethyl)-aminomethyl-pyridine-6-carboxyl-histidyl-3 -aminobutyryl-glycyl]-2',4-bithiazole-4-carboxamido]-propyl]- dimethylsulphonium iodide (AMBI-A2), which includes both AMPHIS and a judiciously chosen synthetic bithiazole. This compound, the synthesis of which is described here, has been shown to mimic the chelating and binding properties of the parent drug bleomycin A2, but to cleave DNA at higher concentration.

Bleomycin↗
PubMed1987

Design of two metal-chelating, DNA-binding models: molecular combinations of bleomycin and amsacrine anti-tumour drugs.

In the course of studies on bleomycin, we recently showed that the bithiazole ring is a poor intercalator into DNA. Therefore we have designed new models, replacing this heterocyclic moiety by an anilinoacridine ring in order to increase the affinity for DNA. This work presents results obtained for two model compounds showing (i) that the anilinoacridine nucleus leads to a good stabilization of the DNA helix, and (ii) that the presence of a bulky group near the complexing part of bleomycin is essential to the activation of molecular oxygen.

Amsacrine↗
PubMed1987

Cytotoxic action and cell cycle effects of ALGA, a peptidic derivative of the antileukemic drug amsacrine.

4'-(9-acridinylamino) methanesulfon-m-anisidide (amsacrine or AMSA), an antitumor drug which has been tested in clinical trials, is known to bind to DNA by the intercalation of its 9-amino acridine moiety between DNA base pairs. Like AMSA, a peptidic derivative of 4-(9-acridinylamino) aniline, 4-(9-acridinylamino)-N-(lysylglycyl) aniline (ALGA) binds to DNA by intercalation and its affinity for the target was found to be higher than the parent drug. The antitumor effect of AMSA and ALGA has been monitored by drug exposure assays on EMT 6 cells. AMSA showed a slightly higher cytotoxic activity. The cell cycle effects of both drugs were studied using flow cytofluorimetry; an accumulation of cells in the S phase followed by a cycle arrest in the G2 phase, characteristic of intercalating drugs, was observed.

Amsacrine↗
PubMed1987

Grossularine-1 and grossularine-2, alpha carbolines from Dendrodoa grossularia, as possible intercalative agents.

Dendrodoine A, grossularines-1 and -2, metabolites isolated from the tunicate Dendrodoa grossularia, have exhibited a cytotoxic activity on L1210 leukemia cells in culture. The inhibition of DNA synthesis induced by grossularines and the plane structure of the alpha-carboline common moiety were in favor of an intercalative process for their mechanism of action. In fact, the results of viscometry, fluorescence quenching and DNA melting experiments clearly indicated the intercalative properties of grossularine-2 explained by its quasi-planar structure and the non-intercalative DNA binding of grossularine-1 explained by the presence of a bulky indole chain at the 2-position of the alpha-carboline ring.

Animals↗