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Biomedical subjects

J L Bernier

Publications and source records attributed to J L Bernier.

At least 55 records · Page 3Linked to original sources
PubMed1986

Molecular interaction between bleomycin and amsacrine in the presence of cupric ions.

The antineoplastic activity of m-AMSA [4'-(9-acridinylamino)-methanesulfon-m-anisidide] has been related to its ability to produce oxygenated free radical during its oxidation to a quinonimine form, in the presence of cupric ions. It has been demonstrated here that the rate of the oxidation is greatly increased by the addition of bleomycin (Blm), another antitumor agent, which is able to complex metallic ions. The catalytic role of Blm has been established on the basis of kinetics measurements and the occurrence of an intermediary ternary complex Blm-m-AMSA-Cu(II) has been demonstrated by circular dichroism and polarography experiments.

Aminoacridines↗
PubMed1986

A new bithiazole derivative with intercalative properties.

In the course of studies related to new molecules with intercalative properties, we have been led to design and synthesize a bithiazole derivative, namely the 2-phenyl-6-[2'-(4'-(ethoxy-carbonyl)thiazolyl)]thiazolo[3,2- b][1,2,4]triazole (PETT). Its interaction with calf thymus DNA was studied using thermal denaturation and viscometry. Our results set in evidence that PETT acts as an intercalator, giving delta Tm, elongation and unwinding of DNA comparable to the values obtained for daunorubicin. The discrepancy between the data presented herein and those precedently obtained for bleomycin and bleomycin models provide evidence that these bithiazole derivatives interact differently with DNA.

Animals↗
PubMed1985

Is the bithiazole moiety of bleomycin a classical intercalator?

Bleomycin is a widespread anticancerous drug, the biological activity of which having been extensively studied. Its metal ion-chelating portion has been shown to cleave DNA whereas the role of the bithiazole moiety is still questionable. In order to elucidate this problem some 2', 4-disubstituted bithiazoles structurally related to the "tripeptide S" moiety of bleomycin were synthesized and their interaction with DNA was studied using delta Tm, fluorescence, EPR and viscometry techniques. The results of delta Tm and fluorescence quenching determinations were in favour of a binding of the bithiazole part by an intercalation process. Nevertheless, the use of the spin-label probes indicated only a partial intercalation of the ring between the base-pairs. Moreover, viscometry data which clearly exhibited a slight decrease of DNA length in the presence of bithiazole derivative led to the proposal of a binding model involving a partial insertion of a thiazole ring which wedges in between the bases at a bending point of DNA.

Animals↗
PubMed1985

Copper(II)- and iron(II)-complexes of methyl 2-(2-aminoethyl)-aminomethyl-pyridine-6-carboxyl-histidinate (AMPHIS), a peptide mimicking the metal-chelating moiety of bleomycin. An ESR investigation.

Methyl 2-(2-aminoethyl)-aminomethyl-pyridine-6-carboxyl-histidinate (AMPHIS), a synthetic analogue of the chelating part of bleomycin (BLM), has been studied for its metal binding properties. Electron spin resonance parameters of AMPHIS-Cu(II) and BLM-Cu(II) have been found to be closely similar likewise spectra of oxygen radicals spin-adducts induced by AMPHIS-Fe(II)-O2 and BLM-Fe(II)-O2 systems. Thus, AMPHIS could constitute a very useful tool for the study of BLM mode of action.

Binding Sites↗
PubMed1985

Design of a new DNA-polyintercalating drug, a bisacridinyl peptidic analogue of Triostin A.

The synthesis of a new bifunctional compound in which two aminoacridine chromophores are linked by the bicyclic depsipeptidic backbone of des-N-tetramethylTriostin A is described. The molecule, bis-[(9-acridinyl)-D-seryl-L-alanyl-L-cysteinyl-L-valine] dilactone disulphide, structurally analogous to the antibiotic anti-tumour drug Triostin A, is shown to possess a high affinity to DNA and to act as a bis-intercalator on the basis of spectroscopic, viscosimetric and thermal-denaturation studies. This model constitutes the first attempt of a synergic association between a peptidic moiety that mimics a naturally occurring drug and aminoacridine, the two parts themselves each exhibiting a high affinity for the DNA target.

Aminacrine↗
PubMed1985

5-Cinnamoyl-6-aminouracil derivatives as novel anticancer agents. Synthesis, biological evaluation, and structure-activity relationships.

A biological evaluation in the series of 5-cinnamoyl-6-aminouracils has been undertaken. These compounds have been found to be in an extended planar conformation fitting well with a possible stacking interaction between the nucleic bases of DNA; thus an eventual anticancer activity by intercalation could be hoped. 1,3-Dimethyl-5-cinnamoyl-6-aminouracil was found to be active when administered ip against ip-implanted P388 leukemia in vivo (percent T/C = 124). Two other compounds, 1,3-dimethyl-5-cinnamoyl-6-[(2-morpholinoethyl)amino]uracil and 1,3-dimethyl-5-cinnamoyl-6-[(2-piperidinoethyl)amino]uracil, bearing a hydrophilic side chain on the 6-amino group, have exhibited cytoxic activity in vitro against L1210 leukemia. Structure-activity relationships have been determined from these results and from studies of biological interactions with DNA.

Animals↗
PubMed1984

Conformation of physalaemin.

The conformational and spatial configuration of the biologically active undecapeptide physalaemin was studied using 350-MHz1H NMR. The NMR analyses suggested the existence of a strong hydrogen bond between the amide proton of the Phe7 and a carbonyl group in the N-terminal moiety, most likely the Pro4 one. Other bondings were postulated, involving the side-chain amine of Lys6 and the side-chain amide of Asn5 and respectively the side-chain carboxyl of Asp3 and the terminal amide carbonyl of Met-NH2. Thus unlike its shorter peptidic fragments, physalaemin exhibited a stable molecular structure in solution, giving some insight into the conformation required for interaction at the biological receptor of tachykinins.

Hydrogen Bonding↗
PubMed1984

Preferential binding to delta-receptors of the enkephalin-like tetrapeptide Tyr-Ile-Phe-Val. Electrophysiological and conformation studies.

The technique of microiontophoresis was used to study the effects of leucine-enkephalin [( Leu]enkephalin) and the tetrapeptide Tyr-Ile-Phe-Val on spontaneous and evoked activity of guinea-pig hypothalamic neurons. The inhibitory effects of the tetrapeptide were similar to those of [Leu]enkephalin on some neurons. However, in other cases, [Leu]enkephalin was inhibitory whereas Tyr-Ile-Phe-Val was without effect. These data and the fact that naloxone caused a different antagonism of inhibitory effects by these two peptides suggest the existence of two types of opiate receptors on some hypothalamic neurons and that Tyr-Ile-Phe-Val preferentially binds to delta-receptors. Conformational features of Tyr-Ile-Phe-Val have been established by 1H-NMR spectroscopy and were found to be in accordance with the above considerations. The peptide has a peculiar folded conformation called gamma-turn. Due to the restricted flexibility of this structure, the aromatic moieties (Tyr and Phe) and the hydrophobic (Val) or hydrophilic (terminal NH2 and CO2H) parts are positioned in a specific spatial relationship which can be related to an optimal binding to delta-receptors.

Animals↗
PubMed1984

Subcellular distribution of spin-labeled bithiazoles and bleomycin in living KB cells: an ESR study.

Spin-labeled derivatives of bithiazole and bleomycin were studied with respect to their uptake and localization in KB cells in vivo. It was found that the amidification of the C-terminal carboxylic group of bleomycinic acid was essential for the penetration of the probes in the cells and that the subcellular localization depended on the number and spacing of positively charged groups.

Bleomycin↗
PubMed1983

Subcellular distribution of nitroxide spin-labelled 9-aminoacridine in living KB cells.

A spin-labelled derivative of 9-aminoacridine, the AATEMPO, was studied with respect to its localization in KB cells in vivo. It was found that both nuclear and mitochondrial DNAs were targets for this intercalating dye. The observed speed of intercalation and the absence of a blocked signal in cellular membranes suggested that no receptor -or carrier- proteins were implied in the penetration process. No changes in cell membrane fluidity were observed following the administration of m-AMSA, the unlabelled structural analog, to the living cells, which seemed to exclude the plasma membrane as a possible site of action of 9-aminoacridines. Side effects of phenol/chloroform mixtures and high-salt concentrations on the intercalation phenomenon were also described.

Binding Sites↗
PubMed1982

Identification of calcium palmitate in gallstones by infra-red spectroscopy.

Crystallographic studies have shown that calcium palmitate was the fourth most frequent crystalline constituent of gallstones, but it has never been detected using an infra-red technique. This report demonstrates that IR spectroscopy represents an accurate and easy method for detection of this compound in gallstones. First, palmitic acid has been unequivocally identified from gallstones after chloroformic extraction in an acidic medium, on the basis of 1H NMR and mass spectra. Secondly, the characteristic bonds of pure calcium palmitate have been well established (2920, 2850, 1575, 1540, 1470, 1430, 1412, 1110, 710 cm-1) enabling the identification of this compound isolated or in association with other components of calculi.

Bilirubin↗
PubMed1982

Interaction of 4-(9-acridinylamino)aniline and derivatives with DNA. Influence of a lysylglycyl side chain on the binding parameters.

N-[4-(9-Acridinylamino)-3-methoxyphenyl]methanesulfonamide, an antitumor drug which has been tested in clinical trials, is known to bind to DNA by the intercalation of its 9-aminoacridine moiety between DNA base pairs and its anilino side chain would then be located in the narrow groove. The intercalatice binding of the drug has been studied here, using ESR through competition with a spin-labelled 9-aminoacridine. In addition the affinity parameters of the parent compound 4-(9-acridinylamino)aniline and a new peptidic derivative, 4-(9-acridinylamino)-N-(lysylglycyl)aniline, have been evaluated by the same technique. Thus the influence of the side chains structures on the dissociation constant values was determined. The results reported here suggest that the affinity of this drug to DNA could be increased by the introduction of a lysyl residue.

Aminoacridines↗
PubMed1981

Design, synthesis and DNA-binding capacity of a new peptidic bifunctional intercalating agent.

A lysyl-lysine bifunctional derivative of 9-aminoacridine has been synthesized and its DNA-binding capacity established by electron-paramagnetic-resonance study. For this purpose the binding parameters of a spin-labelled aminoacridine probe were estimated and the affinities of the lysylacridinyl-lysyldiamino-octane dimer and of 9-amino-acridine could be evaluated by competitive assays. The competition study provided quantitative results concerning the dissociation constant (KD) of the dimer. The obtained value was closely similar to the KD of 9-aminoacridine determined by the same method and to the KD previously reported for the anti-tumour and antibiotic bifunctional intercalator quinomycins.

Aminacrine↗
PubMed1980

Synthesis and structure--activity relationship of a pyrimido[4,5-d]pyrimidine derivative with antidepressant activity.

The synthesis and antidepressant properties of a new pyrimido[4,5-d]pyrimidine are described. Spectral data determined in solution and in the solid state allowed establishment of the relationship between the activity and the conformation of the molecule. The spatial structure seems to be in accordance with a possible binding at the presynaptic alpha-receptor sites.

Antidepressive Agents↗