[Interaction of bleomycin with the plasmid membrane: changes in the fluidity and peroxidation of lipids].
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Bleomycin↗
Biomedical subjects
R Houssin
Publications and source records attributed to R Houssin.
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
Structure and antiarrhythmic activity of three ketophosphonium salts.
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Animals↗
Conformational analysis of a new analgesic triazolinethione. Structural comparisons with antipyrine.
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Analgesics↗
Structure-neuromuscular blocking activity relationships of ketophosphonium salts.
Three ketophosphonium salts containing a morpholino group were prepared and evaluated for their neuromuscular blocking effect. Solution and crystal conformations were studied. An attempt was made to explain, in structural terms, different activity levels in connection with the interatomic distances.
Animals↗
Opiate receptor interaction of a new analgesic drug 2-piperidinoethyl dibenzylglycolate.
The pharmacological properties of a new analgesic drug, 2-piperidinoethyl dibenzylglycolate (PDG), have been demonstrated by classical tests. The technique of iontophoresis was used in order to compare the effects of PDG with those of Tyr-D-Ser-Gly-Phe-Leu-Thr (DSTLE), syndyphalin, morphine and naloxone (NAL) on hypothalamic neurones. PDG as other four substances evoked only inhibitory responses. Some neurones, on which were tested three substances, were sensitive to one, two or three of these substances. The differential responses so obtained suggested that PDG does not act on mu- and delta-receptors but on an unidentified receptor for which morphine and NAL have a high affinity as agonist. Structural requirements for activity on different receptors were also proposed on the basis of crystallographic data and the above results.
Action Potentials↗
Antitumor combilexin. A thiazole-containing analogue of netropsin linked to an acridine chromophore.
We report the synthesis, DNA-binding properties and antitumor activity of ThiaNetGA, a hybrid molecule in which are conjugated a thiazole-lexitropsin and an intercalating anilinoacridine chromophore. This combilexin molecule binds to DNA via a bimodal process involving minor groove binding of the lexitropsin moiety and intercalation of the acridine moiety. The uptake and distribution of the hybrid in L1210 leukemia cells were investigated by ESR spectroscopy using a spin-labeled derivative. The nitroxide-containing conjugate accumulates preferentially in the cell nuclei and rapidly saturates the nuclear receptor sites. Both in vitro and in vivo assays indicate that the drug is practically nontoxic but exhibits moderate antitumor activity against P388 leukemia cells in mice.
Acridines↗
[1-(2-hydroxyethyl)-1,2,4-triazole esters].
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Animals↗
[Conformational analysis of peptide antagonists in the design of pseudopeptide and non-peptide antagonists].
The comparative conformational analysis of four Substance P antagonists (NK1-) having different chemical structures allowed to formulate an hypothesis for a peptidic NK1 pharmacophore. The salient features of this pharmacophore (three aromatic groups and two carbonyl functions) belong to a beta-turn conformation. Thus, this kind of conformation might be the basis for the design of newer pseudo-peptidic and non-peptidic NK1 antagonists.
Amino Acid Sequence↗