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Biomedical subjects

J M Lehn

Publications and source records attributed to J M Lehn.

At least 19 recordsLinked to original sources
PubMed1994

Synthetic polyamines stimulate in vitro transcription by T7 RNA polymerase.

The influence of nine synthetic polyamines on in vitro transcription with T7 RNA polymerase has been studied. The compounds used were linear or macrocyclic tetra- and hexaamine, varying in their size, shape and number of protonated groups. Their effect was tested on different types of templates, all presenting the T7 RNA promoter in a double-stranded form followed by sequences encoding short transcripts (25 to 35-mers) either on single- or double-stranded synthetic oligodeoxyribonucleotides. All polyamines used stimulate transcription of both types of templates at levels dependent on their size, shape, protonation degree, and concentration. For each compound, an optimal concentration could be defined; above this concentration, transcription inhibition occurred. Highest stimulation (up to 12-fold) was obtained by the largest cyclic compound called [38]N6C10.

Bacteriophage T7↗
PubMed1992

Computational simulations of the conformational behaviour of the adhesive proteins RGDS fragment.

Many adhesive proteins present in extracellular matrices and in blood contain the tetrapeptide sequence -Arg-Gly-Asp-Ser- (or RGDS) at their cell recognition site. Since this sequence, or similar ones, was found in many proteins involved in major biological mechanisms, conformational investigations were performed on the RGDS fragment. A preliminary review of available crystal structures indicates that the RxDy sequences exhibit 3 well-defined structural patterns: one corresponding to a strong interaction between the Arg and Asp ionic side chains which are only about 4 A apart, one with the ions separated by about 8 A, and another in which the side chains are further apart (about 11 A). The conformational behaviour of the isolated RGDS fragment was next tackled using sequential building, Monte Carlo and molecular dynamics computational techniques. Analysis of the RGDS sequence conformational possibilities, as simulated in vacuum and in water solution, indicates that they can be classified into several conformational classes, which correspond roughly to the behaviour of the RGDS fragment as observed in protein matrices. This suggests the possibility of understanding the biological role of the RGDS or parent sequences in recognition processes.

Amino Acid Sequence↗
PubMed1991

Possible catalytic activity of DNA in the reaction between the antitumor drug cis-diamminedichloroplatinum(II) and the intercalator N-methyl-2,7-diazapyrenium.

The platinum(II) complex cis-[Pt(NH3)2(N7-N-methyl-2-diazapyrenium)Cl]2+ formed in the reaction between cis-diamminedichloroplatinum(II) and N-methyl-2,7-diazapyrenium reacts with N7 of guanine residues in DNA. The resulting adduct is kinetically inert within single-stranded DNA. Within double-stranded DNA, it is kinetically inert in 1 M NaClO4 and becomes labile as the salt concentration is decreased. Two products, cis-[Pt(NH3)2(N7-N-methyl-2-diazapyrenium)H2O]3+ and N-methyl-2,7-diazapyrenium, are released. The conformation of the platinated DNA is different in low- and high-salt conditions as shown by the chemical probe diethyl pyrocarbonate. These results are discussed in relation with a possible catalytic role played by the double-stranded DNA.

Base Sequence↗
PubMed1990

Interaction of porphyrin-containing macrotetracyclic receptor molecule with single-stranded and double-stranded polynucleotides. A photophysical study.

Photophysical methods have been used to study the interaction with nucleic acids of a macrotetracyclic cryptand molecule, Pbiph, containing a porphyrin groups, two macrocycles, and a biphenyl bridge. Pbiph binds with a higher affinity to single-stranded polynucleotides than to double-stranded ones. This selectivity, observed by binding and competition studies, using absorption and fluorescence spectroscopy, is pH dependent. Pbiph does not intercalate into double helices and is suggested to bind into the major groove. These features, selective single-strand binding and nonintercalation, are attributed to steric effects of the bulky Pbiph molecule, resulting from the macropolyclic cryptand cage structure.

DNA↗
PubMed1990

DNH deoxyribonucleohelicates: self assembly of oligonucleosidic double-helical metal complexes.

Nucleic acids, because of their key biological role, are prime targets for the design of either analogues that may mimic some of their features or of complementary ligands that may selectively bind to and react with them for regulation or reaction. Whereas there has been much work on the latter topic since the elucidation of the double-helical structure of DNA, comparatively little has been done on structural and/or functional models, probably owing to the lack of self-organizing molecular systems. Here we present a class of artificial systems, the nucleohelicates, which are of interest from both points of view because they combine the double-helical structure of the double-stranded metal complexes, the helicates, with the selective interaction features of nucleic-acid bases. These functionalized species allow the study of structural effects on the formation of the double helix and on the binding to other entities, in particular to nucleic acids.

DNA↗
PubMed1990

Formation of a DNA monofunctional cis-platinum adduct cross-linking the intercalating drug N-methyl-2,7-diazapyrenium.

Our purpose was to better understand the mutual influence of cis-diamminedichloroplatinum (II) (cis-DDP) and intercalating drugs in their interactions with DNA. The present study deals with the intercalating drug N-methyl-2,7-diazapyrenium (MDAP). Two sets of experiments have been performed. In one set, the reaction between cis-DDP and nucleic acid was carried out in the presence of MDAP. The main adduct is a guanine residue chelated by platinum to a MDAP residue. It has the same spectroscopic properties as the synthesized compound cis-[Pt (NH3)2 (N7-d-guanosine) (N7-MDAP)] , the structure of which has been determined by 1H NMR. This adduct was only formed with double-stranded nucleic acids which reveals the importance of DNA matrix in orienting favorably the reactants. In the second set of experiments, the triamine complex cis-[Pt(NH3)2 (MDAP)CI]++ was reacted with the nucleic acids. At molar ratios drug over nucleotide residue equal or less than 0.10, all the added triamine complexes bind by covalent coordination to double-stranded nucleic acids. With natural DNA, the major adduct is cis-[Pt(NH3)2(d-guanosine) (MDAP)] . Thus the same adduct is formed on one hand in the reaction between DNA, MDAP and cis-DDP and on the other hand in the reaction between the triamine complex and DNA. The triamine complex offers the possibility to study the biological role of the new adduct.

Cisplatin↗
PubMed1989

Interactions of the dimethyldiazaperopyrenium dication with nucleic acids. 1. Binding to nucleic acid components and to single-stranded polynucleotides and photocleavage of single-stranded oligonucleotides.

The binding of dimethyldiazaperopyrenium dication (1) with nucleosides, nucleotides, and single-stranded polynucleotides has been studied by photophysical methods. It has been shown that 1 may be a potential selective fluorescent probe for A- and/or T-rich polynucleotides. 1 efficiently cleaves oligonucleotides at guanine sites, under illumination with visible light, and therefore may be used as a sequence-specific artificial photonuclease.

Base Sequence↗
PubMed1989

Interactions of the dimethyldiazaperopyrenium dication with nucleic acids. 2. Binding to double-stranded polynucleotides.

The interactions of dimethyldiazaperopyrenium dication (1) with DNA have been studied by spectroscopic methods: absorption, static and dynamic fluorescence, and linear dichroism. 1 binds strongly to DNA at 250 mM NaCl, with a higher affinity for G-C pairs as compared to A-T pairs. The dye fluorescence is enhanced when it is bound to A-T pairs, whereas the emission is quenched in the vicinity of G-C pairs. Evidence for intercalation has been obtained via energy transfer and linear dichroism measurements.

Base Composition↗
PubMed1987

Efficiency, Na+/K+ selectivity and temperature dependence of ion transport through lipid membranes by (221)C10-cryptand, an ionizable mobile carrier.

The kinetics of Na+ and K+ transport across the membrane of large unilamellar vesicles (LUV) were determined at two pH's when transport was induced by (221)C10-cryptand (diaza-1,10-decyl-5-pentaoxa-4,7,13,16,21-bicyclo [8.8.5.] tricosane) at various temperatures, and by nonactin at 25 degrees C and (222)C10-cryptand at 20 and 25 degrees C. The rate of Na+ and K+ transport by (221)C10 saturated with the cation and carrier concentrations. Transport was noncooperative and exhibited selectivity for Na+ with respect to K+. The apparent affinity of (221)C10 for Na+ was higher and less pH-dependent than that for K+, and seven times higher than the affinity for Na+ of nonactin. Its enthalpy was higher than that of (222)C10 for K+ ions (20.5 vs. 1.7 kcal . mole-1). The efficiency of (221)C10 transport of Na+ was pH- and carrier concentration-dependent, and was similar to that of nonactin; its activation energy was similar to that for (222)C10 transport of K+ (35.5 and 29.7 kcal . mole-1, respectively). The reaction orders in cation n(S) and in carrier m(M), respectively, increased and decreased as the temperature rose, and were both independent of carrier or cation concentrations; in most cases, they varied slightly with the pH. n(S) varied with the cation at pH 8.7 and with the carrier for Na+ transport only, while m(M) always depended on the type of cation and carrier. Results are discussed in terms of the structural, physico-chemical and electrical characteristics of carriers and complexes.

Bridged Bicyclo Compounds↗
PubMed1987

Spontaneous assembly of double-stranded helicates from oligobipyridine ligands and copper(I) cations: structure of an inorganic double helix.

Two oligobipyridine ligands containing two and three 2,2'-bipyridine subunits separated by 2-oxapropylene bridges have been synthesized and some of their complexation properties with metal ions have been investigated. In particular, with copper(I) they form, respectively, a dinuclear and a trinuclear complex containing two ligand molecules and two or three Cu(I) ions. In view of the pseudotetrahedral coordination geometry of Cu(I) X bis(bipyridine) sites and of NMR data indicating that the present complexes are chiral, one may assign to these dinuclear and trinuclear species a double-helical structure in which two molecular strands are wrapped around two or three Cu(I) ions, which hold them together. These complexes may thus be termed "double-stranded helicates." Determination of the crystal structure of the trinuclear species has confirmed that it is indeed an inorganic double helix, possessing characteristic features (helical parameters, stacking of bipyridine bases) reminiscent of the DNA double helix. This spontaneous formation of an organized structure by oligobipyridine ligands and suitable metal ions opens ways to the design and study of self-assembling systems presenting cooperativity and regulation features. Various further developments may be envisaged along organic, inorganic, and biochemical lines.

2,2'-Dipyridyl↗
PubMed1986

Transport of alkali cations through thin lipid membranes by (222)C10-cryptand, an ionizable mobile carrier.

The kinetics of K+ and Na+ transport across the membrane of large unilamellar vesicles (L.U.V.) were compared at two pH's, with two carriers: (222)C10-cryptand (diaza-1,10-decyl-5-hexaoxa-4,7,13,16,21,24-bicyclo[8.8.8.]+ ++hexacosane) and valinomcyin, i.e. an ionizable macrobicyclic amino polyether and a neutral macrocyclic antibiotic. The rate of cation transport by (222)C10 saturated as cation and carrier concentrations rose. The apparent affinity of (222)C10 for K+ was higher and less pH dependent than that for Na+ but resembled the affinity of valinomycin for K+. The efficiency of (222)C10 transport of K+ decreased as the pH fell and the carrier concentration rose, and was about ten times lower than that of valinomycin. Noncompetitive K+/Na+ transport selectivity of (222)C10 decreased as pH, and cation and carrier concentrations rose, and was lower than that of valinomycin. Transport of alkali cations by (222)C10 and valinomycin was noncooperative. Reaction orders in cation n(S) and carrier m(M) varied with the type of cation and carrier and were almost independent of pH; n(S) and m(M) were not respectively dependent on carrier or cation concentrations. The apparent estimated constants for cation translocation by (222)C10 were higher in the presence of Na+ than of K+ due to higher carrier saturation by K+, and decreased as pH and carrier concentration increased. Equilibrium potential was independent of the nature of carrier and transported cation. Results are discussed in terms of the structural, physiocochemical and electrical characteristics of carriers and complexes.

Bridged Bicyclo Compounds↗
PubMed1983

pH regulation of divalent/monovalent Ca/K cation transport selectivity by a macrocyclic carrier molecule.

The lipophilic dicarboxylic acid-dicarboxamide macrocycle 1 is an efficient carrier for calcium and potassium transport through a liquid membrane. The process involves competitive Ca2+/K+ symport coupled to proton antiport in a pH gradient. It presents a very pronounced phenomenon of pH regulation of transport selectivity from preferential K+ transport to preferential Ca2+ transport as the pH increases from 2 to 9 in the starting aqueous phase containing the metal ions. The results demonstrate how carrier design allows control of the rate and selectivity of divalent/monovalent M2+/M+ cation transport.

Calcium↗