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PubMed1992

[Ligands possessing affinity to specific DNA base pair sequences. IX. Synthesis of netropsin and distamycin A analogs having sarcolysin residues or a platinum(II) atom].

In search for compounds capable of forming covalent bonds with DNA AT-pair clusters, distamycin A and netropsin analogues containing DL-sarcolysin or platinum (II) atom at the N-terminus of the molecule were synthesized, as well as bis-netropsin and bis-distamycin in which two netropsin- or distamycin-like fragments are bound via a cis-diammineplatinum (II) residue. It is shown that these substances can be used for the DNA selective cleavage.

Base Composition↗
PubMed1975

On the mechanism of inhibition of enzyme induction in Escherichia coli by distamycin A.

The mechanism of the interference of the antiviral antibiotic distamycin A with the bacterial cell has been investigated. Labelled distamycin A is firmly bound by E. coli cells and the binding process does not require metabolic energy as indicated by the use of inhibitors. The antibiotic does not induce gross alteration in the cell membrane but inhibits cyclic AMP accumulation in the cells exposed to a glucose-free medium. This inhibition is concomitant with that exerted on the synthesis of an inducible enzyme such as beta-galactosidase. By the method of pulse induction it appears that distamycin A exterts its inhibiting effect on inducible synthesis at the level of transcription. This effect is probably related to an interference with the positive control of enzyme synthesis performed via the system represented by cyclic AMP and the CRP protein.

Binding Sites↗
PubMed1980

[hyperchromic spectra of DNA complexes with phenosafranine and distamycin A].

Least squares have been applied to study the hyperchromic spectra of thermal denaturation of the complexes of DNA with distamycin A and phenosafranine. Respective components of hyperchromic spectra were found and used to describe the melting of A.T and G.C base pairs and the dissociation of the dye. The interaction of distamycin A with DNA is A.T-specific; this specificity is manifested by inversion of stability of A.T. and G.C base pairs in the course of thermal denaturation. In contrast interaction of phenosafranine with DNA shows only little A.T-specificity. The migration of the ligand is followed as a function of temperature, maximum concentration of the bound ligand is attained at 55-57 degrees for phenosafranine and 65-68 degrees for distamycin A.

Chemical Phenomena↗
PubMed1975

(dA-dT) dependent inactivation of the DNA template properties by interaction with netropsin and distamycin A.

The inhibitory effect of the polypeptide antibiotics netropsin and distamycin A on DNA dependent nucleic acid synthesis has been shown to be related to the base composition of the template DNA. A number of natural DNA's of quite different dA-dT content as well as poly (dI-dC)-poly (dI-dC), poly (dA-dT)-poly (dA-dT), poly (dA) - poly (dT) and poly (dG) - poly (dC) has been studied as templates in DNA and in part in RNA polymerase reaction. The highest binding efficiency of netropsin existing for (dA-dT) - containing DNA polymers and the less pronounced interaction with the (dI-dC)-containing polymer shown by the melting and CD spectrral behaviour of the complexes are entirely reflected in the template inactivation. The same is evident for distamycin A. However, in contrast to netropsin the antibiotic distamycin A exhibits some binding tendency to poly (dG) - poly (dC). Binding effects of a netropsin derivative to DNA and (dA-dT) -containing polymers suggest the importance of hydrogen bonds of the peptide groups in the complex formation.

Adenine Nucleotides↗
PubMed1973

Interaction between deoxyribonucliec acid and distamycin A studied by transformation in Bacillus subtilis.

Distamycin A inhibits deoxyribonucleic acid (DNA)-mediated transformation and transfection in Bacillus subtilis at doses with little or no antibacterial effect. The inhibition of transformation parallels the inhibition of DNA uptake; further-more, during the transformation process, donor DNA molecules become distamycin and deoxyribonuclease resistant at the same time. This demonstrates that the drug acts by inhibiting DNA uptake. Although the drug is known to bind DNA, the inhibition is not related to affinity of the drug for DNA. This is shown by the lack of dependence of the extent of inhibition on DNA concentration, whereas the degree of inhibition depends upon cell concentration. Supporting this view is the fact that transformation by single-stranded DNA was also inhibited, even though the drug does not bind to denatured DNA. Distamycin A probably interferes with transformation by competing with DNA for some unknown bacterial component involved in transport of DNA into the cell.

Amidines↗
PubMedDate not supplied

[Structure of the complexes of distamycin type antibiotics and actinomycin D with DNA: new data on the localization of these antibiotics within the DNA narrow groove].

It is shown that antibiotics actinomycin D (AM), netropsin (Nt), distamycin A (DM) and the propyl analogue of distamycin A (pDM) being complexed with DNA are located within the narrow groove of DNA. A comparative investigation of the 3H-dimethyl sulphate methylation extent of free calf thymus DNA and its complexes with AM, Nt, DM and pDM reveals that upon DNA saturation these antibiotics decrease the methylation level of the narrow groove (AM by 30%, pDM by 50%, DM by 65% and Nt by 70%). In the triple complex of DNA+AM+DM the methylation level of the narrow groove drops by 80%. The large groove is not shielded by these antibiotics at all. However, the methylation level of the large groove decreases by 50% for T6 phage DNA due to the presence of glucosyl residues linked to 5-hydroxymethylcytosine within the large groove. The binding of AM to DNA saturated with Nt or with the analogue of distamycin A (DM2) containing the 2 N-methylpyrrole residues has been investigated by spectrophotometry. The apparent number of binding sites for AM in these 2 complexes is about half as much as observed for free DNA while the saturation level of the binding decreased only by about 20%. This proves simultaneous presence of AM and Nt (DM2) within the narrow groove of DNA.

Animals↗
PubMed2002

Carbocyclic analogues of netropsin and distamycin: DNA-binding properties and inhibition of DNA topoisomerases.

Inhibition of DNA topoisomerase and DNA-binding properties of a series of benzene-containing and C-terminus-modified analogues of distamycin and netropsin are described. These analogues contain two or three benzene units, respectively. Dibenzene analogues did not inhibit the topoisomerases, I and II. In this case, relaxation of DNA was inhibited with tribenzene analogues. Data from the ethidium displacement assay showed that these compounds were able to bind in the minorgroove binding mode in AT sequences of DNA. Molecular modelling experiments were performed to rationalize the lower binding affinity of tribenzene analogues of distamycin and netropsin, 3 and 4, compared to dibenzene analogues, 1 and 2. The superior DNA-binding afforded by 1 and 2 in comparison to 3 and 4 results from their more effective penetration into the minor groove of DNA and smaller perturbation of molecular structure upon complex formation.

Animals↗
PubMed1989

Interactions of nucleic acids with distamycins. The drug monomeric chromophore.

A study of the monomeric chromophore of the oligopeptides netropsin (1), distamycin III (2), and distamycin V (3) by polarization spectroscopy techniques and molecular orbital calculations is reported. Linear dichroism spectra of the monomeric model compounds 1-methyl-2(ethylcarbamoyl)-4-acetamido-pyrrole (4) and 1-methyl-2(ethylcarbamoyl)-pyrrole (5) dissolved and oriented in lyotropic and thermotropic liquid crystals provide, together with the magnetic CD spectra, experimental checks of the theoretical calculations. The polarization directions of the investigated transition obtained by these means in this study allow us to build up in the following paper the exciton states of (1)-(3) and these provide a stereochemical interpretation of the flow linear dichroism spectra of the complexes of DNA with (2) and (3).

DNA↗
PubMed2002

Electrospray ionization tandem mass spectrometric characteristics and fragmentation mechanisms of distamycin analogues.

The electrospray ionization tandem mass spectrometric (ESI-MS/MS) characteristics and fragmentation mechanisms of eight distamycin analogues containing N-methylpyrrole and N-methylimidazole were investigated. The members of two isomeric groups of distamycin analogues with the same elemental composition can be distinguished by MS/MS spectra of protonated molecules and of significant fragment ions.

Antiviral Agents↗
PubMed1980

Carcinogen-DNA interaction: differential effects of distamycin-a and spermine on the formation of 7-methylguanine in DNA by N-methyl-N-nitrosourea, methylmethanesulfonate, and dimethylsulfate.

Experiments were designed to determine whether DNA conformation and sequence play any role in its methylation by N-methyl-N-nitrosourea, methylmethanesulfonate, and dimethylsulfate, agents that are known to methylate DNA by different mechanisms but yield 7-methylguanine as the major product. The approach taken was to bind ligands to DNA that interact with it stereospecifically and to study their effect on the formation of 7-methylguanine by the three methylating agents. The results indicate that both distamycin A and spermine shielded the formation of 7-methylguanine in vitro in rat liver DNA by N-methyl-N-nitrosourea but not by methylmethanesulfonate or dimethylsulfate; they did not, however, protect 2-deoxyguanylic acid against methylation by N-methyl-N-nitrosourea. Based on the mechanism by which the methylating agents and the ligands react with DNA, these results are interpreted to suggest that 1) guanines methylatable at the N-7 position by N-methyl-N-nitrosourea are located at, or close to, the binding sites of the ligands, probably the A-T-rich regions, and those methylatable by methylmethanesulfonate and dimethylsulfate are distal to these regions, and/or 2) the conformation DNA assumes in the presence of distamycin A or spermine permits methylation by methylmethanesulfonate and dimethylsulfate but not by N-methyl-N-nitrosourea. The study implicates DNA structure and/or its sequences in carcinogen-DNA interaction.

Animals↗
PubMed1996

Studies on cooperative binding of an extended distamycin A analogue in the minor groove of DNA by NMR spectroscopy.

An analogue of the DNA minor groove binding antibiotic distamycin A, P4+, was found to bind in a 2:1 cooperative manner into the narrow groove of oligodeoxybibonucleotide d(CGTATATACG)2 by 1D-NMR titration. The resulting 2:1 ligand-DNA complex was characterized by 2D NMR experiments including NOESY, COSY, and TOCSY. Two molecules are oriented side by side opposite to each other; each has the N terminus to C terminus direction parallel to the 5' to 3' direction of its adjacent DNA strand. This study corroborates our previous CD and ethidium fluorometry results and provides new support for the generality of the antiparallel side by side binding motif first observed with distamycin A.

Anti-Bacterial Agents↗
PubMed2000

DNA binding properties of novel distamycin analogs that lack the leading amide unit at the N-terminus.

First examples of distamycin (Dst) analogs which lack hydrogen bond donor or acceptor groups at the N-terminus have been synthesized. The first molecule of this series, which is a bispyrrole peptide, did not exhibit any detectable binding with double-stranded (ds) DNA. However, all other analogs did bind strongly to AT-rich sequences of ds-DNA, with the binding affinities increasing as a function of the number of repeating pyrrole carboxamide units. These results imply that a hydrogen bond donor or acceptor atom per se at the N-terminus is not a prerequisite for DNA binding in the case of pyrrole carboxamide-based Dst analogs. However, in the absence of H-bond donor or acceptor at the N-terminus, a minimum of three pyrrole carboxamide units is necessary for the onset of DNA binding. Beyond this minimum number, the binding affinity increases as a function of the number of pyrrole units, as a result of the greater availability of hydrogen bonding and van der Waals surface. Experiments with poly[d(G-C)] have shown that the presence of the N-terminus formamide group is not inevitable for GC binding of this class of molecules. The observation that the N-terminus formamide unit can be dispensed with suggests that these molecules, which are much easier to synthesize and functionalize, can be used in place of the conventional analogs of distamycin for the development of novel minor groove binders with extended sequence recognition properties.

Binding Sites↗
PubMed1997

Crystal structures of the side-by-side binding of distamycin to AT-containing DNA octamers d(ICITACIC) and d(ICATATIC).

To understand the recognition interactions between AT-containing alternating DNA and minor groove binding drugs, the crystal structures of the side-by-side binding of two distamycin molecules to the DNA octamers d(ICITACIC)2 and d(ICATATIC)2, referred to here as TA and ATAT, respectively, have been determined at 1.6 A and 2.2 A, respectively. Compared to the previous 2:1 all-IC d(ICICICIC)2-distamycin complex, the substitutions of the I x C base-pairs by the A x T base-pairs enable the interactions of the drug with its natural target to be studied. Both complexes assume side-by-side drug binding, isomorphous to the all IC counterpart in the tetragonal space group P4(1)22 (a = b = 28.03 A, c = 58.04 A and a = b = 27.86 A, c = 58.62 A, respectively). The ATAT complex also crystallized in a new polymorphic monoclinic space group C2 (a = 33.38 A, b = 25.33 A, c = 28.11 A and beta = 120.45 degrees) and was solved at 1.9 A resolution. The structures of the three double drug x DNA complexes are very similar, characterized by systematic hydrogen bonding and van der Waals interactions. Each drug hydrogen bonds with the bases of the proximal DNA strand only and stacks with the sugar moiety, while the side-by-side drugs themselves exhibit pyrrole ring-peptide stacking. The pyrrole-peptide interaction is crucial for the side-by-side binding mode of the distamycin/netropsin family of drugs. The purine-pyrimidine alternation is probably responsible for the striking alternation in the helical and backbone conformations. The structures are conserved between the pure IC complex and the AT substituted complexes but further details of the side-by-side binding to DNA are provided by the 1.6 A resolution structure of TA.

Antiviral Agents↗
PubMed1987

The superstructure of chromatin and its condensation mechanism. IV. Enzymatic digestion, thermal denaturation, effect of netropsin and distamycin.

Changes in the structure of chicken erythrocyte chromatin fibres at low ionic strength resulting from enzymatic digestion, thermal denaturation and binding of Netropsin and Distamycin were monitored by synchrotron X-ray solution scattering. Digestion with micrococcal nuclease confirms the previous assignment of the 0.05 nm-1 band to an interference between nucleosomes with an average distance of 23 nm. The results of thermal denaturation indicate that above 40 degrees C there is a progressive increase of the internucleosomal distance and that above 60 degrees C the characteristic structure of the chromatin fibre is destroyed. Binding of Netropsin and Distamycin also results in an increase of the internucleosomal distance which can be estimated to correspond to about 0.2 nm/mol.

Animals↗
PubMed1981

Heterogeneity of human chromosome 9 constitutive heterochromatin as revealed by sequential distamycin A/DAPI staining and C-banding.

Distamycin A/DAPI staining and sequential C-banding of human lymphocyte chromosomes reveals the regular occurrence of differentially staining subfractions of chromosome 9 constitutive heterochromatin. These subfractions are regionally organized as two subsegments: a distal one, which fluoresces brightly with DAPI after preincubation with distamycin A and a proximal one, which stains intensely with Giemsa after sequential C-banding. Observations are presented that indicate an occasionally independent genetic behavior of these heterochromatin subfractions.

Amidines↗
PubMed1983

Familial fragility on chromosome 16 (fra 16q22) enhanced by both interferon and Distamycin A.

A family with a "fragile site" at 16q22, inducible by both interferon and Distamycin A, is reported. Immunological problems were found in the family. In a sibship of ten, eight children had died in infancy. Our study led to the conclusions that interferon and Distamycin A induce fragility at the same site, which has the same characteristics as the spontaneous fragile site; that a viral hypothesis for this fragility may be supported; and that immunoincompetence of one kind or another must be considered in families presenting a fragile site at 16q22.

Adult↗
PubMed1979

Demonstration of Y/autosomal translocations using distamycin A.

The condensation of the brightly fluorescing Y-heterochromatin is prevented by cultivating leukocytes in a medium containing distamycin A. This technique provides a reliable method for the identification of those Y/autosomal translocations in which Y heterochromatin is involved. A case of a familiar Y/22 translocation and the distamycin A technique are described.

Chromosomes, Human, 21-22 and Y↗
PubMed1975

Accessibility of the minor groove of DNA in chromatin to the binding of antibiotics netropsin and distamycin A.

The interaction of the antibiotics distamycin A, distamycin analogue and netropsin with chromatin of calf thymus has been studied by circular dichroism measurements and by gel filtration. The minor groove of DNA in chromatin is accessible by 83-89% to the binding of these antibiotics as compared with that of free DNA. The present results combined with our data on the methylation of chromatin with dimethylsulphate [3] strongly suggest that the minor groove of DNA in chromatin is not occupied by chromatin proteins.

Animals↗