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At least 289 records · Page 16Linked to original sources
PubMed1986

Binding of non-intercalating antibiotics to B-DNA: a theoretical study taking into account nucleic acid flexibility.

A detailed theoretical study has been made for five antibiotics which all bind selectively to AT sequences in the minor groove of B-DNA: SN-18071, NSC-101327, distamycin-2, distamycin-3 and netropsin. The optimal complexes were found for systems in which the flexibility of DNA, as well as that of the antibiotics, was taken into account. Explicit, mobile counterions and a dielectric function modelling aqueous solution were also included. The binding geometries of the most strongly interacting antibiotics, distamycin-3 and netropsin, are compared in considerable detail and it is shown that notable differences exist between them. The results for netropsin are also discussed in the light of recent disagreements concerning its exact binding location within DNA.

Anti-Bacterial Agents↗
PubMed1996

DNA minor groove cleaving agents: synthesis, binding and strand cleaving properties of anthraquinone-oligopyrrolecarboxamide hybrids.

Three 9,10-anthraquinone-oligopyrrolecarboxamide hybrids have been prepared as potential DNA minor groove cleaving agents. Each conjugate was designed to contain a bis- or tris-pyrrolecarboxamide moiety related to netropsin or distamycin covalently linked to a 2-substituted anthraquinone chromophore capable of triggering photocleavage of DNA. AQ(NC)-Dist, having three pyrrole rings, is related to distamycin. AQ(NC)-Net and AQ(CN)-Net are related to netropsin; they differ only by the orientation of the amide bond between the anthraquinone and the netropsin moiety. The binding properties of these compounds to various natural DNAs have been studied by footprinting and circular dichroism. The introduction of the chromophore does not abolish the capacity of the drugs to recognize AT-rich sequences in DNA selectively. There is apparently little correlation between this property and the ability to trigger photo-induced DNA cleavage. AQ(CN)-Net is almost totally inactive in the cleavage assays whereas it manifestly binds selectively to AT-rich tracts. With AQ(NC)-Net and AQ(NC)-Dist, complete conversion of form I to form II of circular DNA is obtained. Moreover, in most cases the cleavage of DNA proved to be non-specific.

Amides↗
PubMed1994

Quantitative footprinting analysis.

This review outlines the steps for obtaining relative binding constants for drugs from footprinting data. After correcting the autoradiographic spot intensities for differing amounts of radioactive DNA loaded into the lanes of a sequencing gel, footprinting plots, showing individual spot intensities as a function of drug concentration, are constructed. The initial relative slopes of footprinting plots are proportional to the binding constant of the drug for its DNA site. Slopes of plots outside of drug binding sites can be used to identify locations of altered DNA structure. It illustrates the power of quantitative footprinting analysis by analyzing the binding of the antiviral agent netropsin to a 139-base pair restriction fragment in the presence of the antitumor agent actinomycin D. While two netropsin binding regions are unaffected by actinomycin D a third region experiences enhanced binding in the presence of the antitumor agent.

Autoradiography↗
PubMed1979

Studies on the substrate specificity of the DNA methylase activity from Escherichia coli K-12.

A partially purified extract of DNA methylases from E. coli K-12 containing DNA-adenine as well as DNA-cytosine methylase activities has been examined with respect to different DNA species as substrates. The results show that the natural content of 6-MAP) in the applied DNA represses the DNA-adenine methylase activity. On the other hand, 5-MC, already present in the substrate does not influence the activity of the DNA-cytosine methylase. DNA from Micrococcus radiodurans, which is completely free of methylated bases served as comparison. Since netropsin preferentially binds to AT-rich regions of DNA, the influence of this oligopeptide antibiotic on the methylation of DNA was investigated. As expected the antibiotic predominantly inhibits adenine methylation of DNA. The degree of inhibition depends on the molar ratio of netropsin to DNA phosphate.

Animals↗
PubMed1995

Distinct patterns of cell cycle disturbance elicited by compounds interfering with DNA topoisomerase I and II activity.

DNA topoisomerases are enzymes governing the multitude of conformational changes DNA undergoes during the cell cycle. Several compounds are likely to interfere with specific steps of the catalytic cycle of these enzymes. Camptothecin arrests the activity of DNA topoisomerase I by provoking the formation of a single-stranded DNA break with the enzyme molecule covalently attached to the DNA. Exposure to m-AMSA arrests DNA topoisomerase II by the formation of a ternary complex involving the drug, the enzyme, and DNA carrying a double-stranded break. Netropsin, distamycin A, and berenil inhibit DNA topoisomerase-mediated relaxation of supercoiled DNA by an as-yet unknown mechanism. Here, we analyze the cell cycle kinetic effects of exposure to camptothecin, m-AMSA, netropsin, distamycin A, and berenil by using continuous bromodeoxyuridine labeling followed by bivariate Hoechst 33258/ethidium bromide flow cytometry. Camptothecin elicits an accumulation of cells in all compartments of the cell cycle, while exposure to m-AMSA leads mainly to retention of cells in the G0/G1 compartment and to accumulation in the G2 phase. Neither camptothecin nor m-AMSA shows a synergism with bromodeoxyuridine incorporation into the DNA. These results point toward distinct functions of the two DNA topoisomerases in the process of cell cycle traverse. The compounds binding to the minor groove of DNA interfere with all phases of the cell cycle, but with a relative emphasis on the G2 phase. Neither camptothecin nor m-AMSA exhibits a synergistic effect in combination with berenil. Hence, at the level of perturbed cell cycle kinetics a distinction can be made between compounds provoking an abortive inhibition of the catalytic cycle of DNA topoisomerases (e.g., camptothecin, m-AMSA) and those interfering with the activity of the enzyme by a distinct mechanism.

Amsacrine↗
PubMed1980

Energy transfer and binding competition between dyes used to enhance staining differentiation in metaphase chromosomes.

The ability of electronic energy transfer and direct binding competition between pairs of dyes to enhance contrast in human or bovine metaphase chromosome staining patterns is illustrated, and the relative effectiveness of these two mechanism compared. The existence of energy transfer between quinacrine or 33258 Hoechst and 7-amino-actinomycin D in doubly stained chromosomes is demonstrated directly by microfluorometry. The ability of the dyes 7-amino-actinomycin D, methyl green, or netropsin, acting as counterstains, to displace quinacrine, 33258 Hoechst, or chromomycin A3 from chromosomes, is estimated by quantitative analysis of energy transfer data, by photobleaching of the counterstains, or by selective removal of counterstains by appropriate synthetic polynucleotides. Effects on the fluorescence of soluble 33258 Hoechst-DNA complexes due to energy transfer or binding displacement, by actinomycin D or netropsin, respectively, are further differentiated by nanosecond fluorescence decay measurements. Examples are presented of dye combinations for which (a) energy transfer is the primary mechanism operative, (b) binding competition exists, with consequences reinforcing those due to energy transfer, or (c) binding competition is the most important interaction. These analyses of mechanisms responsible for contrast enhancement in doubly stained chromosomes are used to derive information about the relationship between chromosome composition and banding patterns.

Animals↗
PubMed1996

Influence of minor groove binders on the eukaryotic topoisomerase II cleavage reaction with 41 base pair model oligonucleotides.

This report deals with the cleavage reaction of calf thymus (CT) topoisomerase II with oligonucleotides containing one main cleavage site and adjacent binding sites for minor groove binders. The sequences of the oligonucleotides were derived from a pBR 322 sequence, which contains one main topoisomerase II cleavage site. The cleavage reaction was performed under increasing concentrations of minor groove binders and it showed characteristic inhibition dependences of topoisomerase II to the binding sites and to the binding length of the minor groove binders. The extension of the minor groove binder length on DNA from 4 to 10 base pairs (bp) by netropsin and bis-netropsin, respectively, causes a strong increase of the topoisomerase II cleavage inhibition. The same is observed by the introduction of a second minor groove binder sequence symmetrically positioned around the topoisomerase II main cleavage site. The combination of two different minor groove binders can lead to an increased topoisomerase II inhibition but also to a prevention of total inhibition as shown with chromomycin A3 and distamycin A at concentrations of 0.1 and 0.25 microM, respectively.

Animals↗
PubMed1986

Interference with sporulation can stimulate the rate of a proteinase synthesis in Bacillus megaterium.

Bacillus megaterium, in which sporulation was blocked either by mutation or with netropsin, synthesizes during the stationary phase more exocellular proteinase than the sporulating culture. The asporogenic mutant synthesizes the enzyme at a higher rate and for a longer time than does the sporulating population. The culture, whose sporulation was inhibited by netropsin, produces the proteinase at a higher rate, although for only a limited time interval.

Bacillus megaterium↗
PubMed1986

Origin of sequence-specific recognition of DNA by non-intercalating anti-tumor antibiotics.

Partitioning of energy in the interaction of non-intercalating antibiotics (netropsin, netropsin without its cationic ends and two analogs of distamycin A) with different base sequences of B-DNA is studied here by the atom-atom potential technique and geometry optimization procedures. The results show that electrostatic forces contribute substantially to the stabilization energy as well as to the sequence specificity. The hydrogen-bonding term is also sequence specific and is significant in properly orienting the drug molecule. Relative roles of the hydrogen bonding and electrostatic interactions depend on the dielectric property of the medium.

Antibiotics, Antineoplastic↗
PubMed1993

Selective toxicity to malaria parasites by non-intercalating DNA-binding ligands.

The DNA of malarial parasites is significantly richer in A and T than that of mammalian cells. Antibiotics which bind to the minor groove of B-DNA with a preference for AT-rich sequences, such as distamycin A, netropsin, 4'-6-diamidino-2-phenylindole (DAPI) and bis-benzimide (Hoechst 33258) were found to inhibit the growth and propagation of Plasmodium falciparum in culture. Distamycin A readily inhibited nucleic acid and protein synthesis and was more toxic to the ring stage than to the trophozoite stage in various parasite strains, irrespective of their susceptibility to chloroquine. Distamycin A, netropsin, DAPI and Hoechst 33258 were considerably more toxic to parasites than to mammalian cells, while chromomycin A3 and mithramycin A, which bind preferentially to GC-rich sequences, were either equally toxic or more harmful to mammalian cells. These results suggest that the mere difference in DNA base composition of parasites and host cells may account for the selective toxicity of minor groove ligands. Distamycin A, DAPI and Hoechst 33258 were also found to be more toxic to Saccharomyces cerevisiae grown on glycerol than to yeast cells grown on glucose, consistent with the preferential binding of these ligands to the relatively AT-rich mitochondrial DNA of yeast cell. These results underscore the generality of selective toxicity of minor groove binders endowed by the DNA base composition.

Animals↗
PubMed1997

Conformational transitions of the phosphodiester backbone in native DNA: two-dimensional magic-angle-spinning 31P-NMR of DNA fibers.

Solid-state 31P-NMR is used to investigate the orientation of the phosphodiester backbone in NaDNA-, LiDNA-, MgDNA-, and NaDNA-netropsin fibers. The results for A- and B-DNA agree with previous interpretations. We verify that the binding of netropsin to NaDNA stabilizes the B form, and find that in NaDNA, most of the phosphate groups adopt a conformation typical of the A form, although there are minor components with phosphate orientations close to the B form. For LiDNA and MgDNA samples, on the other hand, we find phosphate conformations that are in variance with previous models. These samples display x-ray diffraction patterns that correspond to C-DNA. However, we find two distinct phosphate orientations in these samples, one resembling that in B-DNA, and one displaying a twist of the PO4 groups about the O3-P-O4 bisectors. The latter conformation is not in accordance with previous models of C-DNA structure.

Crystallography, X-Ray↗
PubMedDate not supplied

The binding of CC-1065 to thymidine and deoxyadenosine oligonucleotides and to poly(dA).poly(dT).

In this work, we report on the binding of the novel antitumor agent CC-1065 to poly(dA).poly(dT) and to mixtures of dA and dT oligomers as determined by electronic absorption and circular dichroism (CD) methods. In addition, the DNA binding properties of CC-1065 and its binding mechanism are compared to those of netropsin. CC-1065 binds to the polymer by at least three mechanisms to produce one irreversibly and two reversibly bound species. One reversibly bound species is moderately stable, but in time (days), it converts to the irreversibly bound species. Both of these species bind within the minor groove of the polymer and exhibit intense CC-1065 induced CD spectra. The other reversibly bound species does not acquire an induced CD. CC-1065 forces B-form duplex formation between mixtures of single strand dA and dT oligomers and binds irreversibly to the duplexes without showing the presence of an intermediate, reversibly bound species. The induced CD increases with increasing length of the oligomer, from the 5-mer (barely detectable CD) to the 14-mer (intense CD). The 7-, 10- and 14-mer mixtures bind about 1, between 1 and 2, and between 2 and 3 CC-1065 molecules, respectively. Computer graphic models of the CC-1065-DNA complex show that the covalent adduct of CC-1065 and unreacted CC-1065 can attain the same close van der Waals contacts between adenine C2 hydrogens and antibiotic CH groups that were observed in the crystal structure of the netropsin-DNA complex. These contacts may account for the dA-dT base pair binding specificity of CC-1065 and for the stability of the reversibly bound CC-1065 species.

Binding Sites↗
PubMedDate not supplied

Poly(pyrrolecarboxamides) linked to photoactivable chromophore isoalloxazine. Synthesis, selective binding, and DNA cleaving properties.

In an attempt to obtain DNA sequence-specific cleaving molecules, we have synthesized two types of hybrid groove binders composed of an isoalloxazine (flavin) chromophore linked through a polymethylenic chain to either a bis- or a tris(pyrrolecarboxamide) moiety related to netropsin and distamycin, respectively. In both types of molecules, the polymethylenic chain is linked to the alloxazine ring either in the N10 position or in the N3 position. As netropsin and distamycin, the hybrid derivatives preferentially bind to A + T-rich sequences and recognize sequences such as 5'-ATTT. Upon visible light irradiation the flavin moiety undergoes a redox cycling process generating superoxide anion and hydroxyl radical. Generation of oxy radicals appears to be more efficient with the hybrids in which the polymethylenic chain is linked at the N10 position. The generation of oxy radicals results in the occurrence of single strand break in supercoiled DNA. Breaks preferentially occur in the vicinity of A + T-rich sequences. The advantage of flavin relative to other oxy radicals generating compounds such as ferrous-EDTA is that it does not require chemical reduction but can be reduced either by visible light or by cellular enzymes, both conditions being compatible with pharmacological constraints.

Amides↗
PubMed1994

Selective binding to polynucleotides of the hybrid intercalating groove binder bis(pyrrolecarboxamide)-oxazolopyridocarbazole: a molecular modeling study.

In order to further characterize the binding of the hybrid molecule NetOPC [bis(pyrrolecarboxamide)-oxazolopyridocarbazole conjugate] to double-stranded DNA, we have performed a molecular modeling study to investigate the binding modes of the complexes possibly formed between NetOPC and synthetic polynucleotides poly [(dA-dT)]2, poly [(dA).d(T)], and poly [d(G-C)]2 and interpreted the results in the light of the experimentally determined binding parameters. In agreement with experimental data, the modeling study suggests that whatever was the binding mode of the complex formed, the complexation energy is markedly lower (thus favorable) for AT-containing polynucleotides than for poly d[(G-C)]2. With both poly [d(A).d(T)] and poly [d(A-T)]2, the most energetically favored complex has netropsin and OPC moieties bound simultaneously in the minor groove of DNA. The second favored complex exhibits the bimodal binding, i.e., intercalation of OPC and minor groove binding of the netropsin moiety. For both types of complex, the energy of complex formation is slightly lower with poly [d(A).d(T)]. The binding site sizes of the modeled complexes are about seven and four base pairs to the full groove and bimodal binding, respectively.

Binding Sites↗
PubMed1985

Mode of reversible binding of neocarzinostatin chromophore to DNA: evidence for binding via the minor groove.

Two general approaches have been taken to understand the mechanism of the reversible binding of the nonprotein chromophore of neocarzinostatin to DNA: (1) measurement of the relative affinity of the chromophore for various DNAs that have one or both grooves blocked by bulky groups and (2) studies on the influence of adenine-thymine residue-specific, minor groove binding agents such as the antibiotics netropsin and distamycin on the chromophore-DNA interaction. Experiments using synthetic DNAs containing halogen group (Br, I) substituents in the major groove or natural DNAs with glucosyl moieties projecting into the major groove show that obstruction of the major groove does not decrease the binding stoichiometry or the binding constant for the DNA-chromophore interaction. Chemical methylation of bases in both grooves of calf thymus DNA, resulting in 13% methylation of N-7 of guanine in the major groove and 7% methylation of N-3 of adenine in the minor groove, decreases the binding affinity and increases the size of the binding site for neocarzinostatin chromophore. Similar results were obtained whether binding parameters were determined directly by spectroscopic measurements or indirectly by measuring the ability of the DNA to protect the chromophore against degradation. On the other hand, netropsin and distamycin compete with neocarzinostatin chromophore for binding to the minor groove of DNA, as shown by their decrease in the ability of poly(dA-dT) to protect the chromophore against degradation and their reduction in chromophore-induced DNA damage as measured by thymine release.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Isohelical analysis of DNA groove-binding drugs.

Many antitumor drugs, and many carcinogens, act by binding within the minor groove of double-helical DNA, interfering with both replication and transcription. Several of these, including netropsin and distamycin, are quite base specific, recognizing and binding only to certain base sequences. The repeating pyrrole-amide unit of netropsin, and the repeated benzimidazole unit of the DNA stain and carcinogen Hoechst 33258, both are approximately 20% too long for synchronous meshing with base pairs along the floor of the minor groove in B DNA. We have carried out a systematic computer search for possible repeating drug backbones that are isohelical with DNA and that also provide chemical groups capable of reading and differentiating between A X T and G X C base pairs. These isohelical sequence-reading drug polymers or "isolexins" should offer the possibility of targeting synthetic drug analogues specifically against one region of a genome rather than another, or against neoplastic cells in preference to normal cells.

Bisbenzimidazole↗
PubMed1988

Novel DNA groove binding alkylators: design, synthesis, and biological evaluation.

A group of oligopeptides has been synthesized that are structurally related to the natural antiviral antitumor agents netropsin and distamycin but which bear alkylating functions. Cytostatic activity against both human and murine tumor cell lines as well as their in vitro activity against a range of viruses is reported. The biological activity of these agents is discussed both in terms of their alkylating reactivity and of their structural differences. The incorporation of alkylating moieties into these minor groove DNA binders results in up to 45-fold increase in cytostatic activity compared with netropsin and up to 18 times the activity of distamycin.

Alkylating Agents↗
PubMed1994

Ligand-induced formation of nucleic acid triple helices.

We demonstrate that ligand binding can be used to induce the formation of triplex structures that would not otherwise form. Specifically, we show that binding of berenil or 4',6-diamidino-2-phenylindole DAPI) induces formation of the poly(rA).poly(rA).poly(dT) triplex, providing an example of an RNA(purine).RNA(purine).DNA(pyrimidine) triplex. We also show that binding of berenil, DAPI, ethidium, or netropsin can induce formation of the poly(dT).poly(rA).poly(dT) triplex, thereby overcoming a practical limitation to the formation of DNA.RNA.DNA triplexes with a purine RNA strand. Based on the enhanced thermal stabilities of the drug-bound poly(dT).poly(rA).poly(dT) complexes at 18 mM Na+, we define the relative triplex-inducing efficiencies of these four ligands to be: berenil > DAPI > ethidium > netropsin. Our results demonstrate that ligand binding can be used to induce the formation of triplex structures that do not form in the absence of the ligand. This triplex-inducing capacity has potentially important implications in the design of novel antisense, antigene, and diagnostic strategies.

Circular Dichroism↗