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PubMed1997

The interaction of DNA with intercalating agents probed by sodium-23 NMR relaxation rates.

We have investigated the changes of Na-23 NMR spin-lattice and spin-spin relaxation rates of Na-DNA in dilute aqueous solutions, induced by the intercalating drugs ethidium, propidium, 6,7-dihydro-pyrido[2',1':3,4]pyrazino[1,2-f]-phenanthridinediium dihydrate (dq2pyp) and by the electrostatic binder Mg2+. It has been found that the Na-23 spin-lattice relaxation is monoexponential, while the spin-spin relaxation follows a biexponential law. From the linear trends of the relaxation rates observed in the titration experiments of Na-DNA with the drugs we inferred the validity of a two-site model in the fast exchange limit. The relaxation rates of sodium in the bound state have been estimated by using the fraction of bound sodium ions per phosphate charge, predicted by the counterion condensation theory, and the number of sodium ions released per bound drug, calculated from salt dependent equilibrium binding studies. The results show that the addition of the competitors slow down the broad component of the spin-spin relaxation rate of bound sodium in the order dq2pyp approximately propidium < ethidium < Mg2+. This reduction is shown to be due mainly to the decrease of the quadrupolar coupling constant for the slow motions, thus indicating a decrease of the average electric field gradient at the sodium ions close to the DNA surface. We also show that the broad component of the spin-spin relaxation rate linearly correlates with the relative non-polyelectrolyte free energy. This result is discussed in terms of the non-polyelectrolyte interactions affecting R2bB, which can be partitioned into stacking interaction and interactions involving the molecular moieties of the intercalators exposed to the solvent in the minor groove.

Binding, Competitive↗
PubMedDate not supplied

Conjugates of oligonucleotides with triplex-specific intercalating agents. Stabilization of triple-helical DNA in the promoter region of the gene for the alpha-subunit of interleukin 2 (IL-2R alpha).

The stabilization of triple-helical DNA under physiological conditions is an important goal for the control of gene expression using the antigen strategy, an approach whereby an oligonucleotide binds to the major groove of double-helical DNA to fom a triple helix. To this end, triplex-specific intercalators, namely benzopyridoindole (BPI) and benzopyridoquinoxaline (BPQ) derivatives, have been conjugated to the 5' end or to an internucleotide position of a 15-mer oligonucleotide. These conjugates were then tested, using thermal denaturation experiments, for their ability to form and stabilize a triple-helical structure involving a 42-mer duplex target. All of the conjugates were found to do so. The B[h]PQ derivatives stabilized particularly well when attached to the 5' end with a delta Tm of 15 degrees C and -delta delta G degrees 37 of 3.4 kcal mol-1 (pH 6.9, 140 mM KCI, 15 mM sodium cacodylate, 2 mM MgCl2, 0.8 mM spermine). Though most of the derivatives when attached to the internucleotide position were not able to stabilize triple-helical DNA as well as when attached to the 5' end, one B[f]PQ derivative with an internucleotide attachment did so, with a delta Tm of 13 degrees C and -delta delta G degrees 37 of 2.8 kcal mol-1. To a lesser degree, these conjugates were also able to stabilize duplex structures with single-stranded targets. Results were compared to the stabilization obtained with acridine conjugates as well as to a similar study performed with a different sequence.

DNA↗
PubMed1977

Action of intercalating agents on the activity of DNA polymerase I.

The effect of intercalating compounds such as 9-aminoacridine, quinacrine (atebrin), proflavine and daunomycin on the activity of DNA polymerase I(EC 2.7.7.7) was studied in vitro and compared with the binding of these acridines to native DNA. The enzyme kinetics were followed at various concentrations of DNA 3'-OH primer end groups and constant concentrations of deoxynucleosidetriphosphates as well as under the opposite conditions. The Km values for the DNA 3'-OH end groups were 16--38 nM and for the deoxynucleosidetriphosphates 2--5 micrometer, depending on the buffer and pH used in the enzymatic assay. All acridine derivates inhibit the DNA polymerase; at variable DNA concentrations a competitive inhibition was observed, where the Ki values ranged between 0.87 and 8.5 micrometer. At variable concentrations of deoxynucleosidetriphosphates and constant DNA concentration a non-competitive inhibition was observed. On denatured 3'-OH DNA as well as on poly(dA) - (dT)10 as substrate no inhibition by 9-aminoacridine was observed. 5'--3' exonuclease activity of DNA polymerase is inhibited by 9-aminoacridine but 3'--5' exonuclease activity on denatured DNA is not influenced by this intercalating compound. The affinity of the acridines to DNA was determined spectrophotometrically under conditions similar to those in the enzymatic assay and the computed frequency of intercalation was related to the inhibition of enzymatic activity. The mechanism of inhibition is explained by a disturbance of the structure of the double helical DNA due to the interaction of the bound acridine derivates.

Acridines↗
PubMed1985

Oligonucleotides covalently linked to intercalating agents. Influence of positively charged substituents on binding to complementary sequences.

A pentamethylene chain was used to covalently link the 3'-phosphate of oligothymidylates to the 9-amino group of an acridine derivative. Positively charged substituents were further attached to the 3'-phosphate group to form 3'-phosphotriesters. These molecules form specific complexes with poly(rA) which involve the formation of a number of A X T base pairs equal to that of thymines in the oligonucleotide. Absorption changes induced in the acridine absorption bands are similar to those expected upon intercalation of the acridine dye between A X T base pairs. The acridine covalently linked to the 3'-phosphate strongly stabilizes the complexes formed with poly(rA) as compared with the corresponding unsubstituted oligodeoxynucleotide. The presence of a positively charged substituent on the 3'-phosphate together with the acridine dye further enhances the interaction. The effect of salt concentration on complex stability depends on the number of negatively charged phosphate groups of the oligodeoxynucleotide and on the nature of the substituents borne by the 3'-phosphate group. When the oligothymidylate is substituted by an acridine dye, the stability of the poly(rA) complexes increases when salt concentration increases. If an additional positively charged substituent is present on the 3'-phosphate group, stability decreases when salt concentration increases for the shortest oligonucleotide (trimer) and increases with longer oligonucleotides. Thermodynamic parameters have been calculated from the concentration dependence of melting temperatures.

Base Sequence↗
PubMed1986

Specific inhibition of mRNA translation by complementary oligonucleotides covalently linked to intercalating agents.

Synthetic oligodeoxynucleotides that are covalently linked at their 3' end to an acridine derivative and are complementary to the repeated sequence UUAAAUUAAAUUAAA adjacent to the ribosome binding site of the gene 32-encoded mRNA from phage T4 have been used to regulate the synthesis of gene 32-encoded protein in vitro. These modified, synthetic oligonucleotides specifically block the translation of gene 32-encoded mRNA with a higher efficiency than the homologous unsubstituted oligonucleotides. The inhibition produced by these short "anti-messengers" is due to the formation of specific mRNA . oligodeoxynucleotide hybrids that are stabilized by the intercalation of the acridine ring in the RNA . DNA duplex.

Acridines↗
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↗
PubMed1981

[Affinity between CrIII and purified DNA, studied by competition with an intercalating agent: ethidium bromide].

The affinity between CrIII and purified calf- thymus DNA was studied at neutral pH by competition with ethidium bromide. Competition results indicated an affinity between CrIII and DNA of the order of 10(5) 1/mole. These results are in good agreement with previous results CrIII - DNA affinity was studied by the independent method of equilibrium dialysis and chromium dosage by atomic spectrometry.

Animals↗
PubMed1982

Nilemycin, an intercalating agent for deoxyribonucleic acid.

1. Nilemycin (NM) is found to exert an inhibitory effect on the mouse tumor Sarcoma 180 near toxic doses but not with Leukemia 1210. 2. In Yoshida rat sarcoma cells NM inhibits cellular de novo nucleic acid synthesis and protein to a much lesser extent. 3. More than 50% inhibition by NM to de novo synthesis of RNA, in a system using calf thymus DNA as a template, could be observed. 4. Suitable levels of NM reduce the S values of DNA. 5. The antibiotic induced metachromatic changes in the u.v. spectrum of DNA solutions. 6. NM markedly inhibited the polynucleotide ligase repairing action on DNase-1-nicked DNA. 7. It is presumed that NM intercalates nicked DNA into such a configuration that the reactive sites of the polynucleotides are inaccessible to the ligase activities.

Animals↗
PubMed2005

Cyanine dyes as intercalating agents: kinetic and thermodynamic studies on the DNA/Cyan40 and DNA/CCyan2 systems.

The interaction of cyanines with nucleic acids is accompanied by intense changes of their optical properties. Consequently these molecules find numerous applications in biology and medicine. Since no detailed information on the binding mechanism of DNA/cyanine systems is available, a T-jump investigation of the kinetics and equilibria of binding of the cyanines Cyan40 [3-methyl-2-(1,2,6-trimethyl-4(1H)pyridinylidenmethyl)-benzothiazolium ion] and CCyan2 [3-methyl-2-[2-methyl-3-(3-methyl-2(3H)-benzothiazolylidene)-1-propenyl]-benzothiazolium ion] with CT-DNA is performed at 25 degrees C, pH 7 and various ionic strengths. Bathochromic shifts of the dye absorption band upon DNA addition, polymer melting point displacement (DeltaT = 8-10 degrees C), site size determination (n = 2), and stepwise kinetics concur in suggesting that the investigated cyanines bind to CT-DNA primary by intercalation. Measurements with poly(dA-dT).poly(dA-dT) and poly(dG-dC).poly(dG-dC) reveal fair selectivity of CCyan2 toward G-C basepairs. T-jump experiments show two kinetic effects for both systems. The binding process is discussed in terms of the sequence D + S left arrow over right arrow D,S left arrow over right arrow DS(I) left arrow over right arrow DS(II), which leads first to fast formation of an external complex D,S and then to a partially intercalated complex DS(I) which, in turn, converts to DS(II), a more stable intercalate. Absorption spectra reveal that both dyes tend to self-aggregate; the kinetics of CCyan2 self-aggregation is studied by T-jump relaxation and the results are interpreted in terms of dimer formation.

Animals↗
PubMed1983

The unwinding of circular DNA by intercalating agents as determined by gel electrophoresis.

The conventional counting of electrophoretically resolvable topoisomers is an attractive technique for determining the number of superhelical turns in a closed circular DNA molecule. The method can be extended in order to determine the unwinding produced by a drug, if its binding constants are known under similar environmental conditions. Ethidium bromide was found to unwind a DNA molecule derived from the plasmid pBR322 by 26.0 degrees in a magnesium-containing buffer. The method is convenient for investigating the possible effects of different environmental changes (such as ionic strength, ionic species, or temperature) on the unwinding angle produced by a particular drug. It can also give an early indication of multiple modes of binding.

Animals↗
PubMed1988

Site-specific cleavage of single-stranded and double-stranded DNA sequences by oligodeoxyribonucleotides covalently linked to an intercalating agent and an EDTA-Fe chelate.

An oligodeoxythymidylate, oligo [d(T8)], was covalently linked to an acridine derivative via its 3' end and to EDTA via its 5' end. The octathymidylate was targeted to a single-stranded DNA fragment 27 nucleotides in length containing an octadeoxyadenylate sequence. In the presence of Fe(II) and a reducing agent (dithiothreitol) cleavage reactions were induced in the nucleotide sequence. The extent of the reaction was dependent on oligo concentration, salt concentration and temperature. Dissociation of the complexes at high temperature or low salt concentration abolished the site-specific cleavage reactions. Treatment of the reacted DNA with piperidine or piperidine-formiate strongly enhanced the yield of cleavage reactions demonstrating that damages were induced on nucleic acid bases by the EDTA-Fe complex covalently linked to the octathymidylate. At high salt concentration (1 M NaCl) or in the presence of spermine and ethylene-glycol a triple helix was formed involving the 27-mer DNA fragment and two oligo[d(T8)]. One of the oligo[d(T8)] was bound parallel and the other antiparallel to the oligo[d(A8)] complementary sequence. Cleavage reactions were induced on both sides of this oligo[d(A8)] target sequence. When a 27-mer duplex was used as a target the oligo[d(T8)] was bound in a parallel orientation with respect to the oligo[d(A8)]-containing strand in the major groove of the double helix. Cleavage reactions were induced on the oligo[d(A8)]-containing strand by the EDTA-Fe chelate attached to the 5' end of the oligo[d(T8)].

Acridines↗
PubMed1990

Kinetic and equilibrium binding studies of amsacrine-4-carboxamides: a class of asymmetrical DNA-intercalating agents which bind by threading through the DNA helix.

Detailed equilibrium and kinetic studies of the DNA interaction of the amsacrine-4-carboxamide class of compounds suggest that they bind by intercalating the acridine chromophore at near-maximal overlap with the base pairs, locating their two dissimilar side chains in specific grooves of the double helix. The first step is a fast bimolecular association to form an outside-bound complex (probably in the major groove). Insertion of the less bulky carboxamide side chain then occurs in a process governed largely by the rate of transient opening of the double helix by natural "breathing" motions and is followed by further monomolecular rearrangements to allow the carboxamide side chain to find its highest affinity binding sites in the minor groove. Dissociation of the complexes are much more ligand structure dependent, but also involve opening of the double helix to allow disengagement. Compounds of this type, which locate their two distinguishable side chains one in each DNA groove, form a unique class of DNA-binding ligand, with considerable potential for regiospecific delivery of reactive functionality to DNA. Although natural products which also have such specific binding modes are known (e.g. nogalamycin), the amsacrine-4-carboxamides discussed here are the first class of readily modified synthetic compounds with this property.

Amides↗