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PubMed1992

Static and dynamic conformational properties of AT sequences in B-DNA.

A theoretical study of the optimal conformations of nucleic acid oligomers containing tracts of AT base pairs is presented. The oligomers are studied in isolation and complexed with netropsin, a minor groove binding ligand. The flexibility of the oligomers and of their complexes is calculated by adiabatic mapping with respect to the total winding angle. The results of this study show that in uncomplexed oligomers the dinucleotide junctions AA, AT and TA have very different structural parameters and different responses to winding stress. The TA junction is clearly the most flexible and is the principal site for accommodating the imposed overwinding. Complexation by netropsin leads to two important effects: firstly, the three junctions adopt more uniform structures, the largest changes again being observed for TA, secondly, the differences in flexibility as a function of sequence are strongly attenuated.

Base Composition↗
PubMed1992

FTIR study of specific binding interactions between DNA minor groove binding ligands and polynucleotides.

The use of FTIR spectroscopy is made to study the interactions between polynucleotides and two series of minor groove binding compounds. The latter were developed and described previously as part of an ongoing program of rational design of modified ligands based on naturally occurring pyrrole amidine antibiotic netropsin, and varying the structure of bisbenzimidazole chromosomal stain Hoechst 33258. Characteristic IR absorptions due to the vibrations of thymidine and cytosine keto groups in polynucleotides containing AT and GC base pairs respectively are used to monitor their interaction with the added ligands. Although the two thiazole based lexitropsins based on netropsin structure differ in the relative orientation of nitrogen and sulfur atoms with respect to the concave edge of the molecules, they interact exclusively with the thymidine C2 = O carbonyl groups in the minor groove of the alternating AT polymer as evidenced by specific changes in the IR spectra. In the second series of compounds based on Hoechst 33258, the structure obtained by replacing the two benzimidazoles in the parent compound by a combination of pyridoimidazole and benzoxazole, exhibits changes in the carbonyl frequency region of poly dG.poly dC which is attributed to the ligand interaction at the minor groove of GC base pairs. In contrast, Hoechst 33258 itself interacts only with poly dA.poly dT. Weak or no interaction exists between the ligands and any of the polynucleotides at the levels of the phosphate groups or the deoxyribose units.

Bisbenzimidazole↗
PubMed1997

Influence of drug binding on DNA flexibility: a normal mode analysis.

DNA-drug complexes are important because of their pharmacological interest but, in addition, they provide a useful model to study the essential aspects of DNA recognition processes. In order to investigate the influence of ligand binding on the dynamic properties of DNA we have carried out normal mode analysis for complexes with drugs of two types: a typical intercalator, 9-aminoacridine, and a typical groove binder, netropsin. Normal modes are analysed in terms of helicoidal parameter variations with special attention being paid to global deformations of the double helix. The results show that the influence of these two drugs is very different. Intercalation of 9-aminoacridine leads to an increase in the flexibility of the intercalated dinucleotide step, with notably larger vibrational amplitudes for both roll and twist parameters compared to free DNA. In contrast, the groove binding of netropsin induces a stiffening of the DNA segment which is in contact with the drug reflected by decreased vibrational amplitudes for backbone angles and inter base pair helicoidal parameters and an increase in vibrations for adjacent base pairs in terms of buckle and propeller twist.

Aminacrine↗
PubMed1985

Molecular recognition of B-DNA by Hoechst 33258.

The binding sites of Hoechst 33258, netropsin and distamycin on three DNA restriction fragments from plasmid pBR322 were compared by footprinting with methidiumpropyl-EDTA X Fe(II) [MPE X Fe(II)]. Hoechst, netropsin and distamycin share common binding sites that are five +/- one bp in size and rich in A X T DNA base pairs. The five base pair protection patterns for Hoechst may result from a central three base pair recognition site bound by two bisbenzimidazole NHs forming a bridge on the floor of the minor groove between adjacent adenine N3 and thymine O2 atoms on opposite helix strands. Hydrophobic interaction of the flanking phenol and N-methylpiperazine rings would afford a steric blockade of one additional base pair on each side.

Base Sequence↗
PubMed1979

Antibiotic induced electrophoretic mobility shifts of DNA restriction fragments.

Several antibiotics, netropsin, distamycin A, actinomycin D, Hoechst 33258 and olivomycin, which demonstrate base specificity in their DNA binding properties have been found to alter the electrophoretic mobility of DNA restriction fragments in native polyacrylamide gels. The antibiotics mostly reduced the migration of larger DNA fragments, but netropsin and Hoechst 33258 were observed to increase the migration rate of several DNA fragments of intermediate size. DNA fragments of similar molecular weight which comigrate as a single gel band can at times be separated as the result of differential mobility shifts promoted by antibiotic DNA complex formations.

Anti-Bacterial Agents↗
PubMed1981

The effect of several nucleic acid binding drugs on the cleavage of d(GGAATTCC) and pBR 322 by the Eco RI restriction endonuclease.

The endonucleolytic action of the EcoRI restriction enzyme on the double-stranded oligonucleotide d(GGAATTCC) and the supercoiled plasmid DNA pBR 233 is inhibited by actinomycin D, ethidium bromide, proflavin, distamycin A and netropsin. Half-maximal inhibition is observed at around 100 microM concentrations for the intercalating drugs, and around 0.1 to 1 microM concentrations for netropsin and distamycin A. The inhibitory activity of these drugs can be correlated with their affinity to the oligonucleotide and the plasmid DNA. Since at high concentrations of the drugs a complete inhibition is observed, it is concluded that the effect of the drugs on the stereochemistry of the EcoRI site is such that recognition is excluded.

Circular Dichroism↗
PubMed2005

Quantitative methods of analysis of footprinting diagrams for the complexes formed by a ligand with a DNA fragment of known sequence.

The regulation of gene expression is based on the interaction of DNA with different ligands. A model of adsorption was considered that can be applied to the quantitative analysis of footprinting diagrams for the complexes formed by a ligand with a DNA fragment of known structure. This model allows the probabilities of ligand binding to DNA sites with a known sequence to be calculated and the variance of probabilities of ligand binding with a specified binding site to be estimated. The model was used for quantitative analysis of diagrams of DNAse footprinting for the complexes of the dimeric analogue of the antitumor antibiotic netropsin. Experimental and theoretically calculated profiles of distribution of netropsin bound on DNA are in good agreement with one another.

Antibiotics, Antineoplastic↗
PubMed1996

Novel aromatic urea derivatives with DNA-binding ability.

Several aromatic urea derivatives were designed and synthesized as DNA-targeting agents. N,N'-Dimethyl-N,N'-bis[(4-amidylphenyl)aminocarbonyl]-2,6-di aminopyridine (1) and 1,3-bis[5-(glycylamino)pyrid-2-yl]urea (3) showed remarkable DNA-binding abilities as determined by ultrafiltration assay using calf thymus DNA, their potencies being equal to and half that of netropsin, respectively. Compound 1 inhibited the proliferation of both L1210 cells and KB cells with similar IC50 values to netropsin.

Animals↗
PubMed2005

Temperature dependence of the volumetric parameters of drug binding to poly[d(A-T)].Poly[d(A-T)] and Poly(dA).Poly(dT).

We report the temperature and salt dependence of the volume change (DeltaVb) associated with the binding of ethidium bromide and netropsin with poly(dA).poly(dT) and poly[d(A-T)].poly[d(A-T)]. The DeltaV(b) of binding of ethidium with poly(dA).poly(dT) was much more negative at temperatures approximately 70 degrees C than at 25 degrees C, whereas the difference is much smaller in the case of binding with poly[d(A-T)].poly[d(A-T)]. We also determined the volume change of DNA-drug interaction by comparing the volume change of melting of DNA duplex and DNA-drug complex. The DNA-drug complexes display helix-coil transition temperatures (Tm several degrees above those of the unbound polymers, e.g., the Tm of the netropsin complex with poly(dA)poly(dT) is 106 degrees C. The results for the binding of ethidium with poly[d(A-T)].poly[d(A-T)] were accurately described by scaled particle theory. However, this analysis did not yield results consistent with our data for ethidium binding with poly(dA).poly(dT). We hypothesize that heat-induced changes in conformation and hydration of this polymer are responsible for this behavior. The volumetric properties of poly(dA).poly(dT) become similar to those of poly[d(A-T)].poly[d(A-T)] at higher temperatures.

Binding Sites↗
PubMed2006

Hydration changes accompanying the binding of minor groove ligands with DNA.

4',6-diamidino-2-phenylindole (DAPI), netropsin, and pentamidine are minor groove binders that have terminal -C(NH2)2+ groups. The hydration changes that accompany their binding to the minor groove of the (AATT)2 sequence have been studied using the osmotic stress technique with fluorescence spectroscopy. The affinity of DAPI for the binding site decreases with the increasing osmolality of the solution, resulting in acquisition of 35+/-1 waters upon binding. A competition fluorescence assay was utilized to measure the binding constants and hydration changes of the other two ligands, using the DNA-DAPI complex as the fluorescence reporter. Upon their association to the (AATT)2 binding site, netropsin and pentamidine acquire 26+/-3 and 34+/-2 additional waters of hydration, respectively. The hydration changes are discussed in the context of the terminal functional groups of the ligands and conformational changes in the DNA.

Binding Sites↗
PubMed1996

Activation of the intracellular Ca(2+)-dependent serine protease ISP1 of bacillus megaterium by purification or by high Ca2+ concentrations.

The total proteolytic activity of ISP1 determined after its partial purification by size exclusion HPLC increased 3.0, 7.3 and 27.3 times in sporulating, growing and netropsin-treated cells, respectively, as compared with the corresponding original activity in crude cytoplasmic preparations at the same CaCl2 concentration of 3 mM. A similar rise in proteolytic activity occurred on increasing the Ca2+ concentration in the crude cytoplasm from 3 to 30 mM. This activation in the cytoplasm of netropsin-treated and sporulating cells was not reversed by subsequent lowering of CaCl2 concentration back to 3 mM by dialysis. Moreover, a similar activation appeared even after the same dialysis of cytoplasm that had not been exposed to 30 mM CaCl2. The activation was probably due to the processing of ISP1, as established by SDS-PAGE and immunoblotting, but an involvement of additional regulation factor(s), e.g. an inhibitor or other molecules, is possible.

Anti-Bacterial Agents↗
PubMed1995

Design of B-DNA cross-linking and sequence-reading molecules.

We report the design of hybrid molecules to bind in the minor groove of B-DNA, which combine DNA alkylating and cross-linking ability for increased chemotherapeutic efficacy, with sequence specificity, to minimize side effects. Optimal linkage geometries have been determined for the synthesis of bis-anthramycin and anthramycin-netropsin hybrid molecules. Earlier studies on linked drugs have typically been based on molecular mechanics calculations. This work, in contrast, uses the observed crystal structures of a netropsin/DNA complex and a new anthramycin/DNA complex to determine the exact spacing between two individual drugs when bound in the minor groove of B-DNA. Molecular linkers then are designed and tested between these two experimental positions, to form a chimeric or bis-linked compound molecule. A linked anthramycin-netropsin molecule has been designed specifically to target the polypurine tract second-strand primer site of the reverse transcriptase of HIV-1.

Base Sequence↗
PubMed1989

Design, synthesis, DNA binding, and biological activity of a series of DNA minor-groove-binding intercalating drugs.

A group of pseudopeptides, molecular combination of the natural antitumor agents distamycin or netropsin and the anilinoacridine chromophore (which is related to the synthetic antileukemic drug amsacrine) has been synthesized. Their DNA binding properties were determined and discussed in terms of their structural differences and in relation to their observed base-dependent binding. Binding data are consistent with a model in which the acridine nucleus occupies an intercalation site and the netropsin or distamycin residue resides in the DNA minor groove. Cytostatic and cytotoxic activities against a murine cell line are reported, as well as significant differences in the inhibition of DNA synthesis.

Animals↗
PubMed1978

The use of base pair specific DNA binding agents as affinity labels for the study of mammalian chromosomes.

The fluorochromes Hoechst 33258 and olivomycin are base pair specific DNA binding agents. The fluorescence enhancement of Hoechst 33258 and olivomycin in the presence of DNA can be directly related to the A--T and G--C content of the interacting DNA respectively. Cytological observations of metaphase chromosomes treated with these two compounds suggest that the fluorescent banding patterns produced are the reverse of one another.--Non-fluorescent base pair specific DNA binding agents have been used as counterstains in chromosome preparations to enhance the contrast of the banding patterns produced by the base specific fluorochromes. The non-fluorescent G--C specific antibiotic actinomycin-D enhanced the resolution of fluorescent bands produced by the A--T specific fluorochrome Hoechst 33258. Similarly the non-fluorescent A--T specific antibiotic netropsin was found to enhance resolution of the bands produced by the G--C -specific fluorochrome olivomycin. Netropsin was also found to increase the differential fluorescent enhancement of complexes of olivomycin with DNAs of various base composition in solution. These findings suggest that counterstaining agents act through a base sequence dependent inhibition of subsequent binding by base pair specific fluorochromes.--The base specific DNA binding agents have been used to differentiate different types of constitutive heterochromatin in mammalian species, and to facilitate chromosome identification in somatic cell hybrids.

Affinity Labels↗
PubMed2001

Synthesis, molecular modelling, and antiproliferative and cytotoxic effects of carbocyclic derivatives of distamycin with chlorambucil moiety.

New carbocylic analogues of distamycin and netropsin with chlorambucil moieties 5-8 have been synthesised. Data from the ethidium displacement assay showed that these compounds bind in the minor groove of DNA. The observed reduced affinity to AT pairs and increased affinity towards GC sequences of the carbocyclic lexitropsins with chlorambucil moiety 5-8 in comparison with netropsin and distamycin was observed and rationalised by means of molecular modelling techniques. All of the compounds 5-8 showed antiproliferative and cytotoxic effects in the standard cell line of the mammalian tumour MCF-7.

Antineoplastic Agents↗
PubMed1994

Crystal structure of a covalent DNA-drug adduct: anthramycin bound to C-C-A-A-C-G-T-T-G-G and a molecular explanation of specificity.

A 2.3-A X-ray crystal structure analysis has been carried out on the antitumor drug anthramycin, covalently bound to a ten base pair DNA double helix of sequence C-C-A-A-C-G-T-T-G-G. One drug molecule sits within the minor groove at each end of the helix, covalently bound through its C11 position to the N2 amine of the penultimate guanine of the chain. The stereochemical conformation is C11S, C11aS. The natural twist of the anthramycin molecule in the C11aS conformation matches the twist of the minor groove as it winds along the helix; a C11aR drug would only fit into a left-handed helix. The C11S attachment is roughly equatorial to the overall plane of the molecule, whereas a C11R attachment would be axial and would obstruct the fitting of the drug into the groove. The six-membered ring of anthramycin points toward the 3' end of the chain to which it is covalently attached or toward the end of the helix. The acrylamide tail attached to the five-membered ring extends back along the minor groove toward the center of the helix, binding in a manner reminiscent of netropsin or distamycin. The drug-DNA complex is stabilized by hydrogen bonds from C9-OH, N10, and the end of the acrylamide tail to base pair edges on the floor of the minor groove. The origin of anthramycin specificity for three successive purines arises not from specific hydrogen bonds but from the low twist angles adopted by purine-purine steps in a B-DNA helix. Binding of anthramycin induces a low twist at T-G in the T-G-G sequence of this DNA-drug complex, by comparison with the structure of the free DNA. The origin of anthramycin's preference for adenines flanking the alkylated guanine arises from a netropsin-like fitting of the acrylamide tail into the minor groove.

Anthramycin↗
PubMedDate not supplied

Effects of anticancer drugs on transcription in vitro.

The effects of DNA interacting drugs on: (1) total RNA synthesis catalyzed by E. coli and T7 RNA polymerase; (2) synthesis of the initiating dinucleotide (pppApU) by E. coli RNA polymerase ("abortive initiation"); (3) elongation of RNA chains synthesized by T7 RNA polymerase on pT7-7 plasmid DNA bearing T7 RNA polymerase promoter phi 10 with human Cu/Zn superoxide dismutase coding sequence, (4) interaction of transcription factor Sp1 and its binding site were studied. Intercalating ligands which form quickly dissociating complexes with DNA (anthracyclines, proflavine, ethidium bromide) are compared with the slowly dissociating drug of d(G x C) specificity (actinomycin D), the non-intercalating, d(A x T) specific pyrrole antibiotics (netropsin and distamycin A) and covalently binding to DNA 1-nitroacridine derivative (nitracrine). The obtained results indicate that rapidly dissociating ligands, proflavine and ethidium bromide, inhibit total RNA synthesis in vitro and the abortive initiation to a similar extent while they do not induce discrete elongation stops of RNA polymerase. Actinomycin D and nitracrine exhibit a high inhibitory effect on total RNA synthesis and induce stops of RNA polymerase while not affecting abortive initiation. Pyrrole antibiotics primarily inhibit the initiation, while no elongation stops are induced. Actinomycin D inhibits complex formation between nuclear proteins and the Sp1 binding site. Netropsin, ethidium bromide, proflavine and other intercalating acridines do not affect Sp1 binding. The results indicate that the effects primarily depend on sequence specificity and secondarily on the dissociation rate of ligands from their complexes with DNA.

Antibiotics, Antineoplastic↗
PubMed2006

Oligopyrrole carboxamides linked with a nucleobase as potential DNA minor groove binding ligands: synthesis, DNA binding and biological evaluation.

The synthesis of a series of new oligopyrrole carboxamides closely related to netropsin and distamycin A, linked with a nucleobase is reported. The new compounds possess similar structure elements as the known peptide nucleic acids which are interesting sequence reading DNA ligands. Cytotoxicity in vitro, the DNA binding characteristics and the inhibition of topoisomerase I were studied. Four of the compounds, 27, 31, 33 and 37 bind to DNA probably at AT sequences like netropsin or distamycin A in the minor groove. Surprisingly, no cytotoxicity and no inhibition of topoisomerase I was found.

Antineoplastic Agents↗