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PubMed1999

DNA interactions of cisplatin tethered to the DNA minor groove binder distamycin.

Modifications of natural DNA in a cell-free medium using cisplatin tethered to the AT-specific, minor groove binder distamycin, were studied using various methods of biochemical analysis or molecular biophysics. These methods include: binding studies using differential pulse polarography and flameless atomic absorption spectrophotometry, mapping DNA adducts using a transcription assay, use of ethidium bromide as a fluorescent probe for DNA adducts of platinum, measurement of DNA unwinding by gel electrophoresis, measurement of CD spectra, an interstrand cross-linking assay using gel electrophoresis under denaturing conditions, measurement of melting curves with the aid of absorption spectrophotometry and the use of terbium ions as a fluorescent probe for distorted base pairs in DNA. The results indicate that attachment of distamycin to cisplatin changes several features of the DNA-binding mode of the parent platinum drug. Major differences comprise different conformational alterations in DNA and a considerably higher efficiency of the conjugated drug to form in DNA interstrand cross-links. Cisplatin tethered to distamycin, however, coordinates to DNA with similar base sequence preferences as the untargeted platinum drug. The results point to a unique profile of DNA binding for cisplatin-distamycin conjugates, suggesting that tethering cisplatin to minor groove oligopeptide binders may also lead to an altered biological activity profile.

Antineoplastic Agents↗
PubMed2000

On the kinetics of distamycin binding to its target sites on duplex DNA.

Distamycin A is a well known polyamide antibiotic that can bind in the minor groove of duplex DNA primarily at AT-rich sequences both as a monomer or as a side-by-side antiparallel dimer. The association phase of the distamycin binding reaction has not been studied in either of its binding modes, because of the lack of an adequate UV or CD signal at the low concentrations needed to monitor the fast bimolecular reaction. We report a significant increase in fluorescence amplitude, accompanied by a small red shift, on binding distamycin to its specific target sites. This signal can be used to monitor drug binding in steady-state and time-resolved processes. Distamycin shows extremely fast association with the 1:1 binding site, with a bimolecular rate of 7 x 10(7) M(-1) small middle dots(-1) and also fairly rapid dissociation ( approximately 3 s(-1)). When DNA is in excess, there is a slow component in the association reaction whose rate decreases strongly with increasing DNA concentration. Binding of the drug to the 2:1 site occurs in two distinct steps: fast, sequential binding of each drug molecule to the DNA with a bimolecular rate comparable to that at the 1:1 site, followed by a slow ( approximately 4 s(-1)) equilibration to the final population. Dissociation from the 2:1 site is approximately 40-fold slower than from the 1:1 site. This study provides the groundwork for analysis of the binding kinetics of longer polyamides and covalently linked polyamides that have recently been shown to inhibit transcription in vivo.

Anti-Bacterial Agents↗
PubMed1989

Distamycins inhibit the binding of OTF-1 and NFE-1 transfactors to their conserved DNA elements.

We investigated the effects of the antiviral agent distamycin A and of a distamycin derivative (FCE 24517) which possesses antineoplastic activity on the binding of some regulatory proteins to DNA. Both compounds inhibited the binding to DNA of the ubiquitous octamer binding factor OTF 1 and of the erythroid specific GATAAG protein (NFE 1). This was shown using the electrophoretic mobility shift assay on a DNA fragment of human gamma-globin gene promoter (-156 to -201), on the same fragment with a point mutation (T to C mutation) known to have an increased affinity of binding for NFE 1, on a DNA fragment of human histone H2B promoter and on a DNA fragment of mouse alpha 1 globin promoter. The ability of distamycin or of FCE 24517 to inhibit the binding was specific for AT-rich sequences since neither drug inhibited the binding of nuclear protein factors to the sequence CCACACCC of the human beta globin gene. Binding to DNA was investigated by evaluating the drugs' ability to protect selected sequences from DNase I digestion (DNase footprinting). Distamycins binding was highly preferential for DNA sequences containing stretches of AT. These studies indicate that chemicals which have a high degree of DNA sequence-specific binding can selectively inhibit the binding of regulatory proteins to DNA. These effects might be responsible for modification of the transcription of specific genes and might to some extent account for these drugs' antiviral and antineoplastic activities. This approach offers potential for the investigation of new such drugs.

Base Sequence↗
PubMed1997

Distamycin prolongs E-selectin expression by interacting with a specific NF-kappaB-HMG-I(Y) binding site in the promoter.

The E-selectin cell adhesion protein plays a critical role in mediating adherence of leukocytes to endothelium at sites of inflammation. Cytokine-induced E-selectin expression on the surface of endothelial cells is transient; mRNA expression peaks at 3-4 h after induction and returns to basal levels within 24 h. The mechanism for this transcriptional down-modulation is not known. Promoter binding factors responsible for induced gene expression include NF-kappaB, which binds at three sites within the E-selectin promoter, and HMG-I(Y), which binds to the A/T-rich core found at the centre of these binding sites. Distamycin is an antibiotic that also binds A/T-rich DNA and inhibits HMG-I(Y) DNA binding. To study the role of HMG-I(Y) in E-selectin expression, we have examined the effect of distamycin on the cytokine-induced E-selectin expression cycle. We found that distamycin prolonged E-selectin expression, both by sustaining mRNA transcription and by extending the transcript's half-life. The distamycin effect on transcription was mediated through one of the three NF-kappaB-HMG-I(Y) binding sites (NF-kappaBII) within the promoter. This suggests that the NF-kappaB-HMG-I(Y) complex interacting at the NF-kappaBII site plays a role not only in cytokine induction of E-selectin expression, but also in its down-modulation.

Binding Sites↗
PubMed1976

Protection of particular cleavage sites of restriction endonucleases by distamycin A and actinomycin D.

It is shown here that distamycin A and actinomycin D can protect the recognition sites of endo R.EcoRI, EcoRII, HindII, HindIII, HpaI and HpaII from the attack of these restriction endonucleases. At proper distamycin concentrations only two endo R.EcoRI sites of phage lambda DNA are available for the restriction enzyme--sRI1 and sRI4. This phenomenon results in the appearance of larger DNA fragments comprising several consecutive fragments of endo R.EcoRI complete cleavage. The distamycin fragments isolated from the agarose gels can be subsequently cleaved by endo R.EcoRI with the yield of the fragments of complete digestion. We have compared the effect of distamycin A and actinomycin D on a number of restriction endonucleases having different nucleotide sequences in the recognition sites and established that antibiotic action depends on the nucleotide sequences of the recognition sites and their closest environment

Base Sequence↗
PubMed1977

Specific interactions of distamycin A and its analogs with (A-T) rich and (G-C) rich duplex regions of DNA and deoxypolynucleotides.

The specific interaction of distamycin A and analogs with DNA's and synthetic deoxypolynucleotide duplexes were studied in detail by means of circular dichroism and the data were analyzed together with viscosity results of several natural DNA's. At low ligand to nucleotide ratio the previously reported specific binding to (A-T) pairs of DNA is verified by a highly favoured interaction with (A-T)-enriched segments of distamycins containing four and five methylpyrrole carboxamide units. At higher distamycin concentration a second specific binding to (G-C) pairs most probably through hydrogen bonding is established. Viscometric results suggest a distamycin-induced local bending of the helix and could support the idea of a preferential alignment of the ligand molecule along only one strand in the groove which differs from the netropsin interaction mechanism. The possibility of an overlapping binding of the oligopeptides in the small groove is discussed.

Animals↗
PubMed2005

Molecular dynamics simulations and free energy calculations of netropsin and distamycin binding to an AAAAA DNA binding site.

Molecular dynamics simulations have been performed on netropsin in two different charge states and on distamycin binding to the minor groove of the DNA duplex d(CGCGAAAAACGCG).d(CGCGTTTTTCGCG). The relative free energy of binding of the two non-covalently interacting ligands was calculated using the thermodynamic integration method and reflects the experimental result. From 2 ns simulations of the ligands free in solution and when bound to DNA, the mobility and the hydrogen-bonding patterns of the ligands were studied, as well as their hydration. It is shown that even though distamycin is less hydrated than netropsin, the loss of ligand-solvent interactions is very similar for both ligands. The relative mobilities of the ligands in their bound and free forms indicate a larger entropic penalty for distamycin when binding to the minor groove compared with netropsin, partially explaining the lower binding affinity of the distamycin molecule. The detailed structural and energetic insights obtained from the molecular dynamics simulations allow for a better understanding of the factors determining ligand-DNA binding.

Anti-Bacterial Agents↗
PubMed2002

Distamycin A, a minor groove binder, changes enediyne-induced DNA cleavage sites and enhances apoptosis.

We examined the effects of a minor groove binder, distamycin A, on DNA cleavage and apoptosis induced by an enediyne antitumor antibiotic, C1027, using 32P-labeled DNA fragments obtained from human genes. C1027 alone induced DNA cleavage particularly at the 5'-TTTT-3'/3'-AAAA-5' sequence (cutting sites are underlined). The addition of distamycin A enhanced the double-strand DNA cleavage at the 5'-CCT-3'/3'-GGA-5' and 5'-CCA-3'/3'-GGT-5' sequences, with a two-nucleotide 3'-stagger of the cleaved residues. These results suggest that distamycin A forms a heterodimer with C1027 to bind to DNA at GC-rich regions, resulting in amplification of DNA cleavage at these regions. Distamycin A enhanced C1027-induced DNA ladder formation and cytotoxicity in HL-60 cells. Therefore, amplification of DNA cleavage at GC-rich regions may result in enhancement of apoptosis. The present study on amplifiers of antitumor agents showed a novel approach to the potentially effective antitumor therapy.

Aminoglycosides↗
PubMed2006

Characterization of the binding of distamycin A to damaged DNA: a comparison with the DNA recognition of the human DDB protein.

Distamycin A binds to DNA containing the (6-4) photoproduct, a major UV lesion that is recognized by the damaged DNA-binding (DDB) protein in human cells. We analyzed the binding properties of distamycin A and compared the results with those of the DDB protein. Structural change of the DNA duplex was not observed for distamycin A in two types of experiments, whereas the protein induced a large bending of the helix. Although the substrate specificity was different between the drug and the protein, thymine glycol was recognized by both of them, and inhibition of the DDB protein binding to the (6-4) photoproduct-containing DNA by distamycin A was tested.

Binding Sites↗
PubMed2006

Configurational entropy change of netropsin and distamycin upon DNA minor-groove binding.

Binding of a small molecule to a macromolecular target reduces its conformational freedom, resulting in a negative entropy change that opposes the binding. The goal of this study is to estimate the configurational entropy change of two minor-groove-binding ligands, netropsin and distamycin, upon binding to the DNA duplex d(CGCGAAAAACGCG).d(CGCGTTTTTCGCG). Configurational entropy upper bounds based on 10-ns molecular dynamics simulations of netropsin and distamycin in solution and in complex with DNA in solution were estimated using the covariance matrix of atom-positional fluctuations. The results suggest that netropsin and distamycin lose a significant amount of configurational entropy upon binding to the DNA minor groove. The estimated changes in configurational entropy for netropsin and distamycin are -127 J K(-1) mol(-1) and -104 J K(-1) mol(-1), respectively. Estimates of the configurational entropy contributions of parts of the ligands are presented, showing that the loss of configurational entropy is comparatively more pronounced for the flexible tails than for the relatively rigid central body.

Binding Sites↗
PubMed1994

Synthesis and antiviral activity of three pyrazole analogues of distamycin A.

The synthesis of three new monopyrazole analogues of the antiviral compound distamycin A is reported. Suitably protected 4-amino-1-methylpyrrole-2-carboxylic acid and 3-amino-1-methylpyrazole-5-carboxylic acid derivatives were chosen as starting materials. The construction of the trimeric polyamide framework was accomplished by assembly of the monomeric precursors under condensing conditions by analogy with our previous methodology, although with significant improvements in some pivotal steps. After chromatographic purification and spectroscopic characterisation, the analogues were assayed for antiviral activity. Compounds 7a-c inhibited vaccinia virus at a concentration similar to or lower than distamycin A and the related antibiotic netropsin. Analogues 7b and 7c exhibited an antiviral effect comparable to those of distamycin A and netropsin against HSV-1 and HSV-2, whereas their antiviral activity against several other viruses including HIV-1 and HIV-2 was somewhat lower. The cellular toxicity of 7a-c toward different host cell types proved to be of similar magnitude or lower than those of distamycin A and netropsin.

Animals↗
PubMed1992

DNA-binding properties of a distamycin-ellipticine hybrid molecule.

We have synthesized a distamycin-ellipticine hybrid compound and investigated its interaction with DNA, using various optical and gel electrophoresis techniques. Binding of the hybrid to DNA is evidenced by spectral shifts, fluorescence quenching, and induced linear dichroism. Absorbance measurements have been used to generate Scatchard plots, which reveal that the interaction cannot be described adequately in terms of a single binding mode, probably because of simultaneous intercalation and minor groove binding of the ligand. Competition with added distamycin has been used to verify involvement of the N-methyl-pyrrole portion of the hybrid molecule in the binding reaction. From electric linear dichroism experiments, it is estimated that the orientation of the DNA-bound ellipticine chromophore in the hybrid differs by about 10 degrees from the orientation of the equivalent chromophore lacking a distamycin tail. Topoisomerase assays establish that binding of the hybrid unwinds the DNA helix by a minimum of 11 degrees, which is consistent with intercalation but notably smaller than the unwinding angle of ellipticine. In footprinting experiments, it is found that the AT- and GC-specificity of distamycin and ellipticine, respectively, appear to be merged in the binding of the hybrid, which produces a pattern of protection distinct from the characteristic patterns for either of the parent compounds. The hybrid is an extremely effective inhibitor of cutting by DNase I.

Chelating Agents↗
PubMed1977

[Antiviral properties of analogs of distamycin A].

The effect of 9 analogues of distamycin A was studied in a tissue culture with respect to the virus of a smallpox vaccine and classical avian plague. Three analogues of distamycin A (I, VI, VII) were studied in chick embryos with respect to the smallpox and influenza viruses. The analogues were characterized by a loss or decrease of the activity against the smallpox vaccine virus as compared to distamycin A. In contrast to distamycin A analogue VII had an inhibitory effect on influenza infection in chick embryos.

Antiviral Agents↗
PubMedDate not supplied

[Use of the antibiotics actinomycin D and distamycin A to limit the action of restriction endonucleases and to map DNA].

It is shown that distamycin A and actinomycin D protect the recognition sites of certain restriction endonucleases from the attack by these nucleases due to specific interaction of these antibiotics with double-stranded DNA. Distamycin A protects A-T containing sites and actinomycin G-C rich sites. Among Hind II recognition sites which have alternative structure (GTPyPuAC) distamycin A protects only Hpa I similar sites (GTTAAC). It is shown with several restriction endonucleases that antibiotic action depends on the nucleotide sequences in the recognition sites and in their closest environment. Proper concentrations of antibiotic give rise to larger fragments. Use of both distamycin A and actinomycin D allows to obtain a set of overlapping fragments. The data obtained with various DNAs and restriction endonucleases allow to conclude that these antibiotics may be useful for DNA mapping and for preparation of large functional fragments of DNA.

Base Sequence↗
PubMed1993

Establishment of L1210 leukemia cells resistant to the distamycin-A derivative (FCE 24517): characterization and cross-resistance studies.

N-deformyl-N-[4-N,N-bis(2-chloroethylamino)benzoyl] distamycin-A (FCE 24517) is a new cytotoxic anti-tumor agent in phase-1 clinical trials. We have isolated stable FCE-24517-resistant cell sublines from murine leukemia L1210 cells by in vitro exposure to the drug. FCE 24517 selects a mixed population of resistant cells: the L1210/24517(1) cell line in vitro was in fact resistant to the selecting agent (RI 48.3), as well as to L-PAM (RI 5.4) and DX (RI 8.6) and over-expressed the mdr-I gene. When L1210/24517(1) cells were implanted in vivo and evaluated for sensitivity to the same agents, resistance was observed only to FCE 24517 and partially to L-PAM, whereas DX had the same anti-tumor efficacy as on the sensitive line. The clone derived from the above subline (L1210/24517(2)) was resistant to FCE 24517, distamycin-A and other cytotoxic compounds bearing the distamycin-A skeleton, and fully sensitive to DX and other anti-tumor compounds involved in the multi-drug resistance mechanisms, with a complete disappearance of the mdr phenotype. L1210/24517(2) cell line is partially cross-resistant to L-PAM, this resistance being accounted for by higher GSH intracellular levels, which however do not influence the resistance to FCE 24517. In fact, BSO treatment was capable of significantly modifying only the cytotoxicity of L-PAM. Our data suggest that L1210/24517(2) cells present a mechanism of resistance specific for FCE 24517 and related molecules.

Animals↗
PubMed1993

A model for chromatin opening: stimulation of topoisomerase II and restriction enzyme cleavage of chromatin by distamycin.

Histone H1 preferentially and cooperatively binds scaffold-associated regions (SARs) in vitro via specific interactions with the numerous short A + T-rich tracts (A-tracts) contained in these sequences. Selective titration of A-tracts by the oligopeptide distamycin abolishes this interaction and results in a redistribution of H1. Similarly, treatment of intact cells and isolated nuclei with distamycin specifically enhances cleavage of internucleosomal linkers of SARs by topoisomerase II and restriction enzymes. The increased accessibility of these linkers is thought to result from the unfolding (or opening) of the chromatin fiber and to be due to a reduced occupancy by histone H1. Chromatin extraction and H1 assembly experiments support this view. We discuss a model whereby open, H1-depleted chromatin regions may be generated by titration of A-tracts by putative distamycin analogues; this local opening may spread to adjacent regions assuming highly cooperative H1-H1 interactions in chromatin.

Animals↗
PubMedDate not supplied

Distamycin A affects the stability of NF-kappaB p50-DNA complexes in a sequence-dependent manner.

The effect of two different DNA minor groove binding molecules, Hoechst 33258 and distamycin A, on the binding kinetics of NF-kappaB p50 to three different specific DNA sequences was studied at various salt concentrations. Distamycin A was shown to significantly increase the dissociation rate constant of p50 from the sequences PRDII (5'-GGGAAATTCC-3') and Ig-kappa B (5'-GGGACTTTCC-3') but had a negligible effect on the dissociation from the palindromic target-kappaB binding site (5'-GGGAATTCCC-3'). By comparison, the effect of Hoechst 33258 on binding of p50 to each sequence was found to be minimal. The dissociation rates for the protein--DNA complexes increased at higher potassium chloride concentrations for the PRDII and Ig-kappaB binding motifs and this effect was magnified by distamycin A. In contrast, p50 bound to the palindromic target-kappaB site with a much higher intrinsic affinity and exhibited a significantly reduced salt dependence of binding over the ionic strength range studied, retaining a K(D) of less than 10 pM at 150 mM KCl. Our results demonstrate that the DNA binding kinetics of p50 and their salt dependence is strongly sequence-dependent and, in addition, that the binding of p50 to DNA can be influenced by the addition of minor groove-binding drugs in a sequence-dependent manner.

Base Sequence↗
PubMed1990

DNA-induced distamycin A fluorescence.

The fluorescent properties of the antibiotic distamycin A were investigated in a range of materials including Trypanosoma cruzi epimastigotes, chicken erythrocytes, calf thymus DNA and synthetic polynucleotides using both microscopic and spectroscopic techniques. A bright blue-white fluorescence was observed from kinetoplast DNA and chromatin after treatment with distamycin A under ultraviolet (365 nm) excitation. Considerable enhancement of distamycin A fluorescence (emission peak at 455 nm under 320-340 nm excitation) was found in the presence of DNA and poly(dA-dT).poly(dA-dT). We discuss a possible explanation for this unexpected fluorescent emission, as well as its implications for microscopic and fluorimetric studies.

Animals↗