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PubMed1992

Hoechst 33258, distamycin A, and high mobility group protein I (HMG-I) compete for binding to mouse satellite DNA.

The experiments described were designed to test the hypothesis that the (A+T)-specific DNA binding ligands Hoechst 33258 and distamycin A affect the condensation of mouse centromeric heterochromatin by competing for binding to satellite DNA with one or more chromosomal proteins. The studies focused on the nonhistone chromosomal protein HMG-I since its binding properties predict it would be a target for competition. Gel mobility shift assays show that HMG-I forms specific complexes with satellite DNA and that the formation of these complexes is competed for by both Hoechst and distamycin. In addition, methidium propyl EDTA Fe(II) [MPE Fe(II)] footprints of ligand-satellite DNA complexes showed essentially the same protection pattern for both drugs and a similar, but not identical, HMG-I footprint. If these in vitro results reflect the in vivo situation then the incomplete condensation of centromeric heterochromatin observed when mouse cells are grown in the presence of either chemical ligand could be a consequence of competition for binding of HMG-I (and possibly other proteins) to satellite DNA.

Animals↗
PubMed1982

Structure at restriction endonuclease MboI cleavage sites protected by actinomycin D or distamycin A.

Restriction endonuclease MboI cleavage of DNA was inhibited by actinomycin D and distamycin A. The two inhibitors protected different subsets of the 8 cleavage sites in polyoma DNA. The cleavage reactions were analyzed both in the presence of minimal inhibitory concentrations of the compounds and at higher concentrations, allowing cleavage at only 1 site/DNA molecule. The experiments showed that cleavage sites most efficiently protected by actinomycin D had putative inhibitor binding sites at a distance of 1-2 base pairs from the MboI recognition sequence. Distamycin A, in contrast, apparently has to bind immediately adjacent to the MboI recognition sequence to protect from cleavage.

Base Sequence↗
PubMed1989

Specific inhibition of DNA binding to nuclear scaffolds and histone H1 by distamycin. The role of oligo(dA).oligo(dT) tracts.

Scaffold-associated regions (SARs) are A + T-rich sequences defined by their specific interaction with the nuclear scaffold. These sequences also direct highly specific binding to purified histone H1, and are characterized by the presence of oligo(dA).oligo(dT) tracts, which are a target for the drug distamyin, an antibiotic with a wide range of biological activities. The interaction of distamycin with SAR sequences results in the complete suppression of binding to either scaffolds or histone H1, suggesting that (dA.dT)n tracts play a direct role in mediating these specific interactions and that histone H1 and nuclear scaffold proteins may recognize a characteristic minor groove width or conformation. The effect of distamycin on these specific DNA-protein interactions in vitro suggests that binding of SARs to the nuclear scaffold and SAR-dependent nucleation of H1 assembly might be important targets of the drug in vivo.

Animals↗
PubMed1995

Novel sulfonated and phosphonated analogs of distamycin which inhibit the replication of HIV.

A series of novel distamycin-related polyanionic compounds were compared for their anti-HIV activity. Several were highly potent inhibitors of HIV virus-induced cell killing and viral replication of a wide variety of laboratory isolates, as well as a monocytotropic virus and a clinical isolate in human peripheral blood lymphocytes. These compounds are structurally different from other sulfonic acid containing compounds reported to be potent inhibitors of the human immunodeficiency virus (HIV) in two respects: (1) they are structurally related to the non-toxic minor groove DNA binder distamycin; and (2) a number of them contain the aromatic phosphonic acid group. The compounds that were evaluated can be categorized into monomeric or dimeric ureido structural classes incorporating the bisamido-N-methylpyrrolenaphthalene-sulfonic acid group, with differences in the number and position of the sulfonic acids on the naphthalene rings. Broader structure-activity studies were made possible through the synthesis and evaluation of the compounds containing only a single N-methylpyrrole unit, those incorporating the N-methylpyrazole structure, and compounds having the isosteric phosphonic acid group substituted for the sulfonic acid group. One of the most potent of the inhibitors was 2,2'[4,4'[[aminocarbonyl]amino]bis[N,4'-di[pyrrole-2-carboxamide- 1,1'-dimethyl]]-4,6,8 naphthalenetrisulfonic acid] hexasodium salt, NSC 651015. This compound, the phosphonic acid analog NSC 662162, and the monomeric compound NSC 651018 were studied to determine the mechanism of their inhibitory activity. Mechanistic studies revealed that inhibition was due to the disruption of virus attachment to CD(4+)-susceptible cells and a further restraint on fusion of virus and cell membranes. The relative tolerance of these compounds in mice suggests that sufficient antiviral concentrations could be reached in vivo and thus may prove valuable in the treatment of AIDS patients.

Amino Acid Sequence↗
PubMed1992

Characterization of the toxicity of distamycin derivatives on cancer cell lines and rat heart.

The cytotoxicity and cardiotoxicity of benzoyl mustard (FCE 24517) and epoxamido (FCE 24561) synthetic derivatives of distamycin A were reported in the present study. The 50% inhibiting concentration (IC50) of colony formation of FCE 24517 on human SNB-19 glioblastoma, A2780 ovarian cancer and DU 145 prostate cancer was at least three times lower than that of FCE 24561; on the same cell lines the IC50 of DXR was up to 14 and 240 times higher than that of FCE 24561 and FCE 24517, respectively. Isolated rat hearts perfused with concentrations of both derivatives equivalent to their respective IC50 values did not show any significant change in ECG parameters, contractility and coronary flow. Compared to control hearts, FCE 24517 10(-6) M induced a significant increase in PR interval, reduction in + dF/dtmax, heart rate and coronary flow, while FCE 24561 10(-6) M produced a modest but significant increase in S alpha T segment and decrease in + dF/dtmax. Rats treated with FCE 24561 3, 6 or 12 mg/kg, intravenously (i.v.), once weekly for 3 weeks had a modest increase in S alpha T segment and QRS complex duration, while a slight alteration of S alpha T segment and QRS complex duration were observed in rats given FCE 24517 1 or 2 mg/kg i.v. once weekly for 3 weeks. No cardiac histologic alterations were found in hearts from rats receiving FCE 24517 or FCE 24561. For comparison, the cardiotoxicity of doxorubicin (DXR) was evaluated in the same experimental models; perfusion of hearts with DXR 10(-6) M induced severe alterations in all parameters of the isolated hearts; the administration of DXR 3 mg/kg i.v. once a week for 3 weeks was associated with a widening of the S alpha T segment and QRS complex and cardiac histologic picture was markedly altered. In conclusion, distamycin A derivatives display elevated cytotoxicity while no substantial cardiotoxicity was observed.

Animals↗
PubMed1980

Thermal denaturation of distamycin A--DNA complexes as followed by hyperchromic spectra.

Interaction of distamycin A with calf spleen DNA is investigated by the method of hyperchromic spectra. Hyperchromic spectra of complexes are partitioned into the components corresponding to the denaturation A . T and G . C base pairs and dissociation of the ligand, fractions of respective components are found as a function of temperature. A scheme of melting of successive regions of DNA with different G+C content together with the scheme of distamycin A redistribution in the course of thermal denaturation is presented.

Animals↗
PubMed2004

Effects of a hairpin polyamide on DNA melting: comparison with distamycin and Hoechst 33258.

We have used DNase I footprinting and fluorescence melting studies to study the interaction of the hairpin polyamide Im-Py-Py-Py-(R)H2Ngamma-Im-Py-Py-Py-beta-Dp with its preferred binding sites (5'-WGWWCW; W=A or T) and other sequences. DNase I footprinting confirmed that the ligand binds to the sequence AGAACA at nanomolar concentrations and that changing the terminal A to G causes a dramatic decrease in affinity, while there was no interaction with the reverse sequence WCWWGW. Fluorescence melting studies with 11-mer duplexes showed that the polyamide had very different effects on the forward (TGWWCT) and reverse (TCTAGT) sequences. At low concentrations, the polyamide produced biphasic melting curves with TGATCT, TGTACT and TGAACT, suggesting a strong interaction. In contrast, the melting profiles with TCTAGT were always monophasic and showed much smaller concentration dependent changes in Tm. The polyamide also showed weak binding to the sequence TGATCT when one of the central AT pairs was replaced with an AC mismatch. These melting profiles were compared with those produced by the AT-selective minor groove binding agents distamycin and Hoechst 33258 at the same sites and at similar sequences containing A5 and (AT)3, which are expected to bind distamycin in the 1:1 and 2:1 modes, respectively. These ligands produced simple monophasic melting curves in which the Tm steadily increased as the ligand concentration was raised.

Base Pair Mismatch↗
PubMed1998

A distamycin A-inducible fragile site, FRA8E, located in the region of the hereditary multiple exostoses gene, is not involved in HPV16 DNA integration and amplification.

The rare fragile site is a specific point on a chromosome that is expressed as an isochromatid gap or break under certain conditions of cell culture and is inherited in a Mendelian codominant fashion. Five folate-sensitive fragile sites were cloned, and the molecular basis of fragile site mutation was shown to be a new class of mutation, called dynamic mutation, resulting from an allelic expansion of (CCG)n repeats. The mechanism responsible for other types of rare fragile sites, i.e., distamycin A-inducible and BrdU-requiring, is unknown, although cytogenetic studies suggested that these fragile sites play a mechanistic role in breakage and recombination and may also be integration and modification sites of foreign viral DNA genomes. A distamycin A-inducible fragile site, FRA8E, is mapped to 8q24.1 in which various loci implicated in genomic instability are located. Here we identified a YAC clone spanning both FRA8E and the hereditary multiple exostosis (EXT1) gene, using fluorescence in situ hybridization (FISH) analysis of a yeast artificial chromosome (YAC) contig. By using P1 clones as probes, the FRA8E locus was further localized to a 400-kb region including the EXT1 gene. Furthermore, the integration and amplification site of human papillomavirus 16 DNA in the ASCC (argyrophil small cell carcinoma) cells were shown not to coincide with FRA8E, but to be involved in an extensively broad genomic region of 8q24.1, including the c-myc gene.

Chromosome Fragile Sites↗
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↗
PubMed2000

Cytotoxic alpha-bromoacrylic derivatives of distamycin analogues modified at the amidino moiety.

The design, synthesis, in vitro and in vivo activities of novel alpha-bromoacrylic derivatives of distamycin A, modified at the amidino moiety by the replacement with basic or non-basic groups are reported. In spite of the relevance of these modifications of distamycin frame, the new derivatives are potent cytotoxics. The presence of the amidino moiety, is, therefore; not an absolute requirement for the activity. In particular due to a favorable myelotoxicity/cytotoxicity ratio, guanidino derivative PNU 166196 was selected for clinical development.

Amidines↗
PubMed2000

Synthesis of hybrid distamycin-cysteine labeled with 99mTc: a model for a novel class of cancer imaging agents.

The synthesis of a hybrid constituted by distamycin A and cysteine labeled with the gamma-emitting radionuclide 99mTc to afford the conjugate complex 5 is reported. This new radiopharmaceutical is of potential interest as tumor imaging agent in diagnostic nuclear medicine. The preparation of the hybrid distamycin A-cysteine 4 has been achieved by coupling deformyldistamycin A and Boc-Dmt-OH. Compound 4 was then successfully labeled with 99mTc by reaction with the novel, high-electrophilic, metal-containing fragment [99mTc(N)(PP)]2+ (PP = diphosphine ligand) yielding the 1:1 complex 5.

Cysteine↗
PubMed2000

Phenyl sulfur mustard derivatives of distamycin A.

The design, synthesis, and cytotoxic activity of novel benzoyl and cinnamoyl sulfur mustard derivatives of distamycin A are described and structure activity relationships are discussed. These sulfur mustards are more potent cytotoxics than corresponding nitrogen mustards in spite of the lower alkylating power, while their sulfoxide analogues are substantially inactive. Cinnamoyl sulfur mustard derivative (7) proved to be one of the most active distamycin-derived cytotoxics, about 1000 times more potent than melphalan.

Distamycins↗
PubMed2002

Synthesis and DNA binding properties of saturated distamycin analogues.

A series of saturated heterocyclic analogues of distamycin were prepared and examined. A fluorescent intercalator displacement (FID) assay conducted on p[dA]-p[dT] DNA to obtain C(50) values and a hairpin deoxyoligonucleotide containing an A/T-rich binding site was used to evaluate DNA binding affinity. It is observed that saturated heterocycles greatly reduce the DNA binding relative to distamycin.

DNA↗
PubMed1995

Sequence specificity of alkylation for a series of nitrogen mustard-containing analogues of distamycin of increasing binding site size: evidence for increased cytotoxicity with enhanced sequence specificity.

The covalent sequence specificity of a series of nitrogen mustard-containing analogues of distamycin was determined using modified sequencing techniques. The analogues tether benzoic acid mustard (BAM) and possess either one, two, or three pyrrole-amide units. Previous characterization of the biological profile of the series revealed an increase in cytotoxicity for each corresponding increase in the number of pyrrole units, while showing poor cross-link formation in isolated and cellular DNA. Examination of the sequence specificity revealed that BAM produced guanine-N7 lesions in similar manner to other conventional nitrogen mustards. The monopyrrole BAM conjugate also produced guanine-N7 alkylation in a similar pattern to BAM. However, alkylation of adenines was also seen that was found to be minor groove adenine-N3 lesions. The dipyrrole and tripyrrole conjugates did not produce detectable guanine-N7 alkylation but only alkylated in AT tracts. In addition, the tripyrrole conjugate preferentially alkylated only a subset of those sites alkylated by the monopyrrole and dipyrrole conjugates. Two sites, 5'-TTTTGG and 5'-TTTTGA, confirmed as guanine-N3 and adenine-N3 lesions, respectively, were strongly alkylated by the tripyrrole conjugate in preference to other similar sites including three occurrences of 5'-TTTTAA. Footprinting studies comparing distamycin and the tripyrrole conjugate showed identical non-covalent recognition of AT-rich sites. Hence, the drug that possessed the most enhanced sequence specificity for alkylation was also the most cytotoxic of this series.

Antineoplastic Agents, Alkylating↗
PubMed1993

GC base sequence recognition by oligo(imidazolecarboxamide) and C-terminus-modified analogues of distamycin deduced from circular dichroism, proton nuclear magnetic resonance, and methidiumpropylethylenediaminetetraacetate-iron(II) footprinting studies.

The DNA binding properties of a series of imidazole-containing and C-terminus-modified analogues 4-7 of distamycin are described. These analogues contain one to four imidazole units, respectively. Data from the ethidium displacement assay showed that these compounds bind in the minor groove of DNA, with the relative order of binding constants of 6 (Im3) > 7 (Im4) > 5 (Im2) > 4 (Im1). The reduced binding constants of these compounds for poly(dA-dT) relative to distamycin, while they still interact strongly with poly(dG-dC), provided evidence of GC sequence acceptance. The preferences for GC-rich sequences by these compounds were established from a combination of circular dichroism (CD) titration, proton nuclear magnetic resonance (1H-NMR), and methidiumpropylethylenediaminetetraacetate-iron(II) [MPE.Fe-(II)] footprinting studies. In the CD studies, these compounds produced significantly larger DNA-induced ligand bands with poly(dG-dC) than poly(dA-dT) at comparable ligand concentrations. 1H-NMR studies of the binding of 5 to d-[CATGGCCATG]2 provided further evidence of the recognition of GC sequences by these compounds, and suggested that the ligand was located on the underlined sequence in the minor groove with the C-terminus oriented over the T residue. MPE footprinting studies on a GC-rich BamHI/SalI fragment of pBR322 provided unambiguous evidence for the GC sequence selectivity for some of these compounds. Compounds 4 and 7 produced poor footprints on the gels; however, analogues 5 and 6 gave strong footprints.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1986

1H NMR studies on the interaction between distamycin A and a symmetrical DNA dodecamer.

High-resolution NMR techniques have been used to examine the structural and dynamical features of the interaction between distamycin A and the self-complementary DNA dodecamer duplex d-(CGCGAATTCGCG)2. The proton resonances of d(CGCGAATTCGCG)2 have been completely assigned by previous two-dimensional NMR studies [Hare, D. R., Wemmer, D. E., Chou, S. H., Drobny, G., & Reid, B. R. (1983) J. Mol. Biol. 171, 319-336]. Addition of the asymmetric drug molecule to the symmetric dodecamer leads to the formation of an asymmetric complex as evidenced by a doubling of DNA resonances over much of the spectrum. In two-dimensional exchange experiments, strong cross-peaks were observed between uncomplexed DNA and drug-bound DNA resonances, permitting direct assignment of many drug-bound DNA resonances from previously assigned free DNA resonances. Weaker exchange cross-peaks between formerly symmetry related DNA resonances indicate that the drug molecule flips head-to-tail on one duplex with half the frequency at which it leaves the DNA molecule completely. In experiments performed in H2O, nuclear Overhauser effects (NOEs) were observed from each drug amide proton to an adenine C2H and a pyrrole H3 ring proton. In two-dimensional nuclear Overhauser experiments performed on D2O solutions, strong intermolecular NOEs were observed between each of the three pyrrole H3 resonances of the drug and an adenine C2H resonance, with weaker NOEs observed between the drug H3 resonances and C1'H resonances. The combined NOE data allow us to position the distamycin A unambiguously on the DNA dodecamer, with the drug spanning the central AATT segment in the minor groove.

Base Sequence↗
PubMed1988

Determination of equilibrium binding affinity of distamycin and netropsin to the synthetic deoxyoligonucleotide sequence d(GGTATACC)2 by quantitative DNase I footprinting.

A new method for determining the equilibrium binding constant of antitumor drugs to specific DNA sequences by quantitative DNase I footprinting is presented. The use of a short synthetic DNA oligomer to define a homogeneous population of DNA binding sites enables the calculation of the free drug concentration and the fraction of DNA sites complexed with drug in solution and is described for the first time. Since a 1:1 stoichiometry is observed for each drug-oligomer DNA complex, it becomes possible to calculate equilibrium binding constants in solution. By use of this technique, the binding affinities of the nonintercalating drugs netropsin and distamycin to the synthetic oligonucleotide d(GGTATACC)2 are determined to be Ka (25 degrees C) = 1.0 X 10(5) and 2.0 X 10(5) M-1, respectively. Quantitation of the temperature dependence associated with complex formation results in a determination of standard enthalpies of -3.75 and -8.48 kcal mol-1 for the binding of netropsin and distamycin, respectively. Calculation of other thermodynamic parameters are found to be in agreement with previous studies and indicate that the DNA binding process for these compounds is predominantly enthalpy driven. This method of quantitative DNase I footprinting is demonstrated to be a useful technique for the measurement of drug affinities to specific binding sites on DNA oligomers which are designed and synthesized expressly for this purpose. Applications of the technique to the determination of drug binding affinities at specific sites within native DNA sequences are discussed.

Binding Sites↗