Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Distamycins”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 91 records · Page 5Linked to original sources
PubMed1986

Familial fragile site found at the cancer breakpoint (1)(q32). Inducibility by distamycin A, concomitance with fragile (16)(q22).

A normal baby was cytogenetically examined immediately after birth for the possible presence of a fragile (16)(q22), which had been found in her mother and in her retarded sister with a 46,XX;46,XX,del(16)(q22) mosaic karyotype. Distamycin A was added to the cultures to enhance the fragile (16)(q22) expression. The response of the baby to the action of distamycin A in vitro was much greater than that of her family members. A fragile (16)(q22) was induced in many cells as well as a fragile (1)(q32), which was also found in her mother. This fragile site, which is known to be a cancer breakpoint, has not been reported so far either to be familial or to be inducible by distamycin A. The concomitance of fragile (1)(q32) with fragile (16)(q22) and their possible significance are considered.

Cells, Cultured↗
PubMed1988

A new rare distamycin A-inducible fragile site, fra(11) (p15.1), found in two acute nonlymphocytic leukemia (ANLL) patients with t(7;11)(p15-p13;p15).

Fragile sites were analyzed in normal peripheral lymphocytes from two acute nonlymphocytic leukemia patients with t(7;11)(p15-p13;p15) leukemic cells. To induce expression of fragile sites, cultures were exposed to folate deprivation (M-F10), BrdU, distamycin A, or Hoechst 33258. Fragility at 11p15.1 was induced by distamycin A and Hoechst 33258 but was not seen in M-F10, BrdU, and control cultures. Fra(11)(p15.1) was found neither in healthy Japanese subjects (0 in 845) nor in patients with leukemia or other hematologic disorders without the t(7;11) (0 in 126). From these results, fra(11)(p15.1) can now be classified as a rare distamycin A-inducible fragile site. Furthermore, this fra(11)(p15.1) coincided with one of the breakpoints of the t(7;11)(p15-p13;p15).

Adolescent↗
PubMed1979

DNA-binding antibiotics. X-ray structure of the distamycin A analog.

The crystal structure of the antibiotic distamycin A analog containing two pyrrol carboxamide fragments has been determined. The space group of the crystals is P21/b; the unit-cell dimensions are a = 11.169, b = 21.535, c = 7.863 A, alpha = beta = 90 degrees, gamma = 122.45 degrees, Z = 4. The structure is solved by direct methods, and refined with the full-matrix least-squares procedure. The data on the structure of the pyrrol carboxamide backbone allow the following conclusions to be made about the molecular structure of the distamycin type antibiotics: (i) the amide groups have normal trans-configuration with slightly shortened C-C and C-N bonds adjacent to the pyrrol rings, (ii) the N-methyl groups of the pyrrol rings and the oxygen atoms of the amide groups have the same orientation with respect to the backbone. In the distamycin A analog molecule the pyrrol rings and amide group between them are approximately coplanar.

Chemical Phenomena↗
PubMed1980

Magnetic circular dichroism study of the binding of netropsin and distamycin A with DNA.

The magnetic circular dichroism (MCD) of netropsin and distamycin-A is reported. New data for the interaction with dA ; dT base pairs in DNA were obtained from the MCD of their complexes with DNA duplex polymers. The MCD results allow an interpretation of the induced Cotton effects in the natural CD spectra of netropsin and distamycin-A complexes with DNA. While large distortions of the bases in DNA by the oligopeptide interaction is excluded, some subtle conformational variations of the DNA might explain the inhibition of the enzyme function of netropsin and distamycin-A on DNA.

Circular Dichroism↗
PubMed1986

DNA-binding characteristics of a synthetic analogue of distamycin.

The interaction between a synthetic analogue (structure shown in fig. 1) of distamycin, and DNA has been studied with a view to understanding the conformational and chemical basis of the sequence specific binding of distamycin with DNA. The complex formation between the trimer and DNA is apparent from the red shift in the UV spectrum and appearance of the induced CD band in 300nm-350nm region. The relevant data suggest: (i) the binding is A-T base specific though the specificity is not as pronounced as in distamycin (1,2) and (ii) it occurs via the minor groove of DNA. The partial loss in A-T base specificity may be due to the replacement of N-methyl pyrrole by benzene or the increase in curvature of the backbone of the ligand as a result of this replacement.

Binding Sites↗
PubMed1995

Effects of two distamycin-ellipticine hybrid molecules on topoisomerase I and II mediated DNA cleavage: relation to cytotoxicity.

Two distamycin-ellipticine conjugates were examined for their ability to modulate topoisomerase I and topoisomerase II-DNA cleavable complex formation in vitro. Hybrid molecules Distel (1+) and Distel (2+) both contain a DNA-intercalating chromophore and a tris-pyrrole element capable of binding within the minor groove of DNA. The two drugs differ only in the nature of the side chain attached to the distamycin moiety. The monocationic hybrid Distel (1+) is a dual topoisomerase I and II inhibitor with characteristics differing from those of the parent compounds distamycin and ellipticine. By contrast, the biscationic hybrid Distel (2+) exerts no significant effects on either topoisomerase I or II. The cytotoxic properties of the two drugs towards P388 leukaemic cells sensitive and resistant to camptothecin correlate with topoisomerase inhibitory properties but not with DNA-binding properties.

Animals↗
PubMed1988

Distamycin A-inducible fragile sites and cancer proneness.

To determine the baseline frequency of autosomal rare fragile sites in cancer patients, we conducted a population cytogenetic study of 370 patients with leukemias, solid tumors, and other neoplastic disorders. Twenty carriers of rare fragile sites were detected in this patient group. The rare autosomal fragile sites were at fra(8)(q24), fra(11)(p15), fra(16)(p12.1), fra(16)(q22), and fra(17)(p12). All of these fragile sites were found to be distamycin A inducible. Compared with a population incidence in healthy subjects (44 of 845, 5.21%), the overall incidence of distamycin A-inducible fragile sites was not higher in the patient group (20 of 370, 5.41%). Analysis of these individual fragile sites and particular diseases, however, suggests that the distamycin A-inducible fragile sites may play a role in the etiology of leukemia, myeloproliferative disorders, and benign tumors.

Chromosome Fragile Sites↗
PubMed1981

Aspects of specific DNA-protein interaction; local bending of DNA molecules by in-register binding of the oligopeptide antibiotic distamycin.

Distamycin A binds strongly/moderately to DNA below/above r = 0.08 molecules bound per DNA phosphate. Titration viscometric measurements for high and low molecular weight DNA yielded the relative changes of DNA persistence length, delta alpha/alpha 0, and contour length, delta L/L0 (Nucl. Acids Res. 7 (1979) 1375). delta L/L0 is negligible/positive in the range below/above r = 0.09 at 0.2 M Na+! A two-line covering of the small groove by ligand molecules explains the increase of contour length. The characteristic delta alpha/alpha 0 drop is quantitatively interpreted by local DNA bending (kinking). The underlying theoretical basis is presented in two appendices and applied, in a third one, to literature data for the DNA-actinomycin system. The angle gamma of local DNA bending as induced by complex formation with different distamycin derivatives is presented for DNA species of different base composition. By means of appropriate model, a length mismatch per dinucleotide of (0.03(2) +/- 0.01)nm [or (0.04(3) +/- 0.01)nm] was derived from the experimentally obtained bending angle per dinucleotide of (1.6 +/- 0.4)0 [or (2.1 +/- 0.05)0], independent of DNA base composition and distamycin chain length.

Animals↗
PubMed1995

Alteration of the expression of human estrogen receptor gene by distamycin.

The effects of distamycin on the expression of the estrogen receptor gene were determined in the MCF7 human breast cancer cell line. Estrogen receptor (ER) RNA transcripts were analyzed by Northern blotting and RT-PCR using specific oligonucleotides for the 5' upstream region and for ER cDNA. After ex vivo distamycin treatment of the cells the expression of the canonical ER mRNA isoform of 6.3 kb is strongly inhibited, without appreciable alteration of the accumulation of 5' upstream ER mRNA isoforms. These results suggest that distamycin alters the transcriptional activity of the ER gene causing a change in the ratio between the canonical transcript and other isoforms containing 5' upstream regions.

Antiviral Agents↗
PubMed2006

Hybrid molecules between distamycin A and active moieties of antitumor agents.

The DNA minor groove is an attractive target for the design and development of molecules able to specifically recognize predetermined DNA sequences. The pyrrole-amide skeleton of distamycin A has been also used as DNA sequence selective vehicle for the delivery of alkylating functions to DNA targets. Selectivity for specific sequences may be of particular importance in affecting the activity of regulatory genes (oncogenes and tumor suppressor genes). Recent work on a number of hybrid compounds, in which known antitumor compounds or simple active moieties of known antitumor agents have been tethered to distamycin frame or hairpin polyamides derived from distamycin, is reviewed. The DNA alkylating and growth inhibition activities against several tumor cell lines are reported and discussed in terms of their structural differences in relation to both the number of N-methyl pyrrolic rings and the type of the alkylating unit tethered to the oligopyrrolic frame.

Animals↗
PubMedDate not supplied

Antimalarial activity of synthetic analogues of distamycin.

Malaria, one of the most serious diseases transmitted by arthropods, is largely present in tropical and even temperate zones in endemic or epidemic form. More than 40% of the world's population lives in areas at risk for exposure, and the World Health Organization reports that approximately 300 million people are affected by the infection (mostly caused by the species Plasmodium falciparum), with 1-2 million deaths per year. These data, and the fact that malaria is becoming increasingly refractory to treatment through resistance of the parasite to antimalarial agents currently in use, e.g., chloroquine, emphasize the need to develop new drugs. The well-known antiparasitic activity of oligopyrrolamidine natural products, such as distamycin and netropsin, suggested the antimalarial evaluation of related compounds obtained by new chemical modifications. Besides possessing antiviral and antitumoural properties, distamycin exhibits interesting in vitro activity against P. falciparum. Unfortunately, the high toxicity associated with this product precludes its development as a drug. However, some synthetic analogues of distamycin proved to be highly active against chloroquine-sensitive and -resistant strains of P. falciparum, besides showing low toxicity in vitro.

Animals↗
PubMed2003

Synthesis and growth inhibition activity of alpha-bromoacrylic heterocyclic and benzoheterocyclic derivatives of distamycin A modified on the amidino moiety.

The design, synthesis and in vitro activities of novel alpha-bromoacryloyl pyrazole, imidazole and benzoheterocyclic derivatives of distamycin A, in which the amidino moiety has been replaced by moieties of different physico-chemical features are described, and the structure-activity relationships are discussed. In spite of the relevance of these modifications on the distamycin frame, these derivatives showed significant growth inhibitory activity against mouse leukemia L1210 cells. Therefore, the presence of the amidino moiety, and in general of a basic moiety, is not an absolute requirement for biological activity of alpha-bromoacrylic derivatives of distamycin.

Acids, Heterocyclic↗
PubMedDate not supplied

Identification of preferred distamycin-DNA binding sites by the combinatorial method REPSA.

The combinatorial method restriction endonuclease protection, selection, and amplification (REPSA) was used to determine the preferred duplex DNA binding sites of the peptide N-methylpyrrolecarboxamide antibiotic distamycin A. After 12 rounds of REPSA, several sequences were identified that bound distamycin with an apparent affinity of 2-20 nM. Among these, the highest-affinity sites averaged 10 bp in length, suggesting that these sites may be occupied by multiple, cooperatively interacting distamycin molecules. Presently, REPSA is the only combinatorial approach that allows the identification of preferred DNA targets for small molecule ligands at physiologically relevant concentrations in solution. As such, it should prove useful in the design and screening of sequence-specific DNA-binding molecules.

Anti-Bacterial Agents↗
PubMed1992

Binding of a distamycin-ellipticine hybrid molecule to DNA and chromatin: spectroscopic, biochemical, and molecular modeling investigations.

A bifunctional molecule in which an ellipticine chromophore is attached to a distamycin residue via a diaminopropyl tether has been designed and synthesized in the expectation of creating a hybrid molecule capable of bidentate binding to DNA by both intercalation and minor-groove interactions. The strength and mode of binding to DNA of this conjugate have been studied by means of circular and linear dichroism as well as by stopped-flow kinetics and measurements of reactivity toward a chemical probe. The results converge to reveal that the ellipticine moiety of the hybrid largely dominates the binding reaction with DNA. In the presence of chromatin, the hybrid molecule binds preferentially to the internucleosomal DNA, a preference dictated by its intercalating chromophore. Theoretical computations were performed on the comparative complexation energies of distamycin, the ellipticine derivative, and the hybrid ligand with a B-representative octanucleotide, d(GCATATGC)2. The best binding configuration of the ellipticine derivative locates its aminoalkyl side chain in the minor groove where distamycin is also present. The molecular modeling analysis fully supports the involvement of a bimodal binding process for the hybrid and reveals that the binding of the conjugate to DNA favors a pronounced bending toward the minor groove. This effect is attributed to intercalation of the ellipticine chromophore. An interesting link is established between the DEPC reactivity experiments and the theoretical computations, suggesting that DEPC can be used as a probe for drug-induced DNA bending. On the basis of these results, we propose the design of a new hybrid ligand bearing an additional positively-charged amidine side chain to confer higher DNA-binding affinity.

Autoradiography↗
PubMed2004

Binding of distamycin A to UV-damaged DNA.

We have found that distamycin A can bind to DNA duplexes containing the (6-4) photoproduct, one of the major UV lesions in DNA, despite the changes, caused by photoproduct formation, in both the chemical structure of the base moiety and the local tertiary structure of the helix. A 20-mer duplex containing the target site, AATT.AATT, was designed, and then one of the TT sequences was changed to the (6-4) photoproduct. Distamycin binding to the photoproduct-containing duplex was detected by CD spectroscopy, whereas specific binding did not occur when the TT site was changed to a cyclobutane pyrimidine dimer, another type of UV lesion. Distamycin binding was analyzed in detail using 14-mer duplexes. Curve fitting of the CD titration data and induced CD difference spectra revealed that the binding stoichiometry changed from 1:1 to 2:1 with photoproduct formation. Melting curves of the drug-DNA complexes also supported this stoichiometry.

Chemical Phenomena↗
PubMed1999

Alpha-bromoacryloyl derivative of distamycin A (PNU 151807): a new non-covalent minor groove DNA binder with antineoplastic activity.

PNU 151807 is a new synthetic alpha-bromoacryloyl derivative of distamycin A. In the present study we investigated the DNA interaction and the mechanism of action of this compound in parallel with the distamycin alkylating derivative, tallimustine. PNU 151807 possesses a good cytotoxic activity in in vitro growing cancer cells, even superior to that found for tallimustine. By footprinting experiments we found that PNU 151807 and tallimustine interact non-covalently with the same AT-rich DNA regions. However, differently from tallimustine, PNU 151807 failed to produce any DNA alkylation as assessed by Taq stop assay and N3 or N7-adenine alkylation assay in different DNA sequences. PNU 151807, like tallimustine, is able to induce an activation of p53, and consequently of p21 and BAX in a human ovarian cancer cell line (A2780) expressing wild-type p53. However, disruption of p53 function by HPV16-E6 does not significantly modify the cytotoxic activity of the compound. Flow cytometric analysis of cells treated with equitoxic concentrations of PNU 151807 and tallimustine showed a similar induction of accumulation of cells in the G2 phase of the cell cycle but with a different time course. When tested against recombinant proteins, only the compound PNU 151807 (and not tallimustine or distamycin A) is able to abolish the in vitro kinase activity of CDK2-cyclin A, CDK2-cyclin E and cdc2-cyclin B complexes. The results obtained showed that PNU 151807 seems to have a mechanism of action completely different from that of its parent compound tallimustine, possibly involving the inhibition of cyclin-dependent kinases activity, and clearly indicate PNU 151807 as a new non-covalent minor groove binder with cytotoxic activity against cancer cells.

Animals↗
PubMed1994

Sequence-specific recognition of the HIV-1 long terminal repeat by distamycin: a DNAase I footprinting study.

Pharmacological modulation of the interaction between transcription factors and target DNA sequences of cellular and viral genes could have important effects in the experimental therapy of a large variety of human pathologies. For instance, alteration of the DNA/protein interaction might be among the molecular mechanisms of action of DNA-binding drugs, leading to an inhibition of the expression of genes involved in the control of in vitro and in vivo growth of neoplastic cells and virus DNA replication. Natural oligopeptides, such as distamycin, are powerful inhibitors of the interaction between nuclear factors and target DNA sequences and, therefore, have been proposed as compounds retaining antibiotic, antineoplastic and antiviral properties. In this study we performed DNAase I footprinting analysis using a PCR product mimicking a region of the long terminal repeat (LTR) of the human immunodeficiency type 1 (HIV-1) retrovirus. The data obtained suggest that distamycin binds to different regions of the HIV-1 LTR depending on the DNA sequence. Electrophoretic mobility shift assays using both crude nuclear extracts from the Jurkat T-lymphoid cell line and the recombinant proteins transcription factor IID and Sp1 suggest that distamycin differentially inhibits the interaction of these two proteins with their specific DNA target sequences, in good agreement with the results obtained by DNAase I footprinting analysis.

Base Sequence↗
PubMed1982

Map of distamycin, netropsin, and actinomycin binding sites on heterogeneous DNA: DNA cleavage-inhibition patterns with methidiumpropyl-EDTA.Fe(II).

We report a direct technique for determining the binding sites of small molecules on naturally occurring heterogeneous DNA. Methidiumpropyl-EDTA.Fe(II) [MPE.Fe(II) cleaves double helical DNA with low sequence specificity. Using a combination of MPE.Fe(II) cleavage of drug-protected DNA fragments and Maxam-Gilbert gel methods of sequence analysis, we have determined the preferred binding sites on a Rsa I-EcoRI restriction fragment from pBR322 for the intercalator actinomycin D and the minor groove binders netropsin and distamycin A. Netropsin and distamycin A gave identical DNA cleavage-inhibition patterns and bound preferentially to A+T-rich regions with a minimal protected site of four base pairs. We were able to observe the effect of increasing concentration on site selection by netropsin and distamycin A. Actinomycin D afforded a completely different cleavage-inhibition pattern, with 4- to 16-base-pair-long protected regions centered around one or more G.C base pairs.

Chemical Phenomena↗