Carbocyclic Analogues of Netropsin and Distamycin: DNA-Binding Properties and Inhibition of DNA Topoisomerases

Bartulewicz, Danuta; Bielawski, Krzysztof; Bielawska, Anna

doi:10.1002/1521-4184(200212)335:9<422::aid-ardp422>3.0.co;2-5

Cited by 13 publications

(11 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2 0 ) [43]. These compounds containing two or three benzene units were designed to provide improved distinction between minorgroove and intercalation binding modes.…”

Section: Fig (3)mentioning

confidence: 99%

Advances in DNA-Ligands with Groove Binding, Intercalating and/or Alkylating Activity: Chemistry, DNA-Binding and Biology

Pindur¹,

Jansen²,

Lemster

2005

CMC

105

View full text Add to dashboard Cite

It is known that DNA is a well-characterized intracellular target but its size and sequential characteristics make it an elusive target for selective drug action. Binding of low molecular weight ligands to DNA causes a variety of significant biological responses. In this context the main consideration is given to recent developments in DNA sequence selective binding agents bearing conjugated effectors because of their potential application in treatment of cancers, in diagnosis as well as in molecular biology. In the present review recent results about analogues of netropsins, distamycin A and of some lexitropsins and combilexins or related hybrid molecules with sequence reading, intercalating or alkylating activity are described and evaluated for prospective applications. Furthermore there exists DNA minor groove binder with different basic structures which does not possess the typical polyamide chain, including dimeric intercalating chromophores. Finally new results about peptide nucleic acids and related nucleic acid bases linked with polyamides are reported. In pronounced examples the structural chemistry, synthesis, DNA binding with several biophysical methods, molecular aspects, structure activity relationship, topoisomerase inhibition, antitumour and antibacterial effects are discussed in detail.

show abstract

“…2 0 ) [43]. These compounds containing two or three benzene units were designed to provide improved distinction between minorgroove and intercalation binding modes.…”

Section: Fig (3)mentioning

confidence: 99%

Advances in DNA-Ligands with Groove Binding, Intercalating and/or Alkylating Activity: Chemistry, DNA-Binding and Biology

Pindur¹,

Jansen²,

Lemster

2005

CMC

105

View full text Add to dashboard Cite

show abstract

“…Due to the significance of DNA binding in drug design, a number of approaches have been developed to probe the interactions between DNA and small organic ligands, including, calorimetry, 34 NMR spectroscopy, 35 viscometry, 36 and fluorescence. 37 Due to the relative low water solubility of our analogues, we were interested in sensitive assays that could measure DNA binding affinity at concentrations in the micromolar range. Therefore, fluorescence measurements were deemed most appropriate.…”

Section: Resultsmentioning

confidence: 99%

“…The direct assay measures the changes in the fluorescence of the ligand of interest after the addition of that ligand into a DNA solution. 36a,37a–d The indirect method, the fluorescent intercalator displacement (FID) assay, involves a second fluorescent molecule that is a standard DNA intercalator such as ethidium bromide (EtBr). 37d–f Instead of monitoring the fluorescence of the ligand being tested, the fluorescence of the standard intercalator is monitored before and after the addition of the ligand.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis and DNA-binding affinity studies of glycosylated intercalators designed as functional mimics of the anthracycline antibiotics

2009

View full text Add to dashboard Cite

Anthracycline antibiotics such as daunomycin (Dauno) and doxorubicin (Dox) are well-known clinically used cancer chemotherapeutics, which, among other mechanisms, bind to DNA, thereby triggering a cascade of biological responses leading to cell death. However, anthracyclines are cardiotoxic, and drug resistance develops rapidly, thus limiting their clinical use. We report here the synthesis and DNA-binding affinity of a novel class of functional anthracycline mimetics consisting of an aromatic moiety linked to a carbohydrate (1–12). In the targets, the aromatic core consists of a 2-phenylbenzo[b]furan-3-yl, 2-phenylbenzo[b]thiophen-3-yl, 1-tosyl-2-phenylindol-3-yl, or 2-phenylindol-3-yl group that is bound to one of three aminosugars (daunosamine, acosamine, or 4-amino-2,3,4,6-tetradeoxy-α-L-hexopyranoside) via a propargyl linker. The DNA binding affinity of these twelve compounds has been evaluated by using both direct and indirect fluorescence measurements. Compared to Dauno and Dox, the DNA binding affinity of these analogues is weaker. However, both aromatic and aminosugar motifs are critical to DNA binding, with more influence coming from the structural features of the aromatic portion.

show abstract

“…Later experiments demonstrated secondary effects of ATbinding by distamycin, which was also shown to interfere with the formation of complexes involving the major groove, including homeodomain/DNA complexes, presumably as a result of drug-induced changes in the conformation of DNA [25,26]. More generally, numerous studies identified distamycin as a potent regulator of DNA/topoisomerase II interactions at the level of both DNA binding and cleavage, suggesting that the activity of this important enzyme, a major target of anticancer drugs, could be regulated by minor groove ligands [27][28][29][30][31][32][33][34].…”

Section: Targeting A+t-rich Sequences: Early Experiments With Distamycinmentioning

confidence: 99%

Target Practice: Aiming at Satellite Repeats with DNA Minor Groove Binders

Susbielle¹,

Blattes²,

Brevet³

et al. 2005

CMCACA

View full text Add to dashboard Cite

Much progress has been made in recent years in developing small molecules that target the minor groove of DNA. Striking advances have led to the design of synthetic molecules that recognize specific DNA sequences with affinities comparable to those of eukaryotic transcription factors. This makes it feasible to modulate or inhibit DNA/protein interactions in vivo, a major step towards the development of general strategies of anti-gene therapy. Examples from anti-parasitic drugs also suggest that synthetic molecules can affect a variety of cellular functions crucial to cell viability by more generally targeting vast portions of genomes based on their biased base composition. This provides a rationale for developing approaches based on selective interactions with broad genomic targets such as satellite repeats that are associated with structural or architectural components of chromatin essential for cellular proliferation. Using examples drawn from the Drosophila melanogaster model system, we review here the use of synthetic polyamides or diamidines that bind the DNA minor groove and can be used as highly selective agents capable of interfering with specific protein/DNA interactions that occur in A+T-rich repeated sequences that constitute a significant portion of eukaryotic genomes. The satellite localization of cellular proteins that bind the minor groove of DNA via domains such as the AT hook motif is highly sensitive to these molecules. A major consequence of the competition between these proteins and their synthetic mimics is an alteration of the nuclear localization and function of proteins such as topoisomerase II, a major target of anti-cancer drugs.

show abstract

Carbocyclic Analogues of Netropsin and Distamycin: DNA-Binding Properties and Inhibition of DNA Topoisomerases

Cited by 13 publications

References 10 publications

Advances in DNA-Ligands with Groove Binding, Intercalating and/or Alkylating Activity: Chemistry, DNA-Binding and Biology

Advances in DNA-Ligands with Groove Binding, Intercalating and/or Alkylating Activity: Chemistry, DNA-Binding and Biology

Synthesis and DNA-binding affinity studies of glycosylated intercalators designed as functional mimics of the anthracycline antibiotics

Target Practice: Aiming at Satellite Repeats with DNA Minor Groove Binders

Contact Info

Product

Resources

About