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Mini Reviews in Medicinal Chemistry Mar 2010The present review focused on the strategies aimed to possibly solve toxicity problems of distamycins. Distamycins are compounds characterized by an oligopeptidic...
The present review focused on the strategies aimed to possibly solve toxicity problems of distamycins. Distamycins are compounds characterized by an oligopeptidic pyrrolocarbamoyl frame ending with an amidino moiety. This class of compounds displays antiviral and antibiotic activity and shows interesting antiprotozoal activity related to the ability to reversibly bind to the minor groove of DNA with a high selectivity for TA-rich sequences. In consideration of their potential therapeutic properties, the synthesis of new distamycin derivatives and especially the development of controlled delivery strategies, could lead to important advantages in the clinical use of these molecules, possibly overcoming or mitigating the low solubility, specificity and toxicity problems associated with their use. To these aims an ensemble of the main synthetic distamycin derived compounds and of the potential drug delivery systems for distamycins described in literature is reviewed.
Topics: Anti-Bacterial Agents; Antiviral Agents; Distamycins; Heterocyclic Compounds; Liposomes; Nitrogen Mustard Compounds
PubMed: 20408803
DOI: 10.2174/138955710791185055 -
Mini Reviews in Medicinal Chemistry 2019The DNA as the depository of genetic information is a natural target for chemotherapy. A lot of anticancer and antimicrobial agents derive their biological activity from... (Review)
Review
The DNA as the depository of genetic information is a natural target for chemotherapy. A lot of anticancer and antimicrobial agents derive their biological activity from their selective interaction with DNA in the minor groove and from their ability to interfere with biological processes such as enzyme catalysis, replication and transcription. The discovery of the details of minor groove binding drugs, such as netropsin and distamycin A, oligoamides built of 4-amino-1-methylpyrrole-2-carboxylic acid residues, allowed to develop various DNA sequence-reading molecules, named lexitropsins, capable of interacting with DNA precisely, strongly and with a high specificity, and at the same time exhibiting significant cytotoxic potential. Among such compounds, lexitropsins built of carbocyclic sixmembered aromatic rings occupy a quite prominent place in drug research. This work is an attempt to present current findings in the study of carbocyclic lexitropins, their structures, syntheses and biological investigations such as DNA-binding and antiproliferative activity.
Topics: Acids, Carbocyclic; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Cell Proliferation; DNA; Distamycins; Drug Design; Humans; Neoplasms; Netropsin
PubMed: 30626311
DOI: 10.2174/1389557518666181009143203 -
Drug Delivery 2004This article describes the production and characterization of two liposome formulations containing antitumor drugs, namely distamycin A (Dist) and a new alkyl derivative...
This article describes the production and characterization of two liposome formulations containing antitumor drugs, namely distamycin A (Dist) and a new alkyl derivative of distamycin A (C16-Dist). Egg-PC/cholesterol liposomes (4:1 mol/mol) were prepared by reverse phase evaporation technique followed by extrusion through polycarbonate filters. The encapsulation efficiency was found to be almost complete for C16-Dist (99.8%), while native distamycin A showed a lower yield (19.0%). The in vitro antiproliferative activity of the distamycins-containing liposomes determined on human leukaemic K562 cells, was 11-fold and 8-fold higher for native and alkyl derivative distamycin A, respectively, compared with that of the corresponding free drugs. Liposomal formulations show an increase in the activity and specificity of distamycins in experimental antitumor therapy.
Topics: Cell Division; Cell Line, Tumor; Distamycins; Dose-Response Relationship, Drug; Growth Inhibitors; Humans; Liposomes
PubMed: 15200006
DOI: 10.1080/10717540490280516 -
Nucleic Acids Research Feb 1989We 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...
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.
Topics: Base Sequence; Binding, Competitive; Cell Line; DNA-Binding Proteins; Distamycins; Histones; Humans; Leukemia, Erythroblastic, Acute; Oligonucleotides; Pyrroles; Transcription Factors
PubMed: 2922260
DOI: 10.1093/nar/17.3.1051 -
Acta Chimica Slovenica Dec 2016The synthesis and biological activity of a variety of analogues to the naturally occurring antibacterial and antifungal Distamycin A were explored by a number of... (Review)
Review
The synthesis and biological activity of a variety of analogues to the naturally occurring antibacterial and antifungal Distamycin A were explored by a number of authors. These compounds were subject to a large array of assays. Some of these compounds showed high activity against a range of Gram-positive, Gram-negative bacteria as well as fungi. To explore the anti-parasitic activity of this class of compounds, specific modifications had to be made. A number of these compounds proved to be active against Trypanosoma brucei. The binding of a number of these compounds to short sequences of DNA were also examined using footprinting assays as well as NMR spectroscopy. Computer modelling was employed on selected compounds to understand the way these compounds bind to specific DNA sequences. A large number of variations were made to the standard structure of Distamycin. These changes involved the replacement of the pyrrole moieties as well as the head and tail groups with a number of heterocyclic compounds. Some of these minor groove binders (MGBs) were also investigated for their capability for the treatment of cancer and in particular lung cancer.
Topics: Animals; Anti-Bacterial Agents; Computer Simulation; DNA; DNA Footprinting; Distamycins; Humans; Magnetic Resonance Spectroscopy; Trypanocidal Agents
PubMed: 28004090
DOI: 10.17344/acsi.2016.2775 -
Biochemical Pharmacology Apr 1993We have measured the effects of eight distamycin and two anthracycline derivatives on polynucleotide joining and self-adenylating activities of human DNA ligase I and... (Comparative Study)
Comparative Study
We have measured the effects of eight distamycin and two anthracycline derivatives on polynucleotide joining and self-adenylating activities of human DNA ligase I and rat DNA ligases I and III. All test drugs show good inhibitory activity against the three enzymes in the poly[d(A-T)] joining assay. Several distamycins also inhibit the DNA-independent self-adenylation reaction catalysed by the human enzyme and, to a lesser extent, by rat DNA ligases. These results confirm that anthracyclines and distamycins express their inhibitory action against DNA joining activities mainly via specific interactions with the substrate, and suggest that the three test DNA ligases utilize similar, if not identical, mechanisms of recognition and interaction with DNA-drug complexes. Our findings also indicate that distamycins have a greater affinity for human DNA ligase I than for rat enzymes, suggesting that, in this respect, rat DNA ligase I is more similar to rat DNA ligase III than to human DNA ligase I.
Topics: Animals; Antibiotics, Antineoplastic; DNA Ligase ATP; DNA Ligases; Distamycins; Humans; Poly-ADP-Ribose Binding Proteins; Rats; Structure-Activity Relationship; Xenopus Proteins
PubMed: 8471077
DOI: 10.1016/0006-2952(93)90057-4 -
Journal of Liposome Research Dec 2010The present article describes a comparative study of the performances of liposomes and ethosomes as specialized delivery systems for distamycin A (DA) and two of its... (Comparative Study)
Comparative Study
The present article describes a comparative study of the performances of liposomes and ethosomes as specialized delivery systems for distamycin A (DA) and two of its derivatives. Liposomes and ethosomes were prepared by classical methods, extruded through polycarbonate filters, and characterized in terms of dimensions, morphology, and encapsulation efficiency. It was found that DA was associated with vesicles (either liposomes or ethosomes) by around 16.0%, while both derivatives of DA showed a percentage of association around 80% in the case of liposomes and around 50% in the case of ethosomes. In vitro antiproliferative activity experiments performed on cultured human and mouse leukemic cells demonstrated that vesicles were able to increase the activity of both derivatives of DA. In addition, it was demonstrated that the aging of both liposomes- and ethosomes-associated distamycin suspensions did not heavily influence the vesicle size, while all samples showed a relevant drug leakage with time. Moreover, according to the different physicochemical characteristics of DA and its derivatives (i.e., log P), vesicle-associated DA showed the highest loss of drug with respect to both its derivatives. In conclusion, the enhancement of drug activity expressed by these specialized delivery systems-associated DD could be interesting to obtain an efficient therapeutic effect aimed at reducing or minimizing toxic effects occurring with distamycins administration.
Topics: Animals; Anti-Bacterial Agents; Biocompatible Materials; Cell Line; Distamycins; Drug Carriers; Drug Stability; Ethanol; Humans; Liposomes; Materials Testing; Mice; Molecular Structure; Particle Size; Time Factors
PubMed: 19961302
DOI: 10.3109/08982100903443057 -
Biochimie Aug 2011This focused review article discusses in detail, all available high-resolution small molecule ligand/G-quadruplex structural data derived from crystallographic and NMR... (Review)
Review
This focused review article discusses in detail, all available high-resolution small molecule ligand/G-quadruplex structural data derived from crystallographic and NMR based techniques, in an attempt to understand key factors in ligand binding and to highlight the biological importance of these complexes. In contrast to duplex DNA, G-quadruplexes are four-stranded nucleic acid structures folded from guanine rich repeat sequences stabilized by the stacking of guanine G-quartets and extensive Watson-Crick/Hoogsteen hydrogen bonding. Thermally stable, these topologies can play a role in telomere regulation and gene expression. The core structures of G-quadruplexes form stable scaffolds while the loops have been shown, by the addition of small molecule ligands, to be sufficiently adaptable to generate new and extended binding platforms for ligands to associate, either by extending G-quartet surfaces or by forming additional planar dinucleotide pairings. Many of these structurally characterised loop rearrangements were totally unexpected opening up new opportunities for the design of selective ligands. However these rearrangements do significantly complicate attempts to rationally design ligands against well defined but unbound topologies, as seen for the series of napthalene diimides complexes. Drawing together previous findings and with the introduction of two new crystallographic quadruplex/ligand structures we aim to expand the understanding of possible structural adaptations available to quadruplexes in the presence of ligands, thereby aiding in the design of new selective entities.
Topics: Acridines; Binding Sites; Crystallography; Daunorubicin; Distamycins; G-Quadruplexes; Gene Expression Regulation; Ligands; Naphthalenes; Porphyrins; Telomere
PubMed: 21635933
DOI: 10.1016/j.biochi.2011.05.012 -
Molecular Genetics and Metabolism Jun 2000
Comparative Study Review
Topics: Amino Acid Sequence; Base Sequence; Bromodeoxyuridine; Chromosome Fragile Sites; Chromosome Fragility; DNA; Distamycins; Humans; Minisatellite Repeats; Molecular Sequence Data
PubMed: 10873391
DOI: 10.1006/mgme.2000.2996 -
Cytogenetic and Genome Research 2003The rare human fragile site 16B (FRA16B) has been found to occur spontaneously. Its expression in lymphocyte cultures can also be induced or greatly enhanced by addition... (Review)
Review
The rare human fragile site 16B (FRA16B) has been found to occur spontaneously. Its expression in lymphocyte cultures can also be induced or greatly enhanced by addition of chemicals which are known to bind to AT-rich DNA regions. Following optimal treatment with 150 microg/ml berenil 24 h prior to fixation, the heterozygote frequency of FRA16B is found to be about 5% in populations of European descent. Thus, FRA16B represents the most common of the rare fragile sites. Consistent with cytogenetic observations, the molecular characterization of FRA16B revealed that it is an amplified 33-base pair AT-rich minisatellite repeat. These interindividually variable, extremely large repeat expansions of 15-70 kb in size do not seem to interfere with the expression of genes essential for human development since heterozygotes and homozygotes for FRA16B are normal.
Topics: Chromosome Aberrations; Chromosome Banding; Chromosome Fragile Sites; Chromosomes, Human, Pair 16; Diminazene; Distamycins; Humans; Karyotyping
PubMed: 14526167
DOI: 10.1159/000072841