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Current Medicinal Chemistry.... Jul 2005Much 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... (Review)
Review
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.
Topics: Animals; Antiparasitic Agents; DNA, Satellite; DNA-Binding Proteins; Distamycins; Drug Design; Humans; Nylons
PubMed: 16101491
DOI: 10.2174/1568011054222355 -
Current Topics in Medicinal Chemistry 2004Analogues of naturally occurring antitumor agents, such as distamycin A, which bind in the minor groove of DNA, represent a new class of anticancer compounds currently... (Review)
Review
Analogues of naturally occurring antitumor agents, such as distamycin A, which bind in the minor groove of DNA, represent a new class of anticancer compounds currently under investigation. Distamycin A has driven researcher's attention not only for their biological activity, but also for its non intercalative binding to the minor groove of double-stranded B-DNA, where it forms strong reversible complex preferentially at the nucleotide sequences consisting of 4-5 adjacent AT base pairs. The pyrrole-amide skeleton of distamycin A has been also used as DNA sequence selective vehicles for the delivery of alkylating functions to DNA targets, leading to a sharp increase of its cytotoxicity, in comparison to that, very weak, of distamycin itself. In the last few years, several hybrid compounds, in which known antitumor derivatives or simple active moieties of known antitumor agents have been tethered to distamycin frames, have been designed, synthesized and tested. Several efforts have been made to modify DNA sequence selectivity and stability of the distamycin and the structural modifications have been based on replacement of pyrrole by other heterocycles and/or benzoheterocycles obtaining a novel class of minor groove binding molecules called lexitropsins. The role of the amidino moiety, by means of the substitution with various groups, which includes ionizable, acid or basic, and non-ionizable groups, has been also studied. The synthesis of a hybrid deriving among the combination of the distamycin A and naturally occurring alkylating agent has been also reported. Several classes of distamycin derivatives that have been reported in the published literature have been described in this review article.
Topics: Alkylating Agents; Antineoplastic Agents; DNA; Distamycins; Humans; Mustard Compounds; Nucleic Acid Conformation
PubMed: 14754456
DOI: 10.2174/1568026043451474 -
Molecules (Basel, Switzerland) Aug 2021The recognition of specific DNA sequences in processes such as transcription is associated with a cooperative binding of proteins. Some transcription regulation...
The recognition of specific DNA sequences in processes such as transcription is associated with a cooperative binding of proteins. Some transcription regulation mechanisms involve additional proteins that can influence the binding cooperativity by acting as corepressors or coactivators. In a conditional cooperativity mechanism, the same protein can induce binding cooperativity at one concentration and inhibit it at another. Here, we use calorimetric (ITC) and spectroscopic (UV, CD) experiments to show that such conditional cooperativity can also be achieved by the small DNA-directed oligopeptides distamycin and netropsin. Using a global thermodynamic analysis of the observed binding and (un)folding processes, we calculate the phase diagrams for this system, which show that distamycin binding cooperativity is more pronounced at lower temperatures and can be first induced and then reduced by increasing the netropsin or/and Na+ ion concentration. A molecular interpretation of this phenomenon is suggested.
Topics: DNA; Distamycins; Netropsin; Oligopeptides; Protein Binding; Sodium; Thermodynamics; Transcription, Genetic
PubMed: 34500619
DOI: 10.3390/molecules26175188 -
Current Medicinal Chemistry.... Sep 2004A number of anticancer drugs exert their effect by causing DNA damage and subsequent apoptosis induction. Most anticancer drugs are known to cause severe side effects.... (Review)
Review
A number of anticancer drugs exert their effect by causing DNA damage and subsequent apoptosis induction. Most anticancer drugs are known to cause severe side effects. Nontoxic amplification of DNA-cleaving activity of anticancer drugs would enable to reduce drug dose and side effects, leading to development of effective chemotherapy. As a method to approach new cancer chemotherapy, we have investigated the enhancing effects of DNA-binding ligands ("amplifiers"), especially minor groove binders and intercalators, on anticancer drug-induced apoptosis and DNA cleavage, using human cultured cells and(32)P-labeled DNA fragments obtained from the human genes. We have demonstrated as follows: a) DNA-binding molecules (unfused aromatic cations, distamycin A and synthtic triamides) induced amplification of bleomycin-induced DNA cleavage and apoptosis; b) a minor-groove binder distamycin A enhanced duocarmycin A-induced DNA cleavage; c) actinomycin D altered the site specificity of neocarzinostatin-induced DNA cleavage and distamycin A enhanced C1027-induced apoptosis. The mechanism of amplification of DNA cleavage can be explained by assuming that binding of amplifier changes the DNA conformation to allow anticancer drug to interact more appropriately with the specific sequences, resulting in enhancement of anticancer effect. The study on amplifiers of anticancer agents shows a novel approach to the potentially effective anticancer therapy.
Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antiviral Agents; Apoptosis; Bleomycin; Cations; DNA; DNA Damage; Dactinomycin; Distamycins; Humans; Intercalating Agents; Ligands; Models, Chemical; Neoplasms; Protein Binding; Time Factors
PubMed: 15379695
DOI: 10.2174/1568011043352867 -
Mini Reviews in Medicinal Chemistry Jan 2009In this review article we have reported a series of hybrid compounds characterized by the presence of a alpha-halogenocryloyl alkylating moiety of low chemical... (Review)
Review
In this review article we have reported a series of hybrid compounds characterized by the presence of a alpha-halogenocryloyl alkylating moiety of low chemical reactivity, linked to known antitumor agents or their active moieties. Among them, brostallicin (PNU-166196), was selected for clinical development and is now undergoing Phase II studies in patients with advanced or metastatic soft tissue sarcoma.
Topics: Animals; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Distamycins; Guanidines; Humans; Mice; Pyrroles; Pyrroloiminoquinones
PubMed: 19149662
DOI: 10.2174/138955709787001640 -
Annual Review of Biophysics and... 2000In the past decade, a general design for sequence-specific minor groove ligands has evolved, based on the natural products distamycin and netropsin. By utilizing a basic... (Review)
Review
In the past decade, a general design for sequence-specific minor groove ligands has evolved, based on the natural products distamycin and netropsin. By utilizing a basic set of design rules for connecting pyrrole, imidazole, and hydroxypyrrole modules, new ligands can be prepared to target almost any sequence of interest with both high affinity and specificity. In this review we present the design rules with a brief history of how they evolved. The structural basis for sequence-specific recognition is explained, together with developments that allow linking of recognition modules that enable targeting of long DNA sequences. Examples of the affinity and specificity that can be achieved with a number of variations on the basic design are given. Recently these molecules have been used to compete with proteins both in vitro and in vivo, and a brief description of the experimental results are given.
Topics: Animals; Antiviral Agents; DNA; Distamycins; Drug Design; Ligands; Magnetic Resonance Spectroscopy; Models, Molecular; Netropsin; Nucleic Acid Conformation
PubMed: 10940255
DOI: 10.1146/annurev.biophys.29.1.439 -
Pharmacology & Therapeutics 1997Malaria, 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%... (Review)
Review
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.
Topics: Animals; Anti-Bacterial Agents; Antimalarials; Distamycins; Drug Design; Humans; Malaria; Structure-Activity Relationship
PubMed: 9535174
DOI: 10.1016/s0163-7258(97)00095-8 -
Mutation Research Oct 2007An understanding of the mechanism by which minor groove binding agents interact with DNA has led to the design of agents that can reversibly bind with high selectivity... (Review)
Review
An understanding of the mechanism by which minor groove binding agents interact with DNA has led to the design of agents that can reversibly bind with high selectivity to extended DNA target sequences. Simple compounds, such as the polypyrroles and the bis-benzimidazoles, have been used as carriers for alkylating agents effectively directing alkylation to specific DNA sequences. The spectrum of DNA alkylation and mutation by classical alkylators, such as nitrogen mustards, has been profoundly modified by such attachment. The observed "side-by-side" binding of small polypyrrole antibiotics has led to the design of synthetic hairpin polyamides with programmable DNA sequence selectivity. These compounds are able to compete with natural substrates, such as specific transcription factors, and alter gene expression. They are being developed as artificial transcription factors, able to deliver activating peptides to specific recognition sequences, and as potential protein-DNA dimerization agents. Hairpin polyamides are also being used as carriers for the delivery of alkylators to defined DNA sites. The degree of control of gene expression thus offered by the hairpin polyamides suggests enormous promise for their clinical utility. Recent developments with other minor groove binding small molecules and technological advances are also discussed.
Topics: Antineoplastic Agents; Base Sequence; Benzimidazoles; Binding Sites; DNA; Distamycins; Humans; In Vitro Techniques; Ligands; Mutation; Neoplasms; Netropsin; Nylons
PubMed: 17507044
DOI: 10.1016/j.mrfmmm.2007.03.012 -
Topics in Current Chemistry 2013G-quadruplex ligands are potential anticancer agents as telomerase inhibitors and potential transcriptional regulators of oncogenes. The search for best-in-class drugs...
G-quadruplex ligands are potential anticancer agents as telomerase inhibitors and potential transcriptional regulators of oncogenes. The search for best-in-class drugs is addressed to identify small molecules able to promote and stabilize G-quadruplex structures. What features should the G-quadruplex ligands possess? They should have selective antiproliferative effects on cancer cells and induce telomerase inhibition or oncogene suppression. One of the main challenges in their design and synthesis is to make the ligands selective for G-quadruplex DNA. These features should be amplified by careful analyses of physico-chemical aspects of G-quadruplex-drug interactions. In particular, the study of the energetics of G-quadruplex-drug interactions can enhance drug design by providing thermodynamic parameters that give quantitative information on the biomolecular interactions important for binding. The main methodologies used to gain information on energetics of binding are based on spectroscopic or calorimetric principles. Spectroscopic techniques such as fluorescence and circular dichroism are rapid and cheap methods, but are not sufficient to characterize completely the thermodynamics of interaction. Calorimetric techniques such as isothermal titration calorimetry offer a direct measure of binding enthalpy, in addition to the stoichiometry and affinity constants. With the complete thermodynamic signature of drug-target interaction, dissecting the enthalpic and entropic components of binding is possible, which can be a useful aid to decision-making during drug optimization.
Topics: Animals; Antineoplastic Agents; Antiviral Agents; Carbazoles; Circular Dichroism; Distamycins; Drug Design; G-Quadruplexes; Humans; Ligands; Models, Molecular; Nucleic Acids; Piperidines; Porphyrins; Small Molecule Libraries; Spectrometry, Fluorescence; Thermodynamics
PubMed: 22851158
DOI: 10.1007/128_2012_347 -
Nucleic Acids Research Apr 1991The binding between Distamycin 3 and the palindromic duplexes d(CGTTTAAACG)2 and d(CGTACGTACG)2 was investigated by two independent techniques: UV-Vis absorption in the...
The binding between Distamycin 3 and the palindromic duplexes d(CGTTTAAACG)2 and d(CGTACGTACG)2 was investigated by two independent techniques: UV-Vis absorption in the Job's plot approach and Induced Circular Dichroism. Both decamers bind two molecules of peptide per duplex, with close overall affinities. This result indicates that a row of six A:T base pairs can accommodate two molecules of drug and that the minimal binding site of Distamycin 3 can consist of just two A:T base pairs.
Topics: Base Sequence; Circular Dichroism; Distamycins; Molecular Sequence Data; Nucleic Acid Heteroduplexes; Oligodeoxyribonucleotides; Spectrophotometry, Ultraviolet
PubMed: 2027777
DOI: 10.1093/nar/19.7.1695