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Journal of Biomolecular Structure &... Dec 1999Okazaki fragments represent interesting targets for the design of anticancer drugs because of their selective occurrence during DNA replication, a process often elevated...
Okazaki fragments represent interesting targets for the design of anticancer drugs because of their selective occurrence during DNA replication, a process often elevated in aggressive malignancies. Structural studies have indicated a bend occurs in the helical axis at the junction region (JR) that joins the DNA duplex region (DDR) and the RNA-DNA hybrid duplex region (HDR) of model Okazaki fragments. To identify a structural motif that provides a shape complementary to the Okazaki fragment minor groove, we have investigated the binding of geometrically-constrained bis-distamycins to a model Okazaki fragment, [OKA], with a sequence derived from the genome of simian virus 40 (SV40). Both the JR and the DDR of [OKA] contain consecutive A/T base pairs that could accommodate distamycin binding. Of the six bis-distamycins selected for analysis, the two with a para configuration of the distamycins on the benzene or pyridine scaffold bound [OKA] tightly (Kd approximately 10(-6) M from gel-shift assays; Kd approximately 10(-8) M from deltaT(M)) while the four with a meta orientation did not bind. The two mono-distamycins studied also did not bind [OKA]. Molecular modeling of the complex between the para bis-distamycin MT-9 and [OKA] revealed MT-9 adopted an S- shape complementary to the minor groove of the model Okazaki fragment.
Topics: Antineoplastic Agents; Base Sequence; DNA; DNA Replication; DNA, Viral; Distamycins; Drug Design; Models, Molecular; Nucleic Acid Conformation; Simian virus 40
PubMed: 10636085
DOI: 10.1080/07391102.1999.10508381 -
Current Protocols in Nucleic Acid... Aug 2003Various types of minor groove binders have been attached to synthetic oligodeoxynucleotides, and the interactions of these conjugates (MB-ODNs) with DNA are reviewed... (Review)
Review
Various types of minor groove binders have been attached to synthetic oligodeoxynucleotides, and the interactions of these conjugates (MB-ODNs) with DNA are reviewed here. MB-ODNs have enhanced DNA affinity and have improved the hybridization properties of sequence-specific DNA probes. Short MB-ODNs hybridize with ssDNA to give more stable DNA duplexes than unmodified ODNs with similar lengths. Mismatch discrimination of short MB-ODNs is enhanced in comparison to longer unmodified ODNs. The stronger binding of MB-ODNs allows for more stringent hybridization conditions to be used in DNA probe-based assays. MB-ODNs are especially useful in quantitative "real-time" PCR assays since they bind efficiently during the high-temperature primer extension cycle. The synthesis and biophysical chemistry of MB-ODN conjugates are reviewed here. Four published structural classes of MB-ODNs and their various dsDNA binding modes are discussed, and the well-characterized DPI3-type MB-ODNs and their interactions with ssDNA target strands are described in detail.
Topics: Base Composition; Base Pair Mismatch; Binding Sites; Bisbenzimidazole; Catecholamines; Cyclopropanes; DNA; DNA Probes; DNA, Single-Stranded; DNA-Binding Proteins; Distamycins; Fluorescent Dyes; Imidazolines; Indoles; Models, Biological; Models, Molecular; Nucleic Acid Conformation; Oligonucleotides; Polymerase Chain Reaction; Thermodynamics
PubMed: 18428916
DOI: 10.1002/0471142700.nc0804s13 -
Mutation Research Aug 1998The genomes of higher eukaryotes are not homogeneous in terms of structure or function. Many examples of chromosomal regions particularly prone to involvement in... (Review)
Review
The genomes of higher eukaryotes are not homogeneous in terms of structure or function. Many examples of chromosomal regions particularly prone to involvement in aberrations have been reported. The molecular structures of some of these regions have now been determined, most notably the folate-sensitive fragile sites and FRA16B-a distamycin A-sensitive fragile site. In addition, a number of cytological studies suggest that telomeric sequences can in some circumstances be involved in chromosomal aberrations more frequently than expected. Here, the roles of telomeric DNA sequences, both terminal and interstitial, and telomerase in chromosomal aberration formation are reviewed.
Topics: Chromosome Aberrations; Chromosome Fragile Sites; Chromosome Fragility; DNA; Distamycins; Eukaryotic Cells; Telomerase; Telomere
PubMed: 9729384
DOI: 10.1016/s0027-5107(98)00114-6 -
Trends in Biotechnology Dec 1995Genetic algorithms provide a novel tool for the investigation of combinatorial optimization problems. A genetic algorithm takes an initial set of possible starting... (Review)
Review
Genetic algorithms provide a novel tool for the investigation of combinatorial optimization problems. A genetic algorithm takes an initial set of possible starting solutions, and iteratively improves them by means of crossover and mutation operators that are related to those involved in Darwinian evolution. This approach is illustrated by reference to applications in molecular modelling, the docking of flexible ligands into protein active sites and de novo ligand design.
Topics: Algorithms; Antiviral Agents; Binding Sites; Computer Simulation; Databases, Factual; Distamycins; Evolution, Molecular; Models, Genetic; Models, Molecular; Proteins; Software; Tetrahydrofolate Dehydrogenase
PubMed: 8595137
DOI: 10.1016/S0167-7799(00)89015-0 -
Biopolymers Dec 1989The study of the monomeric chromophore of the distamycins reported in Ref. 1 was used here to build up a description of the electronic states of the whole oligopeptide...
The study of the monomeric chromophore of the distamycins reported in Ref. 1 was used here to build up a description of the electronic states of the whole oligopeptide by the exciton theory. Liquid crystal-linear dichroism (LC-LD) spectra of the distamycins were recorded by using as orienting solvents both thermotropic and lyotropic mesomorphic media. The agreement between the LD spectra and the polarization assignments by the exciton treatment is satisfactory. On this basis the flow-LD spectra of the complex between distamycin V and DNA was interpreted in terms of the preferred relative orientations of the guest and host molecules. A single site location of the distamycin within the minor groove does not perfectly match the experimental order parameters. This orientational distribution function could be too simple to explain the experimental data. It may therefore be assumed that a small fraction of the guest molecules are preferentially aligned more parallel to the host chain axis than the minor groove. Alternatively, and probably more likely, the partial mismatch of the experimental data with the minor groove location may be seen as a manifestation of the well-known stiffening and bending effects at the binding sites, which have already been observed by other techniques.
Topics: DNA; Distamycins; Models, Structural; Nucleic Acid Conformation; Protein Binding; Protein Conformation; Pyrroles
PubMed: 2605316
DOI: 10.1002/bip.360281210 -
ChemMedChem Apr 2008Alkylating agents are a major class of anticancer drugs for the treatment of various cancers including hematological malignancies. Targeting alkylating moieties to DNA... (Review)
Review
Alkylating agents are a major class of anticancer drugs for the treatment of various cancers including hematological malignancies. Targeting alkylating moieties to DNA by attachment of a DNA minor groove binding carrier such as distamycin, netropsin, or Hoechst 33252 reduces the loss of active drug due to reaction with other cell components and makes it possible to direct the alkylation both sequence specifically and regiospecifically. We reported the synthesis and structure-activity studies of amidine analogues of alkylating antineoplastic compounds, which appeared to be a new class of cytotoxic minor groove binders and topoisomerase II inhibitors. Another approach to overcome the toxicity of alkylating agents to normal tissue is to construct a prodrug with lower hydrophobicity and cytotoxicity but is preferentially activated in cancer cells. Overexpression of prolidase in some neoplastic cells suggests that the proline analogue of alkylating agents may serve as a prolidase convertible prodrugs. We have compared several aspects of pharmacological actions of proline analogues of chlorambucil and melphalan in breast cancer cells. The results suggest that prolidase could serve as a target enzyme for the selective action of anticancer agents.
Topics: Antineoplastic Agents, Alkylating; Benzimidazoles; Chlorambucil; DNA; Dipeptidases; Distamycins; Drug Delivery Systems; Enzyme Inhibitors; Melphalan; Prodrugs; Structure-Activity Relationship; Topoisomerase II Inhibitors
PubMed: 18157855
DOI: 10.1002/cmdc.200700229 -
Anticancer Research 1991Antitumor anthracyclines and distamycins behave as strong inhibitors of human replicative DNA ligase. The enzyme appears sensitive to a specific occupancy of the minor...
Antitumor anthracyclines and distamycins behave as strong inhibitors of human replicative DNA ligase. The enzyme appears sensitive to a specific occupancy of the minor groove of DNA. Inhibition by anthracyclines takes place after enzyme adenylation, does not correlate with DNA unwinding potency but strictly correlates with the presence of an amino group on the sugar. In contrast to the non-toxic distamycin A, its antitumor derivative FCE24517 inhibits DNA joining, enzyme adenylation and AMP-driven DNA topoisomerisation. Our data favour a model in which multiple enzymic targets contribute to the activity of these antitumor drugs.
Topics: Antibiotics, Antineoplastic; DNA; DNA Ligases; Distamycins; Humans; Structure-Activity Relationship
PubMed: 1888166
DOI: No ID Found -
Bioconjugate Chemistry 1998
Review
Topics: Antiviral Agents; DNA; Distamycins; Intercalating Agents; Molecular Structure; Netropsin; Nucleic Acid Conformation
PubMed: 9736486
DOI: 10.1021/bc980008m -
Current Medicinal Chemistry Apr 2001DNA is a well characterized intracellular target but its large size and sequential nature make it an elusive target for selective drug action. Binding of low molecular... (Review)
Review
DNA is a well characterized intracellular target but its large size and sequential nature make it an elusive target for selective drug action. Binding of low molecular weight ligands to DNA causes a wide variety of potential biological responses. In this respect the main consideration is given to recent developments in DNA sequence selective binding agents bearing conjugated effectors because of their potential application in diagnosis and treatment of cancers as well as in molecular biology. Recent progress in the development of cross linked lexitropsin oligopeptides and hairpins, which bind selectively to the minor groove of duplex DNA, is discussed. Bis-distamycins and related lexitropsins show inhibitory activity against HIV-1 and HIV-2 integrases at low nanomolar concentrations. Benzoyl nitrogen mustard analogs of lexitropsins are active against a variety of tumor models. Certain of the bis-benzimidazoles show altered DNA sequence preference and bind to DNA at 5'CG and TG sequences rather than at the preferred AT sites of the parent drug. A comparison of bifunctional bizelesin with monoalkylating adozelesin shows that it appears to have an increased sequence selectivity such that monoalkylating compounds react at more than one site but bizelesin reacts only at sites where there are two suitably positioned alkylation sites. Adozelesin, bizelesin and carzelesin are far more potent as cytotoxic agents than cisplatin or doxorubicin. A new class of 1,2,9,9a-tetrahydrocyclo-propa[c]benz[e]indole-4-one (CBI) analogs i.e., CBI-lexitropsin conjugates arising from the latter leads are also discussed.A number of cyclopropylpyrroloindole (CPI) and CBI-lexitropsin conjugates related to CC-1065 alkylate at the N3 position of adenine in the minor groove of DNA in a sequence specific manner, and also show cytotoxicities in the femtomolar range. The cross linking efficiency of PBD dimers is much greater than that of other cross linkers including cisplatin, and melphalan. A new class of PBD-lexitropsin conjugates is also discussed. Certain functional models of the bleomycins (BLMs) show outstanding DNA cleavage activity comparable with that of and positionally distinct from natural BLM.
Topics: Animals; Anthraquinones; Benzimidazoles; Bisbenzimidazole; Bleomycin; Chemistry, Pharmaceutical; Cross-Linking Reagents; DNA; Distamycins; Drug Design; Duocarmycins; Humans; Indoles; Leucomycins; Ligands; Netropsin; Urea
PubMed: 11281837
DOI: 10.2174/0929867003373292 -
Methods in Molecular Biology (Clifton,... 1994
Review
Topics: 2,2'-Dipyridyl; Base Sequence; Binding Sites; DNA; DNA Adducts; DNA Damage; DNA-Binding Proteins; Distamycins; Electrophoresis, Polyacrylamide Gel; Intercalating Agents; Molecular Sequence Data; Organometallic Compounds; Pharmaceutical Preparations; Photochemistry; Protein Binding; Ultraviolet Rays
PubMed: 7921029
DOI: 10.1385/0-89603-258-2:331