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At least 595 records · Page 33Linked to original sources
PubMed2005

A rationally designed small molecule that inhibits the HIF-1alpha-ARNT heterodimer from binding to DNA in vivo.

Modern drug development is focused on two steps: the identification of new molecular targets and the development of drugs that affect these targets. A molecular target can be an enzymatic activity or a macromolecular interface that is important in a disease pathway. Current drugs on the market are biased toward targeting cell surface receptors and intracellular enzymatic activities. However, macromolecular interfaces can also serve as potential molecular targets. A recent paper from Kaelin and Dervan's groups examined an underused molecular target-transcription factor DNA binding. To specifically disrupt transcriptional activation, they used a rationally designed small molecule that binds specifically in the minor groove of a DNA sequence that in vivo is bound by a bHLH heterodimer transcription factor.

Angiogenesis Inhibitors↗
PubMed2007

Unusual thermal stability of RNA/[RP-PS]-DNA/RNA triplexes containing a homopurine DNA strand.

Homopurine deoxyribonucleoside phosphorothioates, as short as hexanucleotides and possessing all internucleotide linkages of RP configuration, form a triple helix with two RNA or 2'-OMe-RNA strands, with Watson-Crick and Hoogsteen complementarity. Melting temperature and fluorescence quenching experiments strongly suggest that the Hoogsteen RNA strand is parallel to the homopurine [RP-PS]-oligomer. Remarkably, these triplexes are thermally more stable than complexes formed by unmodified homopurine DNA molecules of the same sequence. The triplexes formed by phosphorothioate DNA dodecamers containing 4-6 dG residues are thermally stable at pH 7.4, although their stability increases significantly at pH 5.3. FTIR measurements suggest participation of the C2-carbonyl group of the pyrimidines in the stabilization of the triplex structure. Formation of triple-helix complexes with exogenously delivered PS-oligos may become useful for the reduction of RNA accessibility in vivo and, hence, selective suppression/inhibition of the translation process.

Binding Sites↗
PubMed2001

DNA minor groove alkylating agents.

Recent work on a number of different classes of anticancer agents that alkylate DNA in the minor groove is reviewed. There has been much work with nitrogen mustards, where attachment of the mustard unit to carrier molecules can change the normal patterns of both regio- and sequence-selectivity, from reaction primarily at most guanine N7 sites in the major groove to a few adenine N3 sites at the 3'-end of poly(A/T) sequences in the minor groove. Carrier molecules discussed for mustards are intercalators, polypyrroles, polyimidazoles, bis(benzimidazoles), polybenzamides and anilinoquinolinium salts. In contrast, similar targeting of pyrrolizidine alkylators by a variety of carriers has little effect of their patterns of alkylation (at the 2-amino group of guanine). Recent work on the pyrrolobenzodiazepine and cyclopropaindolone classes of natural product minor groove binders is also reviewed.

Alkylating Agents↗
PubMed2001

Recent developments in sequence selective minor groove DNA effectors.

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.

Animals↗
PubMed2001

Sequence recognition of DNA by lexitropsins.

Lexitropsins are modular polyamide molecules that are designed to "read" the base sequence of DNA. Lexitropsins constructed of three types of subunits--pyrrole, imidazole and hydroxypyrrole--allow full recognition of DNA base sequences. Structural studies have revealed the atomic basis of this specificity. Theoretical studies have explored the effectiveness of lexitropsins in targeting a given sequence within a genome, and have been used to analyze and improve lexitropsin design.

Base Pairing↗
PubMed2001

Selection of an unnatural peptide library for dsDNA binding.

More and more, nucleic acids have become prime targets in the development of new compounds, able to control gene expression. For the development of new sequence selective dsDNA binding ligands, one can learn a lot from existing models such as, lexitropsins, combilexins and actinomycin D. This analysis, together with the knowledge of the details on protein-DNA interactions, has inspired the assembly of unnatural amino acids in a combinatorial way to generate a dsDNA recognition library. The first selection round has led to the selection of new DNA binding molecules, which may lead on the long run to the discovery of new DNA binding motifs.

Amino Acids↗
PubMed1985

The stimulation of bioluminescence in Photobacterium leiognathi as a potential prescreen for antitumor agents.

The stimulation of bioluminescence in Photobacterium leiognathi has previously been described as a test for genotoxic compounds. An adaptation of this procedure has been developed which uses a dim variant of P. leiognathi and permits the prescreening of microbial fermentation broths for potential antitumor agents. Bioluminescence in this organism was stimulated by compounds which bind to DNA or affect DNA synthesis. Antibiotics with target sites such as protein, cell wall or RNA synthesis, did not alter bioluminescence. Fermentation broths from over 5,000 soil isolates were prescreened in this assay and 95 (1.6%) were defined as active. Further analysis of selected cultures suggested that about half produced compound(s) with DNA-binding activity. These results suggest that the photobacterium induction assay (PIA) may be useful as a prescreen for potential antitumor agents. The assay is rapid, simple and requires only microgram quantities of material for testing.

Antibiotics, Antineoplastic↗
PubMedDate not supplied

New carbocyclic lexitropsins with dinitromustard as N-terminal fragment. Inhibition of topoisomerases.

A series of carbocyclic lexitropsins was evaluated for their capacity to inhibit human topoisomerases I and II. The synthesized compounds were carbocyclic oligopeptides with dinitromustard as N-terminal fragment. In the topoisomerases I and II assays, the relaxation of DNA were inhibited with all four compounds. This inhibition was directly proportional to the compound concentration.

DNA Topoisomerases, Type I↗
PubMed1991

Control over the sequence specificity of DNA alkylation: syntheses and reactions with 32P-end-labelled DNA of N-alkyl-N-nitrosoureas linked to minor groove binding lexitropsins.

The syntheses of N-2-chloroethyl-N-nitrosoureas (Cl-ENU) that are covalently linked to a series of minor groove binding lexitropsins related to distamycin A are reported. The lexitropsins of 2-Cl-ENU show a sequence specificity for alkylating an adenine toward the ends of its DNA affinity binding domains. The reaction of DNA with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea does not yield these products. Therefore, the linking of the 2-Cl-ENU to the minor groove binder qualitatively and quantitatively alters the DNA observed.

Alkylation↗
PubMed1990

Molecular recognition between oligopeptides and nucleic acids: DNA sequence specificity and binding properties of thiazole-lexitropsins incorporating the concepts of base site acceptance and avoidance.

The DNA binding and sequence specificity of a group of six novel thiazole containing lexitropsins related to the natural anti-tumor antibiotic distamycin have been examined by complementary strand MPE footprinting on two restriction fragments of pBR322 DNA. These lexitropsins comprise two groups in which the hetero atom of the thiazole moiety directed inwards to the floor of the minor groove is respectively nitrogen or sulfur. All of the new lexitropsins bind to DNAs in the minor groove with Kapp comparable with distamycin. The group of lexitropsins bearing nitrogen directed towards the DNA display comparable binding to poly(dA-dT) and to native DNAs, and complementary strand footprinting reveals their ability to accept and bind to mixed AT-GC sequences. The GC recognizing property plausibly arises from the hydrogen bonding between the thiazole nitrogen and G-2-NH2 based on precedents. In contrast the group of lexitropsins bearing sulfur directed towards the floor of the minor groove of DNA exhibit strict preference for AT sequences and are even more discriminating than distamycin. The latter agents, in common with the first group, bind firmly in the minor groove and with a binding site size of either 4 +/- 1 or 5 +/- 1 base pairs indicating intimate contact of all parts of the ligand. Therefore the property of GC site avoidance of these particular thiazole-lexitropsins is attributed to clash between the sterically more demanding sulfur and G-2NH2 groups.

Base Sequence↗
PubMed1986

Overview of the interaction between chemotherapeutic agents and DNA.

Some chemotherapeutic agents, such as the antibiotics mitomycin and bleomycin, modify the structure of DNA by chemical reactions involving the formation or breakage of covalent bonds. Others interact with the macromolecule reversibly to form a transient complex which may be intercalative or nonintercalative in character. Techniques are available to probe the extent of perturbation of DNA structure produced by these drugs, and they reveal subtle differences between the effects of various ligands. In recent years bifunctional intercalating agents such as the quinoxaline antibiotics have been discovered; their binding to DNA is often tighter than seen with simple (monofunctional) intercalators and there is evidence for nucleotide sequence-selectivity. Footprinting experiments have been employed to identify preferred ligand-binding sites in natural DNA fragments (CpG sequences in the case of echinomycin) and have revealed that local perturbations of the helical structure can be propagated into DNA regions flanking the antibiotic-binding sites. Crystallographic evidence suggests that echinomycin and its congeners recognise GC base-pairs by hydrogen bonding between the carbonyl groups of alanine residues in the antibiotic and the 2-amino groups of guanine nucleotides in the minor groove of the DNA helix. Kinetic studies support the hypothesis that sequence-selective antibiotic molecules "shuffle" between different binding sites in the process of locating their optimal (preferred) sites.

Animals↗
PubMed1988

Lexitropsins: rational design of DNA sequence reading agents as novel anti-cancer agents and potential cellular probes.

Alternative approaches to the problem of developing DNA sequence-specific agents for potential use in diagnosis and therapy of cancer are reviewed. The major problems of oligonucleotide probes, i.e. difficulty of cellular uptake and susceptibility to intracellular degradation, suggested as possible alternatives the employment of certain oligopeptide agents. Progress in the development of lexitropsins, or information-reading oligopeptides, which bind selectively to the minor groove of duplex nucleic acids, is discussed. The ability to engineer lexitropsins to recognize and bind to predetermined sequences, the ready cellular uptake and concentration in the cell nucleus may offer advantages in the development of cellular regulatory agents. The anti-cancer efficacy of prototype sequence-specific minor groove alkylators is described.

Antineoplastic Agents↗