Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Netropsin”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 559 records · Page 31Linked to original sources
PubMed2004

Ni(II).Arg-Gly-His-DNA interactions: investigation into the basis for minor-groove binding and recognition.

A study of the minor-groove recognition of A/T-rich DNA sites by Ni(II).L-Arg-Gly-His and Ni(II).D-Arg-Gly-His was carried out with a fluorescence-based binding assay, one- and two-dimensional (1D and 2D) NMR methodologies, and molecular simulations. Fluorescence displacement titrations revealed that Ni(II).L-Arg-Gly-His binds to A/T-rich sequences better than the D-Arg diastereomer, while NMR investigations revealed that both metallopeptides bind to the minor groove of an AATT core region as evidenced by an intermolecular nuclear Overhauser effect (NOE) between each metallopeptide His imidazole C4 proton and the C2 proton of adenine. Results from molecular dynamics simulations of these systems were consistent with the experimental data and indicated that the His imidazole N-H, the N-terminal peptide amine, and Arg side chains of each metallopeptide are major determinants of minor-groove recognition by functioning as H-bond donors to the O2 of thymine residues or N3 of adenine residues.

Aniline Compounds↗
PubMed1980

Structure-activity relationships of pyrrole amidine antiviral antibiotics. 2. Preparation of mono- and tripyrrole derivatives of congocidine.

Representatives of three types of congocidine (1) analogues were synthesized. These were tested for cytotoxicity, inhibition of herpes simplex virus (HSV) replication in cultured cells, and effects on the synthesis of HS DNA in isolated nuclei in vitro, as well as on DNA synthesis by purified HSV DNA polymerase. All synthesized tripyrrole derivatives of congocidine were less cytotoxic and more active than the parent drug in all the three ant iviral tests.

Antiviral Agents↗
PubMed2002

Antitumor imidazotetrazines. 41. Conjugation of the antitumor agents mitozolomide and temozolomide to peptides and lexitropsins bearing DNA major and minor groove-binding structural motifs.

Carboxylic acids derived from the amido groups of the antitumor agents mitozolomide and temozolomide have been conjugated to simple amino acids and peptides by carbodiimide coupling. Solid-state peptide synthesis has been applied to link the acids to DNA major groove-binding peptidic motifs known to adopt alpha-helical conformations. Attachment of the acids to pyrrole and imidazole polyamidic lexitropsins gave a series of potential DNA minor groove-binding ligands. In vitro biological evaluation of a limited number of these novel conjugates failed to demonstrate any enhanced growth-inhibitory activity compared to the unconjugated drugs; sites of alkylation at tracts of multiple guanines were also unaffected. Attachment of additional residues at C-8 of the imidazotetrazines did not perturb the chemistry of activation of the bicyclic nucleus, and biological sequelae can be rationalized by invoking the liberation of a common, diffusible, reactive chemical intermediate, the methanediazonium ion.

Amino Acids↗
PubMed1996

A possible involvement of solvent-induced interactions in drug design.

We propose to study a new factor in designing new drugs. Most approaches to the drug design problem focus on the direct interactions between the drug and the corresponding target. We propose to study specific solvent-induced effects that can contribute to the binding Gibbs energy between the drug and its target. We estimate that these indirect effects will contribute significantly to the binding affinity and hopefully improve the clinical efficiency of the drugs.

Amino Acid Chloromethyl Ketones↗
PubMed1997

Camptothecin and minor-groove binder hybrid molecules: synthesis, inhibition of topoisomerase I, and anticancer cytotoxicity in vitro.

The synthesis, characterization, inhibitory activity against topoisomerase I, and biological evaluation of a series of 14 camptothecin derivatives of polypyrrolecarboxamide (lexitropsin) conjugates of two structural classes: (A) camptothecin-NHCO-lexitropsin 44-51 and (B) camptothecin-CONH-lexitropsin 38-43 are described. All 16 compounds tested, 14 conjugates plus two functionalized camptothecin controls, inhibit topoisomerase I in the concentration range 1.12-16.6 microM that divide into three distinct categories based on activity. The most active enzyme inhibitors belong to structure class A with either cationic dimethylaminium or neutral amide end groups. Generally class B conjugates are less effective in inhibiting topoisomerase I. Cytotoxic potencies of the drugs was tested against four representative human tumor cell lines: SKOV3, SKLVB, HT29, and KB. All 16 drugs gave measurable IC50 values against the KB cell line and fell into two categories with IC50 values of 0.049-0.66 microM (largely structure class B) and 1.0-48 microM (largely class A). Thus the class B conjugates, while less potent against the enzyme, contain two of the most potent drugs, 38 and 39, against KB cell lines. In contrast, in the case of the cell lines SKOV3 and HT29 there was a general correlation between the better topoisomerase inhibitors and their cell cytotoxicities.

Adenocarcinoma↗
PubMed2000

DNA binding, solubility, and partitioning characteristics of extended lexitropsins.

Four new ligands that bind to the minor groove of DNA have been designed, synthesized, and evaluated by DNA footprinting. Two of the ligands are polyamides containing central regions with five or six N-methylpyrrole units, conferring hydrophobicity and good binding affinity but without retaining the correct spacing for hydrogen bonding in the base of the minor groove. The two remaining ligands have central regions which are head-to-head-linked polyamides, in which the linker is designed to improve the phasing of hydrogen bonding of the ligand with the floor of the minor groove. The highest affinity was obtained with the two polypyrroles without headgroup spacers, indicating that H-bond phasing is secondary in determining affinity compared to the major hydrophobic driving force. With a dimethylaminoalkyl group, representing a moiety with modest base strength, at both ends, water solubility is good and pH-partition theory predicts that penetration through lipid membranes will be enhanced, compared to strongly basic amidine analogues of the alkaloid precursors. All four compounds bind to DNA, with strong selectivity for AT sequences but some tolerance of GC base pairs and subtle individual preferences. The data show that very high affinities can be anticipated for future compounds in this series, but drug design must take account of overall physicochemical properties as well as the details of hydrogen bonding between ligands and the floor of the minor groove.

DNA↗
PubMedDate not supplied

Molecular recognition between oligopeptides and nucleic acids: DNA binding selectivity of a series of 1,2,4-triazole-containing lexitropsins.

The synthesis of a series of 1,2,4-triazole-containing oligopeptide lexitropsins related to the natural antitumor antibiotic distamycin is described. The binding properties of these new agents to both native DNAs and synthetic polydeoxyribonucleotides were determined by UV absorption and circular dichroism studies. The DNA binding and sequence selectivity of these agents have been determined by complementary strand MPE footprinting on two restriction fragments of pBR322 DNA. The lexitropsins bearing one 1,2,4-triazole moiety bind to AT sequences like distamycin but also tolerate GC sites. However, 3, which contains two contiguous 1,2,4-triazole moieties, appears not to recognize AT stretches and demands two consecutive GC bases in the middle of a four-base recognition site. The triazole lexitropsins avoid ATTT (4264-4267) and AAAA (4273-4276) to which distamycin binds strongly to the EcoRI/Hind III fragment. Determination of pKa values indicates the 1,2,4-triazole units are protonated under physiological conditions. The avoidance of AT stretches and the recognition of GC base sites by 3 suggest molecular recognition in these cases is determined, not by electrostatic effects, but rather by invoking a hydrogen bond between the triazole 4-nitrogen and G-2NH2 in the minor groove.

Base Sequence↗
PubMedDate not supplied

The in vitro methylation of DNA by a minor groove binding methyl sulfonate ester.

The preparation of sequence and groove specific DNA methylating agents based on N-methylpyrrolecarboxamide subunits appended with an O-methyl sulfonate ester functionality (MeOSO2(CH2)2-Lex) has previously been described [Zhang, Y., Chen, F.-X., Mehta, P., and Gold, B. (1993) Biochemistry 32,7954-7965]. In contrast to simple methyl sulfonate esters, e.g., methyl methanesulfonate (MMS), which predominantly methylate at 7-guanine, MeOSO2-(CH2)2-Lex affords N3-methyladenine (3-MeAde) as its major adduct. Using competitive ELISA determinations, the methylation at major and minor groove sites in calf thymus DNA by MeOSO2(CH2)2-Lex has been precisely quantitated. The yields of N7-methylguanine (7-MeGua), 3-MeAde, and O6-methyldeoxyguanosine (6-Me-dGuo) are 0.424, 3.195, and 0.0027 mmol of adduct/mol of DNA, respectively, using 10 microM MeOSO2(CH2)2-Lex and 100 microM DNA. This compares to 0.773, 0.072, and 0.0033 mmol of adduct/mol of DNA for 7-MeGua, 3-MeAde, and 6-Me-dGuo, respectively, using MMS. The increase in the yield of 3-MeAde due to the minor groove equilibrium binding properties of MeOSO2(CH2)2-Lex is approximately 40-fold relative to MMS.

Adenine↗
PubMed2001

Poly (ADP-ribose) polymerase inhibitor increases apoptosis and reduces necrosis induced by a DNA minor groove binding methyl sulfonate ester.

The poly(ADP-ribose) polymerase (PARP) is involved in cell recovery from DNA damage, such as methylation of N3-adenine, that activates the base excision repair process. In the present study we demonstrated that MeOSO(2)(CH(2))(2)-lexitropsin (Me-Lex), a methylating agent that almost exclusively produces N3-methyladenine, induced different modalities of cell death in human leukemic cell lines, depending on the presence of PARP inhibitor. Growth inhibition, provoked by the combination of Me-Lex and PARP inhibitor, was associated with a marked down-regulation of c-myc, increased generation of single strand breaks and apoptosis. When used as single agent, at concentrations that saturated cell repair ability, Me-Lex induced mainly cell death by necrosis. Surprisingly, addition of a PARP inhibitor enhanced apoptosis and reduced the early appearance of necrosis. Telomerase activity was completely suppressed in cells exposed to Me-Lex alone, by 24 h after treatment, whereas it did not change when Me-Lex was combined with PARP inhibitor. Thereafter, inhibition of telomerase was observed with both treatments. The results suggest new insights on different modalities of cell death induced by high levels of N3-methyladenine per se, or by the methylated base in the presence of PARP inhibitor.

Alkylating Agents↗
PubMed2000

Cytotoxic and clastogenic effects of a DNA minor groove binding methyl sulfonate ester in mismatch repair deficient leukemic cells.

Mismatch repair deficiency contributes to tumor cell resistance to O6-guanine methylating compounds and to other antineoplastic agents. Here we demonstrate that MeOSO2(CH2)2-lexitropsin (Me-Lex), a DNA minor groove alkylating compound which generates mainly N3-methyladenine, has cytotoxic and clastogenic effects in mismatch repair-deficient leukemic cells. Moreover, MT-1 cells, which express p53 upon drug treatment and possess low levels of 3-methylpurine DNA glycosylase activity, are more susceptible to cytotoxicity induced by Me-Lex, with respect to p53-null and 3-methylpurine DNA glycosylase-proficient Jurkat cells. In both cell lines, the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide, which inhibits base excision repair capable of removing N-methylpurines, increases cytotoxicity and clastogenicity induced by Me-Lex or by temozolomide, which generates low levels of N3-methyl adducts. The enhancing effect is more evident at low Me-Lex concentrations, which induce a level of DNA damage that presumably does not saturate the repair ability of the cells. Nuclear fragmentation induced by Me-Lex + 3-aminobenzamide occurs earlier than in cells treated with the single agent. Treatment with Me-Lex and 3-aminobenzamide results in augmented expression of p53 protein and of the X-ray repair cross-complementing 1 transcript (a component of base excision repair). These results indicate that N3-methyladenine inducing agents, alone or combined with poly(ADP-ribose) polymerase inhibitors, could open up novel chemotherapeutic strategies to overcome drug resistance in mismatch repair-deficient leukemic cells.

Antineoplastic Agents↗
PubMed1985

Sequence-specific recognition of B-DNA by oligo(N-methylpyrrolecarboxamide)s.

Four homologous oligopeptide-EDTA molecules, tri-, tetra, penta-, and hexa(N-methylpyrrolecarboxamide)-EDTA, in the presence of Fe(II), O2, and dithiothreitol, cleave 32P-end-labeled restriction fragments from plasmid pBR322 DNA at common locations rich in A X T base pairs that differ in the size of the binding site. From analysis of the cleavage patterns visualized by high-resolution denaturing gel electrophoresis, the oligopeptides with three, four, five, and six N-methylpyrrolecarboxamide units, containing four, five, six, and seven amide NHs, bind sites of A X T-rich DNA consisting of five, six, seven, and eight contiguous base pairs, respectively. The general rule of n amides affording binding site sizes of n + 1 base pairs is consistent with the oligopeptides binding in the minor groove of right-handed DNA, with the amide NH groups forming bridges between the adjacent N-3 and O-2 atoms of adenine or thymine on opposite strands of the DNA helix.

Base Composition↗
PubMed1997

Estimation of the DNA sequence discriminatory ability of hairpin-linked lexitropsins.

Three- and four-ring polyamides containing N-methylimidazole and N-methylpyrrole, and their hairpin-linked derivatives, bind side-by-side in the minor groove of DNA in a sequence-specific manner. The sequences recognized by side-by-side molecules are dependent on the pairings of the polyamide rings to the bases. In this study we report a mathematical model for estimating the free energies of binding for gamma-aminobutyric acid-linked polyamides to 5- and 6-bp DNA sequences. The model parameters are calibrated by a least-squares fit to 35 experimental binding constants. The model performs well in cross-validation experiments and the parameters are consistent with previously proposed empirical rules of polyamide-DNA binding. We apply the model to the design of targeted polyamides, evaluating the ability of the proposed polyamides to bind to a DNA sequence of interest while minimizing binding to the remaining DNA sequences.

Antineoplastic Agents↗
PubMed2000

Specific molecular recognition of mixed nucleic acid sequences: an aromatic dication that binds in the DNA minor groove as a dimer.

Phenylamidine cationic groups linked by a furan ring (furamidine) and related compounds bind as monomers to AT sequences of DNA. An unsymmetric derivative (DB293) with one of the phenyl rings of furamidine replaced with a benzimidazole has been found by quantitative footprinting analyses to bind to GC-containing sites on DNA more strongly than to pure AT sequences. NMR structural analysis and surface plasmon resonance binding results clearly demonstrate that DB293 binds in the minor groove at specific GC-containing sequences of DNA in a highly cooperative manner as a stacked dimer. Neither the symmetric bisphenyl nor bisbenzimidazole analogs of DB293 bind significantly to the GC containing sequences. DB293 provides a paradigm for design of compounds for specific recognition of mixed DNA sequences and extends the boundaries for small molecule-DNA recognition.

Amidines↗
PubMed1998

A chemical and genetic approach together define the biological consequences of 3-methyladenine lesions in the mammalian genome.

DNA-damaging agents produce a plethora of cellular responses that include p53 induction, cell cycle arrest, and apoptosis. It is generally assumed that it is the DNA damage produced by these agents that triggers such responses, but there is limited direct evidence to support this assumption. Here, we used DNA alkylation repair proficient and deficient isogenic mouse cell lines to demonstrate that the signal to trigger p53 induction, cell cycle arrest, and apoptosis in response to alkylating agents does emanate from DNA damage. Moreover, we established that 3-methyladenine, a relatively minor DNA lesion produced by most methylating agents (which form mainly 7-methylguanine), can specifically induce sister chromatid exchange, chromatid and chromosome gaps and breaks, S phase arrest, the accumulation of p53, and apoptosis. This study was made possible by the generation of 3-methyladenine DNA glycosylase null mutant cells by targeted homologous recombination and by the chemical synthesis of a methylating agent that almost exclusively produces 3-methyladenine DNA lesions. The combined use of these two experimental tools has defined the biological consequences of 3-methyladenine, a DNA lesion produced by endogenous cellular metabolites, environmental carcinogens, and chemotherapeutic alkylating agents.

Adenine↗
PubMed1999

Relationship between DNA methylation and mutational patterns induced by a sequence selective minor groove methylating agent.

Me-lex, a methyl sulfonate ester appended to a neutral N-methylpyrrolecarboxamide-based dipeptide, was synthesized to preferentially generate N3-methyladenine (3-MeA) adducts which are expected to be cytotoxic rather than mutagenic DNA lesions. In the present study, the sequence specificity for DNA alkylation by Me-lex was determined in the p53 cDNA through the conversion of the adducted sites into single strand breaks and sequencing gel analysis. In order to establish the mutagenic and lethal properties of Me-lex lesions, a yeast expression vector harboring the human wild-type p53 cDNA was treated in vitro with Me-lex, and transfected into a yeast strain containing the ADE2 gene regulated by a p53-responsive promoter. The results showed that: 1) more than 99% of the lesions induced by Me-lex are 3-MeA; 2) the co-addition of distamycin quantitatively inhibited methylation at all minor groove sites; 3) Me-lex selectively methylated A's that are in, or immediately adjacent to, the lex equilibrium binding sites; 4) all but 6 of the 33 independent mutations were base pair substitutions, the majority of which (17/33; 52%) were AT-targeted; 5) AT --> TA transversions were the predominant mutations observed (13/33; 39%); 6) 13 out of 33 (39%) independent mutations involved a single lex-binding site encompassing positions A600-602 and 9 occurred at position 602 which is a real Me-lex mutation hotspot (n = 9, p < 10(-6), Poisson's normal distribution). A hypothetical model for the interpretation of mutational events at this site is proposed. The present work is the first report on mutational properties of Me-lex. Our results suggest that 3-MeA is not only a cytotoxic but also a premutagenic lesion which exerts this unexpected property in a strict sequence-dependent manner.

Adenine↗