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Robert Häner

Publications and source records attributed to Robert Häner.

15 recordsLinked to original sources
PubMed2006

Selectivity in DNA interstrand-stacking.

The synthesis and spectroscopic investigation of DNA hybrids containing non-nucleosidic pyrene and phenanthrene building blocks is reported. It was found that interstrand-stacking of the polyaromatic compounds in the DNA duplex takes place with a high degree of selectivity.

Base Pairing↗
PubMed2006

The incommensurately modulated structure of a tricyclic natural-product-like compound of empirical formula C22H20O3.

3,4-Diphenyl-2a,5a,6,7,8,8a,8b-heptahydro-furo[4,3,2-de]chromen-2-one (1) was prepared as part of a project aimed at the synthesis of polycyclic natural-product-like scaffolds. X-ray analysis of crystals grown from ethanol revealed an incommensurately modulated structure. Data include main and satellite reflections up to second order. The modulation vector was refined using the NADA program. The modulated character of the structure of the organic compound C(22)H(20)O(3) is interpreted in terms of the intermolecular C-H...O hydrogen bonds and close-contact approximation.

Benzopyrans↗
PubMed2005

Natural product-like libraries based on non-aromatic, polycyclic motifs.

Diversity-oriented synthesis is an intriguing approach for creating structurally diverse compounds that cover the pharmaceutically relevant chemical space in an optimal way. On the other hand, an over-proportionally large number of drugs or lead structures originate from compounds isolated from natural sources. Thus, not surprisingly, an increasing number of combinatorial libraries are based on motifs resembling natural products. A particular aspect of many natural products is the presence of non-aromatic, polycyclic core structures. The fusion of several rings leads to geometrically well-defined structures and, thus, holds the promise of a high functional specialisation. In this review we present several actual examples of natural product-like libraries with non-aromatic polycyclic motifs based on naturally occurring compounds.

Biological Factors↗
PubMed2004

Elaboration of D-(-)-ribose into a tricyclic, natural product-like scaffold.

The construction of natural product-like, tricyclic compounds is reported. Starting from a D-(-)-ribose-derived dihydrofurane, the tricyclic scaffold is prepared via an intramolecular hetero-Diels-Alder reaction. The reaction proceeds with very high diastereoselectivity through an endo transition state, as established on the basis of X-ray structural analysis of the products. Further modification and derivatization of the obtained products is described.

Crystallography, X-Ray↗
PubMed2004

A metal-coordinating DNA hairpin mimic.

A self-complementary oligodeoxynucleotide containing a 6,6"-substituted terpyridine was found to adopt a highly stable, hairpin-like structure. In addition to serving as a hairpin-loop mimic, the terpyridine can act as a coordination site for metals. Thus, the binding of several divalent transition metals (Zn(2+), Co(2+), Ni(2+), Cu(2+) and Pd(2+)) to the terpyridine hairpin mimic was investigated. The terpyridine-modified hairpin mimic forms a stable secondary structure in the presence of these metals. The stability of the metal-coordinated hairpin mimic was found to be lower than in the absence of metal. Furthermore, the T(m) of the metallohairpin is strongly influenced by the type of the bound metal, with T(m)'s increasing in the order Co(2+) approximately Ni(2+) < Zn(2+) < Cu(2+) < Pd(2+). Model considerations suggest that a conformational change of the terpyridine ligand is required to allow coordination of the metal.

Circular Dichroism↗
PubMed2004

A simple, non-nucleosidic base surrogate increases the duplex stability of DNA containing an abasic site.

Abasic sites represent a common type of lesion in DNA. If not repaired, they can lead to mutations during replication or to cell death. Due to their biological importance, there is a strong interest in methods of recognizing abasic sites in DNA both for diagnostic and also for potential pharmaceutical applications. Extended aromatic residues can have a substantial positive influence on the stability of double-stranded DNA containing abasic sites. We report here the use of a simple, non-nucleosidic phenanthrene as a base surrogate, which effectively enhances the duplex stability of DNA with an abasic site. The influence of the linker length on the stability of the duplex is investigated. Data and model considerations indicate that stabilization is a result of stacking interactions between the phenanthrene and DNA base pairs.

Base Pairing↗
PubMed2003

mRNA fusion constructs serve in a general cell-based assay to profile oligonucleotide activity.

A cellular assay has been developed to allow measurement of the inhibitory activity of large numbers of oligonucleotides at the protein level. The assay is centred on an mRNA fusion transcript construct comprising of a full-length reporter gene with a target region of interest inserted into the 3'-untranslated region. Luciferase and fluorescent reporter genes were used in the constructs. The insert can be from multiple sources (uncharacterised ESTs, partial or full-length genes, genes from alternate species, etc.). Large numbers of oligonucleotides were screened for antisense activity against a number of such constructs bearing different reporters, in different cell lines and the inhibitory profiles obtained were compared with those observed through screening the oligonucleotides against the corresponding endogenous genes assayed at the mRNA level. A high degree of similarity in the profiles was obtained indicating that the fusion constructs are suitable surrogates for the endogenous messages for characterisation of antisense oligonucleotides (ASOs). Furthermore, the results support the hypothesis that the secondary structure of mRNAs are divided into domains, the nature of which is determined by primary nucleotide sequence. Oligonucleotides whose activity is dependent on the local structure of their target mRNAs (e.g. ASOs, short interfering RNAs) can be characterised via such fusion RNA constructs.

Animals↗
PubMedDate not supplied

Artificial ribonucleases: efficient and specific in vitro cleavage of human c-raf-1 RNA.

We report here the first successful sequence-specific cleavage of large RNA using artificial ribonucleases. A series of uniformly 2'-methoxyethoxy-modified oligonucleotides bearing a europium complex were investigated as artificial ribonucleases specific for the human c-raf-1 mRNA. The efficiency and specificity of these oligonucleotide-metal conjugates to bind and to cleave 571 and 2,977 nucleotides long c-raf-1 RNA transcripts in vitro in a sequence-specific manner is demonstrated. Quantitative analysis reveals a cleavage efficiency of 60-70% within 4 h at 37 degrees C. Precise mapping of cleavage sites using primer extension analysis shows that cleavage generally occurs at two or three major sites adjacent to the 3'-end of the RNA target region. Cleavage is preferentially observed after purine nucleotides. This study demonstrates the potency of artificial ribonucleases targeting large, biologically relevant RNAs.

Europium↗
PubMedDate not supplied

Synthesis and bioconjugation of diene-modified oligonucleotides.

The preparation of diene-modified oligonucleotides as well as their properties and further derivatization are described. Self-complementary oligonucleotides containing a diene moiety in the loop region form stable, hairpin-like secondary structures. These hairpin mimics can be further derivatized via the Diels-Alder reaction. Diene modification in the stem region leads, in contrast, to a marked destabilization of the hairpin structure. No further reduction in stability is observed, however, upon conjugation of the stem-modified derivatives via the Diels-Alder reaction with an N-substituted maleimide dienophile.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Copper complex-assisted DNA hybridization.

2,2'-Bipyridine (bpy) or 1,10-phenanthroline (phen) metal-binding domains were covalently attached to oligonucleotides, and the influence of metal ions on the hybridization of the conjugates was investigated. Metal-binding domains were attached to oligonucleotides at 3'- and 5'-terminal positions, thus placing them in juxtaposed positions after hybridization to a common target strand. While the ligands alone had a positive effect (increased Tm) on hybrid stability, the duplex was further stabilized by the addition of copper(I) and/or copper(II) through the formation of a metal complex in which the two short sequences are linked through {Cu(bpy)2}, {Cu(phen)}, or {Cu(bpy)(phen)} domains. The increase in Tm, due to formation of the {Cu(bpy)2}, {Cu(phen)2}, {Cu(bpy)(phen)} motifs is reversed upon addition of EDTA, consistent with the stripping of copper from the ligands. The effect of metal complex formation on the duplex strength was shown to be highest if the two metal-coordinating ligand strands are placed as close to each other as possible.

Copper↗