Design and Synthesis of Artificial Nucleobases for Sequence-Selective DNA Recognition within the Major Groove.

We present the design and synthesis of artificial specific nucleobases, each one recognizing a single base pair within the major groove of duplex DNA. Computational calculations indicate that PNAs modified with these nucleobases enable the formation of highly stable triple helices with no sequence restrictions through multiple hydrogen bonding and π⋅⋅⋅π stacking interactions, without significantly widening the DNA double helix. New synthetic routes were developed to the structures of these fused heterocycles which have rarely been described in the literature. NMR titration experiments indicate specific hydrogen bonding at the Hoogsteen sites. The new building blocks allow the construction of four PNA monomers for each canonic base pair and their covalent connection to PNA oligomers. These can be designed complementary to any given DNA sequence. With high efficiency and relative simplicity of operation, the described methodologies and strategies hence form the basis for a new supramolecular ligand system targeting double-stranded DNA without strand invasion.

A Diastereoselective Cascade Annulation Approach to Bridged Polycyclic Heterocycles Involving an Unexpected Rearrangement.

A diastereoselective cascade annulation between allenoates and in-situ generated isoquinoline N-oxides generating sp3-rich bridged polycyclic heterocycles is disclosed. The reaction proceeds through an unprecedented non-rearomatized rearrangement and allows access to a broad range of bridged heterocycles in 38-93% yields with excellent functional group tolerance and high diastereoselectivity. Density functional theory calculations provided key insights into the possible reaction pathway and the stereoselectivity of this procedure.

Direct access to isoxazolino and isoxazolo benzazepines from 2-((hydroxyimino)methyl)benzoic acid via a post-Ugi heteroannulation.

A diversity-oriented access to isoxazolino and isoxazolo benzazepines is elaborated via a post-Ugi heteroannulation involving intramolecular 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes and alkynes. This sequence offers an interesting multicomponent entry to a library of isoxazolino and isoxazolo benzazepines under mild reaction conditions in good to excellent yields.

DNA Binding and Recognition of a CC Mismatch in a DNA Duplex by Water-Soluble Peptidocalix[4]arenes: Synthesis and Applications.

Water-soluble peptidocalix[4]arenes were synthesized by the introduction of arginine-rich narrow groove-binding residues at lower rims through solid-phase synthesis. The study of binding of these water-soluble bidentate ligands to well-matched and mismatched DNA duplexes by fluorescent titrations, ethidium bromide (EB) displacement assays, DNA-melting experiments, and circular dichroism (CD) analysis revealed a sequence-dependent groove-binding mechanism.