Synthesis of functional molecules. Molecular recognition and catalysis by anion receptors. Small molecule ligands for RNA.
The group is interested in the synthesis of catalytically active receptor molecules able to transform substrates within host-guest complexes. Stereoselective C-C bond forming reactions are studied as well as the sequence specific cleavage of nucleic acids. Molecular recognition of biopolymers, especially of RNA, is an important topic. In an concerted effort of the SFB 579, the group works on the identification of novel HIV inhibiting and antibacterial lead structures. Template controlled oligomerization of RNA is a further research project.
Hydrogen bond mediated organocatalysis: Chiral amidinium ions as "metal free Lewis acids"
In the absence of polar solvents and coordinating counterions, amidinium ions such as 1 or 2 will associate via hydrogen bonds with noncharged carbonyl groups. Appropriate dienophiles are activated towards cycloadditions in a way reminiscent of mild Lewis acid catalysis. A Diels-Alder reaction forming the skeleton of estrone, for instance, is accelerated 3000fold by dication 2. Significant enantioselectivities and good yields are obtained with catalysts of type 2 in quantities as low as 3 mol %. These studies have demonstrated for the first time that cycloadditions may be enantioselectively controlled by hydrogen bonds.
Fig. 1: Structures of the axially-chiral amidine 1 and of the C2-symmetrical bisamidine 2
Design, synthesis, and evaluation of HIV inhibiting heterocycles
Structure based design has allowed to prepare small heterocyclic molecules able to associate selectively with HIV-1 TAR RNA.
Stereoselective synthesis of amino acids
Several synthetic pathways have been developed towards non-natural aromatic and heteroaromatic amino acids. They are based on chirally-conserving transformations of natural amino acids followed by transition metal induced cross coupling steps. The resulting products are used as building blocks for RNA binding peptides with antiviral and antibiotic properties.
Fig. 2: A selection of synthetic α-amino acids
Tris(2-aminobenzimid-azole) 3 was developed by us as one of the most active metal free RNA cleavers. 3 catalyzes the formation of 2',3' cyclic phosphates, most probably by electrostatic transition state stabilization combined with general acid/base catalysis. Conjugation of 3 with oligonucleotides gives rise to the best organo catalytic sequence selective artificial ribonuclease known today(4).
Fig. 3: Structures of RNA cleavers 3 and 4 and of DNA cleavers 5 and 6
DNA cleaving artificial phosphodiesterases
Based on earlier work on phosphodiester cleaving bis(guanidinium) alcohols, compounds 5 was developed. The OH group of 5 rapidly attacks different types of phosphodiester substrates when bound as ion pair complexes. Even plasmid DNA is cleaved under physiological conditions. The analogous compound 6 reacts with plasmids in the low µmolar concentration range. The aim of current work is to conjugate compound 6 with sequence specific DNA binders (See above, Fig. 3).
Template controlled oligomerization of RNA
Based on the work of L. Orgel, the experiment shown below was designed. A template strand is hybridized with a dye labeled RNA primer and with activated 5' phosphates of monomeric building blocks. Guided by Watson-Crick base pairing, covalent primer extension then starts step by step. A DNA sequencer allows the online detection of this process. Current experiments are run to find out the prospects and limitations for self-replication phenomena of RNA.
Fig. 4: Activated monomers associate with the single stranded part remaining after hybridization of primer and template. Primer extension now occurs in the resulting double helical aggregate