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University of Helsinki Laboratory of Organic Chemistry
 

Laboratory of Organic Chemistry

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Laboratory of Organic Chemistry
Department of Chemistry
University of Helsinki
P.O. Box 55
FI-00014 UNIVERSITY OF HELSINKI

Chemistry of nucleosides and nucleotides

Kuva

Project Leaders: Professor Mikko Oivanen and University Lecturer Petri Heinonen
Researchers: Tom Lagerwall, Sami Virtanen

Dynamic combinatorial chemistry
Dynamic combinatorial chemistry (DCC) was introduced in the late 1990s as a su ­ pramolecular and combinatorial method for target - oriented search of biologically active compounds. A dynamic combinatorial library (DCL) is formed of an equilib­rium mixture of several functionalities on a defined chemical basis. For one exam­ple, aldehydes react with a selection of amines to produce a versatile equilibrium mixture based on imine exchange. Addition of the target molecule – e. g. a receptor, protein or an enzyme – into the DCL solution shifts the equilibrium, and the com­pounds having the greatest affinity to the target can be selected. The present project is directed on building dynamic combinatory libraries on the basis of nucleoside derivatives . One target is to enhance methods for screening of the biological activities of potential drug compounds . The main research effort is, however, put in the biological reactivities, reaction mechanisms and factors steering the bonding of nucleoside analogs in the complexes . The interrelation of the components of the DCLs is studied in a quantitative manner (reaction mechanisms and kinetics). Analytical methods are developed on NMR , mass spectrometry and HPLC chromatogra­phy. For screening of the biological activities, for example enzyme inhibition, spe­cial applications based on spectrophotometry and chromatography will be required. (Oivanen, Hakanen, Lagerwall, Heinonen; in collaboration with the research group at the Engelhardt Institute of Molecular Biology, Moscow )

Molecular recognition of nucleosides for site-selective reactions
The molecular recognition of small molecule ligands by artificial receptors has gained increasing interest during the past few decades. The recognition of nucleic acid bases (A-T and C-G pairs) in DNA is the most important molecular recognition process in nature. The binding force is based mainly on hydrogen bonding but, in addition, also the p-p-stacking interactions of the aromatic nucleobases play a role in formation of the 3D-structure of DNA. The aim in our project is to use these “natural” weak interactions in the design of the artificial receptors for nucleosides. The purpose is to apply the approach with the reactive receptors bound on a solid support, which would allow development of recyclable reagents for introducing various groups to the selected site of the nucleoside. The mode of action of these artificial receptors resembles that of natural enzymes. The chemistry involves synthesis of branched and cyclic structures using synthetic methods such as transition metal catalysis, solid phase synthesis and protection group chemistry. (Heinonen and Oivanen).

Physico-chemical properties of nucleic acid constituents
Nucleoside analogues and derivatives used in various biological applications are often susceptible to hydrolytic degradation. The stability of the N -glycosidic linkage or the modified heteroaromatic base may be the critical factors. The formation and cleavage of the internucleosidic phosphoester linkage of nucleic acids are two of the most es ­ sential reactions of biopolymers. Mechanisms of the solvol ysis reactions of nucleoside and nucleotide derivatives are studied by kinetic methods. The work is, for one side, aimed at understand­ing the intrinsic chemical reactivity of the biologi ­ cally important compounds, but also to provide a solid chemical basis for the appli ­ cations of nucleotide analogs in biological and medical studies. (Oivanen, Lagerwall )

Pro-drug strategies of antisense oligonucleotides

One of the main problems for the use of oligonucleotide analogs, such as phosphorothioates, is the poor cellular uptake of the ionic oligomers. The present project is aimed at developing pro-drug strategies to enhance the transport of oligonucleotide analogs and artificial nucleases into the cell. The lipophilicity of the oligonucleotide is increased by masking the ionic phosphoester moieties with biolabile protection groups, which are cleaved by the action of intracellular enzymes to release the antisense oligonucleotide in cytoplasm. (Oivanen, in collaboration with the research group at the Department of Chemistry, University of Turku )