engleski

SYNTHESIS OF NEW NUCLEOS(T)IDE ANALOGUES AND EVALUATION OF THEIR CHOLINESTERASE INIBITORY ACTIVITIES

Nucleosides and nucleotides are essential biomolecules in multiple biological processes, such as the synthesis of nucleic acids, cell cycle or cell signaling. These events are essential in health and also for the progress of diseases, such as cancer and viral infections, in which they are overactivated. Hence, the synthesis of nucleoside and nucleotide analogues may be a useful therapeutic strategy, aiming at interfering or inhibiting these processes. Besides having potential anticancer and antiviral properties, other types of bioactivities for these groups of molecules have been reported, including the ability to inhibit cholinesterases, which are biological targets for Alzheimer’s disease therapy. In particular, previous results from our group showed the potent inhibition of acetylcholinesterase by isonucleosides comprising a theobromine or a triazole motif linked to C-5 or C-6 of a monosaccharide unit. In this context, in this communication we present the synthesis of various xylofuranosyl isonucleosides comprising various types of nucleobases at C-5 of the sugar moiety. Their access was based on the Mitsunobu coupling between a purine or pyrimidine derivative and a partially protected xylofuranose. Moreover, isosteric functions for a phosphate group, such as a sulfonamide or a phosphoramidate, were installed at the isonucleoside anomeric position, leading to isonucleotides, which constitute a rather unexploited type of nucleotide analogs. The ability of the new isonucleos(t)ides to inhibit cholinesterases was studied and some compounds showed potent activities with Ki values in the micromolar concentration range. The synthetic work and the results of the bioactivity evaluation will be disclosed and discussed.

Isonucleosides ; Anticancer ; Acetylcholinsterase inhibitor

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