Nuno Manuel Xavier
University of Lisbon, Portugal
Title: Exploring the synthesis and the biological potential of new structurally diversified N-glycosyl compounds as nucleoside analogs or mimetics of glycosyl phosphates and nucleotides
Biography
Biography: Nuno Manuel Xavier
Abstract
Nucleoside and nucleotide analogs or mimetics have attracted considerable attention as synthetic targets due to their ability to interfere with biological pathways in which their natural counterparts are involved, such as nucleic acid synthesis and cell division. Such physiological processes are deregulated in diseases such as cancer or viral infections and therefore these classes of compounds constitute potential anticancer or antiviral agents. Other biological effects that have been reported for nucleoside analogs include antimicrobial efficacies and cholinesterase inhibitory abilities. The access to structurally new analogs or mimetics of nucleosides and nucleotides and the exploitation of their biological profile remains of interest.
In this communication, the synthesis of glucuronic acid and glucuronamide-derived N-glycosyl compounds, including derivatives containing potential bioisostere groups for a phosphate functionality and nucleosides, will be presented.
Molecules of higher structural complexity intended to mimic nucleotides were also prepared, namely glucuronamide-based hybrids containing both a benzyltriazole moiety and an anomeric sulfonamide or a phosphoramidate function and pyranosyl/furanosyl nucleoside phosphoramidates.
The new compounds were subsequently evaluated for their cytotoxicity to cancer cells and for their inhibitory activities towards enzymes of therapeutic relevance, such as cyclin-dependent kinases, cholinesterases and carbonic anhydrase II. Some molecules were shown to be bioactive with inhibition constants or IC50 values in the micromolar concentration range. The synthetic work and the findings of the bioactivity evaluation will be disclosed.
References
1. Jordheim LP, Durantel D, Zoulim F, Dumontet C (2013) Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nature Reviews Drug Discovery 12:447–464.
2. Winn M, Goss RJM, Kimura K-i, Bugg T D H (2010) Antimicrobial nucleoside antibiotics targeting cell wall assembly: recent advances in structure-function studies and nucleoside biosynthesis.
3. Xavier NM, Schwarz S, Vaz PD, Csuk R, Rauter AP (2014) Synthesis of Purine Nucleosides from D-Glucuronic Acid Derivatives and Evaluation of Their Cholinesterase-Inhibitory Activities. European Journal of Organic Chemistry 2014:2770–2779.
4. Batista D, Schwarz S, Loesche A, Csuk R, Costa PJ, Oliveira MC, Xavier NM (2016) Synthesis of glucopyranos-6′-yl purine and pyrimidine isonucleosides as potential cholinesterase inhibitors. Access to pyrimidine-linked pseudodisaccharides through Mitsunobu reaction. Pure and Applied Chemistry 88:363–379.