Seminar: September 24 | 2.30 p.m.-3.30 p.m. | Room 1.3.14
Nuno Manuel Xavier, Centro de Química Estrutural, Institute of Molecular Sciences (CQE-IMS), Faculty of Sciences, University of Lisbon
Exploring the Synthesis and the Bioactivity Profile of Novel Nucleos(t)ide Analogs
The synthesis of nucleosides and nucleotide analogs has attracted a significant interest in (bio)organic and in medicinal chemistry due to their propensity to interfere with nucleos(t)ide-dependent biological events that are crucial for life as well as for the progress of various diseases. The anticancer and antiviral efficacies of nucleos(t)ide analogs are demonstrated by the various examples of such compounds approved as anticancer and antiviral drugs,[1] while their antimicrobial potential has been well reported.[2] However, some drawbacks are associated with their clinical use, namely their low bioavailability and chemotherapeutic resistance. Therefore, the search for new nucleos(t)ide-like structures that may exhibit alternative mechanisms of action and overcome such limitations remains relevant in nucleos(t)ide medicinal chemistry.
In our Team, we have been dedicated to the development of different types of novel potentially bioactive nucleos(t)ide analogs or mimetics, by exploring structural variations at the different key moieties contained in a nucleos(t)ide parent structure.
In this talk, the synthesis and biological evaluation of selected groups of molecules, which are representative of our research in this field, namely nucleos(t)ide analogs constructed on uncommon glycosyl templates, such as xylofuranosyl units or D-glucuronamide-based moieties, will be presented. The structural moieties embodied in the compounds include purine, pyrimidine or triazole units, which are N-linked to the anomeric or to a non-anomeric position (i.e. isonucleosides) of the sugar moiety, phosphoramidate or phosph(on)ate groups, or guadinine moieties.
The synthetic methodologies used azido xylofuranoses or D-glucuronolactone as precursors and employed key steps such as azide-alkyne 1,3-dipolar cycloaddition, N/O-phosphorylation, Arbuzov reaction, Staudinger reaction, N-glycosylation, or guanidinylation.
Biological assays revealed the therapeutic potential of these groups of molecules towards cancer, bacterial infections or neurodegenerative diseases, with some compounds showing in-vitro bioactivities comparable or higher than those of reference drugs.
References
[1] a) L. Hruba et al., Biochem. Pharmacol. 2023, 215, 115741; b) PN Kamzeeva et al., Curr. Issues Mol. Biol. 2023, 45, 685.
[2] M. Serpi et al., J. Med. Chem. 2016, 59, 10343.