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Journal of Biotechnology and Phytochemistry
Volume 1 Issue 3
Chemistry World 2017
Page 21
November 13-15, 2017 Athens, Greece
7
th
World Congress on
Chemistry
Synthesis of novel types of nucleosides and nucleotide
mimetics as potential anticancer agents
Nuno Manuel Xavier
University of Lisbon, Portugal
S
ynthetic nucleosides, nucleotides and their analogs or
mimetics constitute relevant groups of molecules in
medicinal chemistry, due to their propensity to exhibit
biological activities. A number of compounds of these types
are in clinical use against cancer and viral infections, acting
through incorporation into nucleic acids and/or by inhibition
of enzymes involved in their biosynthesis. However, some
drawbacks limit their use, such as low oral bioavailability and
the acquisition of resistance by cancer cells or virus towards
their action. The development of novel bioactive nucleoside/
nucleotide-like structures that may overcome these issues and
act by innovative mechanisms of action remains of interest.
Within this context, in this communication the synthesis
of novel azido nucleosides, their phosphoramidates and
of structurally diverse N-glycosyl derivatives containing
D-glucuronamide moieties will be presented. Azido
furanosyl and pyranosyl nucleosides were synthesized by
N-glycosylation of purine or pyrimidine derivatives with azido
1-O-acetyl glycosyl donors and were subsequently converted
into nucleoside phosphoramidates as potential mimetics of
nucleoside monophosphates. 1-O-Acetyl glucuronamides
were prepared and employed as precursors for the access to
N-glycosylsulfonamides and N-glycosylphosphoramidates,
in which the sulfonamide and the phosphoramidate moieties
were planned as phosphate bioisosteres. N-Substituents of
different polar character were introduced at C-6. Among
the motifs installed was the benzyltriazole system, leading to
novel types of potential nucleotide mimetics. Glucuronamide-
based nucleosides as well as related N-glycosyl triazole
analogs were also accessed. The evaluation of the compounds’
antiproliferative effects on cancer cells revealed some active
molecules at micromolar concentration range. Studies aiming
at giving insight into the mode of action of the most potent
compounds were performed. The synthetic methods and the
results of the biological assays will be disclosed herein.
Recent Publications
1.
L P Jordheim, DDurantel, F Zoulim and CDumontet (2013)
Advances in the development of nucleoside and nucleotide
analogues for cancer and viral diseases. Nature Reviews.
Drug Discovery 12(6):447-464.
2.
N M Xavier (2017) Recent advances on nucleotide analogs
and mimetics: synthesis and biological properties in Elsevier
Reference Module in Chemistry, Molecular Sciences and
Chemical Engineering, DOI: 10.1016/B978-0-12-409547-
2.12655-1.
3.
MSerpi, V Ferrari and F Pertusati (2016) Nucleoside derived
antibiotics to fight microbial drug resistance: new utilities
for an established class of drugs? Journal of Medicinal
Chemistry 59(23):10343–10382.
4.
N M Xavier, R Gonçalves-Pereira, R Jorda, E Řezníčková,
V Kryštof and M C Oliveira (2017) Synthesis and
antiproliferative evaluation of novel azido nucleosides
and their phosphoramidate derivatives. Pure Appl. Chem.
89(9):1267–1281.
5.
N M Xavier, A Porcheron, D Batista, R Jorda, E Řezníčková,
V Kryštof and M C Oliveira (2017) Exploitation of
new structurally diverse d-glucuronamide-containing
N-glycosyl compounds: synthesis and anticancer potential.
Organic and Biomolecular Chemistry 15(21):4667-4680.
Biography
Nuno M. Xavier (b. Nov. 1982, Vila Real, Portugal) graduated in Chemistry
from the University of Lisbon in 2005. He received a dual Ph.D. degree
in Organic Chemistry from the University of Lisbon and from the National
Institute of Applied Sciences of Lyon (INSA Lyon) in 2011, where he worked
in the development of new carbohydrate-based antimicrobial agents. He was
afterwards a Postdoctoral Researcher at the University of Natural Resources
and Life Sciences of Vienna (BOKU), where he focused on the synthesis of new
heptose derivatives of antibacterial potential. After another post-doctoral period
at the Faculty of Sciences, University of Lisbon, he became in 2014, Researcher
(FCT Investigator) at this Institution. His scientific interests are within Organic
and Medicinal Chemistry and are devoted to the development, using efficient
synthetic methodologies, of new bioactive carbohydrate-containing molecules
of potential therapeutic application. He has been particularly dedicated to the
design and synthesis of structurally new nucleosides and nucleotide analogues
as potential anticancer agents. His research activities have been reported in
ca. 30 publications and are frequently presented and discussed in international
scientific symposia.
nmxavier@fc.ul.ptNuno Manuel Xavier, J Biotech and Phyto 2017