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TRANSCRIPT
Synthesis of difluorinated galactose-UDP
for studies against tuberculosis
Quí-Hiển Nguyễn, Dr. Julien Malassis, Prof. Bruno Linclau*
*School of Chemistry, University of Southampton, Southampton, SO17 1BJ
Introduction
• M.tuberculosis cell wall uses the furanose form of
galactose, converted from galactopyranose-UDP
in an enzymatic process:
• Design of inhibitors based on galactose can lead
to novel therapeutic approach to cure TB.
Edvard Munch’s The Sick
Child, 1896, depicting the
artist’s sister dying of
tuberculosis.1
(Photo in public domain)
• Tuberculosis is still one of the most feared
diseases to human.
• WHO estimated 1.5 million people died of TB in
2014.
• Drug-resistant TB strains are major concerns
nowadays.
References (1) E. Munch, Det syke barn, 1896,
https://commons.wikimedia.org/wiki/File:Munch_Det_Syke_Barn_1896.jpg,
(2) I. N’Go, S. Golten, A. Ardá, J. Cañada, J. Jiménez-Barbero, B. Linclau, and S. P. Vincent,
Chem. Eur. J., 2014, 20, 106 – 112.
(3) K. E. van Straaten, J. R. A. Kuttiyatveetil, C. M. Sevrain, S. A. Villaume, J. Jiménez-
Barbero, B. Linclau, S. P. Vincent, D. A. R. Sanders, J. Am. Chem. Soc., 2015, 137, 1230
– 1244.
(4) C. Dalvit, C. Invernizzi and A. Vulpetti, Chem. Eur. J., 2014, 20, 11058 -11068.
(5) T. S. Ramussen and H. H. Jensen, Org. Biomol. Chem., 2010, 8, 433–441.
(6) L. Mtashobya, L. Quiquempoix and B. Linclau, J. Fluorine Chem., 2015, 171, 92-96.
Previous studies and aims of this project
• Both show to be good inhibitors to UGM.
• Crystal structures have revealed similar binding
modes to that of normal Galp-UDP.3
Our group has been using fluorinated sugars as an
approach to design inhibitors that have higher
affinity to UGM than galactose-UDP.
Previously, we have synthesised and assayed 2,3-
tetrafluorinated Galp and Galf-UDP.2
F4-Galp-UDP F4-Galf-UDP
This project aims to synthesise the 2,3-difluorinated
Galp-UDP and Galf-UDP to continue the search for
potent UGM inhibitors.
• Use this system to study the effect of fluorination
motifs on binding of carbohydrates to proteins
(probed by electron density on fluorine atoms).4
F4-Galp-UDP F4-Galf-UDP
Synthesis of difluorinated galactose-UDP • Preparation of Černý epoxide from levoglucosan.5
• Fluorine substituents introduced to C2-C3 subsequently.6
Galp UDP Galf
• C4 inversion by SN2 reaction led to galactose configuration.
• 1,6-ether bridge deprotected by acetolysis, followed by
hydrolysis to give free F2-Galp.
• Acetal protection of F2-Galp gave access to both protected F2-
Galp and F2-Galf (α-anomer for acetal-F2-Galp proven by X-ray)
• Anomeric phosphorylation, deprotection steps and final UMP
coupling to reach target molecules.
Crystal structure of
acetal-F2-Galp
Conclusion • Synthetic access to the phosphorylated sugars is
possible, ready for UMP-coupling for final targets.
• Spectral characterisation for furanose is in
progress.
• Optimisation for the final steps is underway.