ORGANISATION/COMPANYUniversité de Montpellier
RESEARCH FIELDChemistry › Organic chemistry
RESEARCHER PROFILEFirst Stage Researcher (R1)
APPLICATION DEADLINE15/05/2021 20:00 - Europe/London
LOCATIONFrance › Montpellier
TYPE OF CONTRACTTemporary
HOURS PER WEEK40
OFFER STARTING DATE01/10/2021
PhD Proposal – 2021-2024
Sustainable approaches for the synthesis of nucleotides and P-stereogenic derivatives
Nucleotides (5’-(poly)-phosphorylated nucleosides), their conjugates and analogues are organophosphorus compounds widely used as biological tools (DNA sequencing, cap analogues for in vitro synthesis of mRNAs,…).1 Moreover, many structural analogues interfere with the biosynthesis of nucleic acids, and hence are used as antiviral or anticancer drugs (administrated in their nucleoside form or as nucleotide prodrugs).2 For exemple, ProTides are very effective in the treatment of viral infections (Sofosbuvir/Hepatitis C) and harbor a chiral phosphorus atom as a special feature.3 The stereoselective synthesis of these P-stereogenic compounds usually involves the use of chiral auxiliaries or enantiopure chiral P-reagents.4
The aim of this project is to develop original and/or eco-compatible synthetic methods to gain access to nucleotides and derivatives based on the use of alternatives solvents for green chemistry (instead of N,N-dimethylformamide, N-methylpyrrolidinone chlorinated solvents) or mecanochemistry. The new molecules obtained will be valued through collaborations with external partners.
The first part of the thesis stems from our previous research,5 and will be devoted to the development of eco-compatible synthetic procedures to obtain dinucleoside 5’,5’-tetraphosphates as well as cap analogues. The second part will focus on the conception and the development of innovative methods to synthesize P-stereogenic compounds.
Keywords : Organic synthesis, phosphorus chemistry, stereoselectivity, green chemistry, dinucleotides, prodrugs.
1) Roy, B.; Depaix, A.; Périgaud, C.; Peyrottes, S. Chem. Rev 2016, 116, 7854-7897.
2) Pastuch-Gawołek, G.; Gillner, D.; Król, E.; Walczak, K.; Wandzik, I. Eur. J. Pharmacol. 2019, 865, 172747.
3) Yu, H.; Yang, H.; Shi, E.; Tang, W. Medicine in Drug Discovery 2020, 8, 100063.
4) Lemouzy, S.; Giordano, L.; Hérault, D.; Buono, G. Eur. J. Org. Chem. 2020, 3351-3366.
5) Appy, L.; Depaix, A.; Bantreil, X.; Lamaty, F.; Peyrottes, S.; Roy, B. Chem.–Eur. J. 2019, 25, 2477–2481.
The candidate must hold a Master's degree in organic chemistry or equivalent. Knowledge in the chemistry of phosphorus biomolecules and/or analysis of biomolecules (NMR, MS, HPLC,...) will be a major advantage. Motivation, curiosity and autonomy are highly desirable qualities.
EURAXESS offer ID: 615903
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