Synthesis of fluorinated acyclic nucleoside phosphonates with 5-azacytosine base moiety

0509814 - ÚOCHB 2020 RIV GB eng J - Journal Article
Pomeisl, Karel - Krečmerová, Marcela - Pohl, Radek - Snoeck, R. - Andrei, G.
Synthesis of fluorinated acyclic nucleoside phosphonates with 5-azacytosine base moiety.
Tetrahedron. Roč. 75, č. 39 (2019), č. článku 130529. ISSN 0040-4020. E-ISSN 1464-5416
R&D Projects: GA MŠMT(CZ) LM2015064; GA MŠMT(CZ) LO1304
Institutional support: RVO:61388963
Keywords : acyclic nucleoside phosphonates * 5-azacytosine * fluorinated nucleotides * prodrugs * phosphonates
OECD category: Organic chemistry
Impact factor: 2.233, year: 2019
Method of publishing: Limited access
https://www.sciencedirect.com/science/article/pii/S0040402019308622?via%3Dihub

With respect to the strong antiviral activity of (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine various types of its side chain fluorinated analogues were prepared. The title compound, (S)-1-[3-fluoro-2-(phosphonomethoxy)propyl]-5-azacytosine (FPMP-5-azaC) was synthesised by the condensation reaction of (S)-2-[(diisopropoxyphosphoryl)methoxy)-3-fluoropropyl p-toluenesulfonate with a sodium salt of 5-azacytosine followed by separation of appropriate N-1 and O-2 regioisomers and ester hydrolysis. Transformations of FPMP-5-azaC to its 5,6-dihydro-5-azacytosine counterpart, amino acid phosphoramidate prodrugs and systems with an annelated five-membered imidazole ring, i.e. imidazo [1,2-a][1,3,5]triazine derivatives were also carried out. 1-(2-Phosphonomethoxy-3,3,3-trifluoropropyl)-5-azacytosine was prepared from 5-azacytosine and trifluoromethyloxirane to form 1-(3,3,3-trifluoro-2-hydroxypropyl)-5-azacytosine which was treated with diisopropyl bromomethane-phosphonate followed by deprotection of esters. Antiviral activity of all newly prepared compounds was studied. FPMP-5-azaC diisopropyl ester inhibited the replication of herpes viruses with EC50 values that were about three times higher than that of the reference anti-HCMV drug ganciclovir without displaying cytotoxicity.
Permanent Link: http://hdl.handle.net/11104/0300433