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

TETRAHEDRON

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Article

Pomeisl, Karel^1,2  Krecmerova, Marcela¹  Pohl, Radek¹  Snoeck, Robert³  Andrei, Graciela³ 

[1] Czech Acad Sci, Inst Organ Chem & Biochem, Flemingovo Nam 2, CZ-16610 Prague 6, Czech Republic

[2] Czech Acad Sci, Inst Phys, Slovance 1999-2, Prague 18221 8, Czech Republic

[3] Katholieke Univ Leuven, Rega Inst Med Res, Herestr 49,Box 1043, B-3000 Leuven, Belgium

关键词: Acyclic nucleoside phosphonates;    5-Azacytosine;    Fluorinated nucleotides;    Prodrugs;    Phosphonates;   

DOI  :  10.1016/j.tet.2019.130529

来源: Elsevier

【 摘 要 】

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. (C) 2019 Elsevier Ltd. All rights reserved.

【 授权许可】

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