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

Abstract

a b s t r a c tWith 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 bromomethanephosphonate 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 EC 50 values that were about three times higher than that of the reference anti-HCMV drug ganciclovir without displaying cytotoxicity.

Enzymatic synthesis of fluorinated compounds

“…Moreover, fluorine can change the p K a , affinity, dipole moment, stability, lipophilicity, and bioavailability of adjacent groups (Dos Santos et al 2020 ; Khosravan et al 2017 ; Muller et al 2007 ). Therefore, the target compounds doped with fluorine are endowed with stronger activity and stability, longer half-life, and better bioabsorbability (Moschner et al 2019 ; Ni and Hu 2016 ; Reichel and Karaghiosoff 2020 ), especially in the fields of pharmaceutical intermediates (Gillis et al 2015 ; Swallow 2015 ; Zhdankin et al 2017 ; Zou et al 2019 ), cancer treatment (Meanwell et al 2020 ), antiviral agents (Pomeisl et al 2019 ), photovoltaics, diagnostic probes and bioinspired materials (Moschner et al 2019 ). Besides, natural proteins incorporating fluorinated amino acids showed also many unique characteristics, which are used in the biotherapeutics protein–protein interaction and the synthesis of high value-added chemicals (Arias et al 2020 ; Awad and Ayoup 2020 ; Bucci et al 2019 ; Liu et al 2019 ; Mei et al 2020a ; Remete et al 2018 ; Sisila et al 2021 ; Vaughan et al 2016 ; Wang and Matthews 2020 ; Won et al 2019 ).…”

New enzymatic strategies for the preparation of pharmaceutically important enantiomeric β-amino acid derivatives

“…Additionally, the pKa, affinity, dipole moment, stability, lipophilicity, and bioavailability of groups adjacent to fluorine can be altered [15][16][17]. Therefore, fluorine-containing compounds are providing stronger activity and stability, longer half-life, and better bioabsorbability [18][19][20], especially in the fields of pharmaceutical intermediates [21][22][23][24], cancer treatment [25], antiviral agents [26], photovoltaics, diagnostic probes, and bioinspired materials [18]. In addition, natural proteins incorporating fluorinated amino acids also showed many unique characteristics.…”