4′-Fluoro-nucleosides and nucleotides: from nucleocidin to an emerging class of therapeutics

Abstract

An overview of the history and development of 4′-fluoro-nucleosides as a privileged motif for bioactives is presented.

Discovery of C-Linked Nucleoside Analogues with Antiviral Activity against SARS-CoV-2

“…However, based on analysis of samples in cell culture media, 7e appeared to convert to adenine with an estimated half-life of about 2 h. Likely, the electronegative fluorine in a 4′-geminal fluorohydrin motif also enhanced the proclivity of the 1′-aminal bond for hydrolysis. 39 The 4′-fluoroaristeromycin 7f is free of these potentially labile motifs but demonstrated reduced activity, with an increase in cytotoxicity; an indication that the methylene was not a tolerated replacement for the ribose oxygen. The 2′,4′-difluorinated compound 7g emerged from the rationale described above for 7d combined with 7-deazaadenine as nucleobase�a less labile leaving group than adenine, employed previously in other RdRp inhibitors.…”

“…Unfortunately, except for the 2′,4′-difluorinated analogue 7g described above, no other active 2′-modified nucleosides were identified among the tested compounds. The 2′-disubstituted analogues like anti-HCV or antiflavivirus examples 8b , 8c , 8f – h ,,− (Figure ) and several corresponding phosphoramidate prodrugs (not shown) were tested. HCV-active 2′ spiro-oxetane and spiro-cyclopropane nucleosides like 8d and 8e and their phosphoramidates were also inactive.…”

“…Conversely, 4′-α-fluoroadenosine 7e (Table ) demonstrated improved EC 50 values (<100 nM in SARS-CoV-2/A549-hACE) and favorable selectivity. However, based on analysis of samples in cell culture media, 7e appeared to convert to adenine with an estimated half-life of about 2 h. Likely, the electronegative fluorine in a 4′-geminal fluorohydrin motif also enhanced the proclivity of the 1′-aminal bond for hydrolysis . The 4′-fluoro-aristeromycin 7f is free of these potentially labile motifs but demonstrated reduced activity, with an increase in cytotoxicity; an indication that the methylene was not a tolerated replacement for the ribose oxygen.…”

Recent Advances in Molecular Mechanisms of Nucleoside Antivirals

“…Many reviews dealing with nucleoside antivirals were published. Recent examples are accounts on fluorinated nucleosides [ 10 , 11 ], 4′-modified nucleosides [ 12 ], oxetanocin [ 13 , 14 ], marketed nucleosides [ 15 ], antiviral nucleosides and analogues [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ], and the chemistry of nucleoside drugs [ 36 , 37 , 38 ]. However, these reviews predominantly consider chemical and structural aspects, with some discussion on the main nucleoside mechanisms of antiviral action [ 21 , 22 , 24 , 29 , 30 , 34 , 39 ].…”

Synthesis of gem-Difluorinated 2,3-Dihydrobenzofurans Using Freon-22 via [4 + 1] Annulation of Difluorocarbene and Antitumor Activity Evaluation

“…D ue to the fluorine atom's unique combination of strong electronegativity, small atomic radius (similar to the hydrogen atom), and high dissociation energy of the C−F bond, gem-difluoromethyl-containing compounds have found widespread applications in life sciences, materials, agrochemicals, and magnetic resonance imaging ( 19 F MRI). 1 Additionally, the CF 2 motif is frequently utilized in designing lead compounds for medicinal chemistry because it can serve as a bioisostere of carbonyl or ether units, which enhances the metabolic stability and lipophilicity of drug molecules. 2 As a result, many effective methods have been developed to directly incorporate a CF 2 motif into organic molecules through nucleophilic, electrophilic, carbene, and free radical difluoromethylation pathways.…”