Stereoselective Synthesis and Biological Evaluations of Novel 3′-Deoxy-4′-azaribonucleosides as Inhibitors of Hepatitis C Virus RNA Replication

Abstract

3′-Deoxy-4′-azaribonucleosides (15a-d) were synthesized starting from the commercially available (4R)-trans-4-hydroxy-L-proline 7. From biological evaluations, 15b and 15d emerged as potent inhibitors of HCV replication on a replicon assay. These findings demonstrate that synthesized pyrrolidine nucleosides represent a new template for antiviral or other biological studies and could be considered for novel combination therapy against HCV infection using nucleoside inhibitors and non-nucleoside inhibitors of HCV NS5B.

Truncated phosphonated C-1′-branched N,O-nucleosides: A new class of antiviral agents

“…[17][18][19][20][21][22] Following intracellular phosphorylation to their 5 0 -triphosphate forms, they are able to serve as chain terminators, thus acting as inhibitors in the viral reverse transcription reaction. 18,19 Several strategies to overcome the initial selective phosphorylation step have been designed; 23 in particular, phosphonate analogues, 20 by miming the nucleoside monophosphates, overcome the instability of nucleotides towards phosphodiesterase and enhance the cellular uptake by bypassing the initial phosphorylation step.…”

Synthesis by microwave-assisted 1,3-dipolar cycloaddition of 1,2,3-triazole 1′-homo-3′-isoazanucleosides and evaluation of their anticancer activity

“…Compound (±)-2 (0.31 g, 88%) was isolated as a colourless oil after removal of the solvent. IR (film): 3408, 2976IR (film): 3408, , 2100IR (film): 3408, , 1743IR (film): 3408, , 1681IR (film): 3408, , 1454IR (film): 3408, , 1392IR (film): 3408, , 1365IR (film): 3408, , 1198IR (film): 3408, , 1168IR (film): 3408, , 1137 13 Ethynylbenzene (39.0 mg, 0.042 mL, 0.38 mmol), CuI (3.05 mg, 0.016 mmol) and DIEA (0.11 mL, 0.64 mmol) were added to a solution of azide ester (±)-2 (100 mg, 0.32 mmol) in toluene (3.5 mL) and tert-butanol (1 mL) under argon. The reaction mixture was stirred at 70 C for 22 h. The solvents were removed under reduced pressure to afford a solid residue (130 mg), which was purified by column chromatography on silica gel, hexane/EtOAc (1:1) as eluent.…”

“…13 Compound (±)-6 was prepared using the general procedure described above, by reaction of the azide (±)-2 (50 mg, 0.16 mmol) and 1-ethynyl-2-nitrobenzene (26 mg, 0.18 mmol) for 160 min at 70 C and 100 W. The standard work-up procedure and separation by column chromatography (silica gel, hexane/EtOAc 1:1) gave (±)-6 as a low melting orange solid (28 mg, 38%). IR (solid): 3384, 2978IR (solid): 3384, , 2926IR (solid): 3384, , 1743IR (solid): 3384, , 1682IR (solid): 3384, , 1528IR (solid): 3384, , 1456IR (solid): 3384, , 1392IR (solid): 3384, , 1364IR (solid): 3384, , 1252IR (solid): 3384, , 1166IR (solid): 3384, , 1134IR (solid): 3384, , 1046 Compound (±)-7 was prepared using the general procedure described above, by reaction of the azide (±)-2 (50 mg, 0.16 mmol) and 3-ethynylaniline (20.49 mg, 18 mL, 0.18 mmol) for 45 min at 90 C and 100 W. The standard work-up procedure and separation by column chromatography (silica gel, hexane/EtOAc 1:12) gave (±)-5 as a brownish solid (58 mg, 84%), mp 68e70 C. IR (solid): 3447, 3358, 2922IR (solid): 3447, 3358, , 1740IR (solid): 3447, 3358, , 1682IR (solid): 3447, 3358, , 1614IR (solid): 3447, 3358, , 1590IR (solid): 3447, 3358, , 1455IR (solid): 3447, 3358, , 1365IR (solid): 3447, 3358, , 1252IR (solid): 3447, 3358, , 1167IR (solid): 3447, 3358, , 1134IR (solid): 3447, 3358, , 1045 4.4.5.…”

“…Furthermore, 3 0 -deoxy-4 0 -azaribonucleosides have recently shown significant anti-HCV [13] activity and preliminary biological assays on truncated phosphonated C-1 0 -branched N,O-nucleosides show that these systems are able to inhibit HIV infection in vitro [14].…”

β-Cyclodextrin-grafted on multiwalled carbon nanotubes as versatile nanoplatform for entrapment of guanine-based drugs

“…Although different synthetic procedures have been proposed to obtain cyclodextrin grafted-CNT [15][16][17][18][19][20], at the best of our knowledge, no data are available regarding the effectiveness of ␤-CD-CNT covalently conjugates as delivery system able to sustain the release of small drugs. Our ongoing programme is aimed for the discovery of new antiviral drugs [21][22][23][24][25][26], with enhanced therapeutic efficiency and reduced unwanted side effects. In this direction our interest was focused on the synthesis of a new nanocarrier-based delivery system for the multimodal anchorage of antiviral drugs.…”