Synthesis and anti-HIV activity of l-2′-fluoro-2′,3′-unsaturated purine nucleosides

Choi, Yongseok; Lee, Kyeong; Hong, Joon Hee; Schinazi, Raymond F.; Chu, Chung K.

doi:10.1016/s0040-4039(98)00841-7

Cited by 24 publications

(12 citation statements)

References 22 publications

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“…In a recent communication, we reported the preliminary results of adenine and hypoxanthine derivatives, in which β-L-2′-Fd4A showed moderately potent anti-HIV activity (EC 50 1.5 µM) in human peripheral blood mononuclear (PBM) cells. 18 Herein, we wish to report the full accounts of the synthesis and biological evaluation of the titled nucleosides.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anti-HIV and Anti-HBV Activities of 2‘-Fluoro-2‘,3‘-unsaturated l-Nucleosides

et al. 1999

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The synthesis of L-nucleoside analogues containing 2'-vinylic fluoride was accomplished by direct condensation method, and their anti-HIV and anti-HBV activities were evaluated in vitro. The key intermediate 8, the sugar moiety of our target compounds, was prepared from 1,2-O-isopropylidene-L-glyceraldehyde via (R)-2-fluorobutenolide intermediate 5 in five steps. Coupling of the acetate 8 with the appropriate heterocycles (silylated uracil, thymine, N4-benzoylcytosine, N4-benzoyl-5-fluorocytosine, 6-chloropurine, and 6-chloro-2-fluoropurine) in the presence of Lewis acid afforded a series of 2'-fluorinated L-nucleoside analogues (15-18, 23-26, 36-45). The newly synthesized compounds were evaluated for their antiviral activities against HIV-1 in human peripheral blood mononuclear (PBM) cells and HBV in 2.2.15 cells. Cytosine 23, 5-fluorocytosine 25, and adenine 36 derivatives exhibited moderate to potent anti-HIV (EC50 0.51, 0.17, and 1.5 microM, respectively) and anti-HBV (EC50 0.18, 0.225, and 1.7 microM, respectively) activities without significant cytotoxicity up to 100 microM in human PBM, Vero, CEM, and HepG2 cells.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Anti-HIV and Anti-HBV Activities of 2‘-Fluoro-2‘,3‘-unsaturated l-Nucleosides

et al. 1999

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“…), beginning from the L-glyceraldehyde derivative 542, using a similar synthetic route (via 543). 252,253 Besides the Chu group's method, another route to the 2 0 ,3 0 -dideoxy-2 0 ,3 0 -didehydro-2 0 -fluoro-L-nucleosides 544 (B¼T, A, 5-I- uracil, 5-F-cytosine) was also developed by Chen's group. 254 The noteworthy points of this new route included the stereospecific introduction of a phenylseleno moiety into the lactone 545 through treatment with LHMDS/N-(phenylseleno)phthalimide (N-PSP) and subsequent stereoselective fluorination of 546 with NFSI (Scheme 91).…”

Section: 0 -Monofluorinated Nucleosidesmentioning

confidence: 99%

Recent advances in the synthesis of fluorinated nucleosides

Qiu¹,

Xu²,

Qing³

2010

Tetrahedron

145

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“…The residue was purified by column chromatography on a silica gel (EtOAc:hexanes ) 1:100) to give 6 (13.5 g, 68%) as a pale yellow syrup: [R] 27 1, 128.9, 130.7 (t, J ) 252. 5 Hz),128.8,128.5,127.9,127.8,127.7,127.6,127.0,86.8,75.0,70.8,61 (-)-(2R,4R)-1,1-Difluoro-4-hydroxy-2-hydroxymethyl-cyclopentane (7). To a solution of 6 (12.7 g, 26.2 mmol) in anhydrous CH 2 Cl 2 (300 mL) was added iodotrimethylsilane (11.2 mL, 78.6 mmol) at -20°C.…”

Section: Anal Calcd For (C 32 H 30 O 3 ) C H (+)-(2r4r)-4-o-benmentioning

confidence: 99%

d- and l-2‘,3‘-Didehydro-2‘,3‘-dideoxy-3‘-fluoro-carbocyclic Nucleosides: Synthesis, Anti-HIV Activity and Mechanism of Resistance

et al. 2007

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Introducing 2'-fluoro substitution on the 2',3'-double bond in carbocyclic nucleosides has provided biologically interesting compounds with potent anti-HIV activity. As an extension of our previous works in the discovery of anti-HIV agents, D- and L-2',3'-unsaturated 3'-fluoro carbocyclic nucleosides were synthesized and evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. Among the synthesized L-series nucleosides, compounds 18, 19, 26 and 28 exhibited moderate antiviral activity (EC50 7.1 microM, 6.4 microM, 10.3 microM, and 20.7 microM, respectively), while among the D-series, the guanosine analogue (35, D-3'-F-C-d4G) exhibited the most potent anti-HIV activity (EC50 0.4 microM, EC90 2.8 microM). However, the guanosine analogue 35 was cross-resistant to the lamivudine-resistant variants (HIV-1M184V). Molecular modeling studies suggest that hydrophobic interaction as well as hydrogen-bonding stabilize the binding of compound 35 in the active site of wild type HIV reverse transcriptase (HIV-RT). In the case of L-nucleosides, these two effects are opposite which results in a loss of binding affinity. According to the molecular modeling studies, cross-resistance of D-3'-F-C-d4G (35) to M184V mutant may be caused by the realignment of the primer and template in the HIV-RTM184V interaction, which destabilizes the RT-inhibitor triphosphate complex, resulting in a significant reduction in anti-HIV activity of the D-guanine derivative 35.

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Synthesis and anti-HIV activity of l-2′-fluoro-2′,3′-unsaturated purine nucleosides

Cited by 24 publications

References 22 publications

Synthesis and Anti-HIV and Anti-HBV Activities of 2‘-Fluoro-2‘,3‘-unsaturated l-Nucleosides

Synthesis and Anti-HIV and Anti-HBV Activities of 2‘-Fluoro-2‘,3‘-unsaturated l-Nucleosides

Recent advances in the synthesis of fluorinated nucleosides

d- and l-2‘,3‘-Didehydro-2‘,3‘-dideoxy-3‘-fluoro-carbocyclic Nucleosides: Synthesis, Anti-HIV Activity and Mechanism of Resistance

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