X.Z. Fu et al. / Chinese Chemical Letters 22 (2011) 1387–1390
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Table 1
Anti-HBV evaluation of mono (2, 2, 2-trifluoroethyl) esters, mono L-amino acid ester prodrugs of acyclic nucleoside phosphonates.
Compoundsa
SId
b
EC50 (mmol/L)
c
CC50 (mmol/L)
1a
1b
11.40
4.95
3.02
0.01
0.69
3.13
0.43
1030
>8000
2940
90.35
>1616
973
>8 Â 105
>11,594
1021
1c
1d
>8000
>8000
3170
1e
MCC-478
Adefovir dipivoxil
610
1400
a
Obtained as hydrochloride salts.
b
Concentrations of compounds achieving 50% inhibition of cytoplasmic HBV-DNA synthesis.
Concentrations of compounds required for 50% extinction of HepG2 2.2.15 cells.
c
d
Selective index CC50/EC50
.
and incubated for 2 h at 37 8C. At the end of the incubation period, the supernatant was removed and 150 mL DMSO
was added to each well to dissolve the formazan. The OD value was measured at 570 nm. The data was analyzed using
Icycler IQ 3.0. EC50, CC50 and SI of these compounds are reported in Table 1. Adefovir dipivoxil and alamifovir
(MCC-478) were used as positive controls.
As indicated in Table 1, all synthesized compounds [16] exhibited potent anti-HBV activity with EC50 values of
0.01–11.40 mmol/L and lower cytotoxicities with CC50 values of 1030 to >8000 mmol/L compared with those of
adefovir dipivoxil and MCC-478. Compound 1d and 1e exhibited more potent anti HBV activity than alamifovir
(MCC-478) with EC50 values of 0.01 and 0.69 mmol/L respectively, especially compound 1d exhibited more potent
anti-HBV activity than adefovir dipivoxil with EC50 values of 0.01 mmol/L. The preliminary SAR research revealed
that the compounds with 4-methoxy phenylthio substitution at 6-position of purine ring 1c, 1d and 1e showed higher
anti-HBVactivity than that of the corresponding compounds with cyclopropylamine substitution at the same position
1a, 1b. In addition, respective comparisons of 1a with 1b, and 1c with 1d, 1e indicated that compounds with larger bulk
of the amino acid alkyl group, 1b, 1d and 1e, showed higher anti-HBV activity and SI than that of the corresponding
compounds 1a and 1c with smaller bulk of amino acid alkyl group. All these results suggested that mono (2, 2, 2-
trifluoroethyl) esters, mono L-amino acid ester prodrugs of acyclic nucleoside phosphonates are worthy of further
investigation to discover new anti-HBV agents.
Acknowledgments
This work was supported by the grants from the National Natural Science Foundation of China (No. 20962004), the
Provincial Social Development Foundation of Guizhou, China (No. QKHSYZ [2009] 3081), Provincial Special
Assistant Foundation for High-level Talents of Guizhou, China (No. TZJF-2009-36), and Science and Technology
Foundation of Guizhou Province, China (No. QKHJZ [2008] 2140).
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