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OU Yu, FU Xiaozhong, ZHA Yufeng, ZHANG Shun, SU Hang, DONG Yongxi. Synthesis and biological evaluation of mixed phosphonate derivatives of substituted acyclonucleoside phosphonates[J]. Journal of China Pharmaceutical University, 2014, 45(6): 649-656. DOI: 10.11665/j.issn.1000-5048.20140605
Citation: OU Yu, FU Xiaozhong, ZHA Yufeng, ZHANG Shun, SU Hang, DONG Yongxi. Synthesis and biological evaluation of mixed phosphonate derivatives of substituted acyclonucleoside phosphonates[J]. Journal of China Pharmaceutical University, 2014, 45(6): 649-656. DOI: 10.11665/j.issn.1000-5048.20140605
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Synthesis and biological evaluation of mixed phosphonate derivatives of substituted acyclonucleoside phosphonates

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  • In order to find structural optimization strategy for substituted mixed phosphonates of acyclonucleoside phosphonates, mono L-amino acid ester, mono NSAID carboxylic ester prodrugs of adefovir was used as lead compound. Based on the structural features of abacavir and alamifovir, sub-structure combination method was used to introduce substituted phenylthio or amino fragments at 6-position of purine ring. Therefore, purine ring substituted acyclonucleside phosphonate mixed phosphonate ester derivatives( 9a-9l )were designed and synthesized, and their structures were confirmed by 1H NMR, ESI-MS, and ESI-HRMS. HepG2. 2. 2. 15 and HK-2 cell line were used for in vitro anti-HBV activity and renal cell toxicity evaluation models, respectively. Several compounds exhibited anti-HBV activity, of which compound 9a displayed the most potent antiviral activity with higher selectivity index(EC50 0. 48 μmol/L, SI 763. 72), lower renal cell toxicity, and higher chemical and enzymatic stability, making it a potential anti-HBV candidate for further investigation.
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