title: Design and synthesis of novel bis(L-amino acid) ester prodrugs of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) with improved anti-HBV activity.
abstract: A series of novel bis(L-amino acid) ester prodrugs of 9-[2-(phosphonomethoxy)ethyl] adenine (PMEA) was synthesized and their anti-HBV activity was evaluated in HepG 2 2.2.15 cells. Compounds 11, 12, 21, 22, 26, and 27 demonstrated more potent anti-HBV activity and higher selective index (SI) than adefovir dipivoxil, which was used as a positive control. Compound 11, which was found to be the most potent one, was five times more potent than adefovir dipivoxil with EC50 value of 0.095 microM and CC50 value of 6636 microM. The SI value (>69,000) of compound 11 was 60 times and 24 times higher than those of adefovir dipivoxil and lamivudine, respectively. In vitro stability studies showed that compound 11 was relatively more stable than adefovir dipivoxil with t1/2 of 270 min. These findings suggested that compound 11 could be considered as a promising candidate for further in vivo studies.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Science, Shanghai 201203, China.
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Fu
authors.forename: Saihong
authors.initials: S
authors.lastname: Jiang
authors.forename: Chuan
authors.initials: C
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Xin
authors.forename: Yushe
authors.initials: Y
authors.lastname: Yang
authors.forename: Ruyun
authors.initials: R
authors.lastname: Ji
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D006207:Half-Life; D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D007202:Indicators and Reagents; D063065:Organophosphonates; D011355:Prodrugs; C053001:adefovir; D000225:Adenine