Reshaping an Acyclic Nucleoside Phosphonate into a Selective Anti-hepatitis B Virus Compound

Minor structural modifications of
acyclic nucleoside phosphonates
can dramatically affect their antiviral properties. This work discloses
a shift in the selectivity spectrum of 3-hydroxy-2-(phosphonomethoxy)­propyl
(HPMP) nucleotides from herpesviruses toward hepatitis B virus (HBV)
induced by their acyclic chain 2-substitution with a nonpolar group.
Two series of racemic (R,S)-2-methyl-3-hydroxy-2-(phosphonomethoxy)­propyl
(MHPMP) and (R,S)-2-ethynyl-3-hydroxy-2-(phosphonomethoxy)­propyl
(EHPMP) nucleotides were initially synthesized. Among these, guanine-containing
derivatives exhibited significant anti-HBV activities in the submicromolar
range. Enantioenriched MHPMPG and EHPMPG analogues were subsequently
obtained by Sharpless asymmetric epoxidation. The (S)-enantiomers possessed an 8- to 26-fold higher potency than the
relative (R)-forms. A further comparison of the EC90 values indicated that (S)-EHPMPG inhibited
HBV replication more effectively than its 2-methyl analogue. A phosphonodiamidate
prodrug of (S)-EHPMPG was thus prepared and found
to exert a remarkably high anti-HBV activity (EC50 = 9.27
nM) with excellent selectivity (SI50 > 10,787), proving
to be a promising candidate for anti-HBV drug development.