Synthesis and biological properties of novel phosphotriesters: a new approach to the introduction of biologically active nucleotides into cells.
A series of aryl bis(3'-O-acetylthymidin-5'-yl) phosphate derivatives have been synthesized in order to find a suitable aryl derivative which would hydrolyze to the bis(nucleosid-5'-yl) phosphate under physiological conditions. The 4-(methylsulfonyl)phenyl derivative was selected and 4-(methylsulfonyl)phenyl bis[(E)-5-(2-bromovinyl)-2'-deoxyuridin-5'-yl] phosphate (6d) and bis[2-(guanin-9-ylmethoxy)ethoxy]-4-(methylsulfonyl)phenyl phosphate (7b) were prepared. The former compound (6d) was stable in human serum and only following hydrolysis to the 5'-5'-linked diester (half-life of 17 h at pH 7.7) was it enzymatically degraded very rapidly by phosphodiesterases. Compounds 6d and 7b were evaluated for antiherpesvirus effects, both in vitro and in vivo. Their antiviral spectrum and potency was remarkably similar to that of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and 9-[(2-hydroxyethoxy)-methyl]guanine (ACV), suggesting that they only act as prodrugs of BVDU and ACV, respectively. However, compound 6d did show unexpected toxicity, which could be explained by the liberation of BVDUMP following penetration of the triester into the cell.
Farrow
S N
SN
Chemistry Department, University of Birmingham, Great Britain.
Jones
A S
AS
Kumar
A
A
Walker
R T
RT
Balzarini
J
J
De Clercq
E
E
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis*; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D003856:Deoxyuracil Nucleotides / Q000138:chemical synthesis* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis / Q000627:therapeutic use; D011817:Rabbits; D013329:Structure-Activity Relationship; D014777:Virus Diseases / Q000188:drug therapy
D000998:Antiviral Agents; D003856:Deoxyuracil Nucleotides; D011355:Prodrugs; C063789:bis(2-(guanin-9-ylmethoxy)ethoxy)-4-(methylsulfonyl)phenyl phosphate; C063788:4-(methylsulfonyl)phenyl bis(5-(2-bromovinyl)-2'-deoxyuridin-5-yl)phosphate; D000212:Acyclovir