Pig liver esterase (EC 3.1.1.1) catalysed regioselective hydrolysis of 1-(2,3,5-tri-O-acyl-β-D-arabinofuranosyl)uracil, -cytosine and -adenine to give the corresponding 2′-monoesters effectively and in high yield. This methodology enabled the preparation of 1-(2-O-acyl-β-D-arabinofuranosyl)-5-[(E)-(2-bromovinyl)]uracil prodrugs which, although slightly less active than the parent 1-(β-D-arabinofuranosyl)-5(E)-(2 bromovinyl)uracil (sorivudine; BV-araU), were strongly active in vitro against varicella-zoster virus (ED50 2.4–45 ng/ml). The retarded rates of enzymatic hydrolysis of the 2′-esters imply that they might function as lipophilic prodrugs, leading to increased plasma and cellular concentrations. In view of the marked in vitro activity, they represent an interesting approach to arabinofuranosyl nucleoside prodrugs with improved pharmacokinetics and enzymatic stability.
AlrabiahFA & SacksSL (1996) New antiherpesvirus agents. Drugs52:17–32.
2.
AyisiNWallRWanklinRMachidaHDe ClercqE & SacksSL (1987) Comparative metabolism of E-5-(2-bromovinyl)-2′-deoxyuridine and 1-β-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil in herpes simplex virus-infected cells. Molecular Pharmacology31:422–429.
3.
BakerDHaskellTHPuttS & SloanB (1979) Prodrugs of 9-(β-D-arabinofuranosyl)adenine. 2. Synthesis and evaluation of a number of 2′,3′- and 3′,5′-di-O-acyl derivatives. Journal of Medicinal Chemistry22:273–279.
4.
BaraldiPBazzaniniRManfrediniSSimoniD & RobinsM (1993) Facile access to 2′-O-acyl prodrugs of 1-(β-D-arabinofuranosyl)-5(E)-(2-bromovinyl)uracil (BVAraU) via regioselective esterase-catalyzed hydrolysis of 2′,3′,5′-triesters. Tetrahedron Letters34:3177–3180.
5.
BeranekJ & DrasarP (1977) Analogs of nucleosides. XIII. Selective O-acylation. Preparation of 1-(2,3,5-tri-O-acetyl-β-D-arabinopentofuranosyl)cytosine hydrochloride. Collection of Czechoslovak Chemical Communications42:366–369.
6.
BrownDToddA & VaradarajanS (1956) Nucleotides. Part XXXVII. The structure of uridilyc acids a and b, and a synthesis of spongouridine (3-β-D-arabynofuranosyl-uracil). Journal of the Chemical Society2388–2393.
7.
De ClercqE (1995) Trends in the developments of new antiviral agents for the chemotherapy of infections caused by herpesviruses and retroviruses. Reviews in Medical Virology5:149–164.
8.
HaskellT (1977) Relation of structure and antiviral activity of 9-β-D-arabinouranosyladenine analogs. Annals of the New York Academy of Sciences284:81–90.
9.
IshidoYSakairiNOkazakiK & NakazakiN (1980) Partial protection of carbohydrate derivatives. Part 4. Regioselective 2′-O-deacylation of fully acylated purine and pyrimidine ribonucleosides with hydroxylaminium acetate. Journal of the Chemical Society Perkin Transactions I563–573.
10.
KanoFIjichiKAshidaNWatanabeYSakataS & MachidaH (1994) 5′-O-Alkyl and acyl prodrugs of 1-β-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil. Antiviral Chemistry & Chemotherapy5: 74–82.
11.
KawaguchiTSuzukiYNambuN & NagaiT (1985) Specificity of esterases and structures of prodrug esters. III. Activity of rat tissue homogenates, rat plasma and porcine pig liver esterase for the hydrolysis of 3′,5′-bis-dicarboxylic acid hemiesters of 5-fluoro-2′-deoxyuridine. Chemical and Pharmaceutical Bulletin33:2956–2961.
12.
MachidaH & NishitaniN (1990) Drug susceptibilities of isolates of varicella zoster virus in a clinical study of oral brovavir. Microbiology & Immunology34:407–411.
13.
MachidaHNishitaniM & AshidaN (1994) Effect of BV-araU and acyclovir on varicella-zoster virus replication with various length and timing of drug exposure. Microbiology & Immunology38:109–115.
14.
MachidaHNishitaniMWatanabeYYoshimuraYKanoF & SakataS (1995) Comparison of the selectivity of anti-varicella-zoster virus nucleoside analogues. Microbiology & Immunology39:201–206.
15.
ManfrediniSSimoniDFerroniRBazzaniniRVertuaniSHatseSBalzariniJ & De ClercqE (1997) Retinoic acid conjugates as potential antitumor agents. Synthesis and biological activity of conjugates with ara-A, ara-C, the 3(2H) furanone and aniline mustard moieties. Journal of Medicinal Chemistry40: 3851–3857.
16.
PhilipG & JonesJ (1992) Dilemma regarding an active site model for porcine pancreatic lipase. Tetrahedron Letters112:1399–1402.
17.
RobinsMJ & ManfrediniS (1990) Conversion of vinylsilanes to vinylhalides with xenon difluoride and metal halides. A versatile new route to 5-(2-halovinyl)pyrimidine nucleosides. Tetrahedron Letters31:5633–5636.
18.
SinghHCoteG & SikorskiR (1993) Enzymatic regioselective deacylation of 2′,3′,5′-tri-O-acylribo-nucleosides: enzymatic synthesis of 2′,3′-di-O-acylribonucleosides. Tetrahedron Letters34:5201–5204.
19.
UemuraANozakiKYamashitaJ & YasumotoM (1989) Regioselective deprotection of 3′,5′-O-acylated pyrimidine nucleosides by lipase and esterase. Tetrahedron Letters30:3819–3823.
20.
WongC & WhitesidesG (editors) (1994) Use of hydrolytic enzymes. Enzymes in Synthetic Organic Chemistry, pp. 41–130. Oxford: Pergamon Press.
21.
ZhangW & RobinsM (1992) Removal of silyl protecting groups from hydroxyl functions with ammonium fluoride in methanol. Tetrahedron Letters33:1177–1180.
