Manfredini S, Baraldi P G, Bazzanini R, Bortolotti F, Vertuani S, Ashida N, Machida H
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Italy.
Antivir Chem Chemother. 1998 Jan;9(1):25-31. doi: 10.1177/095632029800900103.
Pig liver esterase (EC 3.1.1.1) catalysed regioselective hydrolysis of 1-(2,3,5-tri-O-acyl-beta-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-beta-D-arabinofuranosyl)-5-[(E)-(2-bromovinyl)]uracil prodrugs which, although slightly less active than the parent 1-(beta-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.
猪肝酯酶（EC 3.1.1.1）能催化1-(2,3,5-三-O-酰基-β-D-阿拉伯呋喃糖基)尿嘧啶、-胞嘧啶和-腺嘌呤进行区域选择性水解，高效且高产率地生成相应的2'-单酯。该方法使得1-(2-O-酰基-β-D-阿拉伯呋喃糖基)-5-[(E)-(2-溴乙烯基)]尿嘧啶前药得以制备，这些前药虽然活性略低于母体1-(β-D-阿拉伯呋喃糖基)-5-(E)-(2-溴乙烯基)尿嘧啶（索立夫定；BV-araU），但在体外对水痘带状疱疹病毒具有很强的活性（半数有效浓度为2.4 - 45纳克/毫升）。2'-酯的酶促水解速率较慢，这意味着它们可能作为亲脂性前药发挥作用，从而提高血浆和细胞内浓度。鉴于其显著的体外活性，它们代表了一种制备具有改善药代动力学和酶稳定性的阿拉伯呋喃糖核苷前药的有趣方法。
