氮杂环卡宾衍生物与4'-氟尿苷前药的合成及评价

Synthesis and evaluation of NHC derivatives and 4'-fluorouridine prodrugs.

作者信息

Xiang Li, Hu Tianwen, Xue Haitao, Pan Wenfang, Xie Yuanchao, Shen Jingshan

机构信息

School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.

出版信息

Org Biomol Chem. 2023 Mar 29;21(13):2754-2767. doi: 10.1039/d3ob00268c.

DOI:10.1039/d3ob00268c

PMID:36917467

Abstract

β-D-N-Hydroxycytidine (NHC) derivatives with structural modifications at the C', O' or C position and 4'-fluorouridine prodrugs were synthesized and evaluated for their antiviral activities against respiratory syncytial virus (RSV) or influenza virus (IFV) . The NHC derivatives were found inactive, but 4'-fluorouridine and its prodrugs had potent anti-RSV and anti-IFV activities. 4'-Fluorouridine was proved to be a nucleoside with poor stability, but the tri-ester prodrugs exhibited enhanced stability, especially tri-isobutyrate ester 1a. This prodrug also showed excellent oral pharmacokinetic properties in rats, with potential to be an oral antiviral candidate.

摘要

合成了在C'、O'或C位置有结构修饰的β-D-N-羟基胞苷（NHC）衍生物以及4'-氟尿苷前药，并评估了它们对呼吸道合胞病毒（RSV）或流感病毒（IFV）的抗病毒活性。发现NHC衍生物无活性，但4'-氟尿苷及其前药具有强效的抗RSV和抗IFV活性。事实证明4'-氟尿苷是一种稳定性较差的核苷，但三酯前药表现出更高的稳定性，尤其是三异丁酸酯1a。这种前药在大鼠中还表现出优异的口服药代动力学特性，有潜力成为一种口服抗病毒候选药物。