Department of Biochemistry, The Ohio State University, Columbus, OH, 43210, USA; The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH, 43210, USA.
Department of Biochemistry, The Ohio State University, Columbus, OH, 43210, USA.
Eur J Med Chem. 2021 Mar 5;213:113135. doi: 10.1016/j.ejmech.2020.113135. Epub 2021 Jan 5.
Many successful anti-viral and anti-cancer drugs are nucleoside analogs, which disrupt RNA and/or DNA synthesis. Here, we present liver-specific prodrugs of the chemotherapy drug gemcitabine (2',2'-difluorodeoxycytidine) for the treatment of hepatitis C virus (HCV) infection and hepatocellular carcinoma. The prodrugs were synthesized by introducing aromatic functional moieties to the cytosine 4-NH group of gemcitabine via amide bonds. The chemical modification was designed to i) enable passive diffusion across cellular membrane, ii) protect the prodrugs from inactivating deamination by cellular enzymes, and iii) allow release of active gemcitabine after amide hydrolysis by high levels of carboxylesterases in the liver. We found that many of our prodrugs exhibited similar toxicity as gemcitabine toward liver- and kidney-derived cancer cell lines but were 24- to 620-fold less cytotoxic than gemcitabine in breast- and pancreas-derived cancer cells, respectively. The prodrugs also inhibited an HCV replicon with IC values ranging from 10 nM-1.7 μM. Moreover, many of the prodrugs had therapeutic index values of >10,000 and have synergetic effects when combined with other Food and Drug Administration-approved anti-HCV small molecule drugs. These characteristics support the development of gemcitabine prodrugs as liver-specific therapeutics.
许多成功的抗病毒和抗癌药物是核苷类似物，它们会破坏 RNA 和/或 DNA 的合成。在这里，我们提出了用于治疗丙型肝炎病毒 (HCV) 感染和肝细胞癌的化疗药物吉西他滨 (2',2'-二氟脱氧胞苷) 的肝特异性前药。这些前药是通过酰胺键将芳香官能团引入吉西他滨的胞嘧啶 4-NH 基团来合成的。这种化学修饰旨在：i) 能够被动扩散穿过细胞膜；ii) 保护前药免受细胞酶失活的脱氨作用；iii) 允许在肝脏中高水平的羧酸酯酶作用下酰胺水解后释放出活性吉西他滨。我们发现，我们的许多前药对肝和肾来源的癌细胞系的毒性与吉西他滨相似，但对乳腺和胰腺来源的癌细胞的细胞毒性分别低 24 至 620 倍。这些前药还抑制 HCV 复制子，IC 值范围为 10 nM-1.7 μM。此外，许多前药的治疗指数值>10,000，并且与其他已获得美国食品和药物管理局批准的抗 HCV 小分子药物联合使用时具有协同作用。这些特性支持将吉西他滨前药开发为肝特异性治疗药物。
