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Abstract Details
Design, synthesis, and evaluation of liver-specific gemcitabine prodrugs for potential treatment of hepatitis C virus infection and hepatocellular carcinoma
Eur J Med Chem. 2021 Jan 5;213:113135. doi: 10.1016/j.ejmech.2020.113135.Online ahead of print.
Anthony A Stephenson1, Sheng Cao2, David J Taggart2, Vinod P Vyavahare2, Zucai Suo3
Author information
1Department of Biochemistry, The Ohio State University, Columbus, OH, 43210, USA; The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH, 43210, USA.
2Department of Biochemistry, The Ohio State University, Columbus, OH, 43210, USA.
3Department 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 Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, 32306, USA. Electronic address: zucai.suo@med.fsu.edu.
Abstract
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-NH2 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 IC50 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.