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.
Subject(s)
Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Deoxycytidine/analogs & derivatives , Hepatitis C/drug therapy , Liver Neoplasms/drug therapy , Prodrugs/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Deoxycytidine/chemical synthesis , Deoxycytidine/chemistry , Deoxycytidine/pharmacology , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Hepacivirus/drug effects , Humans , Liver Neoplasms/pathology , Microbial Sensitivity Tests , Molecular Structure , Prodrugs/chemical synthesis , Prodrugs/chemistry , Structure-Activity Relationship , Virus Replication/drug effects , GemcitabineABSTRACT
Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia. An alternative approach to minimize the risk of hypoglycemia is to use liver-directed GKAs, which are reported to be advancing well in clinical development. Here, we report the discovery and structure-activity relationship (SAR) studies on a novel 2-phenoxy-acetamide series with the aim of identifying a liver-directed GKA. Incorporation of a carboxylic acid moiety as an active hepatocyte uptake recognizing element at appropriate position of 2-phenoxy-acetamide core led to the identification of 26, a potent GKA with predominant liver-directed pharmacokinetics in mice. Compound 26 on oral administration significantly reduced blood glucose levels during an oral glucose tolerance test (oGTT) performed in diet-induced obese (DIO) mice, while showing no sign of hypoglycemia in normal C57 mice over a 10-fold dose range, even when dosed at fasted condition. Together, these data demonstrate a liver-directed GKA has beneficial effect on glucose homeostasis with reduced risk of hypoglycemia.
Subject(s)
Enzyme Activators/chemistry , Enzyme Activators/pharmacology , Glucokinase/metabolism , Hyperglycemia/drug therapy , Hypoglycemia/chemically induced , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Animals , Blood Glucose/metabolism , Cells, Cultured , Enzyme Activators/adverse effects , Enzyme Activators/pharmacokinetics , Humans , Hyperglycemia/blood , Hyperglycemia/metabolism , Hypoglycemia/blood , Hypoglycemia/metabolism , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/pharmacokinetics , Liver/drug effects , Liver/metabolism , Mice, Obese , Molecular Docking Simulation , RatsABSTRACT
Two new C-1 epimeric hydroxymethyl castanospermine congeners 2a and 2b, synthesized by stereocontrolled intramolecular double reductive amination of D-glucose derived beta-keto ester as a key step, showed impressive immuno-potentiating property. The bioactivity was mediated through up-regulation of T(H1)/T(H2) cytokine ratio. The finding suggested that immunmodulatory activity of polyhydroxylated indolizidine alkaloids can be tuned by minor structural/stereochemical alterations.