Synthesis, Characterization, and In Vitro and In Vivo Evaluations of 4-(N)-Docosahexaenoyl 2', 2'-Difluorodeoxycytidine With Potent and Broad-Spectrum Antitumor Activity

Neoplasia. 2016 Jan;18(1):33-48. doi: 10.1016/j.neo.2015.11.012.

Abstract

In this study, a new compound, 4-(N)-docosahexaenoyl 2', 2'-difluorodeoxycytidine (DHA-dFdC), was synthesized and characterized. Its antitumor activity was evaluated in cell culture and in mouse models of pancreatic cancer. DHA-dFdC is a poorly soluble, pale yellow waxy solid, with a molecular mass of 573.3Da and a melting point of about 96°C. The activation energy for the degradation of DHA-dFdC in an aqueous Tween 80-based solution is 12.86kcal/mol, whereas its stability is significantly higher in the presence of vitamin E. NCI-60 DTP Human Tumor Cell Line Screening revealed that DHA-dFdC has potent and broad-spectrum antitumor activity, especially in leukemia, renal, and central nervous system cancer cell lines. In human and murine pancreatic cancer cell lines, the IC50 value of DHA-dFdC was up to 10(5)-fold lower than that of dFdC. The elimination of DHA-dFdC in mouse plasma appeared to follow a biexponential model, with a terminal phase t1/2 of about 58minutes. DHA-dFdC significantly extended the survival of genetically engineered mice that spontaneously develop pancreatic ductal adenocarcinoma. In nude mice with subcutaneously implanted human Panc-1 pancreatic tumors, the antitumor activity of DHA-dFdC was significantly stronger than the molar equivalent of dFdC alone, DHA alone, or the physical mixture of them (1:1, molar ratio). DHA-dFdC also significantly inhibited the growth of Panc-1 tumors orthotopically implanted in the pancreas of nude mice, whereas the molar equivalent dose of dFdC alone did not show any significant activity. DHA-dFdC is a promising compound for the potential treatment of cancers in organs such as the pancreas.

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / chemical synthesis
  • Antimetabolites, Antineoplastic / chemistry*
  • Antimetabolites, Antineoplastic / pharmacology*
  • Calorimetry, Differential Scanning
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / chemical synthesis
  • Deoxycytidine / chemistry
  • Deoxycytidine / pharmacology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Stability
  • Female
  • Humans
  • Mice
  • Mice, Transgenic
  • Solubility
  • X-Ray Diffraction
  • Xenograft Model Antitumor Assays

Substances

  • Antimetabolites, Antineoplastic
  • Deoxycytidine
  • gemcitabine