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

Youssef W. Naguib, Dharmika Lansakara-P., Laura M. Lashinger, B. Leticia Rodriguez, Solange Valdes, Mengmeng Niu, Abdulaziz M. Aldayel, Lan Peng, Stephen D. Hursting, Zhengrong Cui

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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 573.3 Da 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 12.86 kcal/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 105-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 58 minutes. 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.

Original languageEnglish (US)
Pages (from-to)33-48
Number of pages16
JournalNeoplasia
Volume18
Issue number1
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Cancer Research
  • Medicine(all)

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    Naguib, Y. W., Lansakara-P., D., Lashinger, L. M., Rodriguez, B. L., Valdes, S., Niu, M., Aldayel, A. M., Peng, L., Hursting, S. D., & Cui, Z. (2016). Synthesis, Characterization, and In Vitro and In Vivo Evaluations of 4-(N)-Docosahexaenoyl 2', 2'-Difluorodeoxycytidine with Potent and Broad-Spectrum Antitumor Activity. Neoplasia, 18(1), 33-48. https://doi.org/10.1016/j.neo.2015.11.012