%0 Journal Article
%T Synthesis, Characterization, and In Vitro and In Vivo Evaluations of 4-(N)-Docosahexaenoyl 2¡ä, 2¡ä-Difluorodeoxycytidine with Potent and Broad-Spectrum Antitumor Activity
%A Abdulaziz M. Aldayel
%A B. Leticia Rodriguez
%A Dharmika Lansakara-P.
%A Lan Peng
%A Laura M. Lashinger
%A Mengmeng Niu
%A Solange Valdes
%A Stephen D. Hursting
%A Youssef W. Naguib
%A Zhengrong Cui
%J Archive of "Neoplasia (New York, N.Y.)".
%D 2016
%R 10.1016/j.neo.2015.11.012
%X In this study, a new compound, 4-(N)-docosahexaenoyl 2¡ä, 2¡ä-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¡ãC. The activation energy for the degradation of DHA-dFdC in an aqueous Tween 80¨Cbased 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
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965255/