title: Synthesis, Characterization, and In Vitro and In Vivo Evaluations of 4-(N)-Docosahexaenoyl 2', 2'-Difluorodeoxycytidine with Potent and Broad-Spectrum Antitumor Activity.
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.
authors.affiliation: Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712.
authors.forename: Youssef W
authors.initials: YW
authors.lastname: Naguib
authors.affiliation: Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712.
authors.forename: Dharmika
authors.initials: D
authors.lastname: Lansakara-P
authors.affiliation: Department of Nutritional Sciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX 78712.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Lashinger
authors.affiliation: Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712.
authors.forename: B Leticia
authors.initials: BL
authors.lastname: Rodriguez
authors.affiliation: Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712.
authors.forename: Solange
authors.initials: S
authors.lastname: Valdes
authors.affiliation: Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Niu
authors.affiliation: Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712.
authors.forename: Abdulaziz M
authors.initials: AM
authors.lastname: Aldayel
authors.affiliation: Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Lan
authors.initials: L
authors.lastname: Peng
authors.affiliation: Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hursting
authors.affiliation: Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712. Electronic address: zhengrong.cui@austin.utexas.edu.
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Cui
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002152:Calorimetry, Differential Scanning; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D012995:Solubility; D014961:X-Ray Diffraction; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine