Author:
Abdi Khosrou,Khalaj Ali,Ostad Seyed Nasser,Lamei Navid,Khoshayand Mohammad Reza
Abstract
Abstract
Background and the purpose of the study
Several 2, 4-dinitrophenyl and 2,4-dinitrophenylamine tethered 5-FU (5-fluorouracil) compared to their components have shown minimal or no cytotoxicity to HT-29 cell line under aerobic conditions but high cytotoxicity and radiosensitizing effects under hypoxic conditions. In the present study the cytotoxicity and radiation potentiation of three novel analogues of these compounds by replacing 2,4-dinitrophenyl moiety with 2-methyl-5-nitroimidazole, a known radiosensitizer and cytotoxic agent was investigated.
Methods
Tethered compounds 7–9 were prepared by the reaction of 1-(t-butoxycarbonyl)-5-fluorouracil 6 with metronidazole esters 2–4 followed by removal of the t-butoxycarbonyl protecting group. Cytotoxicity of compounds in HT-29 cells with or without radiation were determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), propidium iodide (PI)-digitonin and clonogenic assays.
Results
Tethered compounds 7–9 induced time-and concentration–dependent cytotoxicity under hypoxia but had no significant effect under aerobic conditions. These compounds also showed selective and concentration- dependent radiosensitization effects under hypoxic conditions.
Conclusion
Tethered compounds 7–9 compared to 5-FU 5 showed minimal cytotoxicities under aerobic and selective radiosensitizing activities under hypoxic conditions. Also effects of these compounds were higher than those of metronidazole 1 which is a known cytotoxin and radiosensitizer under hypoxic conditions.
Publisher
Springer Science and Business Media LLC
Subject
Applied Mathematics,General Mathematics
Reference22 articles.
1. Nagasawa H, Uto Y, Kirk KL, Hori H: Design of hypoxia-targeting drugs as new cancer chemotherapeutics. Biol Pharm Bull. 2005, 29: 2335-2342.
2. Wardman P: Chemical radiosensitizers for use in radiotherapy. Clin Oncol. 2007, 19: 397-417. 10.1016/j.clon.2007.03.010.
3. Tao C, Desai NP, Soon-Shiong P, Sandford PA: Dual functional cytotoxic/radiosensitizer compounds and methods for the preparation thereof. PCT Int Appl WO 96 40,091. Chem Abstr. 1996, 126: 131664n-
4. Palmer BD, Wilson WR, Pullen SM, Denny WA: Hypoxia-selective antitumor agents. 5. Synthesis of water-soluble nitroaniline mustards with selective cytotoxicity for hypoxic mammalian cells. J Med Chem. 1990, 35: 3214-3222.
5. Parrick J, Porssa P, Davies LK, Dennis MF, Patel KB, Stratford MRK, Wardman P: Targeting radiosensitizers to DNA by minor groove binding: nitroarenes based on netropsin and distamycin. Bioorg Med Chem Lett. 1993, 3: 1697-1702. 10.1016/S0960-894X(00)80045-1.
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