title: Synthesis, in vitro cytotoxicity and radiosensitizing activity of novel 3-[(2,4-dinitrophenylamino)alkyl] derivatives of 5-fluorouracil.
abstract: Previously, it was reported that 3[3-(2,4-dinitrophenylamino)-propyl]-5-fluorouracil 8c unlike its components 5-fluorouracil (5-FU) 6 and 2,4-dinitroaniline 2 in HT-29 cells under aerobic conditions had no cytotoxicity but showed radiosensitizing activity. In this study several analogues of 8c differing in the number of linking methylene groups were prepared and tested for in vitro cytotoxicity and radiosensitizing activity under both aerobic and hypoxic conditions. Tethered compound 8a was prepared in one pot by the reaction of 5-FU 6 with paraformaldehyde and 2,4-dinitroaniline 2 in the presence of the concentrated hydrochloric acid, and compounds 8b-f were prepared by the reaction of N-(bromoalkyl)-2,4-dinitrobenzeneamines 5b-f with 1-(t-butoxycarbonyl)-5-fluorouracil 7 followed by hydrolysis of the protecting group. The cytotoxicity of the tested compounds were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and propidium iodide (PI)-digitonin assays and values of sensitization enhancement ratio (SER) as a measure of the radiosensitizing activity were measured from radiation survival curves in the absence and presence of each sensitizer for 37% survival respectively. Results showed that tethered compounds 8a-f induced time- and concentration-dependent cytotoxicity under hypoxia but had no significant effect under aerobic conditions. These compounds also showed selective and concentration-dependent radiocytotoxicity under hypoxic conditions.
authors: Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Drug Design & Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors: Ali
authors: A
authors: Khalaj
authors: Khosrou
authors: K
authors: Abdi
authors: Seyed Nasser
authors: SN
authors: Ostad
authors: Mohammad Reza
authors: MR
authors: Khoshayand
authors: Navid
authors: N
authors: Lamei
authors: Hasan Ali
authors: HA
authors: Nedaie
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D005472:Fluorouracil / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D005720:Gamma Rays; D019073:HT29 Cells; D006801:Humans; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D011838:Radiation-Sensitizing Agents; C010934:2,4-dinitroaniline; D005472:Fluorouracil
keywords: 2,4-dinitrophenylamine; 5-fluorouracil; HT-29 cell line; Radiosensitizing; Tethered compounds