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.

The paradox role of caspase cascade in ionizing radiation therapy

“…Nitoaromatic and nitroheterocyclic compounds act as radiosensitizers by formation of nitro-anion radicals like oxygen. The synthesis and in vitro cytotoxicity of several dinitrophenyl derivatives of 5-fluorouracil [69, 70], 3-[(2,4-dinitrophenylamino)alkyl] derivatives of 5-fluorouracil [71], metronidazole tethered 5-fluorouracil [72] as radiosensitizers have been described. These compounds had little or no aerobic cytotoxicity while showed high cytotoxicity and radiosensitizing effect under hypoxic conditions.…”

Synthesis, in vitro aerobic and hypoxic cytotoxicity and radiosensitizing activity of novel metronidazole tethered 5-fluorouracil

“…In continuation of our investigations on this type of bifunctional compounds [ 8 - 11 ] in the present study the cytotoxicity and radiosensitization effects of three novel analogues of these compounds by replacing 2,4-dinitrophenyl moiety with 2-methyl-5-nitroimidazole (metronidazole), a known radiosensitizer and cytotoxic agent [ 2 , 12 ] was investigated. This manuscript describes cytotoxicities and radiosensitizing activities of metronidazole tethered 5-FU through ethyl and labile ester groups which was hypothesized upon in vivo hydrolysis to generate active metabolites which might have synergistic actions.…”