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

Abstract

Background and the purpose of the studySeveral 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.MethodsTethered 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.ResultsTethered 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.ConclusionTethered 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.

The paradox role of caspase cascade in ionizing radiation therapy

“…Following irradiation, cancer cell death may occur mainly through necrosis, autophagy and apoptosis of which autophagy has more complex role and might promote cell survival [3–5]. IR prolongs patient’s survival through decreasing proliferative capacity and killing tumor cells [6–8]. However, re-population of tumor cells during or after radiotherapy is an important obstacle to achieve the desired response [9, 10].…”

“…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 of New Energetic Materials and Ionic Liquids Derived from Metronidazole

“…Apart from the potential uses of the compounds prepared herein as EMs, it is to be noted that compounds 2-6 would be worth screening for use as fungicides, antimicrobials, and enzyme inhibitors. A large number of metronidazole-derived compounds have been previously prepared by various groups seeking antimicrobial, antibacterial, or antiparasitic activity [29][30][31][32], as enzyme inhibitors [33,34] and as candidates for prodrug bioavailability and cytotoxicity studies [35,36]. The structure of azides 3 and 6 in particular suggests their transformation into potentially useful pharmacologically active substances by exploiting the rich chemistry of their organic azide functionality.…”