Cytotoxicity and radiosensitising activity of synthesized dinitrophenyl derivatives of 5-fluorouracil
Journal Title: DARU Journal of Pharmaceutical Sciences - Year 2012, Vol 20, Issue 0
Abstract
Dual functional agents in which nitroaromatic or nitroheterocyclic compounds are attached through a linker unit to mustards and aziridines have shown higher cytotoxicities than the corresponding counterparts to both aerobic and hypoxic cells and enhanced radiosensitizing activity. In the present investigation cytotoxicity and radiosensitizing activity of 2,4-dinitrobenzyl, 2,4-dinitrobenzoyl, and 2,4-dinitrophenacetyl derivatives of 5-fluorouracil which was assumed to release cytotoxic active quinone methidide and 5-fluorouracil under hypoxic conditions on HT-29 cell line under both aerobic and hypoxic conditions was investigated.Methods 5-fluorouracil derivative X-XIII were prepared by the reaction of the corresponding di-nitro substituted benzyl, benzoyl and phenacetyl halides with 5-fluorouracil protected at N-1 with di-t-butoxydicarbonate (BOC) in dimethyl formamide (DMF) in the presence of the potassium carbonate followed by hydrolysis of the blocking group by potassium carbonate in methanol. Cytotoxicity of fluorouracil VIII and tested compounds X-XIII against HT-29 cell line under both aerobic and hypoxic conditions after 48 hrs incubation were measured by determination of the percent of the survival cells using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and percent of the dead cells using propidium iodide(PI)-digitonine assay and results were used to calculate the corresponding IC50 values. Radiosensitization experiments were carried out by irradiation of the incubations with a 60Co source and clonogenic assay was performed to determine the cell viabilities following treatment with the tested compounds and/or radiation. Sensitization Enhancement Ratio (SER) of each tested compound was obtained from the radiation survival curves in the absence and presence of each sensitizer for 37% survival respectively. Results and major conclusion Findings of the present study showed that alkylation or acylation of 5-fluorouracil result in compounds which have little or no cytotoxicity and radiosensitizing activity under aerobic conditions, but have high cytotoxicity and radiosensitizing effects under hypoxic conditions. Furthermore radiosensitizing activities of compounds under hypoxic conditions increased by increase in their concentrations and SER of the tested 5-FU derivatives at concentrations higher than 50 μmol were equal or higher than 1.6 which is the minimum effective SER of a radiosensitizer in an in vitro assay.
Authors and Affiliations
Khosrou Abdi, Ali Khalaj, Syeed-Naser Ostad, Mohammad Reza Khoshayand
Keywords
Related Articles
- EP ID EP135281
- DOI -
- Views 101
- Downloads 0
Biosimilars; a unique opportunity for Iran national health sector and national pharmaceutical industry
In 1980s, medicines produced through recombinant DNA technology created a novel opportunity for management of several debilitating and life threatening diseases. However, these medicines are very expensive and therefore...
The effect of Camellia Sinensis (green tea) mouthwash on plaque-induced gingivitis: a single-blinded randomized controlled clinical trial
Background and the purpose of the Study Complementary medicine received high attention during last decades. We aimed to assess the efficacy of Green tea mouthwash on plaque-induced gingivitis as the most common form of...
Development of a validated HPLC method for the simultaneous determination of flavonoids in Cuscuta chinensis Lam. by ultra-violet detection
Cuscuta species known as dodder, have been used in traditional medicine of eastern and southern Asian countries as liver and kidney tonic. Flavonoids are considered as the main biologically active constituents in Cuscuta...
Financial perspective of private pharmacies in Tehran (Iran); is it a lucrative business?
Background and purpose of the study Pharmacies as direct providers of medicine and pharmaceutical services to patients have an important role in the health status of a society. The assessment of their financial situation...
Effect of vitamin D on insulin resistance and anthropometric parameters in Type 2 diabetes; a randomized double-blind clinical trial
Background & the purpose of the study Prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. To reduce its risk and progression, preventive strategies are needed. Vitamin supplementation such as vitam...