ABSTRACT
A new group of 4-[Imidazolylmethyl] quinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-2 phenyl ring were designed and synthesized as selective COX-2 inhibitors and in-vitro anti breast cancer agents. In-vitro COX-1 and COX-2 inhibition studies showed that all the compounds were potent and selective inhibitors of the COX-2 isozyme with IC[50] values in the potent range 0.063-0.090 microM, and COX-2 selectivity indexes in the 179.9 to 547.6 range. Molecular modeling studies indicated that the methylsulfonyl substituent can be inserted into the secondary pocket of COX-2 active site for interactions with Arg[513]. Cytotoxicity of quinolines 9a-e against human breast cancer MCF-7 and T47D cell lines were also evaluated. All the compounds 9a-e were more cytotoxic against MCF-7 cells in comparison with those of T47D which express aromatase mRNA less than MCF-7 cells. The data showed that the increase of lipophilic properties of substituents on the C-7 and C-8 quinoline ring increased their cytotoxicity on MCF-7cells and COX-2 inhibitory activity. Among the quinolines 9a-e, 4-[[1H-Imidazol-1-yl]methyl] 7,8,9,10-tetrahydro-2-[4-methylsulfonylphenyl]-benzo[h]quinoline [9d]was identified as the most potent and selective COX-2 inhibitor as well as the most cytotoxic agent against MCF-7 cells
Subject(s)
Cyclooxygenase 2 Inhibitors , Breast Neoplasms , In Vitro Techniques , AromataseABSTRACT
A special type of silica-based columns has been recently introduced into the market which is called narrow-bore columns. They have lower internal volume than the standard high-performance liquid chromatography [HPLC] columns and thus reduce the solvent consumption by almost 80%. A simple, accurate and environmentally friendly reversed phase- HPLC [RP-HPLC method] which could be used in fast and high throughput analyses has been developed for the purpose of determining the sildenafil in bulk and pharmaceutical dosage forms, using narrow-bore C[18] column [50 _ 3.2 mm, 5 micro m particle size] in isocratic mode, with mobile phase comprising of buffer [pH = 3] and acetonitrile in the ratio of 75:25 v/v. The flow rate was 0.7 mL/min and the detection was monitored through Ultraviolet detector [UV detector] at 292 nm. Clonazepam was used as the internal standard and the run time was 4 min. The proposed method has permitted the quantification of sildenafil over the linearity in the range of 30-4000 ng/mL and its percentage recovery was found to be 99-105%. Limit of quantitation [LOQ] is determined as 30 ng/mL. The intra-day and inter-day precisions were found 1.2-2.2% and 1.56-3.4% respectively. The solvent consumption was 2.8 mL per sample of which ca 0.7 mL was acetonitrile. This study shows that the application of narrow-bore column instead of the conventional reversed phase column in HPLC analyses has the advantages of shorter run time and less organic solvent consumption. This method is highly sensitive with excellent recoveries and precision and there is no need for special column and pre-column or post-column treatment of the sample. Moreover, the method is free from interference by common additives and excipients, suggesting applications in routine quality control analyses