Synthesis, and anti-tumor evaluation of some new Flurbiprofen derivatives against MCF-7 and WRL-68 cell lines

Abstract

A new series of flurbiprofen derivatives containing thiosemicarbazide moiety (3-7) was synthesized from flurbiprofen as parent nucleus by esterification, hydrazide formation, and heating with different aryl isothiocyanate substituents, respectively. Flurbiprofen was also treated with thiosemicarbazide in the presence POCl3 as a catalyst, to produce 1,3,4 -thiadiazole -2-amine (8). Treatment of (8) with different aryl isothiocyanates produced thiourea derivatives (9-12). Also, the reaction of (8) with different benzoyl chloride substituents produced benzamide compounds (13-15). Eventually, treatment of (8) with ethyl acetoacetate (EAA) produced [1,3,4]thiadiazolo[3,2-a]pyrimidin-7-one (16) .The new compounds were characterized by spectroscopic techniques:FTIR, 1HNMR, and CHNS analysis. A molecular docking study for the synthesized compounds (3-16), against the Vascular Endothelial Growth Factor receptor (VEGFR-2) was applied, and it indicated that compounds 4,7,13, and 15, exhibited the optimum binding energy of -6.77,-6.12,-6.68,-6.43 kcal/mol, respectively. Target compounds were also assessed for their in vitro anticancer effects in a cell-line study. All of the compounds tested showed the most plausible anticancer activity, compared to a positive control (sorafenib), using in vitro MTT cytotoxic assay, against human breast tumor (MCF-7), and normal WRL-68 cell line. The in vitro results revealed that compounds 4,5,10,11,13, and 15 exhibited the highest inhibitory activity at their IC50 concentrations, against MCF-7 cell lines, as follows (122.7,113.9,95,7. 109.1,40.32 and 112.29µg/mL, respectively. While their cytotoxic effect against normal WRL-68 cell line at their IC50 concentrations, as follow 210.2,181.3,151.7,278.7,80.28, and 236µg/mL, respectively. Therefore, such compounds were considered more selective toward MCF-7 than normal WRL-68, and their selectivity index (SI): 1.71,1.59,1.59, 2.55,1.99, and 2.10, respectively. Among the synthesized compounds, the compound 15 was chosen to screen its effect in vitro through multiparameter cytotoxic assay against MCF-7 breast cancer implemented in High Content Screening (ArrayScan XTI, Thermo Scientific),which could be taken in consideration as a starting point for the development of new anticancer drugs.