Mehlika Dilek ALTINTOP, Ahmet ÖZDEMİR, Belgin SEVER, Gülşen AKALIN ÇİFTÇİ

Design, synthesis and biological evaluation of new bis(thiosemicarbazone) derivatives as potential targeted anticancer agents for non-small cell lung cancer

Thiosemicarbazones represent an important class of ligands for targeted therapy of many types of cancerincluding non-small cell lung cancer. In order to identify potential antitumor agents for targeted therapy of lung cancer,new bis(thiosemicarbazone) derivatives (1-11) were prepared via the reaction of 1,4-phenylenebis(thiosemicarbazide)with 5-arylfurfurals. The cytotoxic effects of compounds 1-11 on A549 human lung adenocarcinoma and L929 mousefibroblast cells were investigated using MTT test. Compounds 1, 10 and 11 were the most potent anticancer agents inthis series on A549 cell line with IC50 values of 14.33±0.47 μg/mL, 11.67±2.49 μg/mL and 16.67±5.56 μg/mL, respectivelycompared to cisplatin (IC50= 18.33±0.94 μg/mL). Based on their IC50 values for L929 cell line, their anticancer activitieswere found to be selective. Moreover, flow cytometry-based analyses were performed to examine their effects onapoptosis and mitochondrial membrane potential. The treatment of A549 cells with compounds 1, 10 and 11 at IC50concentrations led to the induction of apoptosis along with mitochondrial membrane depolarization. In order to exploretheir mode of action, compounds 1, 10 and 11 were evaluated for their inhibitory effects on COX-1 and COX-2 in A549cells. In particular, N,N'-(1,4-phenylene)bis(2-((5-(2,5-dichlorophenyl)furan-2-yl)methylene)hydrazine-1-carbothioamide) (10) was identified as a selective COX-2 inhibitor (6.96% for COX-1 and 54.81% for COX-2). Accordingto these results, compound 10 warrants further in vitro and in vivo studies as a potential targeted anticancer agent forthe management of non-small cell lung cancer.

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