Editor-in-Chief İlkay Küçükgüzel Associate Editor Aslı Türe Online ISSN 2630-6344 Publisher Marmara University Frequency Bimonthly (Six issues / year) Abbreviation J.Res.Pharm. Former Name Marmara Pharmaceutical Journal
Journal of Research in Pharmacy 2020 , Vol 24 , Issue 5
Design, synthesis and biological evaluation of new bis(thiosemicarbazone) derivatives as potential targeted anticancer agents for non-small cell lung cancer
Belgin SEVER1,Gülşen AKALIN ÇİFTÇİ2,Ahmet ÖZDEMİR1,Mehlika Dilek ALTINTOP1
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey
2Department of Biochemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskişehir, Turkey
DOI : 10.35333/jrp.2020.222 Thiosemicarbazones represent an important class of ligands for targeted therapy of many types of cancer including 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 mouse fibroblast cells were investigated using MTT test. Compounds 1, 10 and 11 were the most potent anticancer agents in this 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, respectively compared to cisplatin (IC50= 18.33±0.94 μg/mL). Based on their IC50 values for L929 cell line, their anticancer activities were found to be selective. Moreover, flow cytometry-based analyses were performed to examine their effects on apoptosis and mitochondrial membrane potential. The treatment of A549 cells with compounds 1, 10 and 11 at IC50 concentrations led to the induction of apoptosis along with mitochondrial membrane depolarization. In order to explore their mode of action, compounds 1, 10 and 11 were evaluated for their inhibitory effects on COX-1 and COX-2 in A549 cells. 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). According to these results, compound 10 warrants further in vitro and in vivo studies as a potential targeted anticancer agent for the management of non-small cell lung cancer. Keywords : Apoptosis; bis(thiosemicarbazone); cyclooxygenase-2; mitochondrial membrane potential; non-small cell lung cancer
Marmara University