Synthesis and Evaluation of New Benzodioxole- Based Thiosemicarbazone Derivatives as Potential Antitumor Agents

Mehlika Altıntop,Halide Temel,Belgin Sever,Zafer Kaplancıklı,Gülşen Akalın Çiftçi

doi:10.3390/molecules21111598

Mehlika Altıntop, Halide Temel + Show 3 more

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https://doi.org/10.3390/molecules21111598

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Abstract

New benzodioxole-based thiosemicarbazone derivatives were synthesized and evaluated for their cytotoxic effects on A549 human lung adenocarcinoma, C6 rat glioma and NIH/3T3 mouse embryonic fibroblast cells. In order to examine the correlation between anticancer activity and cholinesterases, the compounds were evaluated for their inhibitory effects on AChE and BuChE. The most effective anticancer agents were investigated for their effects on DNA synthesis, apoptosis and mitochondrial membrane potential. 4-(1,3-Benzodioxol-5-yl)-1-([1,1′-biphenyl]-4-ylmethylene)thiosemicarbazide (5) was identified as the most promising anticancer agent against C6 and A549 cell lines due to its inhibitory effects on C6 and A549 cells and low toxicity to NIH/3T3 cells. Compound 5 increased early and late apoptosis in A549 and C6 cells. Compound 5 also caused disturbance on mitochondrial membrane potential and showed DNA synthesis inhibitory activity in A549 and C6 cells. Compound 5 was investigated for SIRT1 inhibitory activity to provide mechanistic insight and for that purpose docking studies were also performed for this compound on SIRT1. On the other hand, compound 5 did not show any inhibitory activity against AChE and BuChE. This outcome pointed out that there is no relationship between anticancer activity of compound 5 and cholinesterases.

Highlights

Cancer is an abnormal cell division caused by some alteration in the expression of plentiful genes in the nucleus or in the mitochondria of cells
Increasing the concentration of compound 5 caused elevated SIRT1 levels compared to control. These results showed that the effects of compound 5 on SIRT1 levels were dose dependent in C6 glioma cells
In order to examine the correlation between anticancer activity with cholinesterases, each derivative was investigated for its ability to inhibit AChE

Summary

Introduction

Cancer is an abnormal cell division caused by some alteration in the expression of plentiful genes in the nucleus or in the mitochondria of cells. These alterations lead to a disorder in the balance between cell reproduction and cell death. Many chemotherapeutic drugs have been developed as anticancer agents, but most of them are insufficient for cancer treatment because of their lack of specificity towards cancer cells and correspondingly their high risk of toxicity to normal cells. AChE has attracted a great deal of interest as a potential therapeutic target for the treatment of cancer due to the involvement of this enzyme in apoptosis and cell adhesion, differentiation, and proliferation [7,8,9]

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