Investigation of the cytotoxic, genotoxic, apoptotic effects of 4-(substituted)-3,4-dihydropyrimidinone compounds on human lung cancer cell and Drosophila melanogaster

This study aimed to determine the possible cytotoxic, genotoxic and anticarcinogenic activities of newly synthesized 4-(Substituted)-3,4-dihydropyrimidinone derivatives (PMe, PPh and PNO2). For this purpose, the possible effects of the compounds were investigated in the A549 human lung cancer cell line, MRC-5 human healthy lung cell line and Drosophila melanogaster. In the study, the WST-8 test method was used to evaluate the cytotoxic effects of the compounds, and the Drosophila wing somatic mutation recombination test (SMART) was used to evaluate the genotoxic effects. Expression levels of compounds, heat shock protein genes, antioxidant genes and genes effective in the apoptotic pathway were determined by RT-PCR method. According to the results of the research, it was determined that the compounds had a cytotoxic effect at 50 and 100µM concentrations on the A549 lung cancer cell line, but did not show a cytotoxic effect on the healthy lung cell line (MRC-5). As a result of SMART, it was determined that all three DHPM derivatives showed genotoxic effects only at very high doses, but did not show a significant toxic effect on the larvae. When the apoptotic effects of the compounds were examined on the A549 cell line, it was observed that all three compounds increased the expression levels of BAX and CASP3 genes, SOD1, CAT and GSS genes, which are genes related to the antioxidant mechanism, and decreased HSP27 gene expression, which is a heat shock protein gene. When the effects of compounds on apoptotic gene expression levels in D. melanogaster in vivo conditions were examined; It was observed that PMe compound increased the expression level of the DEBCL gene compared to the control group, PPh and PNO2 compound decreased the expression level of the DEBCL gene, and all three compounds increased the expression level of the BUFFY gene. Considering the DEBCL/BUFFY ratio, it was determined that all three compounds showed antiapoptotic effects in healthy D. melanogaster individuals. However, it was determined that all compounds increased the expression level of the DRICE gene, which is a D. melanogaster caspase, compared to the control group, only the PMe compound increased the expression level of the DRONC gene, and the PPh and PNO2 compounds decreased the gene expression level. In particular, it was determined that PMe compound increased the expression levels of D. melanogaster heat shock proteins HSP27, HSP60, HSP70 and HSP90 genes and SOD, CAT, GR and GST genes.