A comparison of anticancer effects n-(4-acetylphenyl)-2-(arylthio)acetamide and n'-(3-hydroxy-4-metoxybenzilidene)-2-(4-tosylpiperazine-1-YL)acetohydrazide derivatives in pancreatic cancer with PaRP inhibitors

Pancreatic cancer is a type of cancer that is very difficult to diagnose at early stages and symptoms appear only when the cancer is spread over the entire pancreas. Under these conditions, very few patients have a chance to be treated surgically. Therefore, studies on the development of new treatment methods and new anticancer agents in pancreatic cancer have gained importance. Within the scope of this thesis, N-(4-acetylphenyl)-2-(arylthio)acetamide and N'-(3-hydroxy-4-metoxybenzilidene)-2-(4-tosylpiperazine-1-yl)acetohydrazide derivatives were synthesized which have similar groups with olaparib and rucaparib which are used oral Poly (ADP-ribose) polymerase (PARP) inhibitors as new generation anticancer drug. The cytotoxic and apoptotic effects of the synthesized derivatives on immortalized human normal pancreatic cell (hTERT-HPNE) and human pancreatic cancer cells (PANC-1 and Capan-1) were investigated and compared by in vitro methods. MTT (3-(4,5-dimethylthiazol-2)-2,5-diphenyl tetrazolium bromide) assay was used in order to find effective derivatives and their concentration ranges for the evaluation of the synthesized derivatives on cell viability, the xCELLigence Real Time Cell Analysis System was used to determine the IC50 values. Apoptosis, caspase-3 activation, mitochondrial membrane potential measurements and cell cycle analyzes were performed using the flow cytometer. Morphological images of the cells were photographed, PARP cleavage levels were determined by ELISA and mRNA gene expressions which may be effective were examined with RT-PCR array. As a result, rucaparib showed the highest efficacy. In parallel the synthesized derivatives, LHS-4 and CS-1, that may be PARP inhibitor candidates showed significant anticancer activity on the pancreatic cancer cells, and less toxic effects in normal pancreatic cells. The elucidation of the PARP inhibitory structure-activity and supporting the existing anticancer activities of these derivaties with additional studies will allow the development of new active substances for cancer treatment. Keywords: Olaparib, Rucaparib, PARP inhibitor, Pancreatic cancer, Anticancer effect.