Design, synthesis and investigation of biological activities of new compounds that can be used in cancer treatment

Among the many chemical structures, isatin is used extensively to develop new types of agents against cancer. Indole or isatin derivative (sunitinib, semaxanib, and nintedanib), compounds are currently used as tyrosine kinase inhibitors for the treatment of certain types of cancer. Drugs that contain amide or urea groups such as sorafenib, nilotinib and ponatinib, and Schiff bases such as sunitinib, have a role in cancer treatment as kinase inhibitor anticancer agents. Within the scope of this thesis, designing and synthesizing derivatives of Schiff bases obtained from the third position of the isatin ring, inspired by the structure of sorafenib, containing urea and sulfonamide group, which is the bioisoster of the urea functional group, and testing their anticancer properties against HepG2, PC-3, A549, SH-SY5Y cell lines. In this study, it was aimed to evaluate the relationship between the structure of compounds and binding properties to the receptor by using the Autodock 4.2 program and to determine whether the compounds have drug-like properties according to the ADME prediction data. The chemical structures and purity of 16 synthesized new compounds and intermediate steps were identified using melting point determination, IR spectroscopy, 1H-NMR, LC-MS analyses additionally 13C-NMR analysis for the new compounds. Among the synthesized compounds, the results showed that compounds 7a, 7b, 7c, 7d, 7h, 8a and 8f induce inhibition of cellular proliferation activity against HepG2 cells with IC50 values of 31.97, 42.13, 31.50, 47.98, 32.59, 43.44 and 37.81 µM, respectively, while they have weak cytotoxic effect in healthy NIH/3T3 cells. Molecular Docking studies revealed that 7c, the most active compound, showed effective binding properties with the receptor binding site of NS5B polymerase compared to other active compounds, and all compounds synthesized, were found to have drug-like properties according to ADME prediction studies. In vitro experiments and in silico studies have shown that new urea and sulfonamide derivatives of isatin Schiff bases have activity comparable to the reference compound doxorubicin. It was concluded that this type of compounds may be active against HCV-NS5B causing hepatocellular carcinoma and there is a possibility to find more effective molecules in compounds that will be designed similar to these compounds.