Synthesis, structural elucidation and anticancer activity studies of platinum (II) complex with substituted benzimidazole derivative

Cancer, one of the most significant health problems worldwide, is defined as the uncontrolled growth of abnormal cells in any part of the body. Despite intensive research and advancements in cancer treatment, chemotherapy drugs remain the cornerstone of systemic therapy for many types of cancer. However, their use in clinical practice is limited due to the high occurrence of side effects and the development of resistance. Platinum-based chemotherapeutic drugs, such as cisplatin and its derivatives, are the most commonly prescribed drug group in cancer treatment. Ongoing efforts to develop new platinum complex compounds continue unabated due to their toxic side effects and the development of acquired or direct resistance. In this regard, platinum(II) complexes with reduced side effects and increased therapeutic efficacy are being synthesized by modifying the carrier and dissociating ligands associated with platinum coordination. Benzimidazole ring is an important core system found in various pharmacologically active compounds that target multiple pathways. It resembles the structure of purine bases and is also present in the structure of vitamin B12 derivatives. The low toxicity, high stability, ability to bind with metals, and electronic and steric properties make substituted benzimidazole derivatives increasingly important for drug design in medicinal chemistry. In this thesis study, 2-(1-hydroxyethyl)benzimidazole (TL1) and 5(6)-methyl-2-(1-hydroxyethyl)benzimidazole (TL2) carrier ligands were used instead of the ammonia ligand in the structure of cisplatin. The carrier ligands were synthesized using 1,2-phenylenediamine/4-methyl-1,2-phenylenediamine and lactic acid as starting materials. As for the dissociating ligand, complexes [Pt(TL1)2Cl2] (PtK1) and [Pt(TL2)2Cl2] (PtK3) with a closed formula were synthesized by adding TL1 or TL2 dissolved in ethanol/distilled water solutions, respectively, onto potassium tetrachloroplatinate dissolved in distilled water. For testing the cytotoxic activity of the dissociating ligand, complexes [Pt(TL1)2I2] (PtK2) and [Pt(TL1)2I2] (PtK4) with a closed formula were synthesized by adding TL1 or TL2 dissolved in ethanol/distilled water onto potassium tetraiodoplatinate obtained from the reaction of potassium iodide and potassium tetrachloroplatinate, respectively. The chemical structures of the synthesized ligands were elucidated using IR and 1H NMR spectroscopy, while the chemical structures of the complexes were characterized by IR, 1H NMR, and LC-MS techniques. The synthesized four platinum(II) complexes (PtK1-K4) in vitro cytotoxic effects were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method against MCF-7 (breast cancer, T.R. Ministry of Agriculture and Forestry Alum Institute, Cell Registration Number: 00092502), DU145(prostate cancer, ATCC, HTB-81) and Ishikawa endometrial cancer cell lines.