Platinum(II) complex synthesis, structure elucidation and activity studies

Cisplatin has been successfully used in combination with other chemotherapeutic drugs such as etoposide and bleomycin or radiotherapy to treat testicular, ovarian, bladder, lung, head and neck, pancreatic, breast, endometrial, esophageal, advanced cervical, lymphoma, metastatic osteosarcoma and melanoma. However, side effects such as nephrotoxicity, neurotoxicity, ototoxicity, nausea and vomiting and the development of resistance to this successful platinum complex have led researchers to design and synthesize new molecules. Carboplatin, which started to be used clinically after cisplatin, is a second generation platinum(II) complex that carries a slower hydrolyzing 1,1-cyclobutanedicarboxylate ligand in place of the cleaved chlorine ligand in the cisplatin molecule. Despite the use of higher doses than cisplatin, fewer side effects were observed in patients, but it was not possible to prevent the development of cross-resistance to carboplatin. Oxaliplatin, the third generation platinum complex, was synthesized by replacing the ammonia and chlorine ligands in the cisplatin structure with 1,2-diaminocyclohexane and oxalate, respectively. Cross-resistance to oxaliplatin does not develop and nephrotoxic effects are less common than in patients using cisplatin and carboplatin. In addition to cisplatin, carboplatin and oxaliplatin, which are used clinically worldwide, nedaplatin is regionally approved in Japan for head and neck, testicular, ovarian and lung cancer; heptaplatin in South Korea for gastric cancer; and lobaplatin in China for chronic myeloid leukemia, inoperable metastatic lung cancer and breast cancer. Functional and structural similarity between the active site of the enzyme and the model compound to be selected is an important issue to be considered when designing compounds by modeling enzymes necessary for life. Therefore, the presence of the selected ligand in the structure of physiologically active compounds is considered as a remarkable approach in the design of new platinum complex anticancer drugs. 1H-benzo[d]imidazole and 1H-1,3-diazole rings, a ring system recognized by biological systems, are of great importance for medicinal chemists. In this thesis, cis-dichloro-bis(1H-benzo[d]imidazole)platinum(II) (K1), cis-dichloro-di(1H-1,3-diazole)platinum(II) (K2), Complexes with the closed formula cis-dichloro-bis(2-phenyl-1H-benzo[d]imidazole)platinum(II) (K3) and cis-dichloro-bis(2-phenyl-1H-1,3-diazole)platinum(II) (K4) were synthesized. Their structures were then elucidated by FT-IR (Fourier Transform Infrared) and 1H Nuclear Magnetic Resonance. The cytotoxic effects of the synthesized K1-K4 compounds were tested against prostate (DU-145), endometrium (Ishikawa) and breast cancer (MCF-7) cell cultures by MTT method.