Noninnocent thiosemicarbazones/zonates as dual action drugs

One of the main causes of cancer death is the malignant process itself, which is associated with extensive formation of metastases. In this context it is not generally mentioned that a significant number of immunocompromised cancer patients die due to infections. Despite that cancer patients are very prone to develop infections during chemotherapy, their preventive antibiotic treatment is hampered by additional adverse effects. However, recent clinical evidence demonstrated that benefits of antibiotic prophylaxis of cancer patients outweighed its risks. The simultaneous suppression of pathogenic microorganisms during anticancer chemotherapy could not only interrupt or reduce tumor growth but also eventually protect cancer patients from infection. Hence, the development of novel drugs which exhibit dual anticancer and antibacterial properties in comparable concentration range would affect the malignant process and simultaneously decrease the risk of patients death due to infection is a very important task, which is the main objective of the current research proposal. Preliminary results have shown that thiosemicarbazones (TSCs) and their metal complexes are suitable compounds for investigation of their ability to simultaneously act as both antibacterial/antiviral and anticancer agents. Moreover, to date several TSCs namely, 3-amino-2-pyridinecarboxaldehyde TSC (Triapine), di- 2-pyridylketone4-cyclohexyl-4-methyl-3-thiosemicarbazone(DpC)and (E)-N-(5,6,7,8- tetrahydroquinolin-8-ylidene)-4-(pyridine-2-yl)piperazine-1-carbothiohydrazide (COTI-2) are in phase I/II clinical trials against various types of cancer. Ribonucleotide reductase (RNR) and, in particular, its R2 subunit is one of the main targets for many TSCs. R2 subunit consists of a diferric unit and a tyrosyl radical (Y), which are key elements involved in catalytic conversion of ribonucleotides to deoxyribonucleotides, which is fundamental to DNA-based life, as cells require a constant supply of the four essential deoxyribonucleotides for cellular DNA synthesis and repair. RNRs are particularly important in rapidly dividing cells, such as tumour cells, virally-infected cells, and invading bacteria. All these cells share similar properties, such as high proliferation rates, quick spreading within the host, and aggressive disease progression. Herewith we intend to synthesise novel redox active thiosemicarbazones which can bind into the same pocket of R2 protein as Triapine, but in addition are able to reduce directly the Y leading finally to S-phase arrest of the cell cycle. In addition, (thio)semicarbazide-based macrocycles will be prepared and used for quenching the Y by sequestration of Fe III from the active centre of R2 protein. The work will be performed by the team of Vladimir B. Arion at the Institute of Inorganic Chemistry of the University of Vienna in collaboration with Anatoly Shutalevs group at Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences.

One of the main causes of cancer death is the malignant process itself, which is associated with extensive formation of metastases. In this context it is not generally mentioned that a significant number of immunocompromised cancer patients die due to infections. Despite that cancer patients are very prone to develop infections during chemotherapy, their preventive antibiotic treatment is hampered by additional adverse effects. However, recent clinical evidence demonstrated that benefits of antibiotic prophylaxis of cancer patients outweighed its risks. The simultaneous suppression of pathogenic microorganisms during anticancer chemotherapy could not only interrupt or reduce tumor growth but also eventually protect cancer patients from infection. Hence, the development of novel drugs which exhibit dual anticancer and antibacterial properties in comparable concentration range would affect the malignant process and simultaneously decrease the risk of patients' death due to infection is a very important task, which is the main objective of the current research proposal. Preliminary results have shown that thiosemicarbazones (TSCs) and their metal complexes are suitable compounds for investigation of their ability to simultaneously act as both antibacterial/antiviral and anticancer agents. Moreover, to date several TSCs namely, 3-amino-2-pyridinecarboxaldehyde TSC (Triapine), di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) and (E)-N-(5,6,7,8-tetrahydroquinolin-8-ylidene)-4-(pyridine-2-yl)piperazine-1-carbothiohydrazide (COTI-2) are in phase I/II clinical trials against various types of cancer. Ribonucleotide reductase (RNR) and, in particular, its R2 subunit is one of the main targets for many TSCs. R2 subunit consists of a diferric unit and a tyrosyl radical (Y), which are key elements involved in catalytic conversion of ribonucleotides to deoxyribonucleotides, which is fundamental to DNA-based life, as cells require a constant supply of the four essential deoxyribonucleotides for cellular DNA synthesis and repair. RNRs are particularly important in rapidly dividing cells, such as tumour cells, virally-infected cells, and invading bacteria. All these cells share similar properties, such as high proliferation rates, quick spreading within the host, and aggressive disease progression. Herewith we intend to synthesise novel redox active thiosemicarbazones which can bind into the same pocket of R2 protein as Triapine, but in addition are able to reduce directly the Y leading finally to S-phase arrest of the cell cycle. The work was performed by the team of Vladimir B. Arion at the Institute of Inorganic Chemistry of the University of Vienna in collaboration with Anatoly Shutalev's group at Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences.