Cancer specific N-alkylaminoferrocene-based prodrugs

• Applicant: Professor Dr. Andriy Mokhir
• Subject Area: Pharmacy ; Biological and Biomimetic Chemistry
• Term: from 2014 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260329470

N-alkylaminoferrocene-based (NAAF) prodrugs are activated in the presence of elevated concentrations of reactive oxygen species (ROS) with formation of highly toxic species. These conditions are characteristic for cancer cells, whereas normal cells have low homeostatic ROS levels. Therefore, NAAF-prodrugs kill cancer cells preferably over normal ones as we have established in both in vitro and in vivo experiments. In the framework of the previously DFG-funded previous project we enhanced the efficacy of these prodrugs by their redirection to lysosomes, where the ROS concentration is higher than that in cytoplasm of cancer cells. Moreover, we confirmed that the efficacy of the prodrugs towards both cancer cell lines and primary cells is not p53-dependent. The best NAAF-prodrugs exhibit in vivo anticancer activity at >20-fold higher doses than those predicted based on in vitro data. We observed that at least one of the possible reasons for that is a cell-unspecific oxidation of prodrugs in blood leading to their deactivation. In this project we will approach this problem by redox-tuning of the ferrocene core of the prodrugs without affecting the desirable, cancer specific ROS-triggered activation reaction initiated by cleavage of the B-C bond. Next, we will further enhance the efficacy of the prodrugs down to the nMolar range by making use of a substantially more reactive trigger (peroxynitrite) than that previously used (hydrogen peroxide). The prodrug will be designed / optimized to achieve the efficient reaction of in situ generated ONOO-a with the arylboronic acid trigger thereby avoiding the leakage of ONOO- to the environment that could cause potential side effects. Properties of the resulting prodrug will be evaluated both in vitro in experiments with cell cultures and in vivo in studies of drug distribution and accumulation in tumors and antitumor efficacy of the prodrug in an NK/lymphoma mouse model.

• DFG Programme: Research Grants