Prof. Dr. Andriy Mokhir, Department of Chemistry and Pharmacy, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany

Cancer specific prodrugs

A basal level of reactive oxygen species (ROS) in malignant cells is higher than that one in normal cells. Therefore, the former cells are more vulnerable to the oxidative stress. For example, when malignant and normal cells are treated with exogenous compounds increasing cellular ROS amount, the malignant cells die first. Known ROS generating drugs exhibit dangerous side effects. In particular, apart from killing cancer cells, they also increase ROS amount in normal cells. High ROS stimulates transformation of the cells and induce secondary tumors. We develop prodrugs, which increase ROS concentration in cancer cells, but do not affect ROS concentration in normal cells. These compounds are non-toxic, stable molecules or nano-sized constructs. In the ROS-rich microenvironment of cancer cells they are transformed into cytotoxic agents of two types: type 1 agent impairs an antioxidant system of the cell; type 2 agent generates ROS catalytically. Type 1 agent is an organic electrophile reacting with glutathione (GSH) or other nucleophilic (-SH or -SeH-containing) biomolecules. Type 2 agent is an electron rich organometallic compound (e.g. ferrocene), which is able to cycle between reduced and oxidized states without decomposition. These species act synergistically by inducing strong oxidative stress that leads to apoptosis or necrosis of cancer cells. Our prodrugs are not activated in the microenvironment of normal cells containing low ROS concentration. The previous work from this project has been partially published by our group: J. Med. Chem. 2015, 58, 2015; J. Med. Chem. 2013, 56, 6935; J. Med. Chem. 2012, 55, 924. The excellent antitumor effects were confirmed in cell free settings, experiments with cell cultures and primary cells as well as in vivo in several mouse and one rat models.

We are currently working on further chemical modification of these prodrugs to achieve their targeting to particular organelles of cancer cells (lysosomes, mitochondria, Golgi, endoplasmic reticulum and nucleus) to potentiate their antitumor activity. Preliminary studies have been recently published: Mokhir et al, Angew. Chem., 2017; Mokhir et al, Angew. Chem., 2018. Our progress in this project will be highlighted in the presentation.

Host: Professor Kurt V. Gothelf, iNANO & Dept. of Chemistry, Aarhus University