The folding and export of proteins and hydrolysis of unfolded proteins are disbalanced in the endoplasmic reticulum (ER) of cancer cells, leading to so-called ER stress. Agents further augmenting this effect are used as anticancer drugs including clinically approved proteasome inhibitors bortezomib and carfilzomib. However, these drugs can affect normal cells, which also rely strongly on ER functions, leading, for example, to accumulation of reactive oxygen species (ROS). To address this problem, we have developed ER-targeted prodrugs activated only in cancer cells in the presence of elevated ROS amounts. These compounds are conjugates of cholic acid with N-alkylaminoferrocene-based prodrugs. We confirmed their accumulation in the ER of cancer cells, their anticancer efficacy, and cancer cell specificity. These prodrugs induce ER stress, attenuate mitochondrial membrane potential, and generate mitochondrial ROS leading to cell death via necrosis. We also demonstrated that the new prodrugs are activated in vivo in Nemeth-Kellner lymphoma (NK/Ly) murine model.

Danylo Halytsky Lviv National Medical University Pekarska str 69 79010 Lviv Ukraine

Department of Medicine 5 Heidelberg University Hospital Im Neuenheimer Feld 410 69120 Heidelberg Germany

Else Kröner Fresenius Stiftung Professorship Department of Otorhinolaryngology Head and Neck Surgery Section of Experimental Oncology and Nanomedicine Universitätsklinikum Erlangen Glückstraße 10a 91054 Erlangen Germany

Friedrich Alexander University Erlangen Nürnberg Department of Chemistry and Pharmacy Organic Chemistry Chair 2 Nikolaus Fiebiger Str 10 91058 Erlangen Germany

Hematology Department 1st Affiliated Hospital of Soochow University Suzhou China

Institute of Experimental Botany AS CR Prague Czech Republic

Takeda Pharma Vertrieb GmbH and Co KG Jägerstr 27 1017 Berlin Germany

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