Synthesis of Lasalocid-Based Bioconjugates and Evaluation of Their Anticancer Activity

Using rationally designed bioconjugates is an attractive strategy to develop novel anticancer drugs with enhanced therapeutic potential and minimal side effects compared to the native structures. With respect to the promising activity of lasalocid (LAS) toward various cancer cells, this polyether ionophore seems to be an ideal candidate for bioconjugation. Herein, we describe the synthetic access to a cohort of nine conjugated products of LAS, in which the ionophore biomolecule was successfully combined via covalent bonds with selected anticancer therapeutics or other anticancer active components. The in vitro screening of a series of cancer cell lines allowed us to identify three products with improved anticancer activity profiles compared to those of the starting materials. The results indicate that human prostate cancer cells (PC3) and human primary colon cancer cells (SW480) were essentially more sensitive to exposure to LAS derivatives than human keratinocytes (HaCaT). Furthermore, the selected products were stronger inducers of late apoptosis and/or necrosis in PC3 and SW480 cancer cells, when compared to the metastatic variant of colon cancer cells (SW620). To establish the anticancer mechanism of LAS-based bioconjugates, the levels of interleukin 6 (IL-6) and reactive oxygen species (ROS) were measured; the tested compounds significantly reduced the release of IL-6, while the level of ROS was significantly higher in all the cell lines studied.