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

Abstract

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.

Analysis of electrochemical and liver microsomal transformation products of lasalocid by LC/HRMS

“…Furthermore, LAS acts against gram‐positive mastitis pathogens 1 and protects cells against multiple bacterial toxins 2 . In accordance with other ionophore antibiotics, an exhibited potent anticancer activity for LAS was described 3–5 . Overall, LAS is commercially used as coccidiostat (feed additive) and growth promoter in cattle and poultry farming.…”

“…2 In accordance with other ionophore antibiotics, an exhibited potent anticancer activity for LAS was described. [3][4][5] Overall, LAS is commercially used as coccidiostat (feed additive) and growth promoter in cattle and poultry farming. The biotransformation process of LAS is well investigated; LAS is mainly metabolized in the liver.…”

N-Acylated Ciprofloxacin Derivatives: Synthesis and In Vitro Biological Evaluation as Antibacterial and Anticancer Agents

“…CP conjugates, the parental drug and leading cytostaticsdoxorubicin and cisplatin, were tested at various concentrations (ranged from 1 to 100 μM). They were added on 96-well plates (1 × 10 4 cells per well) with seeded normal and cancer cells and incubated for 72 h. MTT analysis was performed according to a previous study . Untreated cells were used as controls.…”

“…They were added on 96-well plates (1 × 10 4 cells per well) with seeded normal and cancer cells and incubated for 72 h. MTT analysis was performed according to a previous study. 59 Untreated cells were used as controls.…”

Comparative and Functional Analyses Reveal Conserved and Variable Regulatory Systems That Control Lasalocid Biosynthesis in Different Streptomyces Species

“…Recently, this ionophore has been verified as a novel inhibitor that protects cells from multiple deadly bacterial toxins via corrupting vesicular trafficking and Golgi stack homeostasis ( 8 ). Moreover, lasalocid and its synthetic analogs have shown high antiproliferative activity against cancer cell lines and, simultaneously, lower cytotoxicity toward nontumor cells than cisplatin, which hints at their potential to be developed as candidates for cancer treatment ( 2 , 3 , 9 , 10 ).…”