Dual Diomarkers Triggered Prodrugs for Precise Treatment of Melanoma:Design,Synthesis and Activities

Targeted prodrug strategy,which utilizes the endogenous biomarkers in cancer cells as activators to release the active drug,has been well established either in the fundamental research or the clinical treatment.However,many prodrugs suffer from safety concern due to“off-target activation”.Dual or multiple biomarkers triggered prodrug may provide an effective strategy to overcoming the“off-target effect”.Melanoma cells have both high levels of reactive oxygen species(ROS)and tyrosinase(TYR),which makes them significantly different from other tumor cells and normal cells.Here we reported a series of quinazolinone-aryl boronic acid/ester-based prodrugs,which can be activated by the cascade of ROS and TYR and selectively kill melanoma cells.The structure-activity relationship(SAR)analysis revealed that mitochondria-targeting property was vital for their cytotoxicity and the dual activated effector played a significant role in their selectivity towards melanoma cells.Among these candidates,compound 4b showed the highest toxicity to B16,leading to an imbalance of the redox system in melanoma cells,causing mitochondrial DNA damage,and then promoting melanoma cells death.

Chinese Medicine Amygdalin and β-Glucosidase Combined with Antibody Enzymatic Prodrug System As A Feasible Antitumor Therapy

Amarogentin is an efficacious Chinese herbal medicine and a component of the bitter apricot kernel.It is commonly used as an expectorant and supplementary anti-cancer drug.β-Glucosidase is an enzyme that hydrolyzes the glycosidic bond between aryl and saccharide groups to release glucose.Upon their interaction,β-glucosidase catalyzes amarogentin to produce considerable amounts of hydrocyanic acid,which inhibits cytochrome C oxidase,the terminal enzyme in the mitochondrial respiration chain,and suspends adenosine triphosphate synthesis,resulting in cell death.Hydrocyanic acid is a cell-cycle-stage-nonspecific agent that kills cancer cells.Thus,β-glucosidase can be coupled with a tumor-specific monoclonal antibody.β-Glucosidase can combine with cancer-cell-surface antigens and specifically convert amarogentin to an active drug that acts on cancer cells and the surrounding antibodies to achieve a kil ing effect.β-Glucosidase is injected intravenously and recognizes cancer-cel-surface antigens with the help of an antibody.The prodrug amarogentin is infused after β-glucosidase has reached the target position.Coupling of cell membrane peptides with β-glucosidase allows the enzyme to penetrate capillary endothelial cells and clear extracellular deep solid tumors to kill the cells therein.The Chinese medicine amarogentin and β-glucosidase will become an important treatment for various tumors when an appropriate monoclonal antibody is developed.