Study On The Anti-melanoma Prodrugs Cascade-activated By Hydrogen Peroxide And Tyrosinase

Cancer therapy has always been a major issue in the current society.Traditional anticancer chemotherapy drugs have brought non-negligible side effects to patients due to their non-selectivity to cancer cells.Although the development of prodrugs activated by single biomarker has alleviated this problem to some extent in recent years,there is still a certain problem of"off-target effect".Scientists have found that the development of prodrugs activated by double or multiple biomarker based on the unique physiological environment of cancer cells can effectively improve the cancer targeting of drugs and minimize the side effects caused by traditional anticancer drugs.Melanoma is a kind of malignant tumor with strong diffusion and high mortality,so it is urgent to develop a high selective targeting drug for melanoma.In this project,we explored the selective anti-cancer mechanism and anti-cancer effect of coumarin-quinazolinone-phenylboronic acid pinacol ester conjugate（CQB）on melanoma.Specific research contents are as follows:1.The prodrug CQB can be activated by the cascade of hydrogen peroxide（H₂O₂）and tyrosinase（TYR）,and its intermediate products and final products are characterized by mass spectrometry.The formation of the o-quinone structure is further verified by the MBTH color reaction.2.The coumarin-quinazolone motif in the structure of the prodrug CQB is used as fluorescent clusters and mitochondria targeting group.The cell imaging shows that CQB is located in the mitochondria,which realize the fluorescence monitoring.CQB is selectively activated by ROS and TYR in melanoma cells,the actived drug induces mitochondrial dysfunction by affecting the integrity of mitochondrial DNA,further inhibiting cell proliferation and leading to apoptosis in melanoma.However,the prodrug basically has no effect on the other cell lines.In summary,the dual biomarkers-activated prodrug strategy effectively avoids the non-selectivity of traditional anticancer drugs for cancer cells,and reduces the possible"off-target effect"of prodrugs activated by a single biomarker.The prodrug CQB effectively reduces the side effects of drugs through the cascade reaction of H₂O₂and TYR,and exhibits a highly specific and selective anti-melanoma effect.This will provide an effective reference for the development of new bi-biomarkers or multi-biomarkers activated highly selective anti-cancer prodrugs.