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

Undesirable side effects are caused by traditional chemotherapeutics due to the lack of selective to cancer cells.Although targeted prodrugs have been widely used in clinical and alleviated these problems,there are still some inevitable shortcomings,such as"off-target effects".Using organelle precise drug delivery or dual/multiple biomarkers in cancer cells to induce prodrug activation may be an effective way to overcome this shortcoming,it can effectively improve the selective of cancer by prodrug and reduce undesirable side effects.Melanoma is a malignant tumor with strong invasiveness and high mortality.There is an urgent to develop drugs that effectively and specifically treat melanoma.Base on the simultaneous high expression of H₂O₂and TYR in melanoma,we studied the anti-cancer mechanism and effect of quinazolinone-aryl boronic acid/ester derivatives on melanoma,the main research content for:1.Using arylaldehyde derivatives and 2-aminobenzamide derivatives as starting materials,designed and synthesized a series of quinazolinone-aryl boronic acid/ester compounds 3a-3f,4a-4b,mitochondrial targeting compounds 6-7 and quinazolinone-phenol compounds 5a-5e.Characterized the chemical structure of all compounds.2.Mechanism verification of compounds in vitro.The response behavior of compounds to H₂O₂was verified by HPLC.These results proved the successful implementation of the cascade activation prodrug strategy,and showed that to realize the cascade activation of H₂O₂-TYR,the aryl boronic acid/ester group must be connected to the 3-N of the quinazolinone;Fluorescence spectroscopy experiments showed that coumarin substituent compounds had good fluorescence properties.3.The cytotoxicity of all compounds were studied and the results showed that anti-cancer selective effect of compound 4b was stronger than others;Cytology experiments showed that compound 4b was mainly distributed in the mitochondria of B16 cells and destroyed the redox system,resulted in mitochondria DNA damage and pro-apoptotic protein Bax increased,but it had no obvious effect on other cells.In conclusion,based on the highly expression of H₂O₂and TYR in melanoma and preferentially accumulated in the mitochondria,prodrug effectively improving selective therapeutic to melanoma,while avoiding possible"off-target effect".These results provided a useful reference for the development of new dual-activated anti-cancer prodrugs.