The Structural Modification And Antitumor Study Of Salinomycin

Cancer is a disease that seriously endangers human health.According to statistics,more than 3 million malignant tumor cases occur each year,and more than 2 million people died of cancer each year in China.In order to develop new antineoplastic drugs,through high-throughput screening,Gupta's group found that Salinomycin has high selectivity on breast cancer stem cells with activity 100-fold higher than paclitaxel in 2009.The discovery made Salinomycin a hotspot in biomedical research.In 2012,the US FDA approved the clinical study of Salinomycin for breast cancer and head and neck cancer.Although Salinomycin has a wide application prospect in the field of anti-tumor,it still has safety and toxicity issues.To develop new anti-tumor drugs,it is necessary to modify the structure of Salinomycin.Currently,the modification of Salinomycin is mainly focused on the simple derivatization of the 1-carboxyl group,the 9-,20-and 28-hydroxyl groups and the 18-double bond.Firstly,we reversed the C20 configuration by Mitsunobu reaction with azide,and then a series of Salinomycin derivatives were synthesized by CuAAC reaction.Through the cytotoxicity test of the compound library,we found that compound 5w could significantly improve the potency and selectivity to tumor cells and reduce the toxicity to normal cells.Compound 5w has high 19F-NMR sensitivity and its metal ion chelates give a single fluorine signal to achieve 19F-MRI at low concentrations.So compound 5w could serve as a tool molecular for 19F NMR/MRI-guided mechanism study of Salinomycin'S effects on cancer cells and 19F MRI-guided cancer therapy.In order to further study the antitumor activity of Salinomycin,we reduced C20 azide to amino by Staudinger reaction,and amidation reaction provides a convenient way to generate another Salinomycin analog library under mild conditions.Currently,the cytotoxicity of this library is being tested in order to identify high active and selective anti-tumor compounds.