Design And Synthesis Of Hypoxia-targeted Prodrugs Of Gemcitabine Protide

Design and Synthesis of Hypoxic Targeting Prodrug for Gemcitabine ProtideThe threat of cancer to human beings is getting more and more serious.Existing chemotherapeutic drugs can damage normal human cells while killing tumor cells.Due to the rapid growth of tumors,hypoxic regions are produced in the central part of solid tumors.The hypoxic tumor is an important cause of tumor resistance.Drugs targeting tumor hypoxic regions have good prospects for development.Gemcitabine is a nucleoside antitumor drug used in the treatment of pancreatic cancer and non-small cell lung cancer.Protide technology can overcome the problem of tumor drug resistance of nucleoside drugs such as gemcitabine.This paper introduced the nitro hypoxiatargeting group in Protide prodrug of gemcitabine and synthesized some gemcitabine protide prodrugs with tumor hypoxia targeting.In this dissertation,nine hypoxic groups were designed and synthesized.Preliminary research results show that the compounds YL-01?YL-05 had a significant inhibitory effect on the growth of Bx PC-3 cells.YL-01,YL-02,YL-03 had the similar cytostatic effects under hypoxic conditions,and YL-02,YL-03 inhibit cell growth similarly under normoxic and hypoxic conditions.Combined with the results of liver homogenate stability,YL-03 is more stable and has further research value.Copper Catalyzed Synthesis of 4-AminoquinazolinesA highly efficient copper-catalyzed one-pot protocol is developed for the synthesis of 4-aminoquinazolines from easily available 2-iodo-or 2-bromobenzimidamides,aldehydes,and sodium azide.This one-pot approach proceeds via consecutive coppercatalyzed SNAr substitution,reduction,cyclization,oxidation and tautomerization.The corresponding target products(26 examples)are obtained in 50–90% yield.