Hypoxia-activated Prodrug Based On 2-nitroimidazol

In recent years,the incidence and fatality rate of tumor is rising year by year.Chemotherapeutic drugs are important in cancer treatment.The traditional antitumor drugs(such as:paclitaxel and camptothecin)present relevant drawbacks such as severe side effects on normal tissure,poor solubility and multidrug resistance.So the development of high-selective antitumor drug is an important approach to overcome these issues,and more and more researchers focus on the development of prodrugs.Recent years,the development of carbonate prodrugs at 2’-OH of paclitaxel and 20-OH of camptothecin has attracted much attention.However,the low drug release rate in preclinical research limited their application.Therefore,exploiting new carbonate prodrugs of paclitaxel and camptothecin is very important.Hypoxia is an important character of the tumors,which controls the tumor growth,the expression of genes and other physiological processes.2-Nitroimidazole can response to the tumor hypoxic environment.The nitro group can be reduced by reductase,which is highly expressed in hypoxic tumor,then causing the release of active drug.2-Nitroimidazole was widely used in the development of hypoxia-activated prodrugs.In this thesis,firstly,we designed and synthezied the carbonate prodrug of PTX based on the linker of 4-(hydroxymethyl)phenol.However,due to the poor stability of prodrug,the research was discontinued.Then We designed four carbonate prodrugs of paclitaxel and camptothecin on the basis of 2-nitroimidazole.Under the hypoxic condition,they were reduced to the 2-aminoimidazole intermediates,which could promote the hydrolysis of carbonate bond and the release of active drug.This strategy increased the selectivity towards hypoxic tumors.The drug release mechanism was demonstrated by chemical reduction and nitroreductase assay.The stability of prodrugs and the effectiveness of drug release mechanism were demonstrated by stability assay in different buffers(including PBS,human plasma and mouse plasma)and nitroreductase assay.The prodrugs showed considerable stability in different buffer and human plasma,and were reduced rapidly by nitroreductase.Among four prodrugs,compound 13(2C-PTX)relesased 85%PTX after 1 h incubation with nitroreductase.It indicated that the nitroimizdazole could promote the drug release after being reduced.Four prodrugs all showed hypoxia selectivity in vitro cell-proliferation assay.Compound 7(3C-SN38)showed the highest hypoxia-selectivity ration of 2 on H460 cell line,and compound 13(2C-PTX)showed the highest hypoxia-selectivity ration of 3 on HT-29 cell line.The new class of prodrugs with a new drug release mechanism provides a fundamental work for the development of hypoxia-activated prodrugs.