| In recent years,with the increasing number of cancer patients in various countries,the incidence rate and mortality rate of cancer are increasing year by year.Cancer has gradually become a worldwide serious disease which seriously threatens people's health.According to a report published by the Chinese Medical Association in 2018,there are about 3.09 million new cases of malignant tumors and 1.96 million deaths every year in China,which will increase with the increasing aging of the population.Cancer is a complex genetic disease,which needs the interaction of many ways and targets.Cancer can occur from the abnormal cell division and development in any part of the body,and then produce nearly 100 different types of diseases.With the continuous research of scientist,the therapeutic methods for cancer treatment are developing.For the tumor without metastasis,the treatment methods are mainly divided into single surgical resection or combined with radiotherapy and chemotherapy to eliminate the residual cancer cells,but for the tumor with metastasis,chemotherapy is the most effective treatment.It is worth noting that the current common chemotherapy drugs can not only specifically kill tumor cells,but also cause inevitable damage to normal cells while it works,causing side effects such as bone marrow suppression,alopecia,nausea and vomiting.So more and more researchers are working on specific drugs that can selectively kill tumor cells without damaging healthy tissues and cellsIn recent years,benzoquinone reductase type 1(NQO1)has been widely studied as an detoxification enzyme,and NQO2 as its isoenzyme has been found as early as last century,but there are only a few researches on NQO2.NQO2 are highly expressed in many cancer cell lines and there is evidence that NQO2 activity is associated with NF-?B activity and inducing prostate cancer metastasis.NF-?B is considered a potential chemopreventive target,and its activation induces apoptosis inhibition,a common feature of many types of tumors.The Block of NF-?B can lead to cell death and tumor regression,and inhibition of NF-?B signaling pathways can reduce tumor invasion and metastasis in vitro and in vivo.Therefore,NQO2 can be used as an important chemical prevention target.Moreover,inhibition of NQO2 may improve the efficacy of leukemia drugs to a certain extent.Therefore,in recent years,researchers have begun to explore more potent NQO2 inhibitors in order to develop new chemotherapeutic drugs or anti-tumor adjuvant drugs,and hope to further explore the relationship between NQO2 and cancer.In this project,a series of NQO2 inhibitors with different structures were designed and synthesized,including the compounds including the introduction of amido,aminomethyl and hydroxyurea groups into the A-ring(7a?7c,8a?8c,9a?9c,10?10c,12),benzopyrazine compounds(16a?16c,17a?17c,18)and naphthalene compounds(21),etc.The NQO2 inhibitory activity of the resveratrol derivatives was evaluated in vitro.The experimental results showed that compound 21,which has 3,4,5-trimethoxy substitution in B ring and amino substitution in A ring,and trans double bond to naphthalene ring,has good NQO2 inhibitory activity(IC50=8.9 nM).In conclusion,this study designed and synthesized a number of NQO2 inhibitors with good inhibitory activity,which brought more development possibilities for the research of chemical preventive drugs,and provided more references for the further exploration of the structure-activity relationship and the mechanism of action. |
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