Synthesis Of Anti-TNBC NO Donor-Aurovertins Conjugates

Recently,the incidence of breast cancer ranks first among female malignancy in China.Triple negative breast cancer is a subtype with 15% to 20% of patients,but the 5-year survival rate is 70% lower than other breast cancer subtypes.Triple-negative breast cancer exhibits these characteristics including significant invasiveness,higher distant metastasis rate,higher recurrence rate,and shorter overall survival.Furthermore,there are no definite targeted drugs for triple negative breast cancer,and this breast cancer subtype can not effectively address by limited clinical trials.Therefore,the development of effective drugs targeting this subtype is in high demand.Aurovertins,characterized by 2,6-dioxabicyclo [3.2.1] octane ring,is a class of polyketone compounds derived from fungus.It is a total of 21 aurovertin compounds have been found so far.It is found that aurovertin B as an ATP synthase inhibitor can selectively inhibit the proliferation of triple negative breast cancer cells,but the compound has limitations such as large toxicity,narrow therapeutic window,poor water solubility,and difficult to make a drug directly.Therefore,to overcome the shortcomings of aurovertin compounds,this paper aim to obtain candidate compounds with high activity and good water solubility through structural modification.NO donors are a class of compounds that can release NO after simple enzymatic or nonenzymatic actions in the body,and high concentrations of NO can inhibit tumor cell proliferation.NO donors play an important role in structural modification.It can improve pharmacological effects of compound activity and reduce toxicity when NO donors are coupled with active natural products.In the previous research of our group,the benzenesulfonic acid-substituted NO donor was coupled with aurovertin B,and the corresponding NO donor derivatives showed strong anti-negative breast cancer activity.Seven NO donor derivatives,use Aurovtin B as a modifier,were synthesized by our group.The cell lines including A549,MCF-7,MDA-MB-231,MDA-MB-468,and HCC1937 were used to evaluate external activity,and the results showed that this series of compounds had good anti-negative breast cancer activity.In particular,MDA-MB-231 cells had the strongest activity,but the activity on MCF-7 cells was average,and the activity on A549 cells of other strains was poor.In order to further explore the relationship between compound activity and NO release ability,the NO release concentration of this series of compounds was measured using the griess method.The results indicate that the higher the NO concentration released by the compound,the better its anti-negative breast cancer activity,which lays the foundation for further research on the activity of NO donor aurovertin compounds anti triple negative breast cancer.