Primary Studies On Targeted Therapy Of Triple-negative Breast Cancer And Efficient Synthesis Of Diaminobiaryls

Triple-negative breast cancer is a malignant breast cancer with no expression of estrogen receptor,progesterone receptor and HER2.It develops rapidly and is prone to recurrence and metastasis.Therefore,it becomes one of the most refractory cancer.Currently,conventional chemotherapy remains the main methods for the treatment of triple-negative breast cancer,while targeted therapy is relatively lacking.The application of efficient molecular recognition probes to develop new strategies for targeted therapy has important basic research significance and great application potential.It has been reported that the expression of PTK-7 in triple-negative breast cancer is increased,and the knockout of PTK-7 significantly reduces the growth,migration and invasion of triple-negative breast cancer cells.Therefore,PTK-7 is a potential target for the treatment of triple-negative breast cancer.In addition,nucleolin is also one of the highly expressed biomarkers on triple-negative breast cancer cells,and it has been widely used as a molecular target for triple-negative breast cancer.We constructed Sgc8 and AS1411 dual-targeting DNA tetrahedral delivery system（TDN-SA）for the targeted delivery of 5-FUDR and triptolide（TP）,aiming to improve the therapeutic effect of triple-negative breast cancer through dual-targeting effect and combination therapy.（1）Firstly,the target structure TDN-SA was constructed by connecting Sgc8 and AS1411 at two vertices of the DNA tetrahedron through base pairing.At the same time,we also built a series of controlled structure TDN-C,TDN-S and TDN-A.（2）Then,we researched the difference of these structure in targeting ability,endocytosis and stability.And the experiment results showed that TDN-SA has the strongest binding ability with MDA-MB-468 cells,indicating that the two aptamers achieved the bi-specificity.（3）Finally,we studied the toxicity of the two drugs on positive MDA-MB-468 cell and negative HEK293 cells,and then screened the optimal ratio of drug combination therapy.When TP:5-FUDR=2:1,the strong synergistic effect of drug combination therapy can be achieved,and its IC₅₀ value can be as low as 3.028 n M.The TDN-SA structure that we constructed can be used for targeted delivery of TP and 5-FUDR.This system has great research value and application potential in the targeted therapy of triple-negative breast cancer.2,2′-Diaminobiaryls compounds have a wide range of applications in auxiliary ligands,catalysts and molecular imaging.The C-H/C-H oxidative coupling reaction catalyzed by transition metals is an effective strategy for the synthesis of 2,2’-diaminobiaryls compounds,but the substrate usually requires a protecting group as a guiding group.This method requires two additional steps:the protection of substrate and the deprotection of product.Therefore,it is of great significance to develop a novel coupling strategy without protecting groups for the highly selective synthesis of 2,2’-diaminobiaryls compounds.We developed a nickel-catalyzed reductive homo-coupling reaction strategy of 2-haloaniline,which achieved the efficient construction of symmetric 2,2’-diaminobiaryls compounds.The reaction has broad substrate scope,mild reaction condition and good chemoselectivity.