| Tumors have become one of the most important constraint to human health,millions of people around the world die from cancer each year,because it is restricted by the means and methods for the treatment of cancer.Methods for the treatment of cancer in general are surgery,chemotherapy and radiation therapy,chemotherapy is the drug therapy,it is the main treatment of major postoperative clinical treatment and conservative treatment of cancer.Rather specific development of therapeutic drugs catch more and more attention from drug development-workers.Followed by in-depth study of life science,people have a new understanding of the mechanism of tumor,more and more development signal paths are found,the key nodes protein kinases,enzymes or ion channels have become targets of drug development.Tubulin plays an important role in the cell mitosis,in particular,in the rapid proliferation of tumor cells,thereby inhibiting tumor cell mitosis has become an important research direction of drug development.The inhibition of tumor growth can lead to the apoptosis or death.In addition,the carbonic anhydrase enzyme is also a common enzymes.It has been found about 15 isozymes,closely related to the occurrence and development of cancer.We design and evaluate the activity of small molecule inhibitors upon the above two targets.Shikonin is the metabolites from the roots of traditional Chinese herbal medicine,a large number of studies show that it has a wide range of biological activity,such as:anti-inflammatory,anti-cancer,sterilization,anti-virus,antipyretic,hemostasis and so on.Since shikonin itself has a strong toxicity to normal cells,how to get low toxicity and efficient structural modifications becomes a hot research spot.In addition,studies have shown that shikonin and its derivatives have tubulin efficient inhibitory activity.Sulfonamide is anti-cancer drugs’ important active fragment,it is also reported as carbonic anhydrase inhibitors.Therefore,we use molecular docking simulation software filter a plurality of shikonin and sulfonamide fragment active molecules.Experimental results show that moleculars can combine well with tubulin and carbonic anhydrase IX and we get 16 kinds of compounds.We test this new tubulin and carbonic anhydrase inhibitors By in vitro biological activity test.16 kinds of compounds on A549,MCF-7,Hela,HepG2 cells exhibite significant inhibitory activity,in which PMMB-194 molecule on HepG2 cells IC50 value of 2.56 ± 0.04 μM above its lead compound shikonin of 9.22±0.79 μM,apoptosis and mitochondrial membrane potential experiments show the molecule can significantly induce apoptosis in HepG2 cells,and mainly early apoptosis,cell cycle experiments show PMMB-194 molecule can arrest 32.42%of the cells in G2/M phase,and confocal laser shows PMMB-194 molecule can inhibit microtubule polymerization,it is similar as the role of colchicine on microtubules.Thus,we believe that PMMB-194 has the value of in-depth study,and provides a new way for the study of dual-target inhibitors. |
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