Discovery Of N-(6-chloro-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9H-2-purin)-2-ni Trobenzamide Derivatives As HSP90 Inhibitor

HSP90(heat shock protein) overexpresses in tumor cells,and can help tumor cells to overcome multiple environmental stress,thus promoting the excessive growth of tumor cells.At present,HSP90,as a target for cancer treatment,has been widely concerned by the scientific community.HSP90 inhibitors can block the signal transduction pathway promoting tumor cell growth,so as to effectively inhibit the malignant proliferation and metastasis of tumor cells.Therefore,HSP90 inhibitors have broad application prospects in the treatment of cancer.Based on the microenvironment of hypoxia,low p H and high reductase activity in tumor cells different from normal cells,the prodrug produced by o-nitrobenzoic acid series and HSP90 inhibitor BIIB021 was designed by computer simulation technique to improve the original drug's shortcomings such as fast metabolism,serious side effects and so on.We evaluated the synthetic target compounds in a number of ways,including the determination of their physical and chemical properties,biological activity and molecular docking test of computer simulation.(1)First,we synthesized the original drug BIIB021 with the best solution by consulting a variety of literature.And then we adopted the method of acid chloride to synthetize three kinds of target compounds,namely the electronic group,the electron group and the control group,using o-nitroaromatic acid series(different substituents of o-nitrobenzoic acid and o-nitrophenyl acetic acid)and BIIB021 as raw materials.Their structures were confirmed by1H-NMR,13C-NMR and ESI-MS.(2)Tumor cell proliferation inhibition experiments showed that all the target compounds had different inhibitory effects on tumor cells.On the whole,the inhibitory activity of the target compounds on He La cells(IC50 = 0.72 ± 0.07 ~ 17.32 ± 2.39)were better than Hep-G2(IC50 = 1.14 ± 0.16 ~ 41.97 ± 1.86)and A549(IC50 = 1.48 ± 0.33 ~ 53.72 ± 5.75).Through the numerical analysis of antitumor activity,it was concluded that the electronic effect had no effect on the inhibitory activity.The inhibitory activities of compounds a2 and b3 were better,and the IC50 value of a2 was the lowest and equivalent to the original drug BIIB021.(3)The results of cell cycle and apoptosis showed that: a2 and b3,two compounds with the best cell activity,had strong ability of cycle blocking effect and inducing apoptosis;the cycle blocking effect of b3 was strongest and a2 had the strongest ability to induce apoptosis.(4)The results of computer mimetic molecular docking showed that: the target compound molecules formed a hydrophobic interaction and hydrogen –bond interaction with the amino acid residues in the nitro reductase activity chamber,and then formed a good docking with the enzyme.we inferred that the target compound could be treated by nitro reductase reduction in tumor cells,directing to releasing BIIB021.According to the results of cell activity experiment and computer simulation,the binding ability of the target compound to nitro reductase was stronger,the inhibition of tumor cells would be stronger.