Design,Synthesis And Antitumor Activity Of 2-(2-nitrophenoxy)-N-(9-(pyridin-2-ylmethy L)-9H-purin-2-yl)acetamide Analogs As HSP90 Inhibitors

Heat shock protein 90（HSP90）plays an important role in the phenotypic maintenance of tumor cells.Many tumor promoting factors depend on HSP90,and cancer cell proliferation depends on HSP90 function.The study of HSP90 inhibitors which targeted HSP90 has become a hot research field in anti-tumor,and its research for the treatment of cancer has become more and more extensive.As a HSP90 inhibitor,BIIB021 has high bioactivity but poor selectivity and strong side effects.To improve the shortcomings of the original drug BIIB021,our group have synthesized a hybrid drug for o-nitrophenoxyacetic acid and BIIB021.The target compounds were evaluated for biological activity and computer simulations of molecular docking and other tests.The proliferation inhibition test resulted that most of the title compounds had dramaticl selectivity on HL-60 cells(IC₅₀/μM:0.07±0.02¹4.21±0.23)referring to positive control BIIB021(IC₅₀/μM:0.02±0.02),such as compound d1,d2,d3,d7,d8,d10,and d11 all nearly actively equal to the positive control BIIB021,but significantly less toxical(IC₅₀/μM in WI-38cells:more than 53.31±1.28)rather than the positive control BIIB021(IC₅₀/μM in WI-38 cells:27.08±1.26).Compounds d7 and d10 same as positive control BIIB021 strongly induced apoptosis and arrested in G2/M phase in HL-60 cells.Meanwhile,the investigation of molecular docking and molecular dynamics simulation proved docking and stable presence of the complex system between the title compounds including BIIB021 and nitroreductase 1ds7.To sum up,our study discovered that the serious hybrid compounds of o-nitrophenoxyacetic acid and BIIB021,2-（2-nitrophenoxy）-N-（9-（pyridin-2-ylmethyl）-9H-purin-2-yl）acetamide analogs are of potent development for moderate antitumor HSP90 inhibitors with high selectivity and low toxicity.