Design,Synthesis And Activity Evaluation Of O-Nitrophenoxyacetyl CPMPu Derivatives As Antitumor HSP90 Inhibitor

The persistent high expression of HSP90 plays an extremely important role in the process of carcinogenesis,maintaince and improvement of survival ability,cell proliferation,differentiation and motility in tumor cells.HSP90 inhibitors act as targeting drug delivery system,has a widely application prospect in clinic.Unfortunately,most of HSP90 inhibitors development have been forced to stop due to unacceptable side effect at present.Based on the difference of microenvironment between the tumor and normal tissue as well as electrical and steric structures of drug delivery systems,our group have designed three 2-Nitrophenoxyacetic acid derivatives as drug carrier,which were electron-withdrawing group,electron-donating group and steric effect group,respectively.From this aspect,we hope to get a new drug with high selectivity and minor toxic side effect,which could improve clinic efficiency.The synthesis of target compounds were completed by six-step and structure confirmed by ¹H NMR,¹³C NMR and MS.The aim of this project is to study the difference among the three different kind of o-Nitrophenoxyacetyl CPMPu derivatives on the inhibition of tumor cell proliferation,selectivity of cancer cells and normal cells,and choice the better antitumor activity compounds for further study the cell cycle,apoptosis and stability in plasma in vitro.The inhibition of tumor cell proliferation results show that electron-donating group?0.48?M?IC50?20.51?M?has best inhibition effect on tumor cells than electron-withdrawing group?2.74?M?IC50?28.67?M?and steric effect group?1.24?M?IC50?7.87?M?.Derivatives has best inhibitory effect on A-549?0.48?M?IC50?7.21?M?,Hela?1.61?M?IC50?28.67?M?and Hep-G2?0.84?M?IC50?19.50?M?.4d shows the best inhibitory activity to three types of cells.4a-4d?4m-4p and 4j also have better inhibitory activity.Comparing toxicity experiment of BIIB021 and derivatives on WI-38,it can be seen that derivatives has less toxicity to normal cells than BIIB021,which means derivatives have higher selectivity on tumor cell than BIIB021.Apoptosis cell were determined by AnnexinV/PI assay,4d,4n and 4p were selected to examinate the inducing apoptosis effect on A-549.The results show that all derivatives have effect of inducing apoptosis on A-549,among which 4p is the worst one.While three derivatives'ability to induce apoptosis is less than the positive control drug of BIIB021.The cell cycle experiments found that dosing group G0/G1 decreased but G2/M increased.Compound block cell cycle in G2/M phase.The stabilities of 4n and 4p in plasma were investigated by HPLC,and the results shows that the derivatives in plasma is relatively stable in 48 hours.