| Mdm2 is an oncogene detected in recent years. It's expression product, mdm2 oncoprotein, can bind to p53 protein, inhibiting the normal biologic functions of p53. Loss of p53 functions as tumor suppressor is important to tumor development. Theoretically, blockade of the mdm2-p53 interaction is able to resume the normal functions of p53. Therefore, mdm2 may be regarded as a new target in anti-cancer drug design. Recently some peptides have been shown to potently inhibit the p53-mdm2 interaction in vitro, and to stimulate the p53 pathway in tumor cells that express wild type p53. As the peptides possess inherent shortcoming as therapeutics expensive to synthesize, it remains to establish whether small molecules can inhibit the p53-hdm2 interaction in a cellular environment. The crystal structure of p53-mdm2 complex has been resolved in 1996. The 109-residue amino-terminal domain of mdm2 binds to an 11-residue transactivation domain peptide of p53. Mdm2 inactivates p53 by concealing its transactivation domain. In this thesis, a series of small molecules with flexible back-bone as mdm2 inhibitors were designed and synthesized based on crystal structure of mdm2-p53 complex. Molecular diversity has been considered in the design on the aspects of electronic character, hydrophilic and hydrophobic characteristics, site of hydrogen bonding as well as dimension of substituted groups etc. Totally 87 compounds were synthesized, 69 of which are unreported including 38 target molecules. All structures of them were validated by NMR, MS, EA or HRMS. The receptor binding affinity and cell toxicity (MTT) were conducted for all the target compounds and cell apoptosis assays for some of them were performed. The results show that some compounds had inhibitory effect on some tumor cell lines with high expression of p53 (wt) and IC50 of them ranges from 10-5 mol/L to 10-8 mol/L. The cell apoptosis assays approve that the death tumor cell was attritable to the apoptosis. |
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