癌基因MDM2阻断剂的分子结构的NMR研究

STUDY ON THE STRUCTURE OF INHIBITORS OF THE MDM2 ONCOGENE

根据P53-MDM2复合物晶体结构 ,设计合成了非肽类小分子作为MDM2的阻断剂 .利用超导核磁共振波谱仪 ,测定了化合物的1 H谱、1 3C谱、1 H 1 H COSY谱、HMQC和HMBC谱 ,确定了化合物的结构 ,归属了化合物的1 H、1 3C化学位移 ,为筛选抗癌活性化合物提供了理论依据 .

The MDM2 oncoprotein is a cellular inhibitor of the P53 tumor suppressor in that it can bind the transactivation domain of P53 and downregulate its ability to activate transcription. In certain cancers, MDM2 amplification is a common event and contributes to the inactivation of P53. The crystal structure of the MDM2 bound to P53 has been analysised through x-ray crystallography. The crystal structure provides a framework for the discovery of compounds that may prevent the activation of the P53 tumor suppressor by the MDM2 oncogene in cancer. Inhibitors of the MDM2 oncogene have been synthesized on the base of this theory.\; All assignments of inhibitors were obtained from \{\}\+1H、 13 C、\+1H-\+1H COSY、 HMQC and HMBC spectra. With regarded to count space distance of two benzene rings, three-bond coupling constants were utilized to determine the structure of inhibitors. Sterostructures and relative configurations were discussed, and dominant energy was computed by using Sybyl software. \;