The Study Of Design,Synthesis And Antitumor Activity Of AMG232 Analogues And The Chiral Resolution Of Pyrrolidone Pyrazole Compounds

Tumor suppressor gene p53 is a regulatory factor that plays an important role in tumorigenesis.It is widely considered to be the “guardian of the genome” and is involved in the repairing and apoptosis of damaged cells.MDM protein is the most important negative feedback regulator of p53,which can inhibit the activity of p53 protein.MDM2 overexpression often leads to cell proliferation out of control,followed by tumor happening.AMG232 is a type of small molecule inhibitors of piperidine ketone reported by Amgen Corporation,which can inhibit the activity of MDM2 protein by binding to specific sites of MDM2 and blocking the interaction of p53-MDM2.It is excellent in tumor inhibitory activity,at the molecular and cellular levels have reached low nM level,and is the only one successfully entered the clinical phase II test of p53-MDM2 interaction molecular inhibitors,with a high drug prospect.But its carboxyl side chain can easily binding to the glucuronic acid in vivo to beinactivate from metabolic,resulting in a short biological half-life.So,this maybe cause frequent burden on patients with drugs;and its bioavailability also have a certain negative impact.In this study,the AMG232 carboxyl side chain was transformed into esters to prevent its inactivation with glucuronic acid in vivo,thereby prolonging its biological half-life and making its pharmacokinetic properties more excellent.Through the design and synthesis,15 new AMG232 ester derivatives were obtained.In addition,we have explored the synthetic route of these compounds and synthesized an intermediate of the compounds with new routes.The NF-?B pathway is an important immune response mediator in mammals,and is often highly active in many patients with tumors and immune disorders.NF-?B constitutive gene mutations are associated with many chronic inflammation that determines the progression of tumors,and NF-?B also induces tumor cells to be resistant to multiple antineoplastic agents.Our group have obtained a class of high-activity pyrrolone double-target compounds that simultaneously activate the p53 signaling pathway and inhibit the NF-?B signaling pathway by virtual screening.Based on the pyrazone skeleton leader,a more active pyrrolidone pyrazole compound was found by a reasonable rational drug design.Studies on the mechanism of these compounds have shown that R-isomers activate p53 in a dose-dependent manner and inhibiting MDM2 expressionSimultaneously.While the S-isomer has no significant effect on the p53 pathway.The effect of the isomers on the NF-?B pathway is completely opposite to that of the p53 pathway.The S-isomer can activate phosphorylated IKK?,?,? and inhibit the activation of NF-?B,whereas the R-isomer was no effect on NF-?B pathway.In addition,the activation of the single R-isomer to the p53 signaling pathway and the inhibition of the NF-?B signaling pathway by the single S-isomer were significantly lower than the corresponding activity of the metered racemate,indicating that there is a clear interaction between the p53 signaling pathway and NF-?B signaling pathway.In order to study the synergistic effect and antitumor activity of p53 pathway and NF-?B pathway by two kinds of single optical isomers and different proportions of racemates of each active compounds,we studied the pyrrole compounds as asymmetric synthesis,obtained four pairs of high ee values of R and S optical isomers,and studied the optimal ratio of the two optical isomers.