Design, Synthesis And Biological Evaluation Of MDM2 Ubiquitin Ligase Inhibitors As Antitumor Agents

Cancer is the serious disease that threatens human health. p53-MDM2 regulatory loop is a key target for antitumor drug discovery. As an ubiquitin ligase, oncoprotein MDM2 (Mouse Double Minute 2) inhibits p53 transactivation activity and promotes p53 ubiquitination and degradation. Therefore, it becomes a hotspot for medicinal chemists to develop novel MDM2 ubiquitin ligase inhibitors with high efficacy and low toxicity.Based on the lead structure of 10-(3-Chlorophenyl)-7-nitropyrimido[4,5-b]-quinoline-2,4(3H,10H)-dione (HLI98c) and principle of rational drug design, we designed and synthesized 23 pyrimidoquinoline-dione or pyrimidoindoline-dione derivatives (series A/B), whose structures were confirmed by IR,'H NMR,13C NMR and MS. All compounds were tested for their in vitro cytotoxic activities against five human tumor cell lines. Among of them, four sulfur-containing compounds A15-A18 (IC50:0.5～16.8μM) showed improved activities against all tested cell lines when compared to HLI98c. Furthermore, western blot assay demonstrated that they inhibited MDM2-mediated p53 ubiquitinations at 10μM compared with HLI98c in HCT116. Futuremore, FP assay showed compounds A15-A17 displayed moderate p53-MDM2 binding inhibitory potency with IC50 values ranging from 1.2μM to 8.9μM, which allow them to become potent MDM2 dualfunctional inhibitors. In order to find new structure features of MDM2 ubiquitin ligase inhibitors, principle of rational drug design and CADD were utilized and 20 compounds of three different series:phthalimide derivatives (series C), [1,24]triazolo[4,3-a]quinazolin-5(4H)-one or tetrazolo[1,5-a]quinazolin-5(4H)-one derivatives (series D) andβ-carboline derivatives (series MEL) were designed, synthesized, and confirmed by1H NMR and MS. Primary in vitro cytotoxicities suggested that these compounds showed some antitumor activities. Further pharmacological tests are in progress.