Chunqi Hu

Design, synthesis and AChE inhibitory activity of indanone and aurone derivatives.

A new series of indanone and aurone derivatives have been synthesized and tested for in vitro AChE inhibitory activity by modified Ellman method. Most of them exhibit AChE inhibitory activities superior to rivastigmine. Further, the most potent compound 1g was selected to evaluate the effect on the acquisition and memory impairment by mice step-down passive avoidance test.

Design, synthesis and biological evaluation of novel 3,4,5-trisubstituted aminothiophenes as inhibitors of p53-MDM2 interaction. Part 2.

Five series of novel 3,4,5-trisubstituted aminothiophene derivatives and analogs were designed and synthesized based on our previous studies. All target compounds were evaluated for their p53-MDM2 binding inhibitory activities and anti-proliferation activities against A549 and PC3 tumor cell lines. Twelve compounds displayed comparable p53-MDM2 binding inhibitory activities to that of Nutlin-3. Among them, compound 7a exhibited marked binding affinity (IC50=0.086 μM). In addition, most target compounds showed potent anti-proliferation activities with IC50 values at low micromolar level. A good selective profile for wild-type p53 expression cell line was also observed. Molecular docking analysis was performed as well to predict possible binding modes of target compounds with MDM2.

Efficient activation of p53 pathway in A549 cells exposed to L2, a novel compound targeting p53-MDM2 interaction.

The tumor suppressor p53 plays a key role in the regulation of cell cycle, apoptosis, DNA repair, and senescence. It acts as a transcriptional factor, and is able to activate various genes to exert specific functions. MDM2, the main regulator of p53, inhibits the function of p53 through direct interaction. On the basis of this finding, inhibiting the MDM2–p53 interaction can be a potentially important target for cancer therapy. We showed here that L2, an analog of small-molecule MDM2 antagonist nutlins, stabilized p53 and selectively activated the p53 pathway in p53 wild-type A549 cells, resulting in a pronounced antiproliferation effect through inducing cell cycle arrest and apoptosis. Meanwhile, we confirmed by immunoprecipitation analysis that L2 could also inhibit MDM2–p53 interaction, similar to nutlin-1. Real-time PCR results revealed that L2 had no effect on the p53 gene transcriptional level, but it could induce the upregulation of p21 at the transcriptional level, which was the downstream of p53. Therefore, we concluded that the accumulation of p53 caused by L2 was mainly because of the decrease of the protein degradation rather than the elevation of p53 gene expression. Furthermore, no phosphor-p53 formed after L2 treatments, indicating that a genetoxic mechanism was unlikely to contribute to the activation of p53 by L2. In conclusion, the data acquired from A549 cells indicated that L2 exhibited high antiproliferation activity by disrupting MDM2–p53 interaction, and that the mechanism was derived from the activation of p53 and the p53 pathway. It was also surprising that L2 showed high antiproliferation effect against p53 null HL60 cells, which was quite different from nutlin-1. G2/M phase arrest might have contributed to the high antiproliferation activity of L2 on HL60 cells. The changes of p53 and MDM2 protein levels in L2-treated HL60 cells indicated that the mechanisms involved in the cell cycle arrest in A549 and HL60 cells were probably different, to which our future research would be devoted.

Design, synthesis, and biological evaluation of imidazoline derivatives as p53–MDM2 binding inhibitors

Three series of novel imidazoline derivatives were designed, synthesized, and evaluated for their p53-MDM2 binding inhibitory activities, and anti-proliferation activities against PC3, A549, KB, and HCT116 cancer cell lines. Five of the tested compounds showed enhanced p53-MDM2 binding inhibitory potency and anti-proliferation activities in comparison with that of Nutlin-1. Flow cytometric analysis indicated that compound 7c, one of the most potent p53-MDM2 binding inhibitors with a K(i) value of 0.6 μM, showed its ability to arrest cell cycle progression.

Design, synthesis and CoMFA studies of N1-amino acid substituted 2,4,5-triphenyl imidazoline derivatives as p53-MDM2 binding inhibitors.

A series of novel N1-amino-acid substituted 2,4,5-triphenyl imidazoline derivatives was designed and synthesized based on our previous studies. All synthesized target compounds were screened for their p53-MDM2 binding inhibitory activities and anti-proliferative activities against five cancer cell lines. Among them, twelve compounds displayed improved binding inhibitory activities and most compounds showed higher cell growth inhibition activities with IC(50) values in the low micromolar range. Compound 6c exhibited marked p53-MDM2 binding inhibitory activity (IC(50)=0.59 μM) which was eightfold more potent than that of Nutlin-1 (IC(50)=4.78 μM). CoMFA analysis was performed based on obtained biological data and resulted in a statistically significant CoMFA model with high predict abilities (q(2)=0.645, r(2)=0.979).

Synthesis and biological evaluation of novel pyrimido[4,5-b]quinoline-2,4- dione derivatives as MDM2 ubiquitin ligase inhibitors.

A series of pyrimido[4,5-b]quinoline-2,4-dione derivatives was synthesized and evaluated for their cytotoxic activities in vitro against five human cancer cell lines. Selected compounds were tested for their MDM2 E3 ligase inhibitory activities and p53-MDM2 binding inhibitory activities. Among tested compounds, four sulfur-containing compounds (4-7) displayed enhanced cytotoxic activities and better MDM2 E3 ligase inhibitoty activities in comparison with that of HLI98c. Three compounds (4-6) showed better p53-MDM2 binding inhibitory potency with IC50 values ranging from 1.3 μM to 9.0 μM.

Discriminatory analysis based molecular docking study for in silico identification of epigallocatechin-3-gallate (EGCG) derivatives as B-RafV600E inhibitors

Virtual screening and biological testing were utilized to identify novel B-RafV600E inhibitors. The employed LigandFit program was evaluated by examining the accuracy of the binding conformation prediction and binding affinity estimation (scoring function) via discriminative analysis training. Ten novel compound hits from the database screening were selected and subjected to in vitro biological tests. The natural product EGCG (A8) was discovered to have promising B-RafV600E inhibitory, and then we evaluated six structurally similar compounds (B1, B2, B3, C1, C2, and C3) for their B-RafV600E inhibitory activities in order to establish a structure–activity relationship. One of these compounds, B2, demonstrated a promising B-RafV600E inhibitory activity with an IC50 value of 9.1 μM, providing a theoretical basis for the development of novel agents as B-RafV600E inhibitors.