Synthesis and biological evaluation of 4-imidazolidinone-containing compounds as potent inhibitors of the MDM2/p53 interaction.

Inhibition of MDM2/p53 interaction with small-molecule inhibitors stabilizes p53 from MDM2 mediated degradation, which is a promising strategy for the treatment of cancer. In this report, a novel series of 4-imidazolidinone-containing compounds have been synthesized and tested in MDM2/p53 and MDM4/p53 FP binding assays. Upon SAR studies, compounds 2 (TB114) and 22 were identified as the most potent inhibitors of MDM2/p53 but not MDM4/p53 interactions. Both 2 and 22 exhibited strong antiproliferative activities in HCT-116 and MOLM-13 cell lines harboring wild type p53. Mechanistic studies show that 2 and 22 dose-dependently activated p53 and its target genes and induced apoptosis in cells based on the Western blot, qPCR, and flow cytometry assays. In addition, the antiproliferative activities of 2 and 22 were dependent on wild type p53, while they were not toxic to HEK-293 kidney cells. Furthermore, the on-target activities of 2 were general and applicable to other cancer cell lines with wild type p53. These attributes make 2 a good candidate for future optimization to discover a potential treatment of wild-type p53 cancer.

Synergistic effects of acetylated distarch adipate and sesbania gum on gelatinization and retrogradation of wheat starch.

The synergistic effects of the combination of acetylated distarch adipate and sesbania gum (C-ADA-SG) with the ratio of 5:0, 4:1, 2.5:2.5, 1:4, 0:5, accounting for 5% (w/w) of the starch on gelatinization and retrogradation properties of wheat starch (WS) were studied. Scanning Electron Microscopy (SEM) showed that the microstructure of gelatinized WASs (WS added with C-ADA-SG) tended to be smoother. Based on the results of Rapid Visco-Analyzer (RVA) and Differential Scanning Calorimetry (DSC), the pasting characteristics of WS were affected and the gelatinization process was retarded by C-ADA-SG. After seven-day storage at 4 °C, compared to WS, the gel firmness, syneresis, retrogradation enthalpy, and the relative crystallinity of WASs clearly decreased by 17.47-44.36 g, 11.16-17.93%, 0.22-0.80 J·g-1, and 4.06-8.61%, respectively. However, the band ratio 1639:1157 cm-1 by FTIR and loss tangent (tan δ) value were increased with C-ADA-SG addition. Meanwhile, X-Ray Diffraction (XRD) reflected that native WS showed A-type crystal structure, which transferred to B + V type after retrogradation. Furthermore, Low-Field Nuclear Magnetic Resonance (LF-NMR) declared that C-ADA-SG increased the water mobility and limited the diffusion and seepage of water during storage. Generally, ADA and SG produced a synergistic effect on retarding the gelatinization and retrogradation of WS.