RESUMEN
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.
Asunto(s)
Antineoplásicos , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Células HEK293 , Línea Celular Tumoral , Apoptosis , Antineoplásicos/farmacología , Antineoplásicos/química , Proteínas Proto-Oncogénicas/metabolismo , Proteínas de Ciclo Celular/metabolismoRESUMEN
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 17.47-44.36â¯g, 11.16-17.93%, 0.22-0.80â¯J·g-1, and 4.06-8.61%, respectively. However, the band ratio 1639:1157â¯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 Bâ¯+â¯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.