Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein-Protein Interaction.

Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.

Co-delivery of gambogenic acid and VEGF-siRNA with anionic liposome and polyethylenimine complexes to HepG2 cells.

Background and objective: The combination of two or more different mechanisms of drugs in the treatment of cancer has become one of the effective methods. The purpose of this study was to successfully prepare a non-viral delivery system that could efficiently co-delivery siRNA and gambogenic acid (GNA) to improve the anti-cancer efficiency in HepG2 cells. Methods: The delivery system was prepared by a two-step method. First, the GNA-anionic liposome took shape by a solvent evaporation method, and then the liposome was bound to the PEI/siRNA complex by electrostatic interaction to form the final carrier system (lipopolyplexes). Agarose gel electrophoresis, MTT, particle size and zeta potential were detected to analyse the lipopolyplexes formation. The transfection efficiency of siRNA was determined by confocal laser scanning microscopy and flow cytometry. Western blotting was used to assess the VEGF protein expression levels of HepG2 cells. The cell apoptosis assay was used to assess the anti-tumour superiority of lipopolyplexes. Results: GNA-PEI/siRNA-liposome (lipopolyplexes) are significantly less cytotoxicity compared to PEI mediated carriers. Simultaneously, the results of flow cytometry and confocal laser scanning microscopy indicated that the lipopolyplexes could successfully carry siRNA into the cytoplasm, and the western-blot result evidence that the delivery system has a potential for VEGF to express down. Also compared with the control group, the results of apoptosis test suggest that the lipopolyplexes can significantly promote cell apoptosis. Conclusion: The delivery system has a potential in the combination of various drugs for cancer therapy in future.

Increase of rutin antioxidant activity by generating Maillard reaction products with lysine.

Rutin exists in medicinal herbs, fruits, vegetables, and a number of plant-derived sources. Dietary sources containing rutin are considered beneficial because of their potential protective roles in multiple diseases related to oxidative stresses. In the present study, the change and antioxidation activity of rutin in Maillard reaction with lysine through a heating process were investigated. There is release of glucose and rhamnose that interact with lysine to give Maillard reaction products (MRPs), while rutin is converted to less-polar quercetin and a small quantity of isoquercitrin. Because of their high cell-membrane permeability, the rutin-lysine MRPs increase the free radical-scavenging activity in HepG2 cells, showing cellular antioxidant activity against Cu(2+)-induced oxidative stress higher than that of rutin. Furthermore, the MRPs significantly increased the Cu/Zn SOD (superoxide dismutase) activity and Cu/Zn SOD gene expression of HepG2 cells, consequently enhancing antioxidation activity.

Synthesis, characterization, thermal properties and antiproliferative potential of copper(II) 4'-phenyl-terpyridine compounds.

Reactions between 4'-phenyl-terpyridine (L) and several Cu(II) salts (p-toluenesulfonate, benzoate and o-, m- or p-hydroxybenzoate) led to the formation of [Cu(p-SO3C6H4CH3)L(H2O)2](p-SO3C6H4CH3) (1), [Cu(OCOPh)2L] (2), [Cu(o-OCOC6H4OH)2L] (3), [Cu(m-OCOC6H4OH)2L]4·MeOH (·MeOH) and [Cu(p-OCOC6H4OH)2L]5·2H2O (·2H2O), which were characterized by elemental and TG-DTA analyses, ESI-MS, IR spectroscopy and single crystal X-ray diffraction, as well as by conductivimetry. In all structures the Cu atoms present N3O3 octahedral coordination geometries, which, in 2-5, are highly distorted as a result of the chelating-bidentate mode of one of the carboxylate ligands. Intermolecular π···π stacking interactions could also be found in 2-5 (in the 3.569-3.651 Å range and involving solely the pyridyl rings). Medium-strong hydrogen bond interactions lead to infinite 1D chains (in 1 and 4) and to an infinite 2D network (in 5). Compounds 1 and 4 show high in vitro cytotoxicity towards HCT116 colorectal carcinoma and HepG2 hepatocellular carcinoma cell lines. The antiproliferative potential of compound 1 is due to an increase of the apoptotic process that was confirmed by Hoechst staining, flow cytometry and RT-qPCR. All compounds able to non-covalently intercalate the DNA helix and induce in vitro pDNA double-strand breaks in the absence of H2O2. Concerning compound 1, the hydroxyl radical and singlet oxygen do not appear to be involved in the pDNA cleavage process and the fact that this cleavage also occurs in the absence of molecular oxygen points to a hydrolytic mechanism of cleavage.

Small-molecule MDM2-p53 inhibitors: recent advances.

Potent and selective small-molecule inhibitors of the p53-MDM2 interaction intended for the treatment of p53 wild-type tumors have been designed and optimized in a number of chemical series. This review details recent disclosures of compounds in advanced optimization and features key series that have given rise to clinical trial candidates. The structure-activity relationships for inhibitor classes are discussed with reference to x-ray structures, and common structural features are identified.

Effect of cigarette smoking on clinical outcomes of hospitalized Chinese male smokers with acute myocardial infarction.

BACKGROUND: Smoking is known to be a strong risk factor for premature atherosclerosis, acute myocardial infarction (AMI) and sudden cardiac death. According to a cross-sectional survey conducted in 2000 - 2001 in China, the prevalence of smoking among the Chinese men was 60.2%, the highest prevalence in the world. Up to date, the relationship between smoking and AMI in Chinese male smokers is still unclear. This study analyzed the baseline characteristics for male smokers hospitalized with AMI and investigated the effect of cigarette smoking on their clinical outcomes. METHODS: A total of 890 men aged 18 years or over with AMI were prospectively recruited from 1 January 2007 to 31 December 2009 from Shanxi Provincial People's Hospital. Patients were grouped into smokers and nonsmokers. The relationships between baseline characteristics and clinical outcomes were tested using either the chi-square test for trend for discrete variables or analysis of variance for continuous variables. RESULTS: Smokers accounted for 66.7% (594), more than twice of nonsmokers (296 (33.3%)), and were averaged 7 years younger ((56.61 ± 11.44) vs. (63.61 ± 11.62) years, P < 0.001). Smokers had the higher rate of TIMI flow grade 2 or 3 after thrombolytic therapy (42.4% vs. 24.5%, P = 0.002), 1 vessel disease (25.5% vs. 14.5%, P = 0.003) than nonsmokers. Smokers had better in-hospital outcome with lower in-hospital mortality rate than nonsmokers (6.2% vs. 10.8%, P = 0.023). CONCLUSIONS: Male smokers suffered from AMI in this study presented an average of 7 years earlier than nonsmokers and were more than twice as likely to have AMI as nonsmokers in China. Smoking appeared to result in earlier infarction, especially ST elevated myocardial infarction in otherwise healthier patients who are likely to survive.

Dominant expression of 85-kDa form of cortactin in colorectal cancer.

PURPOSE: Cortactin is commonly expressed in several human cancers, which may alter their invasive or metastatic properties. Eighty five kilodalton form (p85) and 80-kDa form (p80) of cortactin are two separate bands in SDS-PAGE representing different conformational states. The objective of this study was to investigate cortactin expression in colorectal cancer (CRC). EXPERIMENTAL DESIGN: Cortactin expression was studied in an eight paired laser capture microdissection (LCM) CRC tissues and matched non-cancerous epithelia by immunoblotting. The expression in 58 CRC and two cell lines, HCT8 and HCT116, was studied respectively by immunohistochemistry and confocal laser scanning immunofluorescence. RESULTS: Dominant expression of p85 was identified in LCM-procured CRC tissues compared with equal intensity of p85 and p80 forms in non-cancerous tissues, while the amount of total cortactin was approximate. Immunohistochemistry analysis demonstrated that cortactin located in the cytoplasm of tumor cells and adjacent non-cancerous cells, and its expression was negatively correlated with TNM staging and lymphatic invasion status. However, the invasion fronts in 3 of 58 primary tumors and 28 of 39 available lymph node metastases were intensively stained. Further, immunofluorescence analysis showed that cortactin was distributed in cytoplasm and enriched in the front of the extending lamellipodia at adhering side of cultured cancer cells. CONCLUSIONS: Our results demonstrated the dominant expression of p85 form of cortactin in CRC for the first time. The enrichment of cortactin in the invasion front of some tumor cells and in the extending lamellipodia of cultured cancer cells suggests that cortactin may help cancer cell movement.