Design, synthesis, and antiproliferative activity of new indole/1,2,4-triazole/chalcone hybrids as EGFR and/or c-MET inhibitors.

A novel group of indolyl-1,2,4-triazole-chalcone hybrids was designed, synthesized, and assessed for their anticancer activity. The synthesized compounds exhibited significant antiproliferative activity. Compounds 9a and 9e exhibited significant cancer inhibition with GI50 ranging from 3.69 to 20.40 µM and from 0.29 to >100 µM, respectively. Both compounds displayed a broad spectrum of anticancer activity with selectivity ratios ranging between 0.50-2.78 and 0.25-2.81 at the GI50 level, respectively. The synthesized compounds were also screened for their cytotoxicity by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazol (MTT) assay and for inhibition of epidermal growth factor receptor (EGFR) and c-MET (mesenchymal-epithelial transition factor). Some of the tested compounds exhibited significant inhibition against EGFR and/or c-MET. Compound 9b showed the highest c-MET inhibition (IC50 = 4.70 nM) compared to foretinib (IC50 = 2.5 nM). Compound 9d showed equipotent activity compared with erlotinib against EGFR (IC50 = 0.052 µM) and displayed significant c-MET inhibition with an IC50 value of 4.90 nM.

Recent progress in biologically active indole hybrids: a mini review.

The indole moiety is one of the most widespread heterocycles found in both natural products and biological systems. Indoles have important biological activities including anticancer, antioxidant, anti-inflammatory, antifungal, anticholinesterase, and antibacterial properties. Scientists are therefore interested in the synthesis of biologically active indole-based hybrids such as indole-coumarin, indole-chalcone, indole-isatin, indole-pyrimidine and so on, with the aim of improving activity, selectivity, and mitigating side effects. This review will discuss the newly synthesized indole-based hybrids along with their biological activity which will be useful in drug discovery and development.

Low Molecular Mass Polypeptide 7 Single Nucleotide Polymorphism is Associated with the Progression of Liver Fibrosis in Patients Infected with Hepatitis C Virus Genotype 4.

BACKGROUND: The hepatitis C virus (HCV) is a leading cause of liver disease and the consequent complications of cirrhosis. However, there is no precise biomarker to predict the patients at high risk of developing progressive disease. We showed previously the implication of low molecular mass polypeptide-7 (LMP-7) single nucleotide varia- tions in the response to combined pegylated IFN and ribavirin therapy in patients infected with HCV genotype 4. In this study, we examined the possible relationship between LMP-7 genotypes and both the degree of liver fibrosis and the transition from end stage of fibrosis to hepatocellular carcinoma (HCC). METHODS: LMP-7 single nucleotide variation at codon 49 (substitution from A to C) was determined using restriction fragment length polymorphism analysis in leucocyte DNA from healthy subjects (n = 36) and HCV-chronically infected patients of genotype 4 either with different grades of liver fibrosis (n = 77) or with hepatocellular carci- noma (n = 25). Chronic HCV-infected patients having liver fibrosis were categorized into two groups based on the degree of fibrosis, early fibrosis (F0-F2, n = 37) and late fibrosis (F3-F4, n = 40). RESULTS: Our results demonstrated that patients with the LMP-7 CA/AA genotypes were more likely to have advanced fibrosis scores than those bearing the CC genotype, although LMP-7 polymorphism does not seem to contribute to the progression from the late stage of fibrosis to hepatocellular carcinoma. CONCLUSIONS: These results suggest that LMP-7 polymorphism is a candidate prognostic marker in mathematical models designed for predicting the progression of HCV-related liver disease. Nevertheless, the mechanism whereby LMP-7 leads to the progression of liver fibrosis remains to be determined.

Health-related quality of life after serious occupational injury in Egyptian workers: a cross-sectional study.

OBJECTIVES: Occupational injuries can have severe socioeconomic consequences; however, little research has examined the health-related quality of life (HRQoL) of workers following occupational injuries, especially in developing countries. This study was to employ the European Quality of Life Five Dimensions (EQ-5D) tool to measure HRQoL 6 months following serious occupational injury sustained by insured workers in the East Delta Region of Egypt. DESIGN: This cross-sectional study was conducted from July to December 2008 among workers injured severely enough to be off work for at least 6 months after an occupational injury. SETTING: The Nile Insurance Hospital in Qalyubia, Egypt. PARTICIPANTS: Adult workers returning for follow-up evaluation after being given 6 months off work by a physician for an occupational injury. OUTCOMES: The workers described their health and quality of life using the EQ-5D instrument. RESULTS: Most study participants were male (n=118 (90%)), with mean age of 41.5 years. Fractures were the most common type of injury (n=96 (73%)), mostly involving the lower limbs (n=70 (53%)). Participants identified persistent problems related to mobility (n=78 (60%)), self-care (n=69 (53%)), performing usual activities (n=109 (83%)), pain/discomfort (n=119 (91%)) and anxiety/depression (n=51 (40%)). The perceived HRQoL estimated by the mean (±SD) visual analogue scale (VAS) score among injured workers was 61.6±17.9. Multivariate linear regression showed an association between poor VAS score and amputations, mobility limitation, self-care problems, pain/discomfort and anxiety/depression. CONCLUSIONS: Some people with occupational injuries experience significant problems such as pain/discomfort, functional limitations and anxiety/depression, long after the injury. Improvement in pain management strategies and physical and psychological rehabilitation may improve their health-related quality of life.