Design and synthesis of dihydrobenzofuran amides as orally bioavailable, centrally active γ-secretase modulators

We report the discovery and optimization of a novel series of dihydrobenzofuran amides as γ-secretase modulators (GSMs). Strategies for aligning in vitro potency with drug-like physicochemical properties and good microsomal stability while avoiding P-gp mediated efflux are discussed. Lead compounds such as 35 and 43 have moderate to good in vitro potency and excellent selectivity against Notch. Good oral bioavailability was achieved as well as robust brain Aβ42 lowering activity at 100 mg/kg po dose.     

A high-throughput screen to identify inhibitors of ATP homeostasis in non-replicating Mycobacterium tuberculosis

Growing evidence suggests that the presence of a subpopulation of hypoxic non-replicating, phenotypically drug-tolerant mycobacteria is responsible for the prolonged duration of tuberculosis treatment. The discovery of new antitubercular agents active against this subpopulation may help in developing new strategies to shorten the time of tuberculosis therapy. Recently, the maintenance of a low level of bacterial respiration was shown to be a point of metabolic vulnerability in Mycobacterium tuberculosis. Here, we describe the development of a hypoxic model to identify compounds targeting mycobacterial respiratory functions and ATP homeostasis in whole mycobacteria. The model was adapted to 1,536-well plate format and successfully used to screen over 600,000 compounds. Approximately 800 compounds were confirmed to reduce intracellular ATP levels in a dose-dependent manner in Mycobacterium bovis BCG. One hundred and forty non-cytotoxic compounds with activity against hypoxic non-replicating M. tuberculosis were further validated. The resulting collection of compounds that disrupt ATP homeostasis in M. tuberculosis represents a valuable resource to decipher the biology of persistent mycobacteria.     

Measurement of γ-H2AX foci,miRNA-101, and gene expression as a means to quantify radiation-absorbed dose in cancer patients who had undergone radiotherapy

Radiation and Environmental Biophysics - Radiological accidents and nuclear terrorism pose an increased threat to members of the public who, following such an event, would need to be assessed for...     

Combined therapeutic efficacy of carvacrol and X-radiation against 1,2-dimethyl hydrazine-induced experimental rat colon carcinogenesis

Molecular and Cellular Biochemistry - Colon cancer is one of the most commonly diagnosed cancers, and is a major cause of cancer morbidity and mortality worldwide. The objective of the present...     

Correction to: Combined therapeutic efficacy of carvacrol and X-radiation against 1,2-dimethyl hydrazine-induced experimental rat colon carcinogenesis

Molecular and Cellular Biochemistry -     

Protection against X-ray radiation-induced cellular damage of human peripheral blood lymphocytes by an aminothiazole derivative of dendrodoine

The present study was aimed to evaluate the radioprotective efficacy of dendrodoine analog (DA), an aminothiazole derivative against X-ray radiation-induced cellular damage in cultured human peripheral blood lymphocytes. Different concentrations of DA (2, 4, 6, 8, 10 μg/ml or 6.15, 12.29, 18.44, 24.59, 30.73 μM) were pre-incubated with lymphocytes for 30 min prior to irradiation [4 Gy] and the micronuclei (MN) scoring and comet assay were performed to fix the effective concentration of DA against 4 Gy irradiation-induced cellular damage. The results indicated that among all the concentrations, 6 μg/ml concentration of DA showed optimum protection by effectively decreasing the MN frequencies and comet attributes. Based on the above results, 6 μg/ml concentration of DA was fixed as the effective dose to further investigate its radioprotective efficacy. This was carried out by pre-incubating the lymphocytes with 6 μg/ml concentration of DA followed by exposure of the lymphocytes to different doses (1, 2, 3 and 4 Gy) of radiation and investigating the radiation-induced genetic damage (MN, comet assay, DNA fragmentation assay) and biochemical changes (changes in the level of enzymic and non-enzymic antioxidants, lipid peroxidation). The results indicated a dose-dependent increase in both genetic damage and thiobarbituric acid reactive substances (TBARS), accompanied by a significant decrease in the antioxidant status in the irradiated groups compared to DA treated groups which modulated the toxic effects through its antioxidant potential. Thus the current study shows DA to be an effective radioprotector against X-ray radiation induced in vitro cellular damage in lymphocytes.