Tricyclic azepine derivatives: pyrimido[4,5-b]-1,4-benzoxazepines as a novel class of epidermal growth factor receptor kinase inhibitors.

A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1 microM in cellular phosphorylation assays (IC(50) 0.47-0.69 microM) and are highly selective against a small kinase panel. Such compounds demonstrate anti-EGFR activity within a class that is different from any known EGFR inhibitor scaffolds. They also provide a basis for the design of kinase inhibitors with the desired selectivity profile.

Synthesis and structure-activity relationships of 1,2,4-triazoles as a novel class of potent tubulin polymerization inhibitors.

A novel triazole-containing chemical series was shown to inhibit tubulin polymerization and cause cell cycle arrest in A431 cancer cells with EC(50) values in the single digit nanomolar range. Binding experiments demonstrated that representative active compounds of this class compete with colchicine for its binding site on tubulin. The syntheses and structure-activity relationship studies for the triazole derivatives are described herein.

Recovering industrial sludge-derived slag as fine aggregate.

This study presents the result of using melting to recover both industrial sludge slag (the main constituent of which is calcium fluoride) and water works sludge slag as fine aggregate in cement. The main characteristics of both slag and cement mortars were measured to evaluate the feasibility of using slag as aggregate. In this study, the slag replacement ratios were 0, 10, 20, 30, 40, and 50% (w/w), and the curing periods were 7, 28, and 90 days. Slag quality was determined according to the standards of fine aggregates in the ASTM specifications, and cement mortars with various slag replacement ratios were evaluated based on their compressive strength, and Toxicity Characteristic Leaching Procedure (TCLP). The crushed slag produced in this study met the ASTM standards for fine aggregate, including gravity, unit weight, absorption, and grading, and the TCLP leached concentrations are far below existing limits, establishing the safety and suitability of slag as fine aggregate. The TCLP leached concentrations of slag and cement mortar were not significantly related to the replacement ratio, and declined with increasing curing period, revealing that the hydration strongly influenced metal leaching. The compressive strength test results of the cement mortars demonstrated that the optimal replacement ratio for maximizing compressive strength was 40%. This study also discussed the effects of replacement ratio and curing periods on cement mortars.

Integrins regulate Rac targeting by internalization of membrane domains.

Translocation of the small GTP-binding protein Rac1 to the cell plasma membrane is essential for activating downstream effectors and requires integrin-mediated adhesion of cells to extracellular matrix. We report that active Rac1 binds preferentially to low-density, cholesterol-rich membranes, and specificity is determined at least in part by membrane lipids. Cell detachment triggered internalization of plasma membrane cholesterol and lipid raft markers. Preventing internalization maintained Rac1 membrane targeting and effector activation in nonadherent cells. Regulation of lipid rafts by integrin signals may regulate the location of membrane domains such as lipid rafts and thereby control domain-specific signaling events in anchorage-dependent cells.