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Dredging generates remobilisation of sediments contaminated by non-degradable compounds such as metals, to which aquatic organisms can be exposed. This study aims at assessing the environmental impact of sediments remobilised in the Rhine River (France) during the dredging of Marckolsheim dam by pumping/dilution in 2013 on metal speciation and organisms' exposure. The monitoring coupling chemical and biological tools was performed 2 years before dredging operation on 2 sampling sites, upstream and downstream from the discharge of pumping/dilution, to acquire data on the natural variability of labile (DGT as passive samplers), dissolved and particulate concentrations of Cd, Co, Cr, Cu, Ni, Mn, Pb and Zn in Rhine during full hydrological cycles. In parallel, size-calibrated zebra mussels were transplanted at both sites to monitor continuously metal bioavailability from particulate and dissolved fractions. This long-term monitoring allowed the establishment of reference baselines of Rhine water and mussels' contamination levels and subsequently, the detection of averred environmental changes due to the dredging. Indeed, Co and Mn accumulations in mussels exposed to the discharge were consistent with increasing labile species in Rhine whereas ones of Cr and Pb were likely due to an enhanced particulate bioavailability. Whatever the exposure route, the mussels recovered their basal metal contents 2 weeks after the end of dredging, suggesting a transient impact of sediment remobilisation on bioaccumulation. This long-term monitoring highlights the interest of coupling chemical and biological time-integrated tools for a better assessment of environmental risks because metallic exchanges between organisms and their media are complex and metal-specific.

We describe a series of indolequinones as efficient mechanism-based inhibitors of NRH:quinone oxidoreductase 2 (NQO2) for use either in cellular or cell-free systems. Compounds were designed to be reduced in the active site of the enzyme leading to loss of a substituted phenol leaving group and generation of a reactive iminium electrophile. Inhibition of NQO2 activity was assessed in both cell-free systems and the human leukemia K562 cell line. Inhibition of recombinant human NQO2 by the indolequinones was NRH-dependent, with kinetic parameters characteristic of mechanism-based inhibition and partition ratios as low as 2.0. Indolequinones inhibited NQO2 activity in K562 cells at nanomolar concentrations that did not inhibit NQO1 and were nontoxic to cells. Computation-based molecular modeling simulations demonstrated favorable conformations of indolequinones positioned directly above and in parallel with the isoalloxazine ring of FAD, and mass spectrometry extended our previous finding of adduction of the FAD in the active site of NQO2 by an indolequinone-derived iminium electrophile to the wider series of indolequinone inhibitors. Modeling combined with biochemical testing identified key structural parameters for effective inhibition, including a 5-aminoalkylamino side chain. Hydrogen bonding of the terminal amine nitrogen in the aminoalkylamino side chain was found to be critical for the correct orientation of the inhibitors in the active site. These indolequinones were irreversible inhibitors and were found to be at least 1 order of magnitude more potent than any previously documented competitive inhibitors of NQO2 and represent the first mechanism-based inhibitors of NQO2 to be characterized in cellular systems. [ABSTRACT FROM AUTHOR]

[Structure: see text] A practical one-pot, regiospecific three-component process for the synthesis of 2,3-disubstituted indoles was developed via consecutive Pd-catalyzed Sonogashira coupling, amidopalladation, and reductive elimination.