Ronan Le Lagadec

Uncoupling Charge Movement from Channel Opening in Voltage-gated Potassium Channels by Ruthenium Complexes

The Kv2.1 channel generates a delayed-rectifier current in neurons and is responsible for modulation of neuronal spike frequency and membrane repolarization in pancreatic β-cells and cardiomyocytes. As with other tetrameric voltage-activated K+-channels, it has been proposed that each of the four Kv2.1 voltage-sensing domains activates independently upon depolarization, leading to a final concerted transition that causes channel opening. The mechanism by which voltage-sensor activation is coupled to the gating of the pore is still not understood. Here we show that the carbon-monoxide releasing molecule 2 (CORM-2) is an allosteric inhibitor of the Kv2.1 channel and that its inhibitory properties derive from the CORM-2 ability to largely reduce the voltage dependence of the opening transition, uncoupling voltage-sensor activation from the concerted opening transition. We additionally demonstrate that CORM-2 modulates Shaker K+-channels in a similar manner. Our data suggest that the mechanism of inhibition by CORM-2 may be common to voltage-activated channels and that this compound should be a useful tool for understanding the mechanisms of electromechanical coupling.

Cyclo- and hydrodimerization of α,β-unsaturated ketones promoted by samarium diiodide

Samarium(II) iodide is a strong one-electron transfer reducing agent, and is effective for the cyclo- and hydrodimerization of cyclic and non-cyclic α,β-unsaturated ketones. The title dimers can easily be prepared in good yields at room temperature under neutral conditions, using two-mole equivalent of SmI2 per mole of starting substrate. The reaction is stereocontrolled. The absence of an alcohol as a proton source is essential in the process and the use of HMPA as a copromoter improves the yield of dimeric products, making the reaction regioselective over the competitive CC double bond reduction. The crystal structures of some of the dimeric derivatives are reported. When η2- or η4-iron-coordinated α,β-unsaturated ketones are used as substrates, the reaction gives mainly the 1,4-reduced products.

In search for chelating TAMLs (tetraamido macrocyclic ligands) with peripheral bidentate donor centers: a cobalt(III) complex of the 3,3′-(2,2′-bipyridindiyl)-tailed TAML

The synthesis of 1,2-C6H4(NHCOCMe2NHCO)2-3,3′-(2,2′-bpy) (3), a TAML (tetraamido macrocyclic ligand) incorporating the peripheral 2,2′-bipyridine unit, is described. Its geometry after optimization by density functional theory (DFT) indicated a rather unfavorable conformation of four N–H amide units for forming macrocyclic transition metal complexes. This explains why the iron(III) derivative of 3 could not be obtained even after deprotonation of the N–H bonds by n-BuLi. Nevertheless, the macrocyclic complex of CoIII was synthesized in moderate yield, characterized, and explored by DFT. Our data suggest a strongly distorted square-planar geometry of the macrocyclic complex between CoIII and 3. The dihedral angle between the pyridine rings equals 80° ruling out the possibility of metal chelation by the bipyridine unit. Graphical Abstract

A redox ruthenium compound directly targets PHD2 and inhibits the HIF1 pathway to reduce tumor angiogenesis independently of p53

Targeting specific tumor metabolic needs represents an actively investigated therapeutic strategy to bypass tumor resistance mechanisms. In this study, we describe an original approach to impact the cancer metabolism by exploiting the redox properties of a ruthenium organometallic compound. This organometallic complex induced p53-independent cytotoxicity and reduced size and vascularization of patients-derived tumor explants that are resistant to platinum drugs. At the molecular level, the ruthenium complex altered redox enzyme activities and the intracellular redox state by increasing the NAD+/NADH ratio and ROS levels. Pathway analysis pointed to HIF-1 as a top deregulated metabolite pathway. Unlike cisplatin, treatment with the ruthenium complex decreased HIF1A protein levels and expression of HIF1A target genes. The rapid downregulation of HIF1A protein levels involved a direct interaction of the ruthenium compound with the redox enzyme PHD2, a HIF1A master regulator. HIF1A inhibition led to decreased angiogenesis in patient-derived xenografted using fragments of primary human colon tumors. Altogether, our results show that a ruthenium compound impacts metabolic pathways acting as anticancer agents in colon cancer via an original mechanism of action that affects redox enzymes differently than platinum-based drugs.

Tandem Michael addition–Claisen-type condensation of anions of O-ethyl carbonates of cyanohydrins to cyclohex-2-en-1-one

ABSTRACT A one pot method for the synthesis of ethyl 2-acetoxy-6-aroylcyclohex-1-ene-1-carboxylates and ethyl 2-acetoxy-6-heterocarbonylcyclohex-1-ene-1-carboxylates through Michael addition of the anions of ethyl carbonates of cyanohydrins to cyclohex-2-en-1-one and subsequent reaction with acetic anhydride is described. These compounds are potential intermediates for the synthesis of 9,10-anthraquinone and heterofused 1,4-naphthoquinone derivatives. GRAPHICAL ABSTRACT