Jean-Pierre Haelters

Pivotal role of the lipid raft SK3-Orai1 complex in human cancer cell migration and bone metastases

The SK3 channel, a potassium channel, was recently shown to control cancer cell migration, a critical step in metastasis outgrowth. Here, we report that expression of the SK3 channel was markedly associated with bone metastasis. The SK3 channel was shown to control constitutive Ca(2+) entry and cancer cell migration through an interaction with the Ca(2+) channel Orai1. We found that the SK3 channel triggers an association with the Orai1 channel within lipid rafts. This localization of an SK3-Orai1 complex seemed essential to control cancer cell migration. This suggests that the formation of this complex in lipid rafts is a gain-of-function, because we showed that none of the individual proteins were able to promote the complete phenotype. We identified the alkyl-lipid Ohmline as a disrupting agent for SK3-Orai1 lipid raft localization. Upon Ohmline treatment, the SK3-Orai1 complex moved away from lipid rafts, and SK3-dependent Ca(2+) entry, migration, and bone metastases were subsequently impaired. The colocalization of SK3 and Orai1 in primary human tumors and bone metastases further emphasized the clinical relevance of our observations. Targeting SK3-Orai1 in lipid rafts may inaugurate innovative approaches to inhibit bone metastases.

Atherton–Todd reaction: mechanism, scope and applications

Summary Initially, the Atherton–Todd (AT) reaction was applied for the synthesis of phosphoramidates by reacting dialkyl phosphite with a primary amine in the presence of carbon tetrachloride. These reaction conditions were subsequently modified with the aim to optimize them and the reaction was extended to different nucleophiles. The mechanism of this reaction led to controversial reports over the past years and is adequately discussed. We also present the scope of the AT reaction. Finally, we investigate the AT reaction by means of exemplary applications, which mainly concern three topics. First, we discuss the activation of a phenol group as a phosphate which allows for subsequent transformations such as cross coupling and reduction. Next, we examine the AT reaction applied to produce fire retardant compounds. In the last section, we investigate the use of the AT reaction for the production of compounds employed for biological applications. The selected examples to illustrate the applications of the Atherton–Todd reaction mainly cover the past 15 years.

A silver-based metal–organic framework material as a ‘reservoir’ of bactericidal metal ions

The silver-based MOF material Ag3(3-phosphonobenzoate) was evaluated as a bactericidal material. A sustainable release of Ag+, which was quantified by cathodic stripping voltammetry, was responsible for bactericidal activity against the 6 bacterial strains tested.

Targeting SKCa Channels in Cancer: Potential New Therapeutic Approaches

Many studies have reported changes in potassium channel expression in many cancers and the involvement of these channels in various stages of cancer progression. By contrast, data concerning SKCa channels (small conductance calcium-activated potassium channels) have only recently become available. This review aims i) to present the structure and physiology of SKCa channels, ii) to provide an overview of published data concerning the SKCa proteins produced in tumor cells, and, whenever possible, the biological function assigned to them and iii) to review previous and novel modulators of SKCa channels. SKCa channels are activated by low concentrations of intracellular calcium and consist of homo- or heteromeric assemblies of α-subunits named SK1, SK2 and SK3. SK2-3 channels are expressed in tumors and have been assigned a biological function in cancer cells: the enhancement of cell proliferation and cell migration by hijacking the functions of SK2 and SK3 channels, respectively. Two major classes of SKCa modulators have been described: toxins (apamin) and small synthetic molecules. Most SKCa blockers are pore blockers, but some modify the calcium sensitivity of SKCa channels without interacting with the apamin binding site. In this review, we present edelfosine and ohmline as atypical anticancer agents and novel SK3 inhibitors. Edelfosine and ohmline are synthetic alkyl-lipids with structures different from all previously described SKCa modulators. They should pave the way for the development of a new class of migration-targeted anticancer agents. We believe that such blockers have potential for use in the prevention or treatment of metastasis.

Lipophosphonate/lipophosphoramidates: A family of synthetic vectors efficient for gene delivery

Lipophophoramidates constitute a class of synthetic vectors which were especially designed for gene delivery. In this family of compounds, the phosphorus functional group links two lipid chains to a spacer ended by a polar headgroup. Such vectors, which can readily be obtained, offer an alternative to the numerous examples of glycerolipid-based vectors that have been more exhaustively studied. Since the pioneering work describing this series of synthetic vectors, several chemical modifications have been proposed with the aim of correlating the molecular structure with the gene transfection efficacy. It has indeed been observed that some modifications which may be considered as minor at first glance, actually have important consequences on both the transfection efficacy and cytotoxic side effects. We herein discuss the modification of the structure of lipophosphoramidates, in particular of their lipidic part and of the nature of the cationic polar head which may be constituted by a trimethylammonium, trimethylphosphonium or trimethylarsonium motif. We also report that, as well as the in vitro transfection efficacy which governs the selection of the most promising vectors for in vivo studies, other aspects related to the synthetic pathway must be also considered for the development of new synthetic vectors (such as modularity of the synthesis, scaling-up).

Synthesis of α-phosphorylated cyclopentanones by intramolecularcarbenoid cyclizations of α-diazo β-keto alkylphosphonates and phosphine oxides

Abstract α-diazo β-ketoalkylphosphonates and phosphine oxides undergo intramolecular carbenoīd cyclizations under rhodium (II) catalysis to afford substituted diethoxyphosphono-2 and diphenylphosphono-2 cyclopentanones which, under Wittig-Horner conditions, lead to α-methylene cyclopentanones.

m-phosphonobenzoic acid and copper(II) as precursors of helical chain and lamellar hybrid materials

A 1D helical-chain material Cu6(H2O)7(m-PO3C6H4CO2)41, characterized by a non-centrosymmetric crystal structure, and a 2D lamellar hybrid material Cu(H2O)(m-PO3C6H4CO2H) 2 have been synthesised starting from m-phosphonobenzoic acid and copper(II). The pH of the reaction media regulates the formation of either 1 or 2.

Cationic Lipophosphoramidates Containing a Hydroxylated Polar Headgroup for Improving Gene Delivery

The structure of the cationic moiety of amphiphiles is a key factor which directly influences their transfection efficacy. Accordingly, in the present work, we have synthesized three new lipophosphoramide-based amphiphilic compounds incorporating a methoxy 5, hydroxyl 6, or dihydroxyl 7 functional group in their cationic part. Gene delivery efficacies of these novel vectors were compared to our benchmark compound, the arsenolipophosphoramidate KLN47, and to its trimethylammonium (TMA) analogue 4. We next studied the characteristics (size, ζ potential) of the nanometric assemblies formed (liposomes and lipid/DNA complexes), and the DNA binding ability of the cationic liposomes was characterized at the physicochemical level. In vitro, all of the cationic lipids evaluated were efficient not only to condense plasmids but also to transfect two types of human airway epithelial cells. Interestingly, in vivo administration to mice (via simple tail vein injection) showed that compound 6 was the most efficient in transfecting the lungs when compared to that of the other cationic lipids studied, including compound KLN47. All of these results suggest that a hydroxyethyldimethylammonium (HE-DMA) polar head could be a valuable alternative to a trimethylarsonium (TMAs) polar head and that they also invite further evaluation of the in vivo potential of compound 6 using more clinically relevant delivery procedures.

On A Safe and Practical Method for The Preparation of β-Keto Phosphonates1

Abstract Acylations of the magnesium enolate derivatives of trimethyl and triethylphosphonoacetates, using a magnesium chloride-triethylamine system, lead to 2-acylphosphonoacetates which are decarbalkoxylated to give β-keto phosphonates.

New Disaccharide‐Based Ether Lipids as SK3 Ion Channel Inhibitors

The SK3 potassium channel is involved in the development of bone metastasis and in the settlement of cancer cells in Ca2+‐rich environments. Ohmline, which is a lactose‐based glycero‐ether lipid, is a lead compound that decreases SK3 channel activity and consequently limits the migration of SK3‐expressing cells. Herein we report the synthesis of three new ohmline analogues in which the connection of the disaccharide moieties (1→6 versus 1→4) and the stereochemistry of the glycosyl linkage was studied. Compound 2 [3‐(hexadecyloxy)‐2‐methoxypropyl‐6‐O‐α‐d‐glucopyranosyl‐β‐d‐galactopyranoside], which possesses an α‐glucopyranosyl‐(1→6)‐β‐galactopyranosyl moiety, was found to decrease SK3 current amplitude (70 % inhibition at 10 μm), displace SK3 protein outside caveolae, and decrease constitutive Ca2+ entry (50 % inhibition at 300 nm) and SK3‐dependent cell migration (30 % at 300 nm) at a level close to that of the benchmark compound ohmline. Compound 2, which decreases the activity of SK3 channel (but not SK2 channel), is a new drug candidate to reduce cancer cell migration and to prevent bone metastasis.