IDEALP PHARMA

Villeurbanne, France

IDEALP PHARMA

Villeurbanne, France

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Ibrahim H.,Toulouse 1 University Capitole | Ibrahim H.,IRD Montpellier | Pantaleo A.,University of Turin | Turrini F.,University of Turin | And 4 more authors.
MedChemComm | Year: 2011

Indolone-N-oxides, long known for their biological activities, possess remarkable anti-infectious properties. With the aim of improving the pharmacological and antimalarial properties of indolone-N-oxide derivatives (INODs), 6-(4-chlorophenyl)-7H-[1,3]dioxolo[4,5-f]indol-7-one-5-oxide, compound 1, was selected to study its penetration and biotransformation in red blood cells (RBC) in vitro. Compound 1 accumulated inside RBCs and was rapidly bio-transformed giving a major fluorescent metabolite, the dihydroanalogue, 1-HH, identified after extraction, through LC-MS and NMR analyses. This bioreductive transformation was (i) observed with other INOD derivatives (i: 1-7); (ii) observed in normal, β-thalassemic and Plasmodium falciparum infected RBCs; (iii) temperature and thiol-dependent; (iv) not observed with heat-denatured RBCs, suggesting an enzyme-dependent biotransformation. The dihydro form, 1-HH, has antiplasmodial activity but lower than the parent compound. Since the RBCs represent 99% of the total cellular space of blood in humans, this leads to extensive metabolism of indolone-N-oxide type compounds. Given the redox events occurring in Plasmodium infected RBCs, this bioreductive transformation may be pivotal for parasite redox balance and antiplasmodial activity. However, it may be a drawback when other pharmacological properties of INODs are investigated. These results show the importance of RBCs as an in vitro model to study the biotransformation of drugs, especially antimalarial drugs in the early discovery stages. © 2011 The Royal Society of Chemistry.


Ibrahim N.,University Paul Sabatier | Ibrahim N.,IRD Montpellier | Ibrahim H.,University Paul Sabatier | Ibrahim H.,IRD Montpellier | And 5 more authors.
Biomacromolecules | Year: 2010

The binding affinity of human serum albumin (HSA) to three antimalarial indolone-N-oxide derivatives, INODs, was investigated under simulated physiological conditions using fluorescence spectroscopy in combination with UV-vis absorption and circular dichroism (CD) spectroscopy. Analysis of fluorescence quenching data of HSA by these compounds at different temperatures using Stern-Volmer and Lineweaver-Burk methods revealed the formation of a ground state indolone-HSA complex with binding affinities of the order 10 4 M -1. The thermodynamic parameters ΔG, ΔH, and ΔS, calculated at different temperatures, indicated that the binding reaction was endothermic and hydrophobic interactions play a major role in this association. The conformational changes of HSA were investigated qualitatively using synchronous fluorescence and quantitatively using CD. Site marker competitive experiments showed that the binding process took place primarily at site I (subdomain IIA) of HSA. The number of binding sites and the apparent binding constants were also studied in the presence of different ions. © 2010 American Chemical Society.


Pantaleo A.,University of Sassari | Ferru E.,University of Turin | Vono R.,University of Turin | Giribaldi G.,University of Turin | And 12 more authors.
Free Radical Biology and Medicine | Year: 2012

Although indolone-N-oxide (INODs) genereting long-lived radicals possess antiplasmodial activity in the low-nanomolar range, little is known about their mechanism of action. To explore the molecular basis of INOD activity, we screened for changes in INOD-treated malaria-infected erythrocytes (Pf-RBCs) using a proteomics approach. At early parasite maturation stages, treatment with INODs at their IC 50 concentrations induced a marked tyrosine phosphorylation of the erythrocyte membrane protein band 3, whereas no effect was observed in control RBCs. After INOD treatment of Pf-RBCs we also observed: (i) accelerated formation of membrane aggregates containing hyperphosphorylated band 3, Syk kinase, and denatured hemoglobin; (ii) dose-dependent release of microvesicles containing the membrane aggregates; (iii) reduction in band 3 phosphorylation, Pf-RBC vesiculation, and antimalarial effect of INODs upon addition of Syk kinase inhibitors; and (iv) correlation between the IC 50 and the INOD concentrations required to induce band 3 phosphorylation and vesiculation. Together with previous data demonstrating that tyrosine phosphorylation of oxidized band 3 promotes its dissociation from the cytoskeleton, these results suggest that INODs cause a profound destabilization of the Pf-RBC membrane through a mechanism apparently triggered by the activation of a redox signaling pathway rather than direct oxidative damage. © 2011 Elsevier Inc.


Belin S.,University of Lyon | Kindbeiter K.,Idealp Pharma | Hacot S.,University of Lyon | Albaret M.A.,University of Lyon | And 4 more authors.
RNA | Year: 2010

The ribosome is the central effector of protein synthesis, and its synthesis is intimately coordinated with that of proteins. At present, the most documented way to modulate ribosome biogenesis involves control of rDNA transcription by RNA polymerase I (RNA Pol I). Here we show that after infection of human cells with herpes simplex virus type 1 (HSV-1) the rate of ribosome biogenesis is modulated independently of RNA Pol I activity by a dramatic change in the rRNA maturation pathway. This process permits control of the ribosome biogenesis rate, giving the possibility of escaping ribosomal stress and eventually allowing assembly of specialized kinds of ribosomes. Published by Cold Spring Harbor Laboratory Press. Copyright © 2010 RNA Society.


Nepveu F.,Toulouse 1 University Capitole | Nepveu F.,IRD Montpellier | Kim S.,Toulouse 1 University Capitole | Kim S.,IRD Montpellier | And 32 more authors.
Journal of Medicinal Chemistry | Year: 2010

A series of 66 new indolone-N-oxide derivatives was synthesized with three different methods. Compounds were evaluated for in vitro activity against CQ-sensitive (3D7), CQ-resistant (FcB1), and CQ and pyrimethamine cross-resistant (K1) strains of Plasmodium falciparum (P.f.), aswell as for cytotoxic concentration (CC50) on MCF7 and KB human tumor cell lines. Compound 26 (5-methoxy-indolone-N-oxide analogue) had the most potent antiplasmodial activity in vitro (<3 nM on FcB1 and = 1.7 nM on 3D7) with a very satisfactory selectivity index (CC50 MCF7/IC50 FcB1: 14623; CC50 KB/IC50 3D7: 198823). In in vivo experiments, compound 1 (dioxymethylene derivatives of the indolone-N-oxide) showed the best antiplasmodial activity against Plasmodium berghei, 62% inhibition of the parasitaemia at 30 mg/kg/day. ©2009 American Chemical Society.

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