Publications by authors named "Kamel Hadj-Kaddour"

11 Publications

  • Page 1 of 1

Synergetic anticancer activity of gold porphyrin appended to phenyl tin malonate organometallic complexes.

Dalton Trans 2021 Apr 11;50(13):4583-4592. Epub 2021 Mar 11.

IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France.

The discovery of novel anticancer chemotherapeutics is fundamental to treat cancer more efficiently. Towards this goal, two dyads consisting of a gold porphyrin appended to organotin(iv) entities were synthesized and their physicochemical and biological properties were characterized. One dyad contains a gold porphyrin connected to a tin(iv) cation via a malonate and two phenyl ligands (AuP-SnPh), while the other contains two tin(iv) cations each chelated to one carboxylic acid group of the malonate and three phenyl ligands (AuP-SnPh). The mode of chelation of Sn(iv) to the malonate was elucidated by IR spectroscopy and Sn NMR. In the solid state, the complexes exist as coordination polymers in which the tin is penta-coordinated and bridged to two different malonate units. In solution the chemical shifts of Sn signals indicate that the tin complexes are in the form of monomeric species associated with a tetra-coordinated tin cation. The therapeutic potential of these new compounds was assessed by determining their cytotoxic activities on human breast cancer cells (MCF-7) and on healthy human fibroblasts (FS 20-68). The study reveals that the dyads are more potent anticancer drugs than the mixture of their individual components (gold porphyrin and reference tin complexes). Therefore, the covalent link of organotin complexes to a gold porphyrin induces a synergistic cytotoxic effect. The dyad AuP-SnPh shows high cytotoxicity (0.13 μM) against MCF-7 along with good selectivity for cancer cells versus healthy cells. Finally, it was also shown that the dyad AuP-SnPh exhibits a very high anticancer activity (LC = 0.024 μM), but the presence of two tin units induces strong cytotoxicity on healthy cells too (LC = 0.032 μM). This study underscores, thus, the potential of the association of gold porphyrin and organotin complexes to develop anticancer metallo-drugs.
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http://dx.doi.org/10.1039/d0dt03792cDOI Listing
April 2021

Imidazo[1,2-a]quinoxalines for melanoma treatment with original mechanism of action.

Eur J Med Chem 2021 Feb 24;212:113031. Epub 2020 Nov 24.

Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, Faculté de Pharmacie, 15 avenue Charles Flahault, BP 14491, 34093, Montpellier Cedex 5, France.

The malignant transformation of melanocytes causes several thousand deaths each year, making melanoma an important public health concern. Melanoma is the most aggressive skin cancer, which incidence has regularly increased over the past decades. We described here the preparation of new compounds based on the 1-(3,4-dihydroxyphenyl)imidazo[1,2-a]quinoxaline structure. Different positions of the quinoxaline moiety were screened to introduce novel substituents in order to study their influence on the biological activity. Several alkylamino or alkyloxy groups were also considered to replace the methylamine of our first generation of Imiqualines. Imidazo[1,2-a]pyrazine derivatives were also designed as potential minimal structure. The investigation on A375 melanoma cells displayed interesting in vitro low nanomolar cytotoxic activity. Among them, 9d (EAPB02303) is particularly remarkable since it is 20 times more potent than vemurafenib, the reference clinical therapy used on BRAF mutant melanoma. Contrary to the first generation, EAPB02303 does not inhibit tubulin polymerization, as confirmed by an in vitro assay and a molecular modelisation study. The mechanism of action for EAPB02303 highlighted by a transcriptomic analysis is clearly different from a panel of 12 well-known anticancer drugs. In vivoEAPB02303 treatment reduced tumor size and weight of the A375 human melanoma xenografts in a dose-dependent manner, correlated with a low mitotic index but not with necrosis.
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http://dx.doi.org/10.1016/j.ejmech.2020.113031DOI Listing
February 2021

Two-Photon Absorbing AIEgens: Influence of Stereoconfiguration on Their Crystallinity and Spectroscopic Properties and Applications in Bioimaging.

ACS Appl Mater Interfaces 2020 Dec 20;12(49):55157-55168. Epub 2020 Nov 20.

Univ. Lyon, ENS Lyon, CNRS, Université Lyon 1, Laboratoire de Chimie, UMR 5182, 46 Allée d'Italie, 69364 Lyon, France.

This paper aims at designing chromophores with efficient aggregation-induced emission (AIE) properties for two-photon fluorescence microscopy (2PFM), which is one of the best-suited types of microscopy for the imaging of living organisms or thick biological tissues. Tetraphenylethylene (TPE) derivatives are common building blocks in the design of chromophores with efficient AIE properties. Therefore, in this study, extended TPE AIEgens specifically optimized for two-photon absorption (2PA) are synthesized and the resulting (/) isomers are separated using chromatography on chiral supports. Comparative characterization of the AIE properties is performed on the pure () and () isomers and the mixture, allowing us, in combination with powder X-ray diffraction and solid-state NMR, to document a profound impact of crystallinity on solid-state fluorescence properties. In particular, we show that stereopure AIEgens form aggregates of superior crystallinity, which in turn exhibit a higher fluorescence quantum yield compared to diastereoisomers mixtures. Preparation of stereopure organic nanoparticles affords very bright fluorescent contrast agents, which are then used for cellular and intravital two-photon microscopy on human breast cancer cells and on zebrafish embryos.
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http://dx.doi.org/10.1021/acsami.0c15810DOI Listing
December 2020

Substantial Cellular Penetration of Fluorescent Imidazoquinoxalines.

J Fluoresc 2020 Dec 10;30(6):1499-1512. Epub 2020 Aug 10.

IBMM, Université de Montpellier, CNRS, ENSCM, Montpellier, France.

Fluorescent tools have revolutionized our capability to visualize, probe, study, and understand the biological cellular properties, processes and dynamics, enabling researchers to improve their knowledge for example in cancer field. In this paper, we use the peculiar properties of our Imiqualines derivatives to study their cellular penetration and distribution in a human melanoma cell line A375 using confocal microscopy. Preliminary results on colocalization with the potent protein target c-Kit of our lead are also described.
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http://dx.doi.org/10.1007/s10895-020-02595-yDOI Listing
December 2020

Imidazo[1,2-a]pyrazine, Imidazo[1,5-a]quinoxaline and Pyrazolo[1,5-a]quinoxaline derivatives as IKK1 and IKK2 inhibitors.

Eur J Med Chem 2017 Sep 19;138:909-919. Epub 2017 Jul 19.

Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, ENSCM, Université de Montpellier, Faculté de Pharmacie, 15 avenue Charles Flahault, BP 14491, 34093 Montpellier Cedex 5, France. Electronic address:

The transcription nuclear factor NF-κB plays a pivotal role in chronic and acute inflammatory diseases. Among the several and diverse strategies for inhibiting NF-κB, one of the most effective approach considered by the pharmaceutical industry seems to be offered by the development of IKK inhibitors. In a former study, two potential IKK2 inhibitors have been highlighted among a series of imidazo[1,2-a]quinoxaline derivatives. In order to enhance this activity, we present herein the synthesis of twenty-one new compounds based on the imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline or pyrazolo[1,5-a]quinoxaline structures. Their potential to inhibit IKK1 and IKK2 activities is also tested.
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http://dx.doi.org/10.1016/j.ejmech.2017.07.021DOI Listing
September 2017

Fluorescence Study of Imidazoquinoxalines.

J Fluoresc 2017 Sep 3;27(5):1607-1611. Epub 2017 May 3.

Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, Faculté de Pharmacie, 15 avenue Charles Flahault, BP 14491, 34093, Montpellier Cedex 5, France.

The fluorescence properties of eleven novel derivatives based on the imidazo[1,2-a]quinoxaline structures have been studied. The absorption and emission spectra of these compounds have been recorded in dimethylsulfoxide solution. The phenyl substituting group on position 1 gives them particular properties thanks to the diverse hydroxy or methoxy decorating moieties, especially when they are multiplied or mixed. The investigated fluorescence auto-quenching revealed that the decreasing fluorescence intensity correlated only with the chemical structures of the aromatic compounds.
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http://dx.doi.org/10.1007/s10895-017-2097-zDOI Listing
September 2017

New imidazoquinoxaline derivatives: Synthesis, biological evaluation on melanoma, effect on tubulin polymerization and structure-activity relationships.

Bioorg Med Chem 2016 06 1;24(11):2433-40. Epub 2016 Apr 1.

Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15, avenue Charles Flahault, BP14491, 34093 Montpellier cedex 5, France.

Microtubules are considered as important targets of anticancer therapy. EAPB0503 and its structural imidazo[1,2-a]quinoxaline derivatives are major microtubule-interfering agents with potent anticancer activity. In this study, the synthesis of several new derivatives of EAPB0503 is described, and the anticancer efficacy of 13 novel derivatives on A375 human melanoma cell line is reported. All new compounds show significant antiproliferative activity with IC50 in the range of 0.077-122μM against human melanoma cell line (A375). Direct inhibition of tubulin polymerization assay in vitro is also assessed. Results show that compounds 6b, 6e, 6g, and EAPB0503 highly inhibit tubulin polymerization with percentages of inhibition of 99%, 98%, 90%, and 84% respectively. Structure-activity relationship studies within the series are also discussed in line with molecular docking studies into the colchicine-binding site of tubulin.
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http://dx.doi.org/10.1016/j.bmc.2016.04.004DOI Listing
June 2016

Lysosomes and unfolded protein response, determinants of differential resistance of melanoma cells to vinca alkaloids.

Fundam Clin Pharmacol 2015 Apr 27;29(2):164-77. Epub 2015 Feb 27.

Laboratoire de Toxicologie du Médicament, Institut des Biomolécules Max Mousseron (UMR5247), UFR des Sciences Pharmaceutiques et Biologiques, Université de Montpellier, 15 Avenue Charles Flahault, BP14491, 34093, Montpellier Cedex 05, France.

On account of its strong ability to become chemoresistant after a primary response to drugs, malignant melanoma (MM) remains a therapeutic challenge. This study focuses on acquired resistance to vinca alkaloids (VAs) using VA-resistant MM cell lines (CAL1R-VCR, CAL1R-VDS, and CAL1R-VRB), established by long-term continuous exposure of parental CAL1-wt cells to vincristine (VCR), vindesine (VDS), or vinorelbine (VRB), respectively. Transcriptomic profiling using rma and rdam methods led to distinguish two cell groups: CAL1R-VCR and CAL1R-VDS, CAL1R-VRB, and CAL1-wt. mgsa of the specifically altered genes in the first group evidenced the GO terms 'lysosomal lumen' and 'vacuolar lumen' linked to underexpressed genes, and 'endoplasmic reticulum (ER) stress response' associated with overexpressed genes. A specific reduction of lysosomal enzymes, independent of acidic vacuole organelle (AVO) turnover, was observed (LTG probe) in CAL1R-VCR and CAL1R-VDS cells. It was associated with the specific lowering of cathepsin B and L, known to be involved in the lysosomal pathway of apoptosis. Confirming gene profiling, the same groups (CAL1R-VCR and CAL1R-VDS, CAL1-wt and CAL1R-VRB) could be distinguished regarding the VA-mediated changes on mean size areas and on acidic compartment volumes. These two parameters were reduced in CAL1R-VCR and CAL1R-VDS cells, suggesting a smaller AVO accumulation and thus a reduced sensitivity to lysosomal membrane permeabilization-mediated apoptosis. In addition, 'ER stress response' inhibition by tauroursodeoxycholic acid induced a higher VA sensitization of the first cell group. In conclusion, lysosomes and unfolded protein response could be key determinants of the differential resistance of MM to VAs.
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http://dx.doi.org/10.1111/fcp.12098DOI Listing
April 2015

Differential involvement of glutathione S-transferase mu 1 and multidrug resistance protein 1 in melanoma acquired resistance to vinca alkaloids.

Fundam Clin Pharmacol 2015 Feb 3;29(1):62-71. Epub 2014 Dec 3.

Laboratoire de Toxicologie du Médicament, Institut des Biomolécules Max Mousseron (UMR5247), UFR des Sciences Pharmaceutiques et Biologiques, Université Montpellier I, 15 avenue Charles Flahault, BP14491, Montpellier, 34093, France.

On account of its extreme intrinsic resistance to apoptosis and of its strong ability to become chemoresistant after a primary response to drugs, malignant melanoma (MM) is still a therapeutic challenge. We previously showed that glutathione S-transferase mu 1 (GSTM1) acts in synergy with multidrug resistance protein 1 (MRP1) to protect GSTM1-transfected human CAL1 melanoma cells from toxic effects of vincristine (VCR). Herein, we investigated the role of these proteins in the acquired resistance of CAL1 cells to vinca alkaloids (VAs). Resistant lines were established by continuous exposure (>1 year) of parental CAL1-wt cells to VCR, vindesine (VDS), or vinorelbine (VRB): CAL1R-VCR, CAL1R-VDS, CAL1R-VRB, respectively. All resistant lines displayed more than 10-fold increase in resistance to their selection VA, and specifically expressed GSTM1. Suggesting a direct interaction between this protein and VAs, each VA specifically decreased the GSTM1-mediated glutathione conjugation activity in cell lysates. Curcumin (GSTM1 inhibitor), BSO (glutathione synthesis inhibitor), and MK571 (MRP1 inhibitor) considerably reversed the acquired resistance to VCR and VDS, but not to VRB. Microarray data analysis revealed similar gene expression patterns of CAL1R-VCR and CAL1R-VDS, and a distinct one for CAL1R-VRB. These data suggest a differential involvement of GSTM1 and MRP1 in acquired resistance to VAs. A coordinated expression and activity of GSTM1 and MRP1 is required to protect CAL1 cells from VCR and VDS, while the simple expression of GSTM1 is sufficient, possibly by a direct drug/protein interaction, to confer resistance against VRB.
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http://dx.doi.org/10.1111/fcp.12093DOI Listing
February 2015

Sequencing of the smallest Apicomplexan genome from the human pathogen Babesia microti.

Nucleic Acids Res 2012 Oct 24;40(18):9102-14. Epub 2012 Jul 24.

Laboratoire de Biologie Cellulaire et Moléculaire (LBCM-EA4558), UFR Pharmacie, Université Montpellier 1, 15, av. Charles Flahault, 34093 Montpellier cedex 5, France.

We have sequenced the genome of the emerging human pathogen Babesia microti and compared it with that of other protozoa. B. microti has the smallest nuclear genome among all Apicomplexan parasites sequenced to date with three chromosomes encoding ∼3500 polypeptides, several of which are species specific. Genome-wide phylogenetic analyses indicate that B. microti is significantly distant from all species of Babesidae and Theileridae and defines a new clade in the phylum Apicomplexa. Furthermore, unlike all other Apicomplexa, its mitochondrial genome is circular. Genome-scale reconstruction of functional networks revealed that B. microti has the minimal metabolic requirement for intraerythrocytic protozoan parasitism. B. microti multigene families differ from those of other protozoa in both the copy number and organization. Two lateral transfer events with significant metabolic implications occurred during the evolution of this parasite. The genomic sequencing of B. microti identified several targets suitable for the development of diagnostic assays and novel therapies for human babesiosis.
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http://dx.doi.org/10.1093/nar/gks700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467087PMC
October 2012

Hydrophobic moeties in recombinant proteins are crucial to generate efficient saponin-based vaccine against Apicomplexan Babesia divergens.

Vaccine 2006 Jan 2;24(5):613-21. Epub 2005 Sep 2.

Laboratoire de Biologie Cellulaire et Moleculaire, ERT 1038 Vaccination anti-parasitaire, Faculté de Pharmacie, 15 Avenue Charles Flahault, BP 14 491, 34093 Montpellier cedex 05, France.

Throughout Europe, bovine babesiosis is mainly caused by Babesia divergens, an Apicomplexan parasite transmitted by tick bites. The intra-erythrocytic development of B. divergens merozoites leads to haemolytic anaemia, and bovine babesiosis is responsible for economic losses in the agro-business industry. A totally efficient recombinant vaccine based on the merozoite surface protein Bd37 and saponin QuilA was recently described. In the present study we determined that protective immunity elicited by the Bd37 recombinant protein was related to the presence of hydrophobic residues in the protein. Using polymeric fusion of Bd37 as well as cell-free in vitro protein expression, we successfully expressed recombinant proteins containing hydrophobic sequences without the need of GST fusion. We used different hydrophobic sequences and different recombinant Bd37 proteins to demonstrate that antigen hydrophobicity affects the immune system, turning an inefficient protein into a 100% protective vaccine. Some hypotheses about the hydrophobic effect and its potential application to other parasitic protozoa vaccine are also discussed.
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http://dx.doi.org/10.1016/j.vaccine.2005.08.073DOI Listing
January 2006
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