@article{bios14010043,

title = {Photonic Crystal Surface Mode Real-Time Imaging of RAD51 DNA Repair Protein Interaction with the ssDNA Substrate},

author = {Galina Nifontova and Cathy Charlier and Nizar Ayadi and Fabrice Fleury and Alexander Karaulov and Alyona Sukhanova and Igor Nabiev},

url = {https://www.mdpi.com/2079-6374/14/1/43},

doi = {10.3390/bios14010043},

issn = {2079-6374},

year  = {2024},

date = {2024-01-01},

urldate = {2024-01-01},

journal = {Biosensors},

volume = {14},

number = {1},

abstract = {Photonic crystals (PCs) are promising tools for label-free sensing in drug discovery screening, diagnostics, and analysis of ligand-receptor interactions. Imaging of PC surface modes has emerged as a novel approach to the detection of multiple binding events at the sensor surface. PC surface modification and decoration with recognition units yield an interface providing the highly sensitive detection of cancer biomarkers, antibodies, and oligonucleotides. The RAD51 protein plays a central role in DNA repair via the homologous recombination pathway. This recombinase is essential for the genome stability and its overexpression is often correlated with aggressive cancer. RAD51 is therefore a potential target in the therapeutic strategy for cancer. Here, we report the designing of a PC-based array sensor for real-time monitoring of oligonucleotide-RAD51 recruitment by means of surface mode imaging and validation of the concept of this approach. Our data demonstrate that the designed biosensor ensures the highly sensitive multiplexed analysis of association-dissociation events and detection of the biomarker of DNA damage using a microfluidic PC array. The obtained results highlight the potential of the developed technique for testing the functionality of candidate drugs, discovering new molecular targets and drug entities. This paves the way to further adaption and bioanalytical use of the biosensor for high-content screening to identify new DNA repair inhibitor drugs targeting the RAD51 nucleoprotein filament or to discover new molecular targets.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36990245,

title = {Synthesis and Biological Evaluation of DIDS Analogues as Efficient Inhibitors of RAD51 Involved in Homologous Recombination},

author = {Alexandre Demeyer and Lucie Fonteneau and Marion Liennard and Claire Foyer and Pierre Weigel and Adèle Laurent and Jacques Lebreton and Fabrice Fleury and Monique Mathé-Allainmat},

doi = {10.1016/j.bmcl.2023.129261},

issn = {1464-3405},

year  = {2023},

date = {2023-03-01},

urldate = {2023-03-01},

journal = {Bioorg Med Chem Lett},

pages = {129261},

abstract = {RAD51 is a pivotal protein of the homologous recombination DNA repair pathway, and is overexpressed in some cancer cells, disrupting then the efficiency of cancer-treatments. The development of RAD51 inhibitors appears as a promising solution to restore these cancer cells sensitization to radio- or chemotherapy. From a small molecule identified as a modulator of RAD51, the 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), two series of analogues with small or bulky substituents on the aromatic parts of the stilbene moiety were prepared for a structure-activity relationship study. Three compounds, the cyano analogue (12), and benzamide (23) or phenylcarbamate (29) analogues of DIDS were characterized as novel potent RAD51 inhibitors with HR inhibition in the micromolar range.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ijms24054347b,

title = {Label-Free Multiplexed Microfluidic Analysis of Protein Interactions Based on Photonic Crystal Surface Mode Imaging},

author = {Galina Nifontova and Irina Petrova and Evgeniia Gerasimovich and Valery N. Konopsky and Nizar Ayadi and Cathy Charlier and Fabrice Fleury and Alexander Karaulov and Alyona Sukhanova and Igor Nabiev},

url = {https://www.mdpi.com/1422-0067/24/5/4347},

doi = {10.3390/ijms24054347},

issn = {1422-0067},

year  = {2023},

date = {2023-02-22},

urldate = {2023-02-22},

journal = {International Journal of Molecular Sciences},

volume = {24},

number = {5},

abstract = {High-throughput protein assays are crucial for modern diagnostics, drug discovery, proteomics, and other fields of biology and medicine. It allows simultaneous detection of hundreds of analytes and miniaturization of both fabrication and analytical procedures. Photonic crystal surface mode (PC SM) imaging is an effective alternative to surface plasmon resonance (SPR) imaging used in conventional gold-coated, label-free biosensors. PC SM imaging is advantageous as a quick, label-free, and reproducible technique for multiplexed analysis of biomolecular interactions. PC SM sensors are characterized by a longer signal propagation at the cost of a lower spatial resolution, which makes them more sensitive than classical SPR imaging sensors. We describe an approach for designing label-free protein biosensing assays employing PC SM imaging in the microfluidic mode. Label-free, real-time detection of PC SM imaging biosensors using two-dimensional imaging of binding events has been designed to study arrays of model proteins (antibodies, immunoglobulin G-binding proteins, serum proteins, and DNA repair proteins) at 96 points prepared by automated spotting. The data prove feasibility of simultaneous PC SM imaging of multiple protein interactions. The results pave the way to further develop PC SM imaging as an advanced label-free microfluidic assay for the multiplexed detection of protein interactions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{le_untargeted_2021,

title = {Untargeted Metabolomics Approach for the Discovery of Environment-Related Pyran-2-Ones Chemodiversity in a Marine-Sourced Penicillium restrictum},

author = {Van-Tuyen Le and Samuel Bertrand and Thibaut Robiou du Pont and Fabrice Fleury and Nathalie Caroff and Sandra Bourgeade-Delmas and Emmanuel Gentil and Cedric Logé and Gregory Genta-Jouve and Olivier Grovel},

url = {https://www.mdpi.com/1660-3397/19/7/378},

doi = {10.3390/md19070378},

issn = {1660-3397},

year  = {2021},

date = {2021-09-15},

journal = {Marine Drugs},

volume = {19},

number = {7},

pages = {378},

abstract = {Very little is known about chemical interactions between fungi and their mollusc host within marine environments. Here, we investigated the metabolome of a Penicillium restrictum MMS417 strain isolated from the blue mussel Mytilus edulis collected on the Loire estuary, France. Following the OSMAC approach with the use of 14 culture media, the effect of salinity and of a musselderived medium on the metabolic expression were analysed using HPLC-UV/DAD-HRMS/MS. An untargeted metabolomics study was performed using principal component analysis (PCA), orthogonal projection to latent structure discriminant analysis (O-PLSDA) and molecular networking (MN). It highlighted some compounds belonging to sterols, macrolides and pyran-2-ones, which were specifically induced in marine conditions. In particular, a high chemical diversity of pyran-2-ones was found to be related to the presence of mussel extract in the culture medium. Mass spectrometry (MS)- and UV-guided purification resulted in the isolation of five new natural fungal pyran-2-one derivatives—5,6-dihydro-6S-hydroxymethyl-4-methoxy-2H-pyran-2-one (1), (6S, 1’R, 2’S)-LL-P880β (3), 5,6-dihydro-4-methoxy-6S-(1’S, 2’S-dihydroxy pent-3’(E)-enyl)-2H-pyran-2-one (4), 4-methoxy-6(1’R, 2’S-dihydroxy pent-3’(E)-enyl)-2H-pyran-2-one (6) and 4-methoxy-2H-pyran-2-one (7)—together with the known (6S, 1’S, 2’S)-LL-P880β (2), (1’R, 2’S)-LL-P880γ (5), 5,6-dihydro-4-methoxy-2H-pyran2-one (8), (6S, 1’S, 2’R)-LL-P880β (9), (6S, 1’S)-pestalotin (10), 1’R-dehydropestalotin (11) and 6-pentyl4-methoxy-2H-pyran-2-one (12) from the mussel-derived culture medium extract. The structures of 1-12 were determined by 1D- and 2D-MMR experiments as well as high-resolution tandem MS, ECD and DP4 calculations. Some of these compounds were evaluated for their cytotoxic, antibacterial, antileishmanial and in-silico PTP1B inhibitory activities. These results illustrate the utility in using host-derived media for the discovery of new natural products.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{demeyer_inhibiting_2021,

title = {Inhibiting homologous recombination by targeting RAD51 protein},

author = {Alexandre Demeyer and Houda Benhelli-Mokrani and B. Chénais and Pierre Weigel and Fabrice Fleury},

url = {https://linkinghub.elsevier.com/retrieve/pii/S0304419X21000949},

doi = {10.1016/j.bbcan.2021.188597},

issn = {0304419X},

year  = {2021},

date = {2021-09-15},

urldate = {2021-09-15},

journal = {Biochimica et Biophysica Acta (BBA) - Reviews on Cancer},

volume = {1876},

number = {2},

pages = {188597},

abstract = {Homologous recombination (HR) is involved in repairing DNA double-strand breaks (DSB), the most harmful for the cell. Regulating HR is essential for maintaining genomic stability. In many forms of cancer, overactivation of HR increases tumor resistance to DNA-damaging treatments. RAD51, HR's core protein, is very often overexpressed in these cancers and plays a critical role in cancer cell development and survival. Targeting RAD51 directly to reduce its activity and its expression is therefore one strategy to sensitize and overcome resistance cancer cells to existing DNA-damaging therapies which remains the limiting factor for the success of targeted therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{velic_molecular_2021,

title = {Molecular Determinant of DIDS Analogs Targeting RAD51 Activity},

author = {Denis Velic and Alexandre Demeyer and Thibaut Peterlini and Houda Benhelli-Mokrani and Monique Mathé-Allainmat and Jean-Yves Masson and Fabrice Fleury},

url = {https://www.mdpi.com/1420-3049/26/18/5460},

doi = {10.3390/molecules26185460},

issn = {1420-3049},

year  = {2021},

date = {2021-09-15},

urldate = {2021-09-15},

journal = {Molecules},

volume = {26},

number = {18},

pages = {5460},

abstract = {RAD51 is the central protein in DNA repair by homologous recombination (HR), involved in several steps of this process. It is shown that overexpression of the RAD51 protein is correlated with increased survival of cancer cells to cancer treatments. For the past decade, RAD51 overexpression-mediated resistance has justified the development of targeted inhibitors. One of the first molecules described to inhibit RAD51 was the 4,4 -diisothiocyanato-stilbene-2,2 -disulfonic acid (DIDS) molecule. This small molecule is effective in inhibiting different functions of RAD51, however its mode of action and the chemical functions involved in this inhibition have not been identified. In this work, we used several commercial molecules derived from DIDS to characterize the structural determinants involved in modulating the activity of RAD51. By combining biochemical and biophysical approaches, we have shown that DIDS and two analogs were able to inhibit the binding of RAD51 to ssDNA and prevent the formation of D-loop by RAD51. Both isothiocyanate substituents of DIDS appear to be essential in the inhibition of RAD51. These results open the way to the synthesis of new molecules derived from DIDS that should be greater modulators of RAD51 and more efficient for HR inhibition.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Meresse2020,

title = {Fucoxanthin, a Marine-Derived Carotenoid from Brown Seaweeds and Microalgae: A Promising Bioactive Compound for Cancer Therapy},

author = {Sarah Méresse and Mostefa Fodil and Fabrice Fleury and Benoît Chénais},

url = {https://www.mdpi.com/1422-0067/21/23/9273},

doi = {10.3390/ijms21239273},

issn = {1422-0067},

year  = {2020},

date = {2020-12-01},

journal = {International Journal of Molecular Sciences},

volume = {21},

number = {23},

pages = {9273},

publisher = {Multidisciplinary Digital Publishing Institute},

abstract = {Fucoxanthin is a well-known carotenoid of the xanthophyll family, mainly produced by marine organisms such as the macroalgae of the fucus genus or microalgae such as Phaeodactylum tricornutum. Fucoxanthin has antioxidant and anti-inflammatory properties but also several anticancer effects. Fucoxanthin induces cell growth arrest, apoptosis, and/or autophagy in several cancer cell lines as well as in animal models of cancer. Fucoxanthin treatment leads to the inhibition of metastasis-related migration, invasion, epithelial–mesenchymal transition, and angiogenesis. Fucoxanthin also affects the DNA repair pathways, which could be involved in the resistance phenotype of tumor cells. Moreover, combined treatments of fucoxanthin, or its metabolite fucoxanthinol, with usual anticancer treatments can support conventional therapeutic strategies by reducing drug resistance. This review focuses on the current knowledge of fucoxanthin with its potential anticancer properties, showing that fucoxanthin could be a promising compound for cancer therapy by acting on most of the classical hallmarks of tumor cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Chabot2020,

title = {Relationships between DNA repair and RTK-mediated signaling pathways},

author = {Thomas Chabot and Yvonnick Cheraud and Fabrice Fleury},

url = {https://linkinghub.elsevier.com/retrieve/pii/S0304419X20302146},

doi = {10.1016/j.bbcan.2020.188495},

issn = {0304419X},

year  = {2020},

date = {2020-12-01},

journal = {Biochimica et Biophysica Acta (BBA) - Reviews on Cancer},

pages = {188495},

publisher = {Elsevier},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Yaremenko2020b,

title = {Synthetic Peroxides Promote Apoptosis of Cancer Cells by Inhibiting P-Glycoprotein ABCB5},

author = {Ivan A Yaremenko and Paolo Coghi and Parichat Prommana and Congling Qiu and Peter S Radulov and Yuanqing Qu and Yulia Yu Belyakova and Enrico Zanforlin and Vladimir A Kokorekin and Yuki Yu Jun Wu and Fabrice Fleury and Chairat Uthaipibull and Vincent Kam Wai Wong and Alexander O Terent'ev},

doi = {10.1002/cmdc.202000042},

issn = {18607187},

year  = {2020},

date = {2020-03-10},

journal = {ChemMedChem},

volume = {15},

number = {13},

pages = {1118--1127},

abstract = {This article discloses a new horizon for the application of peroxides in medical chemistry. Stable cyclic peroxides are demonstrated to have cytotoxic activity against cancer cells: in addition a mechanism of cytotoxic action is proposed. Synthetic bridged 1,2,4,5‐tetraoxanes and ozonides were effective against HepG2 cancer cells and some ozonides selectively targeted liver cancer cells (the selectivity indexes for compounds 11 b and 12 a are 8 and 5, respectively).

In some instances, tetraoxanes and ozonides were more selective than paclitaxel, artemisinin and artenusic acid.

Annexin V flow‐cytometry analysis revealed that the active ozonides 22 a and 23 a induced cell death of HepG2 by apoptosis. Further study showed that compounds 22 a and 23 a exhibited a strong inhibitory effect on P‐glycoprotein (P‐gp/ABCB5)‐overexpressing HepG2 cancer cells. ABCB5 is a key player in the multidrug‐resistant phenotype of liver cancer. Peroxides failed to demonstrate a direct correlation between oxidative potential and their biological activity. To our knowledge this is the first time that peroxide diastereoisomers have been found to show stereospecific antimalarial action against the chloroquine‐sensitive 3D7 strain of Plasmodium falciparum. Stereoisomeric ozonide 12 b is 11 times more active than stereoisomeric ozonide 12 a (IC50=5.81 vs 65.18 μm). Current findings mean that ozonides merit further investigation as potential therapeutic agents for drug‐resistant hepatocellular carcinoma.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Yaremenko2020a,

title = {Catalyst Development for the Synthesis of Ozonides and Tetraoxanes Under Heterogeneous Conditions: Disclosure of an Unprecedented Class of Fungicides for Agricultural Application},

author = {Ivan A Yaremenko and Peter S Radulov and Yulia Yu Belyakova and Arina A Demina and Dmitriy I Fomenkov and Denis V Barsukov and Irina R Subbotina and Fabrice Fleury and Alexander O Terent'ev},

doi = {10.1002/chem.201904555},

issn = {15213765},

year  = {2020},

date = {2020-01-01},

journal = {Chemistry - A European Journal},

volume = {26},

number = {21},

pages = {4734--4751},

abstract = {The catalyst H3+xPMo12−x+6Mox+5O40 supported on SiO2 was developed for peroxidation of 1,3- and 1,5-diketones with hydrogen peroxide with the formation of bridged 1,2,4,5-tetraoxanes and bridged 1,2,4-trioxolanes (ozonides) with high yield based on isolated products (up to 86 and 90 %, respectively) under heterogeneous conditions. Synthesis of peroxides under heterogeneous conditions is a rare process and represents a challenge for this field of chemistry, because peroxides tend to decompose on the surface of a catalyst. A new class of antifungal agents for crop protection, that is, cyclic peroxides: bridged 1,2,4,5-tetraoxanes and bridged ozonides, was discovered. Some ozonides and tetraoxanes exhibit a very high antifungal activity and are superior to commercial fungicides, such as Triadimefon and Kresoxim-methyl. It is important to note that none of the fungicides used in agricultural chemistry contains a peroxide fragment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Vil2020,

title = {Ion exchange resin-catalyzed synthesis of bridged tetraoxanes possessing in vitro cytotoxicity against HeLa cancer cells},

author = {Vera A Vil' and Ivan A Yaremenko and Dmitri I Fomenkov and Dmitri O Levitsky and Fabrice Fleury and Alexander O Terent'ev},

url = {https://doi.org/10.1007/s10593-020-02722-4},

doi = {10.1007/s10593-020-02722-4},

issn = {1573-8353},

year  = {2020},

date = {2020-01-01},

journal = {Chemistry of Heterocyclic Compounds},

volume = {56},

number = {6},

pages = {722--726},

abstract = {Bridged 1,2,4,5-tetraoxanes were prepared using available acidic ion exchange resin with high yields despite the possibility of peroxide decomposition under heterogeneous conditions. The bridged tetraoxanes demonstrated high cytotoxicity against HeLa cancer cells in vitro, which in some cases was higher than that of cisplatin, artesunate, and dihydroartemisinin.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{LAFONT2020129705,

title = {DNA-PKcs Ser2056 auto-phosphorylation is affected by an O-GlcNAcylation/phosphorylation interplay},

author = {Florian Lafont and Fabrice Fleury and Houda Benhelli-Mokrani},

url = {http://www.sciencedirect.com/science/article/pii/S0304416520302178},

doi = {https://doi.org/10.1016/j.bbagen.2020.129705},

issn = {0304-4165},

year  = {2020},

date = {2020-01-01},

journal = {Biochimica et Biophysica Acta (BBA) - General Subjects},

volume = {1864},

number = {12},

pages = {129705},

abstract = {Background DNA dependent Protein Kinase (DNA-PK) is an heterotrimeric complex regulating the Non Homologous End Joining (NHEJ) double strand break (DSB) repair pathway. The activity of its catalytic subunit (DNA-PKcs) is regulated by multiple phosphorylations, like the Ser2056 one that impacts DSB end processing and telomeres integrity. O-GlcNAcylation is a post translational modification (PTM) closely related to phosphorylation and its implication in the modulation of DNA-PKcs activity during the DNA Damage Response (DDR) is unknown. Methods Using IP techniques, and HeLa cell line, we evaluated the effect of pharmacological or siOGT mediated O-GlcNAc level modulation on DNA-PKcs O-GlcNAcylation. We used the RPA32 phosphorylation as a DNA-PKcs activity reporter substrate to evaluate the effect of O-GlcNAc modulators. Results We show here that human DNA-PKcs is an O-GlcNAc modified protein and that this new PTM is responsive to the cell O-GlcNAcylation level modulation. Our findings reveal that DNA-PKcs hypo O-GlcNAcylation affects its kinase activity and that the bleomycin-induced Ser2056 phosphorylation, is modulated by DNA-PKcs O-GlcNAcylation. Conclusions DNA-PKcs Ser2056 phosphorylation is antagonistically linked to DNA-PKcs O-GlcNAcylation level modulation. General significance Given the essential role of DNA-PKcs Ser2056 phosphorylation in the DDR, this study brings data about the role of cell O-GlcNAc level on genome integrity maintenance.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Chabot2019a,

title = {New phosphorylation sites of rad51 by c-met modulates presynaptic filament stability},

author = {Thomas Chabot and Alain Defontaine and Damien Marquis and Axelle Renodon-Corniere and Emmanuelle Courtois and Fabrice Fleury and Yvonnick Cheraud},

doi = {10.3390/cancers11030413},

issn = {20726694},

year  = {2019},

date = {2019-01-01},

journal = {Cancers},

volume = {11},

number = {3},

abstract = {Genomic instability through deregulation of DNA repair pathways can initiate cancer and subsequently result in resistance to chemo and radiotherapy. Understanding these biological mechanisms is therefore essential to overcome cancer. RAD51 is the central protein of the Homologous Recombination (HR) DNA repair pathway, which leads to faithful DNA repair of DSBs. The recombinase activity of RAD51 requires nucleofilament formation and is regulated by post-translational modifications such as phosphorylation. In the last decade, studies have suggested the existence of a relationship between receptor tyrosine kinases (RTK) and Homologous Recombination DNA repair. Among these RTK the c-MET receptor is often overexpressed or constitutively activated in many cancer types and its inhibition induces the decrease of HR. In this study, we show for the first time that c-MET is able to phosphorylate the RAD51 protein. We demonstrate in vitro that c-MET phosphorylates four tyrosine residues localized mainly in the subunit-subunit interface of RAD51. Whereas these post-translational modifications do not affect the presynaptic filament formation, they strengthen its stability against the inhibitor effect of the BRC peptide obtained from BRCA2. Taken together, these results confirm the role of these modifications in the regulation of the BRCA2-RAD51 interaction and underline the importance of c-MET in DNA damage response.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{VELIC2019187,

title = {Interactions of the Rad51 inhibitor DIDS with human and bovine serum albumins: Optical spectroscopy and isothermal calorimetry approaches},

author = {Denis Velic and Cathy Charlier and Milena Popova and Titouan Jaunet-Lahary and Zakaria Bouchouireb and Sébastien Henry and Pierre Weigel and Jean-Yves Masson and Adèle D Laurent and Igor Nabiev and Fabrice Fleury},

url = {http://www.sciencedirect.com/science/article/pii/S0300908419302743},

doi = {https://doi.org/10.1016/j.biochi.2019.09.016},

issn = {0300-9084},

year  = {2019},

date = {2019-01-01},

journal = {Biochimie},

volume = {167},

pages = {187--197},

abstract = {Rad51 is a key protein in DNA repair by homologous recombination and an important target for development of drugs in cancer therapy. 4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS) has been used in clinic during the past 30 years as an inhibitor of anion transporters and channels. Recently DIDS has been demonstrated to affect Rad51-mediated homologous pairing and strand exchange, key processes in homologous recombination. Consequently, DIDS has been considered as a potential revertant of radio- and chemo-resistance of cancer cells, the major causes of therapy failure. Here, we have investigated the behavior of DIDS towards serum albumins. The effects of environmental factors, primarily, solvent polarity, on DIDS stability were evaluated, and the mechanisms of interaction of DIDS with human or bovine serum albumin were analyzed using isothermal calorimetry, circular dichroism and fluorescence spectroscopies. DIDS interaction with both serum albumins have been demonstrated, and the interaction characteristics have been determined. By comparing these characteristics for several DIDS derivatives, we have identified the DIDS moiety essential for the interaction. Furthermore, site competition data indicate that human albumin has two DIDS-binding sites: a high-affinity site in the IIIA subdomain and a low-affinity one in the IB subdomain. Molecular docking has revealed the key molecular moieties of DIDS responsible for its interactions in each site and shown that the IB site can bind two ligands. These findings show that binding of DIDS to serum albumin may change the balance between the free and bound DIDS forms, thereby affecting its bioavailability and efficacy against Rad51.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Deriabin2018,

title = {Similar nature leads to improved properties: Cyclic organosilicon triperoxides as promising curing agents for liquid polysiloxanes},

author = {Konstantin V Deriabin and Ivan A Yaremenko and Mikhail V Chislov and Fabrice Fleury and Alexander O Terent'Ev and Regina M Islamova},

doi = {10.1039/c8nj02499e},

issn = {13699261},

year  = {2018},

date = {2018-01-01},

journal = {New Journal of Chemistry},

volume = {42},

number = {18},

pages = {15006--15013},

publisher = {Royal Society of Chemistry},

abstract = {Cyclic organosilicon triperoxides were found to be vinyl-selective free-radical initiators for thermal curing at 100-180 °C of vinyl-terminated polydimethylsiloxane and trimethylsilyl-terminated polymethylhydrosiloxane producing homogeneous transparent silicone rubbers with antibacterial properties. The usage of the cyclic organosilicon triperoxides as the curing agents does not require free radical inhibitors in comparison with diacyl- and dialkyl peroxides. Among the tested compounds, the peroxide with the Me-Si-Me fragment and two cyclohexane rings is a much more active curing agent (180 °C},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Jaunet-Lahary2018,

title = {Computational simulations determining disulfonic stilbene derivative bioavailability within human serum albumin},

author = {Titouan Jaunet-Lahary and Daniel P Vercauteren and Fabrice Fleury and Adèle D Laurent},

doi = {10.1039/c8cp00704g},

issn = {14639076},

year  = {2018},

date = {2018-01-01},

journal = {Physical Chemistry Chemical Physics},

volume = {20},

number = {26},

pages = {18020--18030},

publisher = {Royal Society of Chemistry},

abstract = {Disulfonic stilbene (DS) derivatives are a member of the large family of compounds widely employed in medicine and biology as modulators for membrane transporters or inhibitors of a protein involved in DNA repair. They constitute interesting compounds that have not yet been investigated within the bioavailability framework. No crystallographic structures exist involving such compounds embedded in the most common drug carrier, human serum albumin (HSA). The present work studies, for the first time, the physico-chemical features driving the inclusion of three DS derivatives (amino, nitro and acetamido, named DADS, DNDS and DATDS, respectively) within the four common HSA binding sites using combined molecular docking and molecular dynamics simulations. A careful analysis of each ligand within each of the studied binding sites is carried out, highlighting specific interactions and key residues playing a role in stabilizing the ligand within each pocket. The comparison between DADS, DNDS and DATDS reveals that depending on the binding site, the conclusions are rather different. For instance, the IB binding site shows a specificity to DADS compounds while IIIA is the most favorable site for DNDS and DATDS. 2018},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Lafont2018,

title = {Assessment of DNA-PKcs kinase activity by quantum dot–based microarray},

author = {Florian Lafont and Nizar Ayadi and Cathy Charlier and Pierre Weigel and Igor Nabiev and Houda Benhelli-Mokrani and Fabrice Fleury},

doi = {10.1038/s41598-018-29256-2},

issn = {20452322},

year  = {2018},

date = {2018-01-01},

journal = {Scientific Reports},

volume = {8},

number = {1},

pages = {1--12},

abstract = {Therapeutic efficacy against cancer is often based on a variety of DNA lesions, including DNA double-strand breaks (DSBs) which are repaired by homologous recombination and non-homologous end joining (NHEJ) pathways. In the past decade, the functions of the DNA repair proteins have been described as a potential mechanism of resistance in tumor cells. Therefore, the DNA repair proteins have become targets to improve the efficacy of anticancer therapy. Given the central role of DNA-PKcs in NHEJ, the therapeutic efficacy of targeting DNA-PKcs is frequently described as a strategy to prevent repair of treatment-induced DNA damage in cancer cells. The screening of a new inhibitor acting as a sensitizer requires the development of a high-throughput tool in order to identify and assess the most effective molecule. Here, we describe the elaboration of an antibody microarray dedicated to the NHEJ pathway that we used to evaluate the DNA-PKcs kinase activity in response to DNA damage. By combining a protein microarray with Quantum-Dot detection, we show that it is possible to follow the modification of phosphoproteomic cellular profiles induced by inhibitors during the response to DNA damage. Finally, we discuss the promising tool for screening kinase inhibitors and targeting DSB repair to improve cancer treatment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Yaremenko2017,

title = {Cyclic peroxides as promising anticancer agents: in vitro cytotoxicity study of synthetic ozonides and tetraoxanes on human prostate cancer cell lines},

author = {Ivan A Yaremenko and Mikhail A Syroeshkin and Dmitri O Levitsky and Fabrice Fleury and Alexander O Terent'ev},

url = {https://doi.org/10.1007/s00044-016-1736-2},

doi = {10.1007/s00044-016-1736-2},

issn = {1554-8120},

year  = {2017},

date = {2017-01-01},

journal = {Medicinal Chemistry Research},

volume = {26},

number = {1},

pages = {170--179},

abstract = {Synthetic ozonides and tetraoxanes were shown to have high cytotoxicity in vitro when tested on androgen-independent prostate cancer cell lines DU145 and PC3, which is in some cases was higher than that of doxorubicin, cisplatin, etoposide, artemisinin, and artesunate. Activity of ozonide stereoisomers differs from each other. This difference in activity and absence of correlation between activity of stereoisomers and their oxidative properties allow us to suggest existence of a quite specific mechanism of cytotoxicity of these endoperoxides different from a traditional mechanism based mainly on oxidative properties of peroxides.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Faucon2017,

title = {Bioconjugated fluorescent organic nanoparticles targeting EGFR-overexpressing cancer cells},

author = {Adrien Faucon and Houda Benhelli-Mokrani and Fabrice Fleury and Stéphanie Dutertre and Marc Tramier and Joanna Boucard and Lénaïc Lartigue and Steven Nedellec and Philippe Hulin and Eléna Ishow},

doi = {10.1039/c7nr06533g},

issn = {20403372},

year  = {2017},

date = {2017-01-01},

journal = {Nanoscale},

volume = {9},

number = {45},

pages = {18094--18106},

publisher = {Royal Society of Chemistry},

abstract = {The field of optical bioimaging has considerably flourished with the advent of sophisticated microscopy techniques and ultra-bright fluorescent tools. Fluorescent organic nanoparticles (FONs) have thus recently appeared as very attractive labels for their high payload, absence of cytotoxicity and eventual biodegradation. Nevertheless, their bioconjugation to target specific receptors with high imaging contrast is scarcely performed. Moreover, assessing the reality of bioconjugation represents high challenges given the sub-nanomolar concentrations resulting from the commonly adopted nanoprecipitation fabrication process. Here, we describe how the combination of a magnetic shell allows us to easily generate red-emitting FONs conjugated with the epidermal growth factor ligand (EGF), a small protein promoting cancer cell proliferation by activating the EGF receptor (EGFR) pathway. Dual color fluorescence correlation spectroscopy combined with immunofluorescence is originally harnessed in its time trace mode to unambiguously demonstrate covalent attachment between the FON and EGF at sub-nanomolar concentrations. Strong asymmetric clustering of EGF-conjugated FONs is observed at the membrane of MDA-MB-468 human breast cancer cells overexpressing EGF receptors using super-resolution fluorescence microscopy. Such high recruitment of EGF-conjugated FONs is attributed to their EGF multivalency (4.7 EGF per FON) which enables efficient EGFR activation and subsequent phosphorylation. The large hydrodynamic diameter (DH ∼ 301 nm) of EGF-conjugated FONs prevents immediate engulfment of the sequestered receptors, which provides very bright and localized spots in less than 30 minutes. The reported bioconjugated nanoassemblies could thus serve as ultra-bright probes of breast cancer cells with EGFR-overexpression that is often associated with poor prognosis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Alligand2017,

title = {Functional effects of diphosphomimetic mutations at cAbl-mediated phosphorylation sites on Rad51 recombinase activity},

author = {Brendan Alligand and Magali {Le Breton} and Damien Marquis and François Vallette and Fabrice Fleury},

url = {http://dx.doi.org/10.1016/j.biochi.2017.05.020},

doi = {10.1016/j.biochi.2017.05.020},

issn = {61831638},

year  = {2017},

date = {2017-01-01},

journal = {Biochimie},

volume = {139},

pages = {115--124},

publisher = {Elsevier Ltd},

abstract = {Homologous Recombination enables faithful repair of the deleterious double strand breaks of DNA. This pathway relies on Rad51 to catalyze homologous DNA strand exchange. Rad51 is known to be phosphorylated in a sequential manner on Y315 and then on Y54, but the effect of such phosphorylation on Rad51 function remains poorly understood. We have developed a phosphomimetic model in order to study all the phosphorylation states. With the purified phosphomimetic proteins we performed in vitro assays to determine the activity of Rad51. Here we demonstrate the inhibitory effect of the double phosphomimetic mutant and suggest that it may be due to a defect in nucleofilament formation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Silva2016,

title = {Rapid diminution in the level and activity of DNA-dependent protein kinase in cancer cells by a reactive nitro-benzoxadiazole compound},

author = {Viviane A O Silva and Florian Lafont and Houda Benhelli-Mokrani and Magali {Le Breton} and Philippe Hulin and Thomas Chabot and Fran{ç}ois Paris and Vehary Sakanyan and Fabrice Fleury},

doi = {10.3390/ijms17050703},

issn = {14220067},

year  = {2016},

date = {2016-05-01},

journal = {International Journal of Molecular Sciences},

volume = {17},

number = {5},

publisher = {MDPI AG},

abstract = {The expression and activity of DNA-dependent protein kinase (DNA-PK) is related to DNA repair status in the response of cells to exogenous and endogenous factors. Recent studies indicate that Epidermal Growth Factor Receptor (EGFR) is involved in modulating DNA-PK. It has been shown that a compound 4-nitro-7-[(1-oxidopyridin-2-yl)sulfanyl]-2,1,3-benzoxadiazole (NSC), bearing a nitro-benzoxadiazole (NBD) scaffold, enhances tyrosine phosphorylation of EGFR and triggers downstream signaling pathways. Here, we studied the behavior of DNA-PK and other DNA repair proteins in prostate cancer cells exposed to compound NSC. We showed that both the expression and activity of DNA-PKcs (catalytic subunit of DNA-PK) rapidly decreased upon exposure of cells to the compound. The decline in DNA-PKcs was associated with enhanced protein ubiquitination, indicating the activation of cellular proteasome. However, pretreatment of cells with thioglycerol abolished the action of compound NSC and restored the level of DNA-PKcs. Moreover, the decreased level of DNA-PKcs was associated with the production of intracellular hydrogen peroxide by stable dimeric forms of Cu/Zn SOD1 induced by NSC. Our findings indicate that reactive oxygen species and electrophilic intermediates, generated and accumulated during the redox transformation of NBD compounds, are primarily responsible for the rapid modulation of DNA-PKcs functions in cancer cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{TerentEv2016,

title = {Selective transformation of tricyclic peroxides with pronounced antischistosomal activity into 2-hydroxy-1,5-diketones using iron (II) salts},

author = {Alexander O Terent'Ev and Zhanna Yu Pastukhova and Ivan A Yaremenko and Roman A Novikov and Dmitry V Demchuk and Lev G Bruk and Dmitri O Levitsky and Fabrice Fleury and Gennady I Nikishin},

url = {http://dx.doi.org/10.1016/j.tet.2016.04.054},

doi = {10.1016/j.tet.2016.04.054},

issn = {14645416},

year  = {2016},

date = {2016-01-01},

journal = {Tetrahedron},

volume = {72},

number = {24},

pages = {3421--3426},

publisher = {Elsevier Ltd},

abstract = {The present work deals with selective transformations of peroxides into organic compounds via the cleavage of the O-O bond using variable valence metals. A selective transformation of tricyclic peroxides promoted by Fe2+ salts was discovered. This selective transformation is unexpected for compounds with structural features which allow diverse decomposition pathways. 2-Hydroxy-1,5-diketones are prepared in yields up to 92% in the reactions of tricyclic peroxides with FeSO4, Fe(ClO4)2, or FeCl2. This is a new preparative method for the synthesis of 1,5-diketones. 2-Hydroxy-1,5-diketones in CDCl3 at 25 °C exist mainly in the open-chain form of the hydroxyketone over the cyclic hemiacetal. The results of this work can be of interest to understand the mechanism of the antiparasitic action of peroxides.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Zdvizhkov2016,

title = {Transformation of 2-allyl-1,3-diketones to bicyclic compounds containing 1,2-dioxolane and tetrahydrofuran rings using the I2/H2O2 system},

author = {Alexander T Zdvizhkov and Alexander O Terent'Ev and Peter S Radulov and Roman A Novikov and Viktor A Tafeenko and Vladimir V Chernyshev and Alexey I Ilovaisky and Dmitri O Levitsky and Fabrice Fleury and Gennady I Nikishin},

url = {http://dx.doi.org/10.1016/j.tetlet.2016.01.061},

doi = {10.1016/j.tetlet.2016.01.061},

issn = {18733581},

year  = {2016},

date = {2016-01-01},

journal = {Tetrahedron Letters},

volume = {57},

number = {8},

pages = {949--952},

publisher = {Elsevier Ltd},

abstract = {A one-pot procedure was developed for the assembly of bicyclic compounds containing 1,2-dioxolane and tetrahydrofuran rings based on the reaction of 2-allyl-1,3-diketones with the I2/H2O2 system. A fivefold molar excess of H2O2 and a twofold excess of I2 are required for the selective formation of tetrahydrofurodioxoles. The synthesis of these structurally complex molecules is unusual in that it does not produce the expected bridged tetraoxanes, products of the addition of several H2O2 molecules to a carbonyl group, or the products of double bond iodoperoxidation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Sakanyan2016,

title = {Activation of EGFR by small compounds through coupling the generation of hydrogen peroxide to stable dimerization of Cu/Zn SOD1},

author = {Vehary Sakanyan and Philippe Hulin and Rodolphe {Alves De Sousa} and Viviane A O Silva and Artur Hambardzumyan and Steven Nedellec and Christophe Tomasoni and Cédric Logé and Charles Pineau and Christos Roussakis and Fabrice Fleury and Isabelle Artaud},

url = {http://dx.doi.org/10.1038/srep21088},

doi = {10.1038/srep21088},

issn = {20452322},

year  = {2016},

date = {2016-01-01},

journal = {Scientific Reports},

volume = {6},

number = {January},

pages = {1--14},

publisher = {Nature Publishing Group},

abstract = {Activation of cell signaling by reactive chemicals and pollutants is an important issue for human health. It has been shown that lipophilic nitro-benzoxadiazole (NBD) compounds rapidly move across the plasma membrane and enhance Epidermal Growth Factor Receptor (EGFR) tyrosine phosphorylation in cancer cells. Unlike ligand-dependent activation, the mechanism of this induction relies on the generation of hydrogen peroxide, which is involved in the activation of the catalytic site of the receptor and the inactivation of protein tyrosine phosphatase PTP-1B. Production of H 2 O 2 during redox transformation of NBD compounds is associated with the transition of a monomeric form of Cu/Zn superoxide dismutase 1 (SOD1) to stable dimers. The highly stable and functionally active SOD1 dimer, in the absence of adequate activities in downstream reactions, promotes the disproportionate production and accumulation of intracellular hydrogen peroxide shortly after exposure to NBD compounds. The intrinsic fluorescence of small compounds was used to demonstrate their binding to SOD1. Our data indicate that H 2 O 2 and concomitantly generated electrophilic intermediates behave as independent entities, but all contribute to the biological reactivity of NBD compounds. This study opens a promising path to identify new biomarkers of oxidative/electrophilic stress in the progression of cancer and other diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Faucon2016,

title = {Tuning the architectural integrity of high-performance magneto-fluorescent core-shell nanoassemblies in cancer cells},

author = {Adrien Faucon and Houda Benhelli-Mokrani and Fabrice Fleury and Laurence Dubreil and Philippe Hulin and Steven Nedellec and Tristan Doussineau and Rodolphe Antoine and Tomas Orlando and Alessandro Lascialfari and Jér{ô}me Fresnais and Léna{ï}c Lartigue and Eléna Ishow},

url = {http://dx.doi.org/10.1016/j.jcis.2016.06.064},

doi = {10.1016/j.jcis.2016.06.064},

issn = {10957103},

year  = {2016},

date = {2016-01-01},

journal = {Journal of Colloid and Interface Science},

volume = {479},

pages = {139--149},

publisher = {Elsevier Inc.},

abstract = {High-density nanoarchitectures, endowed with simultaneous fluorescence and contrast properties for MRI and TEM imaging, have been obtained using a simple self-assembling strategy based on supramolecular interactions between non-doped fluorescent organic nanoparticles (FON) and superparamagnetic nanoparticles. In this way, a high-payload core-shell structure FON@mag has been obtained, protecting the hydrophobic fluorophores from the surroundings as well as from emission quenching by the shell of magnetic nanoparticles. Compared to isolated nanoparticles, maghemite nanoparticles self-assembled as an external shell create large inhomogeneous magnetic field, which causes enhanced transverse relaxivity and exacerbated MRI contrast. The magnetic load of the resulting nanoassemblies is evaluated using magnetic sedimentation and more originally electrospray mass spectrometry. The role of the stabilizing agents (citrate versus polyacrylate anions) revealed to be crucial regarding the cohesion of the resulting high-performance magneto-fluorescent nanoassemblies, which questions their use after cell internalization as nanocarriers or imaging agents for reliable correlative light and electron microcopy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Jaunet-Lahary2016,

title = {A Joint Theoretical and Experimental Study of the Behavior of the DIDS Inhibitor and its Derivatives},

author = {Titouan Jaunet-Lahary and Anaïs Goupille and Denis Jacquemin and Fabrice Fleury and Jérôme Graton and Adèle D Laurent},

doi = {10.1002/cphc.201600107},

issn = {14397641},

year  = {2016},

date = {2016-01-01},

journal = {ChemPhysChem},

volume = {3},

pages = {2434--2445},

abstract = {4,4′-Diisothiocyanostilbene-2,2′-disulfonic acid (DIDS) is a well-known ion-exchange inhibitor targeting cardiac functions and indirectly impeding both radio- and chemo-resistance. A joint computational and experimental study is presented to provide deeper insights into DIDS and other members of this family of compounds. To this end, we applied state-of-the-art density functional theory (DFT) and time-dependent DFT methods, in addition to measuring the optical properties. The experimental data show that such compounds are highly sensitive to their environment and that the optical properties change within as little time as 7 h. However, the optical properties of DIDS are similar in various acidic/basic environments, which were confirmed by pKa computations on both cis and trans isomers. The protonation analysis also highlights that the singly protonated form of DIDS behaves like a proton sponge compound. The experimentally observed redshift that can be seen when going from water to DMSO was reproduced solely by using the solvation model based on density, although the polarization continuum model and implicit/explicit hybrid schemes were also tested. The characteristic broadening of the absorption peak in water and the vibronic fine structure in DMSO were also reproduced thanks to vibronic coupling simulations associated with the solvent reorganization energy. For other stilbene derivatives, a correlation is found between the maximum absorption wavelength and the Hammett parameters.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{biom5043204,

title = {DNA Damage Signalling and Repair Inhibitors: The Long-Sought-After Achilles’ Heel of Cancer},

author = {Denis Velic and Anthony M Couturier and Maria Tedim Ferreira and Amélie Rodrigue and Guy G Poirier and Fabrice Fleury and Jean-Yves Masson},

url = {https://www.mdpi.com/2218-273X/5/4/3204},

doi = {10.3390/biom5043204},

issn = {2218-273X},

year  = {2015},

date = {2015-01-01},

journal = {Biomolecules},

volume = {5},

number = {4},

pages = {3204--3259},

abstract = {For decades, radiotherapy and chemotherapy were the two only approaches exploiting DNA repair processes to fight against cancer. Nowadays, cancer therapeutics can be a major challenge when it comes to seeking personalized targeted medicine that is both effective and selective to the malignancy. Over the last decade, the discovery of new targeted therapies against DNA damage signalling and repair has offered the possibility of therapeutic improvements in oncology. In this review, we summarize the current knowledge of DNA damage signalling and repair inhibitors, their molecular and cellular effects, and future therapeutic use.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Terentev2015,

title = {Organocatalytic peroxidation of malonates, β-ketoesters, and cyanoacetic esters using n-Bu4NI/t-BuOOH-mediated intermolecular oxidative C(sp3)-O coupling},

author = {Alexander O Terent'ev and Alexander T Zdvizhkov and Dmitri O Levitsky and Fabrice Fleury and Roman A Pototskiy and Alena N Kulakova and Gennady I Nikishin},

url = {http://dx.doi.org/10.1016/j.tet.2015.09.047},

doi = {10.1016/j.tet.2015.09.047},

issn = {14645416},

year  = {2015},

date = {2015-01-01},

journal = {Tetrahedron},

volume = {71},

number = {47},

pages = {8985--8990},

publisher = {Elsevier Ltd},

abstract = {A new organocatalytic approach for the synthesis of peroxides based on CH activation of a sp3-hybridized carbon atom is reported. Peroxides were prepared in 31-89% yield by the reaction of malonates, β-ketoesters, and cyanoacetic esters with a Bu4NI/tert-butyl hydroperoxide system. The formation of the expected hydroxylation products was not observed. In the discovered reaction, tert-butyl hydroperoxide plays a dual role by acting as the oxidant and the O-reagent for the C-O coupling. The synthesis can be scaled up to generate gram quantities of the target products.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}