Olivier Provot
Centre national de la recherche scientifique
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Publication
Featured researches published by Olivier Provot.
Journal of Medicinal Chemistry | 2009
Samir Messaoudi; Bret Tréguier; Abdallah Hamze; Olivier Provot; Jean-François Peyrat; Jordi Rodrigo De Losada; Jian-Miao Liu; Jérôme Bignon; Joanna Wdzieczak-Bakala; Sylviane Thoret; Joëlle Dubois; Jean-Daniel Brion; Mouâd Alami
Herein is reported a convergent synthesis of isocombretastatins A, a novel class of potent antitubulin agents. These compounds having a 1,1-diarylethylene scaffold constitute the simplest isomers of natural Z-combretastatins A that are easy to synthesize without need to control the Z-olefin geometry. The discovery of isoCA-4 with biological activities comparable to that of CA-4 represents a major progress in this field.
ChemMedChem | 2011
Samir Messaoudi; Abdallah Hamze; Olivier Provot; Bret Tréguier; Jordi Rodrigo De Losada; Jérôme Bignon; Jian-Miao Liu; Joanna Wdzieczak-Bakala; Sylviane Thoret; Joëlle Dubois; Jean-Daniel Brion; Mouad Alami
The cytotoxic activity of a series of 23 new isoerianin derivatives with modifications on both the A and B rings was studied. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. The most cytotoxic compound, isoerianin (3), strongly inhibits tubulin polymerization in the micromolar range. Moreover, isoerianin leads to G2/M phase cell‐cycle arrest in H1299 and K562 cancer cells, and strongly induces apoptosis. Isoerianin also disrupts the vessel‐like structures formed by human umbilical vein endothelial cells (HUVECs) in vitro, suggesting that this compound may act as a vascular disrupting agent. It clearly appears that in this compound series, the 1,1‐ethane bridge encountered in isoerianin derivatives can replace the 1,2‐ethane bridge of natural erianin with no loss of activity. This reinforces the bioisosteric replacement approach in the combretastatin series previously reported by our research group.
ChemMedChem | 2009
Abdallah Hamze; Anne Giraud; Samir Messaoudi; Olivier Provot; Jean-François Peyrat; Jérôme Bignon; Jian-Miao Liu; Joanna Wdzieczak-Bakala; Sylviane Thoret; Joëlle Dubois; Jean-Daniel Brion; Mouad Alami
The cytotoxic activities of 23 new isocombretastatin A derivatives with modifications on the B‐ring were investigated. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. Compounds isoFCA‐4 (2 e), isoCA‐4 (2 k) and isoNH2CA‐4 (2 s) were the most cytotoxic, and strongly inhibited tubulin polymerization with IC50 values of 4, 2 and 1.5 μM, respectively. These derivatives were found to be 10‐fold more active than phenstatin and colchicine with respect to growth inhibition but displayed similar activities as tubulin polymerization inhibitors. In addition, cell cycle arrest in the G2/M phase and subsequent apoptosis was observed in three cancer cell lines when treated with these compounds. The disruptive effect of 2 e, 2 k and 2 s on the vessel‐like structures formed by human umbilical vein endothelial cells (HUVEC) suggest that these compounds may act as vascular disrupting agents. Both compounds 2 k and 2 s have the potential for further prodrug modification and development as vascular disrupting agents for treatment of solid tumors.
Bioorganic & Medicinal Chemistry Letters | 2008
Céline Mousset; Anne Giraud; Olivier Provot; Abdallah Hamze; Jérôme Bignon; Jian-Miao Liu; Sylviane Thoret; Joëlle Dubois; Jean-Daniel Brion; Mouâd Alami
A series of benzil derivatives related to combretastatin A-4 (CA-4) have been synthesized by oxidation of diarylalkynes promoted by PdI(2) in DMSO. Using this new protocol, 14 benzils were prepared in good to excellent yields and their biological activity has been delineated. Several benzils exhibited excellent antiproliferative activity: for example, 4j and 4k bearing the greatest resemblance to CA-4 and AVE-8062, respectively, were found to inhibit cell growth at the nanomolar level (20-50nM) on four human tumor cell lines. Flow cytometric analysis indicates that these compounds act as antimitotics and arrest the cell cycle in G(2)/M phase. A cell-based assay indicated that compounds 4j and 4k displayed a similar inhibition of tubulin assembly with an IC(50) value similar to CA-4. These results clearly demonstrated that the Z-double bond of CA-4 can be replaced by a 1,2-diketone unit without significant loss of cytotoxicity and inhibition of tubulin assembly potency.
Journal of Organic Chemistry | 2009
Abdallah Hamze; Damien Veau; Olivier Provot; Jean-Daniel Brion; Mouâd Alami
The palladium-catalyzed hydrostannation of terminal arylalkynes was achieved. The regioselectivity of the H-Sn bond addition across the triple bond was found to be controlled by an ortho substituent on the aromatic ring, whatever its electronic nature, to give exclusively alpha-branched vinylstannanes 2 in accordance with Markovnikovs rule. Subsequent Stille cross-coupling reaction of 2 with a variety of aryl halides readily provided, in moderate to good yields, a family of functionalized 1,1-diarylethylenes 1.
ACS Nano | 2014
Andrei Maksimenko; Mouad Alami; Fatima Zouhiri; Jean-Daniel Brion; Alain Pruvost; Julie Mougin; Abdallah Hamze; Tanguy Boissenot; Olivier Provot; Didier Desmaële; Patrick Couvreur
Drug delivery of combined cytotoxic and antivascular chemotherapies in multidrug nanoassemblies may represent an attractive way to improve the treatment of experimental cancers. Here we made the proof of concept of this approach on the experimental LS174-T human colon carcinoma xenograft nude mice model. Briefly, we have nanoprecipitated the anticancer compound gemcitabine conjugated with squalene (SQ-gem) together with isocombretastatin A-4 (isoCA-4), a new isomer of the antivascular combretastatin A-4 (CA-4). It was found that these molecules spontaneously self-assembled as stable nanoparticles (SQ-gem/isoCA-4 NAs) of ca. 142 nm in a surfactant-free aqueous solution. Cell culture viability tests and apoptosis assays showed that SQ-gem/isoCA-4 NAs displayed comparable antiproliferative and cytotoxic effects than those of the native gemcitabine or the mixtures of free gemcitabine with isoCA-4. Surprisingly, it was observed by confocal microscopy that the nanocomposites made of SQ-gem/isoCA-4 distributed intracellularly as intact nanoparticles whereas the SQ-gem nanoparticles remained localized onto the cell membrane. When used to deliver these combined chemotherapeutics to human colon cancer model, SQ-gem/isoCA-4 nanocomposites induced complete tumor regression (by 93%) and were found superior to all the other treatments, whereas the overall tolerance was better than the free drug treatments. This approach could be applied to other pairs of squalenoylated nanoassemblies with other non-water-soluble drugs, thus broadening the application of the “squalenoylation” concept in oncology.
ChemMedChem | 2011
Abdallah Hamze; Evelia Rasolofonjatovo; Olivier Provot; Céline Mousset; Damien Veau; Jordi Rodrigo; Jérôme Bignon; Jian-Miao Liu; Joanna Wdzieczak-Bakala; Sylviane Thoret; Joëlle Dubois; Jean-Daniel Brion; Mouad Alami
A novel class of isocombretastatin A‐4 (isoCA‐4) analogues with modifications at the 3′‐position of the B‐ring by replacement with C‐linked substituents was studied. Exploration of the structure–activity relationships of theses analogues led to the identification of several compounds that exhibit excellent antiproliferative activities in the nanomolar concentration range against H1299, MDA‐MB231, HCT116, and K562 cancer cell lines; they also inhibit tubulin polymerization with potency similar to that of isoCA‐4. 1,1‐Diarylethylenes 8 and 17, respectively with (E)‐propen‐3‐ol and propyn‐3‐ol substituents at the 3′‐position of the B‐ring, proved to be the most active in this series. Both compounds led to the arrest of various cancer cell lines at the G2/M phase of the cell cycle and strongly induced apoptosis. Docking of compounds 8 and 17 in the colchicine binding site indicated that their C3′ substituents guide the positioning of the B‐ring in a manner different from that observed for isoCA‐4.
Journal of Organic Chemistry | 2013
Maxime Roche; Gilles Frison; Jean-Daniel Brion; Olivier Provot; Abdallah Hamze; Mouad Alami
In a fresh approach to the synthesis of N-vinylazoles, a ligand-free palladium catalytic system was found to promote the Csp(2)-N bond-forming reaction utilizing N-tosylhydrazones and N-H azoles. This process shows functional group tolerance; di-, tri-, and tetrasubstituted N-vinylazoles were obtained in high yields. Under the optimized conditions, the reaction proceeds with high stereoselectivity depending on the nature of the coupling partners.
European Journal of Medicinal Chemistry | 2010
Evelia Rasolofonjatovo; Olivier Provot; Abdallah Hamze; Jérôme Bignon; Sylviane Thoret; Jean-Daniel Brion; Mouâd Alami
A series of triarylolefins bearing the combretastatin A-4 and the isocombretastatin A-4 cores were synthesized and evaluated. The cooperative ortho-effect of a labile bromine atom in the regioselective hydrostannation of unsymmetrical diarylalkynes leading to stereodefined triarylolefins is presented.
European Journal of Medicinal Chemistry | 2013
Evelia Rasolofonjatovo; Olivier Provot; Abdallah Hamze; Jordi Rodrigo; Jérôme Bignon; Joanna Wdzieczak-Bakala; Christine Lenoir; Déborah Desravines; Joëlle Dubois; Jean-Daniel Brion; Mouad Alami
A series of novel benzoxepins 6 was designed and prepared as rigid-isoCA-4 analogs according to a convergent strategy using the coupling of N-tosylhydrazones with aryl iodides under palladium catalysis. The most potent compound 6b, having the greatest resemblance to CA-4 and isoCA-4 displayed antiproliferative activity at nanomolar concentrations against various cancer cell lines and inhibited tubulin assembly at a micromolar range. In addition, benzoxepin 6b led to the arrest of HCT116, K562, H1299 and MDA-MB231 cancer cell lines in the G2/M phase of the cell cycle, and strongly induced apoptosis at low concentrations. Docking studies demonstrated that benzoxepin 6b adopt an orientation similar to that of isoCA-4 at the colchicine binding site on β-tubulin.