Publications (8)27.98 Total impact
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Article: Synthesis and biological evaluation of 4-arylcoumarin analogues of combretastatins. Part 2.
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ABSTRACT: A series of A-ring variously methoxylated 4-(3-hydroxy-4-methoxyphenyl)coumarins related to combretastatin A-4 was prepared by cross-coupling reactions. Cytotoxicity studies indicated a potent activity against HBL100 cell line. Substitution patterns on A-ring had only a slight effect on antiproliferative activity. For most cytotoxic compounds, the activity as potential modulators of P-gp and BCRP efflux pumps was evaluated. The results show that compounds 2 and 7 were able to restore mitoxantrone accumulation (BCRP) at concentrations similar to that of cyclosporine A. Compound 7 was the most efficient to reverse P-gp activity. All compounds were found to potently inhibit in vitro microtubule formation via a substoichiometric mode of action for the most part. Compounds 1 and 2 were found to have an apparent affinity binding constant similar to that of combretastatin A-4, i.e., 1 × 10 (6) M(-1). The molecular modeling of coumarin derivatives was performed on the basis of the molecular structure of 7, as determined by single-crystal X-ray crystallography. The calculations suggested that the presence of a methoxy group out of the plane of the chromenone moiety is an important steric hindrance factor embedding the accessibility of those molecules inside the binding pocket on tubulin.Journal of Medicinal Chemistry 05/2011; 54(9):3153-62. · 4.80 Impact Factor -
Article: Synthesis and antiprotozoal activity of 4-arylcoumarins.
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ABSTRACT: A large series of 4-arylcoumarins was synthesized by Suzuki-Miyaura cross-coupling reaction and evaluated for antiprotozoal activity against Plasmodium falciparum and Leishmania donovani. Several compounds were found to strongly inhibit the proliferation of human cell line and/or parasites. The 4-(3,4-dimethoxyphenyl)-6,7-dimethoxycoumarin exhibit a potent activity on L. donovani amastigotes with a selectivity index (SI=265) twice than amphotericin B (SI=140).European journal of medicinal chemistry 10/2009; 45(3):864-9. · 3.27 Impact Factor -
Article: 4-arylcoumarin analogues of combretastatins stimulate apoptosis of leukemic cells from chronic lymphocytic leukemia patients.
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ABSTRACT: To investigate the proapoptotic capacities of four arylcoumarin analogues of combretastatins on leukemic cells from B-cell chronic lymphocytic leukemia (CLL), a malignancy characterized by apoptosis deficiency. The effects of the four compounds on several nuclear, membrane, and mitochondrial events of apoptosis and on expression of proteins controlling the apoptosis were analyzed after treatment of cultured CLL patients' cells. Treatment with all four compounds resulted in a dose-dependent internucleosomal DNA fragmentation, in stimulation of phosphatidylserine externalization, disruption of the mitochondrial transmembrane potential and caspase-3 activation. DNA fragmentation was prevented in the presence of the pan-caspase inhibitor z-VAD-fmk. Two of the compounds downregulated the expression of Mcl-1, a protein thought to be crucial for the antiapoptotic state in CLL, while Bcl-2 expression was unaffected. No effects were observed on the expression of p27kip1 or the inducible nitric oxide synthase, two proteins, which are constitutively overexpressed by CLL cells and downregulated during the apoptosis induced by other plant-derived molecules (flavopiridol, polyphenols, or hyperforin). This suggests different mechanisms of action for the compounds studied here. Furthermore, normal B lymphocytes from healthy donors appeared less sensitive than CLL cells to the proapoptotic activity of the four compounds. The four arylcoumarin analogues were able to promote the apoptosis of CLL cells ex vivo through the caspase-dependent mitochondrial pathway. Therefore, these compounds may be of interest to develop new therapies of CLL based on apoptosis restoration.Experimental Hematology 11/2008; 36(12):1625-33. · 2.90 Impact Factor -
Article: Synthesis and biological evaluation of polymethoxylated 4-heteroarylcoumarins as tubulin assembly inhibitor.
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ABSTRACT: A series of syn-restricted polymethoxylated 4-heteroarylcoumarins--the isostuctural analogs of combretastatin A-4--was synthesized by Suzuki-Miyaura cross-coupling reaction and evaluated for antiproliferative activity. The 4-(1-methyl-1H-indol-5-yl)chromen-2-ones exhibit a potent cytotoxicity against HBL100 epithelial cell line with an IC(50) value amounting to 0.098 and 0.078 microM, respectively. The two compounds, having an indolyl moiety, potent inhibit in vitro microtubule assembly with a substoichiometric mode of action. A structure-activity relationship was discussed and the indolyl moiety was proved to be a good surrogate for the 3-hydroxy-4-methoxyphenyl ring of CA-4.Bioorganic & medicinal chemistry 10/2008; 16(19):8806-12. · 2.82 Impact Factor -
Article: Cascade synthesis of polyoxygenated 6H,11H-[2]benzopyrano-[4,3-c][1]benzopyran-11-ones.
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ABSTRACT: 2-(methoxymethoxymethyl)aryllead triacetates, obtained in situ from the corresponding arylboronic acids, reacted with 4-hydroxycoumarins, leading to 3-(2-methoxymethoxymethyl)aryl-4-hydroxycoumarin derivatives in good to high yields. These compounds underwent a cascade sequence of reactions, deprotection-halogenation-annulation, to afford polyoxygenated tetracyclic 6H,11H-[2]benzopyrano-[4,3-c] [1]benzopyran-11-ones in good yields. Some compounds showed a moderate cytotoxicity against human epithelial mammary HBL100 cells.The Journal of Organic Chemistry 05/2007; 72(9):3293-301. · 4.45 Impact Factor -
Article: Interaction of 4-arylcoumarin analogues of combretastatins with microtubule network of HBL100 cells and binding to tubulin.
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ABSTRACT: The synthesis of different 4-arylcoumarin analogues of combretastatin A-4 led to the identification of two new compounds (1 and 2) with potent cytotoxic activity on a CEM leukemia cell line and a third one completely inactive (compound 3). It was suggested that the cytotoxicity of compounds 1 and 2 may be related to their interaction with microtubules and tubulin, since these compounds inhibit microtubule formation from purified tubulin in vitro [Bailly et al. (2003) J. Med. Chem. 46 (25), 5437-5444]. In the present study, tubulin was identified as the main target of these molecules. We studied structure-activity relationships of these compounds using biological experiments specific for tubulin binding. The modification of cell cycle progression induced by compounds 1 and 2 was characterized by an apoptotic induction on human breast cells (HBL100). In addition, these two molecules disturbed cell survival by depolymerizing the microtubule network, leading to a mitotic block. We then determined the thermodynamic parameters of their interaction with purified tubulin by fluorescence spectroscopy and isothermal microcalorimetry. These results, together with a superimposition of the molecule on colchicine in the X-ray-determined three-dimensional structure model of tubulin-colchicine complex, allowed us to identify the pharmacophore of the combretastatin A-4 analogues responsible for their biological activity.Biochemistry 09/2006; 45(30):9210-8. · 3.42 Impact Factor -
Article: Synthesis and biological evaluation of 4-arylcoumarin analogues of combretastatins.
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ABSTRACT: A series of A-ring polymethoxylated neoflavonoids was prepared by ligand coupling reactions involving either Suzuki or Stille reactions. Cytotoxicity studies indicated a potent activity against a CEM leukemia cell line for the compounds presenting a substitution pattern related to that of combretastatin A-4. The two compounds having a 3'-OH and a 4'-OCH(3) substituents on the 4-phenyl B-ring have no effect on human topoisomerases I and II but potently inhibit, in vitro, microtubule assembly. At the cell level, the active compounds were characterized as proapoptotic agents, but they can also trigger cell death via a nonapoptotic pathway.Journal of Medicinal Chemistry 01/2004; 46(25):5437-44. · 5.25 Impact Factor -
Article: A Simple Synthesis of the Natural 2,5-Dialkylresorcinol Free Radical Scavenger Antioxidant: Resorstatin
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ABSTRACT: 3,5-Dimethoxybenzoic acid 3 has been transformed into olivetol dimethyl ether 6 in three steps in 79% yield. Directed ortho-metallation-alkylation of 6, followed by boron tribromide demethylation resulted in a simple and inexpensive synthesis of resorstatin, in 70% overall yield from 3.Synthetic Communications - SYN COMMUN. 01/1997; 27(21):3769-3778. -
Article: A Convenient Synthesis of Triarylbismuth Diacetates
Synthetic Communications 12/1996; 26(24):4569-4575. · 1.06 Impact Factor
Top co-authors
Top Journals
Institutions
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2009–2011
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Aix-Marseille Université
- • Centre de Recherches en Oncologie biologique et Onco-pharmacologie (UMR_S 911 CRO2)
- • Faculté de Pharmacie
Marseille, Provence-Alpes-Cote d'Azur, France
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2008
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Lomonosov Moscow State University
- Department of Soil Chemistry
Moscow, Moscow, Russia
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