Synthesis, biological evaluation, and structure-activity relationships of tri- and tetrasubstituted olefins related to isocombretastatin A-4 as new tubulin inhibitors
| Autor: | Jérôme Bignon, Jean-François Peyrat, Joanna Wdzieczak-Bakala, Jean-Daniel Brion, Etienne Brachet, Ahmad Yassine, Jessy Aziz, Estelle Morvan, Abdallah Hamze, Mouad Alami, Guillaume Bernadat, Déborah Desravines, Marie Tueni, Joëlle Dubois |
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| Přispěvatelé: | Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5) |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Cell cycle checkpoint
Double bond Stereochemistry macromolecular substances Alkenes 010402 general chemistry 01 natural sciences Biochemistry chemistry.chemical_compound Structure-Activity Relationship Tubulin Cell Line Tumor Stilbenes Cytotoxic T cell Humans [CHIM]Chemical Sciences Physical and Theoretical Chemistry ComputingMilieux_MISCELLANEOUS Cell Proliferation chemistry.chemical_classification biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry [CHIM.ORGA]Chemical Sciences/Organic chemistry Aryl Organic Chemistry Antineoplastic Agents Phytogenic Tubulin Modulators 0104 chemical sciences 3. Good health chemistry Docking (molecular) Cell culture biology.protein Drug Screening Assays Antitumor K562 cells |
| Zdroj: | Organic and Biomolecular Chemistry Organic and Biomolecular Chemistry, Royal Society of Chemistry, 2013, 11 (3), pp.430-42. ⟨10.1039/c2ob26253c⟩ Organic and Biomolecular Chemistry, Royal Society of Chemistry, 2013, 11 (3), pp.430-442. ⟨10.1039/c2ob26253c⟩ |
| ISSN: | 1477-0520 1477-0539 |
| DOI: | 10.1039/c2ob26253c⟩ |
| Popis: | International audience; The synthesis and structure-activity relationships associated with a series of 1,1-diarylethylene tubulin polymerization inhibitors 3 and 4 are described. The key step for their preparation involves a palladium-catalyzed coupling of N-arylsulfonylhydrazones with aryl halides, thus providing flexible and convergent access to tri- and tetrasubstituted 1,1-diarylolefins 3 and 4 related to isocombretastatin A-4 (isoCA-4). These compounds have been evaluated for tubulin polymerization inhibitory activity as well as for cytotoxic activity. The most potent compounds are 1,1-diaryl-2-methoxyethylenes 4b, 4d and 4e having a trisubstituted double bond. They exhibited good antiproliferative activity against various human cancer cell lines (GI(50) = 8-80 nM). Compounds 4b and 4e strongly inhibited tubulin polymerization with IC(50) values of 2 and 3 μM, respectively, and induced cell cycle arrest in the G(2)/M phase in the K562 cell line. Docking studies in the colchicine binding site of tubulin allowed identification of residues most likely to interact with these inhibitors and explain their potent anti-tubulin activity. |
| Databáze: | OpenAIRE |
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