title: Discovery and hit to lead optimization of novel combretastatin A-4 analogues: dependence of C-linker length and hybridization.
abstract: We have synthesized a large variety of CA-4 analogues having a non-isomerizable C-linker between the A- and B-aromatic rings. Most of them displayed a nanomolar level of cytotoxicity against a panel of human cancer cell lines and inhibited tubulin polymerization at a micromolar level. Among all these compounds, the most interesting compounds were undoubtedly isoCA-4 and structural analogues 18-20 as well as benzil derivatives 11 which displayed a comparable level of activity than that of CA-4. Moreover, it has been demonstrated that these drugs arrested cancer cells in the G2/M phase of cellular cycle and induced apoptosis at very low concentrations. In vitro antivascular effects and the binding mode of the most active compounds was also investigated.
authors.forename: Olivier
authors.initials: O
authors.lastname: Provot
authors.forename: Abdallah
authors.initials: A
authors.lastname: Hamze
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Peyrat
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Brion
authors.affiliation: Univ. Paris-Sud 11, CNRS, BioCIS-UMR 8076, LabEx LERMIT, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry, F-92296, France. olivier.provot@u-psud.fr.
authors.forename: Mouad
authors.initials: M
authors.lastname: Alami
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001632:Bibenzyls / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D015195:Drug Design; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007797:Laminin / Q000737:chemistry; D015394:Molecular Structure; D011509:Proteoglycans / Q000737:chemistry; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D050257:Tubulin Modulators; C059485:matrigel; C040105:combretastatin; D003094:Collagen