title: Rigid Analogues of Antimitotic Indolobenzazepinones: New Insights into Tubulin Binding via Molecular Modeling.
abstract: Two rigid analogues of 5-ethylindolobenzazepinone 4, a potent cytotoxic agent and inhibitor of tubulin polymerization, were prepared. The first was the indane derivative 5, in which the ethyl group is attached to the benzo moiety. The second was the pyrrolidine analogue 6, in which the ethyl chain was bound to the lactam nitrogen. While both compounds were considerably less active inhibitors of KB cell growth as compared to 4, inhibition of tubulin polymerization was only moderately reduced. Tubulin docking studies indicated that the aR and aS atropoisomers of 5 and 6 occupy different binding pockets at the colchicine binding site. Conversely, both aS-5 and aS-6 occupy the same binding pocket as aSS-4 but do not benefit from the favorable hydrophobic interactions provided by the C5 alkyl group of 4, thus possibly explaining their lower activities.
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR 2301, Campus de Recherche de Gif, Centre National de la Recherche Scientifique, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Pons
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR 2301, Campus de Recherche de Gif, Centre National de la Recherche Scientifique, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Beaumont
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR 2301, Campus de Recherche de Gif, Centre National de la Recherche Scientifique, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: Marie Elise
authors.initials: ME
authors.lastname: Tran Huu Dau
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR 2301, Campus de Recherche de Gif, Centre National de la Recherche Scientifique, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: Bogdan I
authors.initials: BI
authors.lastname: Iorga
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR 2301, Campus de Recherche de Gif, Centre National de la Recherche Scientifique, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Dodd
keywords: Indolobenzazepinone; atropoisomers; cytotoxicity; molecular docking; tubulin polymerization