title: Cytotoxic activities of novel hexahydroindolizino[8,7-b]indole derivatives prepared by 1,3-dipolar cycloaddition reactions of 3,4-dihydro-beta-carboline ylides.
abstract: A series of 1-cyano and 2-cyanohexahydroindolizino[8,7-b]indole derivatives was prepared by 1,3-dipolar cycloaddition of acrylonitrile with ylides derived from 3,4-dihydro-beta-carboline and its 6-methoxy, 6-benzyloxy, 9-methyl and 9-benzyl analogues. The products, together with their reduced 1- or 2-aminomethyl derivatives, were evaluated for cytotoxic activity in L1210 cancer cells. Compounds derived from 6-benzyloxy or 9-benzyl-3,4-dihydro-beta-carboline were found to be the most active, with IC(50)'s in the 2-50 microM range. Of these, two compounds, the 1- and 2-cyano 8-benzyloxyindolizino[8,7-b]indole derivatives 20a and 20c, respectively, were found by cytometric flux analysis to stop cancer cell growth at the G(2)M and 8N (>G(2)M) stage of the cell cycle. These two compounds also showed no loss of cytotoxic activity in K562R cancer cells resistant to doxorubicin.
authors.affiliation: Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, Gif-sur-Yvette Cedex, France.
authors.forename: M
authors.initials: M
authors.lastname: Bertrand
authors.forename: G
authors.initials: G
authors.lastname: Poissonnet
authors.forename: M H
authors.initials: MH
authors.lastname: Théret-Bettiol
authors.forename: C
authors.initials: C
authors.lastname: Gaspard
authors.forename: G H
authors.initials: GH
authors.lastname: Werner
authors.forename: B
authors.initials: B
authors.lastname: Pfeiffer
authors.forename: P
authors.initials: P
authors.lastname: Renard
authors.forename: S
authors.initials: S
authors.lastname: Léonce
authors.forename: R H
authors.initials: RH
authors.lastname: Dodd
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002243:Carbolines / Q000737:chemistry*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020014:K562 Cells
chemical_list: D000970:Antineoplastic Agents; D002243:Carbolines; D007211:Indoles; C434754:hexahydroindolizino(8,7-b)indole