title: Antiviral Activity of Flexibilane and Tigliane Diterpenoids from Stillingia lineata.
abstract: In an effort to identify new potent and selective inhibitors of chikungunya virus and HIV-1 and HIV-2 virus replication, the endemic Mascarene species Stillingia lineata was investigated. LC/MS and bioassay-guided purification of the EtOAc leaf extract using a chikungunya virus-cell-based assay led to the isolation of six new (4-9) and three known (1-3) tonantzitlolones possessing the rare C20-flexibilane skeleton, along with tonantzitloic acid (10), a new linear diterpenoid, and three new (11, 13, and 15) and two known (12 and 14) tigliane-type diterpenoids. The planar structures of the new compounds and their relative configurations were determined by spectroscopic analysis, and their absolute configurations were determined through comparison with literature data and from biogenetic considerations. These compounds were investigated for selective antiviral activity against chikungunya virus (CHIKV), Semliki Forest virus, Sindbis virus, and, for compounds 11-15, the HIV-1 and HIV-2 viruses. Compounds 12-15 were found to be the most potent and are selective inhibitors of CHIKV, HIV-1, and HIV-2 replication. In particular, compound 14 inhibited CHIKV replication with an EC50 value of 1.2 μM on CHIKV and a selectivity index of >240, while compound 15 inhibited HIV-1 and HIV-2 with EC50 values of 0.043 and 0.018 μM, respectively. It was demonstrated further that potency and selectivity are sensitive to the substitution pattern on the tigliane skeleton. The cytotoxic activities of compounds 1-10 were evaluated against the HCT-116, MCF-7, and PC3 cancer cell lines.
authors.affiliation: †Institut de Chimie des Substances Naturelles, CNRS-ICSN, UPR 2301, Université Paris-Sud, 91198, Gif-sur-Yvette, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Olivon
authors.affiliation: †Institut de Chimie des Substances Naturelles, CNRS-ICSN, UPR 2301, Université Paris-Sud, 91198, Gif-sur-Yvette, France.
authors.forename: Héliciane
authors.initials: H
authors.lastname: Palenzuela
authors.affiliation: ‡Laboratoire de Chimie des Substances Naturelles et des Sciences des Aliments (LCSNSA), Université de La Réunion, 15, Avenue René Cassin, CS 92003-97744 Saint-Denis Cedex 9, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Girard-Valenciennes
authors.affiliation: §Laboratory for Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: §Laboratory for Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.affiliation: †Institut de Chimie des Substances Naturelles, CNRS-ICSN, UPR 2301, Université Paris-Sud, 91198, Gif-sur-Yvette, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Roussi
authors.affiliation: ‡Laboratoire de Chimie des Substances Naturelles et des Sciences des Aliments (LCSNSA), Université de La Réunion, 15, Avenue René Cassin, CS 92003-97744 Saint-Denis Cedex 9, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Grondin
authors.affiliation: §Laboratory for Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.affiliation: †Institut de Chimie des Substances Naturelles, CNRS-ICSN, UPR 2301, Université Paris-Sud, 91198, Gif-sur-Yvette, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Litaudon
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D002646:Chikungunya virus / Q000187:drug effects; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D019665:Euphorbiaceae / Q000737:chemistry*; D005602:France; D045325:HCT116 Cells; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D047028:Macrocyclic Compounds / Q000494:pharmacology; D015394:Molecular Structure; D012672:Semliki forest virus / Q000187:drug effects; D012845:Sindbis Virus / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004224:Diterpenes; D047028:Macrocyclic Compounds; C510266:tonantzitlolone