title: Anacardic Acids from Knema hookeriana as Modulators of Bcl-xL/Bak and Mcl-1/Bid Interactions.
abstract: Proteins of the Bcl-2 family are key targets in anticancer drug discovery. Disrupting the interaction between anti- and pro-apoptotic members of this protein family was the approach chosen in this study to restore apoptosis. Thus, a biological screening on the modulation of the Bcl-xL/Bak and Mcl-1/Bid interactions permitted the selection of Knema hookeriana for further phytochemical investigations. The ethyl acetate extract from the stem bark led to the isolation of six new compounds, three acetophenone derivatives (1-3) and three anacardic acid derivatives (4-6), along with four known anacardic acids (7-10) and two cardanols (11, 12). Their structures were elucidated by 1D and 2D NMR analysis in combination with HRMS experiments. The ability of these compounds to antagonize Bcl-xL/Bak and Mcl-1/Bid association was determined, using a protein-protein interaction assay, but only anacardic acid derivatives (4-10) exhibited significant binding properties, with Ki values ranging from 0.2 to 18 μM. Protein-ligand NMR experiments further revealed that anacardic acid 9, the most active compound, does not interact with the anti-apoptotic proteins Bcl-xL and Mcl-1 but instead interacts with pro-apoptotic protein Bid.
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS-ICSN UPR2301, Université Paris-Saclay , Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gény
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS-ICSN UPR2301, Université Paris-Saclay , Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Gwladys
authors.initials: G
authors.lastname: Rivière
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS-ICSN UPR2301, Université Paris-Saclay , Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Bignon
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS-ICSN UPR2301, Université Paris-Saclay , Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Birlirakis
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS-ICSN UPR2301, Université Paris-Saclay , Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Guittet
authors.affiliation: Department of Chemistry, Faculty of Science, University Malaya , Kuala Lumpur 50603, Malaysia.
authors.forename: Khaljah
authors.initials: K
authors.lastname: Awang
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS-ICSN UPR2301, Université Paris-Saclay , Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Litaudon
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS-ICSN UPR2301, Université Paris-Saclay , Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Roussi
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS-ICSN UPR2301, Université Paris-Saclay , Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Dumontet
mesh_terms: D000098:Acetophenones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D048729:Anacardic Acids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000187:drug effects; D008296:Malaysia; D015394:Molecular Structure; D026324:Myristicaceae / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D024301:Plant Bark / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism*; D012118:Resorcinols / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000098:Acetophenones; D048729:Anacardic Acids; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D012118:Resorcinols; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C412963:resacetophenone