Anacardic Acids from <i>Knema hookeriana</i> as Modulators of Bcl-xL/Bak and Mcl-1/Bid Interactions

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 <i>Knema hookeriana</i> for further phytochemical investigations. The ethyl acetate extract from the stem bark led to the isolation of six new compounds, three acetophenone derivatives (<b>1</b>–<b>3</b>) and three anacardic acid derivatives (<b>4</b>–<b>6</b>), along with four known anacardic acids (<b>7</b>–<b>10</b>) and two cardanols (<b>11</b>, <b>12</b>). 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 (<b>4</b>–<b>10</b>) exhibited significant binding properties, with <i>K</i>_i values ranging from 0.2 to 18 μM. Protein–ligand NMR experiments further revealed that anacardic acid <b>9</b>, 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

Endiandric Acid Analogues from Beilschmiedia ferruginea as Dual Inhibitors of Bcl-xL/Bak and Mcl-1/Bid Interactions

A rapid screening by ¹H and ¹H–¹³C HSQC NMR spectroscopy of EtOAc extracts of Endiandra and Beilschmiedia species allowed the selection of Beilschmiedia ferruginea leaves and flowers extract for a chemical investigation, leading to the isolation of 11 new tetracyclic endiandric acid analogues, named ferrugineic acids A–K (<b>1</b>–<b>11</b>). Their structures were determined by 1D and 2D NMR spectroscopic analysis in combination with HRMS data. These compounds were assayed for Bcl-xL and Mcl-1 binding affinities. Ferrugineic acids B, C, and J (<b>2</b>, <b>3</b>, and <b>10)</b> exhibited significant binding affinity for both antiapoptotic proteins Bcl-xL (<i>K</i>_i = 19.2, 12.6, and 19.4 μM, respectively) and Mcl-1 (<i>K</i>_i = 14.0, 13.0, and 5.2 μM, respectively), and ferrugineic acid D (<b>4</b>) showed only significant inhibiting activity for Mcl-1 (<i>K</i>_i = 5.9 μM)