Limonoids from <i>Guarea guidonia</i> and <i>Cedrela odorata</i>: Heat Shock Protein 90 (Hsp90) Modulator Properties of Chisomicine D

Abstract

Nine new limonoids (<b>1</b>-<b>9</b>) were isolated from the stem bark of <i>Guarea guidonia</i> (<b>1</b>-<b>4</b>) and <i>Cedrela odorata</i> (<b>5</b>-<b>9</b>). Their structures were elucidated using 1D and 2D NMR and MS data and chemical methods as three A2,B,D-<i>seco</i>-type limonoids (<b>1</b>-<b>3</b>), a mexicanolide (<b>4</b>), three nomilin-type (<b>5</b>-<b>7</b>) limonoids, and two limonol derivatives (<b>8</b> and <b>9</b>). A DFT/NMR procedure was used to define the relative configurations of <b>1</b> and <b>3</b>. A surface plasmon resonance approach was used to screen the Hsp90 binding capability of the limonoids, and the A2,B,D-<i>seco</i>-type limonoid 8-hydro-(8<i>S*</i>,9<i>S</i>*)-dihydroxy-14,15-en-chisomicine A, named chisomicine D (<b>1</b>), demonstrated the highest affinity. By means of mass spectrometry data, biochemical and cellular assays, and molecular docking, <b>1</b> was found as a type of client-selective Hsp90 inhibitor binding to the C-terminus domain of the chaperone.