Discovery of Limonoids from <i>Xylocarpus granatum</i> as Potential Leads against Neuroinflammation

Discovery of new natural products with both anti-inflammatory effects on activated microglia and protective activity on dopaminergic neurons is a new strategy to find new drug leads against neuroinflammation in Parkinson's disease. In this work, nine new limonoids, named thaigranatumins A-I (<b>1</b>-<b>9</b>), and two new protolimonoids, named thaigranatumins J (<b>10</b>) and K (<b>11</b>), were obtained from seeds of the Thai mangrove, <i>Xylocarpus granatum</i>. The structures of these compounds were established by analysis of spectroscopic data, single-crystal X-ray diffraction (Cu Kα), and comparison of experimental and calculated ECD spectra. Thaigranatumin A (<b>1</b>), containing a C-16/C-30 δ-lactone ring-D and a <i>tetra</i>-substituted C₈-O-C₁₇-bridged tetrahydrofuran ring-F, is the first limonoid featuring a unique 6/6/6/6/6/5/5-fused heptacyclic framework. Thaigranatumin G (<b>7</b>) exhibited both inhibitory effects on the protein expression of iNOS, COX2, and IL-1β in lipopolysaccharide-stimulated mouse microglia BV2 cells and neuroprotective activity against rotenone-induced injury in mouse midbrain dopaminergic neuron MN9D cells in a dose-dependent manner. Preliminary bioassays indicated that thaigranatumin G might be a valuable lead against neuroinflammation, thus warranting further studies.