Neuroprotective Guanacastane Diterpenoids from the Endophytic Fungus <i>Candolleomyces</i> sp.

Twenty novel guanacastane diterpenoids candollins A-T (<b>1</b>-<b>20</b>) were isolated from <i>Candolleomyces sp.</i> cultured on agar solid medium. The structures were elucidated according to the NMR, HRESIMS, and electronic circular dichroism spectra. Compounds <b>1</b> and <b>3</b> were further confirmed by X-ray crystallography. Compound <b>1</b> was an unprecedented C₁₉ norditerpenoid containing a 3-methyl-2(3<i>H</i>)-furanone constitutional unit. Compounds <b>2</b>-<b>6</b>, <b>8,</b> and <b>9</b> were C₁₉ norditerpenoids with respective demethylation at C-18, C-4, and C-8. Compound <b>7</b> was a novel C₁₇ norditerpenoid with deisopropyl at C-12. Compounds <b>10</b>, <b>11</b>, and <b>16</b> had a novel methyl propionate substituent at C-4, a novel 6/7/5/5-fused tetracyclic ring, and an unprecedented 5/6/7/6-fused tetracyclic backbone, respectively. Compounds <b>4</b>-<b>10</b>, <b>14</b>, <b>15</b>, and <b>17</b>-<b>19</b> showed significant neuroprotective effects with a survival rate of 68.32-97.53% at 20 μM. The neuroprotective activities of compounds <b>7</b> and <b>10</b> were positively correlated with the concentration. Compounds <b>6</b> and <b>8</b> showed neuroprotective effects with survival rates of 76% and 74% at a minimum concentration (0.25 μM), respectively.