Prenylated Coumarins: Natural Phosphodiesterase‑4 Inhibitors from <i>Toddalia asiatica</i>

Bioassay-guided fractionation of the ethanolic extract of the roots of <i>Toddalia asiatica</i> led to the isolation of seven new prenylated coumarins (<b>1</b>–<b>7</b>) and 14 known analogues (<b>8</b>–<b>21</b>). The structures of <b>1</b>–<b>7</b> were elucidated by spectroscopic analysis, and their absolute configurations were determined by combined chemical methods and chiral separation analysis. Compounds <b>1</b>–<b>5</b>, named toddalin A, 3‴-<i>O</i>-demethyltoddalin A, and toddalins B–D, represent an unusual group of phenylpropenoic acid-coupled prenylated coumarins. Compounds <b>1</b>–<b>21</b> and four modified analogues, <b>10a</b>, <b>11a</b>, <b>13a</b>, and <b>17a</b>, were screened by using tritium-labeled adenosine 3′,5′-cyclic monophosphate ([³H]-cAMP) as substrate for their inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease. Compounds <b>3</b>, <b>8</b>, <b>10</b>, <b>10a</b>, <b>11</b>, <b>11a</b>, <b>12</b>, <b>13</b>, <b>17</b>, and <b>21</b> exhibited inhibition with IC₅₀ values less than 10 μM. Toddacoumalone (<b>8</b>), the most active compound (IC₅₀ = 0.14 μM), was more active than the positive control, rolipram (IC₅₀ = 0.59 μM). In addition, the structure–activity relationship and possible inhibitory mechanism of the active compounds are also discussed

Prostaglandin Derivatives: Nonaromatic Phosphodiesterase‑4 Inhibitors from the Soft Coral <i>Sarcophyton ehrenbergi</i>

Ten new prostaglandin derivatives (PGs), sarcoehrendins A–J (<b>1</b>–<b>10</b>), together with five known analogues (<b>11</b>–<b>15</b>) were isolated from the soft coral <i>Sarcophyton ehrenbergi</i>. Compounds <b>4</b>–<b>8</b> represented the first examples of PGs featuring an 18-ketone group. The structures including the absolute configurations were elucidated on the basis of spectroscopic analysis and chemical evidence. All of the isolates and six synthetic analogues (<b>3a</b>, <b>3b</b>, <b>4a</b>, and <b>11a</b>–<b>11c</b>) were screened for inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease. Compounds <b>2</b>, <b>10</b>, <b>11a</b>, <b>11b</b>, and <b>13</b>–<b>15</b> exhibited inhibition with IC₅₀ values less than 10 μM, and compound <b>15</b> (IC₅₀ = 1.4 μM) showed comparable activity to the positive control rolipram (IC₅₀ = 0.60 μM). The active natural PGs (<b>2</b>, <b>10</b>, and <b>13</b>–<b>15</b>) represent the first examples of PDE4 inhibitors without an aromatic moiety, and a preliminary structure–activity relationship is also proposed

Extracellular Signal-Regulated Kinases (ERK) Inhibitors from <i>Aristolochia yunnanensis</i>

Six new sesquiterpenoids, aristoyunnolins A–F (<b>1</b>–<b>6</b>), an artifact of isolation [7-<i>O</i>-ethyl madolin W (<b>7</b>)], and 12 known analogues were isolated from stems of <i>Aristolochia yunnanensis</i>. The structures were determined by combined chemical and spectral methods, and the absolute configurations of compounds <b>2</b>, <b>3</b>, <b>5</b>–<b>7</b>, <b>9</b>, <b>14</b>, and <b>17</b> were determined by the modified Mosher’s method and CD analysis. Compounds <b>1</b>–<b>19</b> were screened using a bioassay system designed to evaluate the effect on mitogen-activated protein kinases (MAPKs) signaling pathways. Among three MAPKs (ERK1/2, JNK, and p38), compounds <b>1</b>, <b>4</b>, <b>10</b>–<b>13</b>, <b>16</b>, <b>18</b>, and <b>19</b> exhibited selective inhibition of the phosphorylation of ERK1/2. Compounds <b>16</b> and <b>19</b> were more active than the positive control PD98059, a known inhibitor of the ERK1/2 signaling pathway

(±)-Torreyunlignans A–D, Rare 8–9′ Linked Neolignan Enantiomers as Phosphodiesterase-9A Inhibitors from Torreya yunnanensis

(±)-Torreyunlignans A–D (<b>1a</b>/<b>1b</b>–<b>4a/4b</b>), four pairs of new 8–9′ linked neolignan enantiomers featuring a rare (<i>E</i>)-2-styryl-1,3-dioxane moiety, were isolated from the trunk of Torreya yunnanensis. The structures were determined by combined spectroscopic and chemical methods, and the absolute configurations were elucidated by ECD calculations. The compounds were screened by using tritium-labeled adenosine 3′,5′-cyclic monophosphate ([³H]-cGMP) as a substrate for inhibitory affinities against phosphodiesterase-9A (PDE9A), which is a potential target for the treatment of diabetes and Alzheimer’s disease. All of the enantiomers exhibited inhibition against PDE9A with IC₅₀ values ranging from 5.6 to 15.0 μM. This is the first report of PDE9A inhibitors from nature

Neolignans from <i>Aristolochia fordiana</i> Prevent Oxidative Stress-Induced Neuronal Death through Maintaining the Nrf2/HO‑1 Pathway in HT22 Cells

Bioassay-guided fractionation of the ethanolic extract of the stems of <i>Aristolochia fordiana</i> led to the isolation of six new dihydrobenzofuran neolignans (<b>1</b>–<b>3</b> and <b>7</b>–<b>9</b>), three new 2-aryldihydrobenzofurans (<b>4</b>–<b>6</b>), a new 8-<i>O</i>-4′ neolignan (<b>10</b>), and 14 known analogues (<b>11</b>–<b>24</b>). The structures of compounds <b>1</b>–<b>10</b> were established by spectroscopic methods, and their absolute configurations were determined by analyses of the specific rotation and electronic circular dichroism data. The neuroprotective effects of compounds <b>1</b>–<b>24</b> against glutamate-induced cell death were tested in hippocampal neuronal cell line HT22. Compounds <b>17</b> and <b>20</b>–<b>24</b> exhibited moderate neuroprotective activity by increasing the endogenous antioxidant defense system. In addition, the neolignans activated the Nrf2 (nuclear factor E2-related factor 2) pathway, resulting in the increase of the expression of endogenous antioxidant protein HO-1 (heme oxygenase-1). The active compounds also preserved the levels of antiapoptotic protein Bcl-2 (B cell lymphoma/leukemia-2), which was decreased by glutamate. Collectively, these results suggested that the active neolignans protect neurons against glutamate-induced cell death through maintaining the Nrf2/HO-1 signaling pathway as well as preserving the Bcl-2 protein and might be promising novel beneficial agents for oxidative stress-associated diseases