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

Abstract

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