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

Abstract

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