Natural Product Libraries to Accelerate the High-Throughput Discovery of Therapeutic Leads

A high-throughput (HT) paradigm generating LC-MS-UV-ELSD-based natural product libraries to discover compounds with new bioactivities and or molecular structures is presented. To validate this methodology, an extract of the Indo-Pacific marine sponge <i>Cacospongia mycofijiensis</i> was evaluated using assays involving cytoskeletal profiling, tumor cell lines, and parasites. Twelve known compounds were identified including latrunculins (<b>1</b>–<b>4</b>, <b>10</b>), fijianolides (<b>5</b>, <b>8</b>, <b>9</b>), mycothiazole (<b>11</b>), aignopsanes (<b>6</b>, <b>7</b>), and sacrotride A (<b>13</b>). Compounds <b>1</b>–<b>5</b> and <b>8</b>–<b>11</b> exhibited bioactivity not previously reported against the parasite <i>T. brucei</i>, while <b>11</b> showed selectivity for lymphoma (U937) tumor cell lines. Four new compounds were also discovered including aignopsanoic acid B (<b>13</b>), apo-latrunculin T (<b>14</b>), 20-methoxy-fijianolide A (<b>15</b>), and aignopsane ketal (<b>16</b>). Compounds <b>13</b> and <b>16</b> represent important derivatives of the aignopsane class, <b>14</b> exhibited inhibition of <i>T. brucei</i> without disrupting microfilament assembly, and <b>15</b> demonstrated modest microtubule-stabilizing effects. The use of removable well plate libraries to avoid false positives from extracts enriched with only one or two major metabolites is also discussed. Overall, these results highlight the advantages of applying modern methods in natural products-based research to accelerate the HT discovery of therapeutic leads and/or new molecular structures using LC-MS-UV-ELSD-based libraries.