10.1021/np200673b.s001 Tyler A. Johnson Tyler A. Johnson Johann Sohn Johann Sohn Wayne D. Inman Wayne D. Inman Samarkand A. Estee Samarkand A. Estee Steven T. Loveridge Steven T. Loveridge Helene C. Vervoort Helene C. Vervoort Karen Tenney Karen Tenney Junke Liu Junke Liu Kenny Kean-Hooi Ang Kenny Kean-Hooi Ang Joseline Ratnam Joseline Ratnam Walter M. Bray Walter M. Bray Nadine C. Gassner Nadine C. Gassner Young Y. Shen Young Y. Shen R. Scott Lokey R. Scott Lokey James H. McKerrow James H. McKerrow Kyria Boundy-Mills Kyria Boundy-Mills Arif Nukanto Arif Nukanto Atit Kanti Atit Kanti Heddy Julistiono Heddy Julistiono Leonardus B. S. Kardono Leonardus B. S. Kardono Leonard F. Bjeldanes Leonard F. Bjeldanes Phillip Crews Phillip Crews Natural Product Libraries to Accelerate the High-Throughput Discovery of Therapeutic Leads American Chemical Society 2011 Natural Product Libraries compound Compound product libraries tumor cell lines brucei HT discovery plate libraries microfilament assembly aignopsane class parasite T 2011-12-27 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Natural_Product_Libraries_to_Accelerate_the_High_Throughput_Discovery_of_Therapeutic_Leads/2568700 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.