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.