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Natural product libraries to accelerate the high-throughput discovery of therapeutic leads.

Authors
  • Johnson, Tyler A1
  • Sohn, Johann
  • Inman, Wayne D
  • Estee, Samarkand A
  • Loveridge, Steven T
  • Vervoort, Helene C
  • Tenney, Karen
  • Liu, Junke
  • Ang, Kenny Kean-Hooi
  • Ratnam, Joseline
  • Bray, Walter M
  • Gassner, Nadine C
  • Shen, Young Y
  • Lokey, R Scott
  • McKerrow, James H
  • Boundy-Mills, Kyria
  • Nukanto, Arif
  • Kanti, Atit
  • Julistiono, Heddy
  • Kardono, Leonardus B S
  • And 2 more
  • 1 Department of Nutritional Sciences & Toxicology, University of California, Berkeley, California 94720, USA. [email protected]
Type
Published Article
Journal
Journal of Natural Products
Publisher
American Chemical Society
Publication Date
Dec 27, 2011
Volume
74
Issue
12
Pages
2545–2555
Identifiers
DOI: 10.1021/np200673b
PMID: 22129061
Source
Medline
Language
English
License
Unknown

Abstract

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 Cacospongia mycofijiensis was evaluated using assays involving cytoskeletal profiling, tumor cell lines, and parasites. Twelve known compounds were identified including latrunculins (1-4, 10), fijianolides (5, 8, 9), mycothiazole (11), aignopsanes (6, 7), and sacrotride A (13). Compounds 1-5 and 8-11 exhibited bioactivity not previously reported against the parasite T. brucei, while 11 showed selectivity for lymphoma (U937) tumor cell lines. Four new compounds were also discovered including aignopsanoic acid B (13), apo-latrunculin T (14), 20-methoxy-fijianolide A (15), and aignopsane ketal (16). Compounds 13 and 16 represent important derivatives of the aignopsane class, 14 exhibited inhibition of T. brucei without disrupting microfilament assembly, and 15 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.

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