Natural Product Libraries to Accelerate the High-Throughput Discovery of Therapeutic Leads
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- 作者：Tyler A. Johnson ; Johann Sohn ; Wayne D. Inman ; Samarkand A. Estee ; Steven T. Loveridge ; Helene C. Vervoort ; Karen Tenney ; Junke Liu ; Kenny Kean-Hooi Ang ; Joseline Ratnam ; Walter M. Bray ; Nadine C. Gassner ; Young Y. Shen ; R. Scott Lokey ; James H. McKerrow ; Kyria Boundy-Mills ; Arif Nukanto ; Atit Kanti ; Heddy Julistiono ; Leonardus B. S. Kardono ; Leonard F. Bjeldanes ; Phillip Crews
- 刊名：Journal of Natural Products
- 出版年：2011
- 出版时间：December 27, 2011
- 年：2011
- 卷：74
- 期：12
- 页码：2545-2555
- 全文大小：611K
- 年卷期：v.74,no.12(December 27, 2011)
- ISSN：1520-6025
文摘
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鈥?b>4, 10), fijianolides (5, 8, 9), mycothiazole (11), aignopsanes (6, 7), and sacrotride A (13). Compounds 1鈥?b>5 and 8鈥?b>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.