Journal
BIOCHEMICAL PHARMACOLOGY
Volume 86, Issue 10, Pages 1411-1418Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2013.08.065
Keywords
3-O-methylthespesilactam; Sesquiterpenoid-alkaloid; Benzo[cd]indole; Anticancer; JAK inhibitor
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Funding
- National Natural Science Foundation of China [31100258, 31170331, 81125022]
- Guangdong Key Science and Technology Special Project [2011A08040 3020]
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Natural product-inspired discovery of new drug leads plays a key role in drug development. Recently, small-molecule JAK inhibitors have been pursued for the development of anticancer therapeutics. However, most of these inhibitors reported up to now are multi-nitrogen polycyclic aromatic heterocycles. Undoubtedly, the discovery of new types of promising JAK-inhibitory leads is pivotal for JAK inhibitor-based anticancer drug development. Herein we report an unprecedented sesquiterpenoid-alkaloid named thespesilactam, containing a benzo[cd]indole scaffold, from the heartwood of the Portia tree, Thespesia populnea. Its 3-O-Me product, i.e. 8-hydroxy-5-isopropyl-3-methoxy-7-methylbenzo[cd]indol-2(1H)-one, named 3-O-methylthespesilactam, of which the structure was identified by NMR investigations and single-crystal X-ray diffraction analysis, was discovered as a new type of small-molecule anticancer pan-JAK inhibitor against A2058 human melanoma cells, and selective and potent inhibitor of JAK1 and TYK2. (C) 2013 Elsevier Inc. All rights reserved.
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