title: 3-O-methylthespesilactam, a new small-molecule anticancer pan-JAK inhibitor against A2058 human melanoma cells.
abstract: 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.
authors.affiliation: Marine Drugs Research Center, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, PR China.
authors.forename: Min-Yi
authors.initials: MY
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Tian
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Ralf
authors.initials: R
authors.lastname: Buettner
authors.forename: Hong-Zhi
authors.initials: HZ
authors.lastname: Li
authors.forename: Lucy
authors.initials: L
authors.lastname: Liu
authors.forename: Yate-Ching
authors.initials: YC
authors.lastname: Yuan
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xiao
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D019660:Malvaceae; D008545:Melanoma; D010766:Phosphorylation; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; D012717:Sesquiterpenes; D053612:Janus Kinases
keywords: 3-O-methylthespesilactam; Anticancer; Benzo[cd]indole; JAK inhibitor; Sesquiterpenoid-alkaloid