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Issue 7, 2019
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Enantioselective syntheses and application of 4-epi-galiellalactone and the corresponding activity-based probe: from strained bicycles to strained tricycles

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Abstract

The [6,5,5] tricyclic fungal metabolite galiellalactone is a Michael acceptor that has been demonstrated to be a covalent inhibitor for Signal Transducer and Activator of Transcription 3 (STAT3). Recognizing the ring strain associated with the skeleton of this natural product, we utilized 1R-5S-bicyclo[3.1.0]hexan-2-one as the starting material and developed two novel approaches to accomplish the enantioselective total synthesis of the C4 epimer of galiellalactone in 5 and 7 steps, respectively, which capitalized on an efficient radical cyclization/fragmentation cascade reaction. Furthermore, an activity-based probe of 4-epi-galiellalactone with a terminal alkyne tag was successfully prepared to enable the experiments of activity-based protein profiling (ABPP). Through western blot and proteomic analysis, we not only confirmed the known target STAT3, but also identified a new target protein ataxin-7, which formed a covalent bond with the probe in intact cells via the Cys-129 residue.

Graphical abstract: Enantioselective syntheses and application of 4-epi-galiellalactone and the corresponding activity-based probe: from strained bicycles to strained tricycles

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Supplementary files

Article information


Submitted
06 Aug 2018
Accepted
28 Aug 2018
First published
29 Aug 2018

Org. Biomol. Chem., 2019,17, 1886-1892
Article type
Paper

Enantioselective syntheses and application of 4-epi-galiellalactone and the corresponding activity-based probe: from strained bicycles to strained tricycles

Y. Lu, S. Zhao, S. Zhou, S. Chen and T. Luo, Org. Biomol. Chem., 2019, 17, 1886
DOI: 10.1039/C8OB01915K

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