Issue 7, 2019

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

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

Supplementary files

Article information

Article type
Paper
Submitted
06 août 2018
Accepted
28 août 2018
First published
29 août 2018

Org. Biomol. Chem., 2019,17, 1886-1892

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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