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Planta Med 2021; 87(09): 701-708
DOI: 10.1055/a-1334-4480
Biological and Pharmacological Activity
Original Papers

Inhibitory Effects of Secondary Metabolites from the Lichen Stereocaulon evolutum on Protein Tyrosine Phosphatase 1B

Thi Huyen Vu
1   University of Rennes, CNRS, ISCR – UMR 6226, Rennes, France
,
Olivier Delalande
2   University of Rennes, CNRS, IGDR – UMR 6290, Rennes, France
,
Claudia Lalli
1   University of Rennes, CNRS, ISCR – UMR 6226, Rennes, France
,
Stefanie Reider
3   Institute of Pharmacy/Pharmacognosy, University of Innsbruck and Center for Molecular Biosciences Innsbruck (CMBI), Innsbruck, Austria
,
Solenn Ferron
1   University of Rennes, CNRS, ISCR – UMR 6226, Rennes, France
,
Joel Boustie
1   University of Rennes, CNRS, ISCR – UMR 6226, Rennes, France
,
Birgit Waltenberger  ‡
3   Institute of Pharmacy/Pharmacognosy, University of Innsbruck and Center for Molecular Biosciences Innsbruck (CMBI), Innsbruck, Austria
,
Françoise Lohézic-Le Dévéhat‡
1   University of Rennes, CNRS, ISCR – UMR 6226, Rennes, France
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Abstract

Protein tyrosine phosphatase 1B plays a significant role in type 2 diabetes mellitus and other diseases and is therefore considered a new drug target. Within this study, an acetone extract from the lichen Stereocaulon evolutum was identified to possess strong protein tyrosine phosphatase 1B inhibition in a cell-free assay (IC50 of 11.8 µg/mL). Fractionation of this bioactive extract led to the isolation of seven known molecules belonging to the depsidones and the related diphenylethers and one new natural product, i.e., 3-butyl-3,7-dihydroxy-5-methoxy-1(3H)-isobenzofurane. The isolated compounds were evaluated for their inhibition of protein tyrosine phosphatase 1B. Two depsidones, lobaric acid and norlobaric acid, and the diphenylether anhydrosakisacaulon A potently inhibited protein tyrosine phosphatase 1B with IC50 values of 12.9, 15.1, and 16.1 µM, respectively, which is in the range of the protein tyrosine phosphatase 1B inhibitory activity of the positive control ursolic acid (IC50 of 14.4 µM). Molecular simulations performed on the eight compounds showed that i) a contact between the molecule and the four main regions of the protein is required for inhibitory activity, ii) the relative rigidity of the depsidones lobaric acid and norlobaric acid and the reactivity related to hydrogen bond donors or acceptors, which interact with protein tyrosine phosphatase 1B key amino acids, are involved in the bioactivity on protein tyrosine phosphatase 1B, iii) the cycle opening observed for diphenylethers decreased the inhibition, except for anhydrosakisacaulon A where its double bond on C-8 offsets this loss of activity, iv) the function present at C-8 is a determinant for the inhibitory effect on protein tyrosine phosphatase 1B, and v) the more hydrogen bonds with Arg221 there are, the more anchorage is favored.

Key words

lichen - depsidones - diphenylethers - protein tyrosine phosphatase 1B - Stereocaulaceae - Stereocaulon evolutum

Supporting Information

    Acetylation of 8, NMR data (1H and 13C) of 1 – 8, LC-MS analysis of 8 in crude S. evolutum extracts, suspected biogenetic relationships between 1, 3 – 7, and 8, concentration-dependent inhibition of PTP1B by the n-hexane and the acetone extract of S. evolutum, concentration-dependent inhibition of PTP1B by 3 – 5 and 7, and contact networks between 1 – 8 and PTP1B are available as Supporting Information.

  • Supporting Information


Publication History

Received: 12 June 2020

Accepted after revision: 01 December 2020

Article published online:
22 February 2021

© 2021. Thieme. All rights reserved.

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