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Discovery of highly functionalized 5,6-seco-grayanane diterpenoids as potent competitive PTP1B inhibitors

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Abstract

Protein tyrosine phosphatase 1B (PTP1B) is an important therapeutic target for type II diabetes mellitus. Mollactones A–C (1–3), three naturally occurring highly functionalized 5,6-seco-grayanane diterpenoids bearing a unique 3-oxa-tricyclo[4,3,2,02,6]undecane motif, and their plausible biosynthetic precursor rhodojaponin III (4) were isolated from Rhododendron molle. The 13C NMR spectrum of 1 exhibited only 11 carbon signals, instead of 20 carbon signals, and this challenging structure was finally defined by single-crystal X-ray diffraction analysis. This abnormal NMR phenomenon was elucidated by quantum chemical calculation. Mollactones A–C (1–3) showed significant PTP1B inhibitory activity in a competitive inhibition mode, and their structure–activity-relationships were investigated. Based on the molecular docking studies, mollactone B 3-O-sulfate (9) was rationally designed and prepared, and exhibited significant PTP1B inhibitory activity with an IC50 value of 0.22 ± 0.05 μM and a Ki value of 6.79 ± 1.28 μM. These results provide a basis to design novel competitive PTP1B inhibitors based on 5,6-seco-grayanane diterpenoids with 3-oxa-tricyclo[4,3,2,02,6]undecane and 5,5-dimethylcyclopent-2-en-1-one motifs.

Graphical abstract: Discovery of highly functionalized 5,6-seco-grayanane diterpenoids as potent competitive PTP1B inhibitors

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Supplementary files

Article information


Submitted
30 Dec 2019
Accepted
27 Jan 2020
First published
04 Feb 2020

Org. Chem. Front., 2020, Advance Article
Article type
Research Article

Discovery of highly functionalized 5,6-seco-grayanane diterpenoids as potent competitive PTP1B inhibitors

J. Zhou, Z. Zuo, J. Liu, H. Zhang, G. Zheng and G. Yao, Org. Chem. Front., 2020, Advance Article , DOI: 10.1039/C9QO01538H

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