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

Organic Chemistry Frontiers Pub Date: 2020-02-04 DOI: 10.1039/C9QO01538H

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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