Structure Elucidation of Prenyl- and Geranyl-Substituted Coumarins in Gerbera piloselloides by NMR Spectroscopy, Electronic Circular Dichroism Calculations, and Single Crystal X-ray Crystallography.

Tuo Li,Daniil Fedotov,Xue Ma,Louise Kjaerulff,Karla Frydenvang,Dan Staerk,Kenneth T Kongstad,Sonia Coriani,Paul Robert Hansen

doi:10.3390/molecules25071706

Abstract

Crude ethyl acetate extract of Gerbera piloselloides (L.) Cass. was investigated by dual high-resolution PTP1B/α-glucosidase inhibition profiling and LC-PDA-HRMS. This indicated the presence of a series of unprecedented prenyl- and geranyl-substituted coumarin derivatives correlated with both α-glucosidase and PTP1B inhibitory activity. Repeated chromatographic separation targeting these compounds led to the isolation of 13 new compounds, of which ten could be isolated as both enantiomers after chiral separation. The structures of all isolated compounds were characterized by HRMS and extensive 1D and 2D NMR analysis. The absolute configurations of the isolated compounds were determined by comparison of experimental and calculated electronic circular dichroism spectra. Compound 6 features a rare furan-oxepane 5/7 ring system, possibly formed through addition of a geranyl unit to C-3 of 5-methylcoumarin, representing a new type of geranyl-substituted coumarin skeleton. Compounds 19 and 24 are the first examples of dimeric natural products consisting of both coumarin and chromone moieties.

Highlights

Diabetes mellitus is a multifactorial disease characterized by insufficient regulation of glucose metabolism, with severe long-term micro- and macrovascular complications such as retinopathy, neuropathy, nephropathy and cardiovascular diseases
Two repeated analytical-scale High-performance liquid chromatography (HPLC) separations were microfractionated into two 96-well microplates each, which after evaporation of the solvent and assaying using protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase, resulted in the dual high-resolution
Dual high-resolution PTP1B/α-glucosidase inhibition profiling for pinpointing new natural products as inhibitors of PTP1B and/or α-glucosidase

Summary

Introduction

Diabetes mellitus is a multifactorial disease characterized by insufficient regulation of glucose metabolism, with severe long-term micro- and macrovascular complications such as retinopathy, neuropathy, nephropathy and cardiovascular diseases. Management of a relatively stable blood glucose in the interval 5–10 mmol/L. Α-Glucosidase constitutes another potential T2D target enzyme [6]. It is found in the brush border of the small intestines, where it hydrolyses terminal non-reducing 1,4-linked α-glucose residues to absorbable monosaccharides for managing a low and stable blood glucose level. There are still no clinically approved PTP1B inhibitors for diabetics, and the clinically approved drugs acarbose, miglitol and voglibose are associated with side effects such as flatulence, diarrhea and stomach ache [7]. There is an unmet need for new PTP1B and α-glucosidase inhibitors as potential T2D drug leads

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