Termitomenins F and G, Two New Lignan Glucosides from Terminalia chebula var. tomentella (Kurz) C. B. Clarke

Graphic abstract The extensive chemical investigation on the branches and leaves of Terminalia chebula var. tomentella (Combretaceae) led to the isolation of two new lignan glucosides with a furofuran skeleton, termitomenins F (1) and G (2). In addition, 19 known compounds including five lignan glucosides (3–7), six hydrolyzable tannins (8–13) and eight simple phenolics (14–21) were also identified. Their structures were determined by comprehensive spectroscopic analyses. It is noted that 8 and 9 were C-glycosidic hydrolyzable tannins with one hexahydroxydiphenoyl and one gallagyl group linked to an open-chain glucosyl C-1/O-2/O-3 and O-4/O-6, respectively, which were rarely found in plants. Nine known compounds, 6–9, 13, and 18–21, were procured from the titled plant for the first time, while 3–5, 10–12 and 14–17 were also found in the fruits. Notably, the known hydrolyzable tannins 8–13 exhibited stronger α-glucosidase inhibitory activities with IC50 values ranging from 0.10 to 3.12 μM, than the positive control, quercetin (IC50 = 9.38 ± 0.33 μM). Supplementary Information The online version contains supplementary material available at 10.1007/s13659-021-00314-z.


Introduction
Terminalia Linn, the second largest genus in the family Combretaceae, is distributed globally in the tropical and subtropical areas. Among which, some species, such as T. catappa Linn, T. bellirica Roxb, and T. chebula Retz, are widely used medicinal plants. Particularly, T. chebula is a famous and commonly used medicinal plant in Ayurveda, Tibetan, and traditional Chinese medicinal systems. So far, 39 Terminalia species have been chemically and pharmacologically studied, from which 368 compounds, including terpenoids, hydrolyzable tannins, flavonoids, lignans, phenols and glycosides with a wide range of bioactivities, e.g., liver and kidney protection, antibacterial, anti-inflammatory, anticancer, immune regulation, anti-diabetes, and wound healing, were reported [1].
Terminalia chebula var. tomentella (Kurz) C. B. Clarke, a medium or large tree, is widely distributed in Himalaya, Madagascar and southern Asia [1]. The fruits have been recorded as Chebulae Fructus in the Chinese Pharmacopoeia, together with those of its original species, T. chebula, for the treatment of diarrhea, hemorrhoids, cough, and sore throat [2]. They have also been used traditionally in Tibetan medicines for the treatments of diabetic, tumor, and microbial infection. Our previous phytochemical investigations on the variety reported that the fruit contains rich hydrolyzable tannins, triterpenes, flavonoids, lignans and simple phenolics [3]. As a part of our efforts to search for unique structural constituents from the genus Terminalia, two new lignan glucosides termitomenins F and G (1-2), were isolated from the branches and leaves of T. chebula var. tomentella, along with five known lignan glucosides (3)(4)(5)(6)(7), six known hydrolyzable tannins (8)(9)(10)(11)(12)(13) and eight simple phenolics (14)(15)(16)(17)(18)(19)(20)(21). Their structures were determined by spectroscopic analyses and comparison of 1D/2D NMR, IR, UV, HRESIMS and calculated ECD analysis. Compounds 1-2 are new lignan glucosides with furofuran skeletons. All the isolates were evaluated for their α-glucosidase inhibitory activities. Herein we describe the isolation, structural elucidation, and α-glucosidase inhibitory activities of these compounds.

ECD Computational Details
Conformational analyzes were conducted by random searching in the Sybyl Software X 2.0 using the MMFF-94S force field with an energy shortoff of 2.0 kcal mol −1 . The results indicated six lowest energy conformers for compounds 1 and 2. Then, the conformers were re-optimized using DFT at the PBE0-D3(BJ)/def2-SVP level in Methanol using the polarizable conductor calculation model by the ORCA-4.2.1 program [20]. The energies, rotational strengths (velocity), and oscillator strengths of the first 60 electronic excitations were calculated using the TDDFT methodology at the PBE0/def-2-TZVP level in Methanol. The electronic circular dichroism spectra were simulated by the overlapping Gaussian function (half the bandwidth at 1/e peak height, σ = 0.30 for all) [21]. Eventually, the electronic circular dichroism spectra of compounds 1 and 2 were gained by weighing the Boltzmann distribution ratio of each geometric conformation.

α-Glucosidase Inhibitory Activity
The α-glucosidase inhibitor screening assay was conducted as reported previously and slightly modified [22]. Quercetin was used as positive control. 4-Nitrophenol-α-dglucopyranoside (PNPG) was used as an enzyme inhibitor screening model. α-glucosidase solution (0.025 U·mL −1 ), PNPG (0.1 M), phosphate buffer (pH 6.8) and test samples (50 μM) were incubated in 96-well plates at 37 °C for 1 h. A microplate reader was recorded by the absorbance at 405 nm. No enzyme as the blank readings were subtracted from each well and compared to the control. In this assay, all reactions were performed in triplicate. The α-glucosidase inhibitory activity was presented as inhibition ratio. The formula to calculate the inhibition rate is as follows: inhibition rate (%) = (1 -OD experimental 405 nm/OD blank 405 nm) × 100%, and IC 50 values were calculated according to the Reed and Muench method [23].

Conflict of interest
The authors declare no competing financial interest.
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