α-Glucosidase-inhibitory iminosugars from the leaves of Suregada glomerulata

doi:10.1016/j.bmc.2013.07.048

Bioorganic & Medicinal Chemistry

Volume 21, Issue 21, 1 November 2013, Pages 6796-6803

https://doi.org/10.1016/j.bmc.2013.07.048 Get rights and content

Abstract

A water extract of the leaves of Suregada glomerulata (Euphorbiaceae) was found to inhibit rat small intestinal α-glucosidase. An examination of the extract afforded 20 iminosugars including one pyrrolidine and 19 piperidines. The structures of the 10 new compounds (11–20) were determined by NMR, and MS spectroscopic data analyses, and chemical correlations. The novelty of the identified compounds mainly stems from the loss of a hydroxy at C-4 and the presence of an 8-hydroxyoctyl side chain. Nine N-alkyl derivatives including N-methyl (1a, 8a, and 13a), N-butyl (1b, 2b, and 9b) and N,N-dimethyl (1c, 2c, and 9c) were synthesized. The compounds were tested for rat small intestinal α-glucosidase inhibitory activity. In total, 15 compounds, including compounds 11, 12, 15, and 19 and the three derivatives 8a, 9b, and 13a, showed inhibitory activity with IC₅₀ values less than 40 μM. In vivo results showed that total alkaloids of S. glomerulata (10 mg/kg) and four major iminosugars 1, 2, 3, and 9 (10 mg/kg) can lower the postprandial blood glucose level after sucrose and starch load in healthy male ICR mice.

Graphical abstract

Introduction

Iminosugars are carbohydrate mimics with a nitrogen atom in place of the ring oxygen. Because of their structural similarities to the natural substrates, iminosugars are potential inhibitors of glycosidases and may be useful against a wide range of diseases including diabetes, cancer, bacterial and viral infections, and lysosomal storage disorders.¹ After about half a century of research, approximately 200 iminosugars have been reported from microorganisms,² plants,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 animals,16, 17 and even marine sponges.18, 19 The two approved iminosugar drugs Glyset and Zavesca are closely related to the naturally occurring iminosugar 1-deoxynojirimycin (DNJ).

Suregada glomerulata is one of only two species in the genus Suregada (Gelonium) that is distributed in China. To our knowledge, there is no report about medicinal use of this plant. In our search for α-glucosidase inhibitors, hundreds of plants have been screened for inhibitory activity against rat small intestinal α-glucosidase, and water extracts of the leaves of S. glomerulata has been showed potent inhibitory activity (IC₅₀ 0.29 μg/mL). This observation prompted us to examine the components responsible for the activity. In our previous work, several diterpenoids20, 21, 22, 23, 24 and water-soluble compounds25, 26 were isolated and only α-homonojirimycin was found to have significant inhibitory activity.²⁵ Based on this result, we believed that iminosugars may contribute to the α-glucosidase inhibitory activity of extracts from the leaves of S. glomerulata. After preliminary purification of the water extracts by ion-exchange chromatography using 001 × 7 [H⁺ form] and 201 × 7 [OH⁻ form], the total alkaloids of S. glomerulata (TASG) were isolated and found to inhibit α-glucosidase activity with an IC₅₀ value of 0.02 μg/mL. Herein, we describe our investigation into the specific compounds contained in the TASG including the structure elucidation of new compounds, evaluation of α-glucosidase inhibitory activity in vitro and in vivo, and preliminary analysis of the structure–activity relationship.

Section snippets

Results and discussion

The molecular formula of compound 11 was determined to be C₁₄H₂₇NO₁₀ based on HRESIMS (m/z 370.1708 [M+H]⁺). The characteristic NMR signals (Table 1) at δ_H 4.44 (d, J = 7.8 Hz) and δ_C 105.5 suggested that 11 was a glycoside of an iminosugar. The HMQC and HMBC spectra established that the carbon signals of δ_C 63.6, 72.6, 76.0, 78.6, 78.8, and 105.5 were derived from the sugar part, and were in accord with those of 7-O-β-d-glucopyranosyl-α-homonojirimycin (9).²⁷ The carbon chemical shifts at δ_C

General experimental procedures

Optical rotations were measured on a Perkin-Elmer 241 digital polarimeter at 20 °C. The ¹H, ¹³C NMR, ¹H–¹H COSY, HSQC, HMBC, and NOESY spectra were run on a Varian Mercury-300, Varian Mercury-400 or Varian VNS-600 spectrometer using sodium 3-(trimethylsilyl)-propionate (TSP) as an internal standard (in D₂O) or using the pyridine-d₅ as a reference. ESIMS were obtained using an Agilent 1100 series LC/MSD Trap SL mass spectrometer. HRESIMS were measured on an Agilent 6520 Accurate-Mass Q-TOF LC/MS.

Acknowledgments

Financial support of the National Science and Technology Project of China (Nos. 2012ZX09103201-043, 2012ZX09301002-002) is gratefully acknowledged.

References and notes (35)

T.M. Cox et al.
Medicinal Use of Iminosugars
A.A. Watson et al.
Phytochemistry
(2001)
N. Asano et al.
Phytochemistry
(2001)
N. Asano et al.
Eur. J. Biochem.
(2001)
G. Kusano et al.
Chem. Pharm. Bull.
(2002)
K. Yasuda et al.
J. Nat. Prod.
(2002)
T. Yamashita et al.
J. Nat. Prod.
(2002)
M. Haraguchi et al.
J. Agric. Food Chem.
(2003)
N. Asano et al.
J. Nat. Prod.
(2004)
N. Asano et al.
J. Nat. Prod.
(2005)

A. Kato et al.

J. Nat. Prod.

(2007)

A. Kato et al.

Phytochemistry

(2008)

A. Michalik et al.

Phytochem. Lett.

(2010)

A. Kato et al.

Phytochem. Lett.

(2010)

L. Jones et al.

Phytochem. Lett.

(2010)

N. Asano et al.

J. Agric. Food Chem.

(2001)

G.X. Zhou et al.

J. Chin. Med. Mater.

(2007)

Cited by (17)

Synthesis and potential antidiabetic and lipid-lowering activities of putative asperidine B and its desmethyl analogue
2023, Bioorganic and Medicinal Chemistry Letters
Putative asperidine B is an unnatural 2,6-disubstituted piperidin-3-ol and a structural isomer of (+)-preussin, a well-known pyrrolidin-3-ol alkaloid. This work reports the first enantioselective synthesis of putative asperidine B and its desmethyl analogue via a chiron approach starting from d-isoascorbic acid as well as evaluation of their free-radical scavenging, antidiabetic, and anti-hyperlipidemic activities. Both putative asperidine B and its desmethyl analogue markedly reduced the total reactive oxygen species (ROS) without cytotoxicity in hepatocellular carcinoma (HepG2) cells. The desmethyl analogue was a potent inducer for two antioxidant gene expression, glutathione peroxidase and superoxide dismutase, whereas putative asperidine B only induced superoxide dismutase. In addition, putative asperidine B exerted potent antidiabetic activity via α-glucosidase inhibition (IC₅₀ = 0.143 ± 0.001 mg/mL) comparable to that of acarbose, an antidiabetic drug. Consistent with the parent asperidine B (preussin), both putative asperidine B and its desmethyl analogue inhibited cholesterol absorption in the intestinal Caco-2 cells. These novel and promising antioxidant, antidiabetic, and lipid-lowering effects of piperidin-3-ols could offer a starting point for this class of compounds for obesity and diabetic drug discovery.
High-throughput virtual screening and microsecond MD simulations to identify potential sugar mimic of the solute-binding protein BlAXBP of the ABC transporter from Bifidobacterium animalis subsp. Lactis
2021, Computational Biology and Chemistry
Xylotetraose is a prebiotic oligosaccharide can be utilized by the ABC transporter of the gut microbiota Bifidobacteria. BlAXBP is the solute binding protein of the ABC transporter, and its complex with xylotetraose has been solved by X-ray crystallography. Here, we have identified novel sugar mimic of BlAXBP by applying a high-throughput virtual screening of ZINC database containing a huge library with ∼22 M compounds. To begin with, we identified 18,571 ligands by a ligand-based virtual screening. Further, a total of 3968 compounds were selected for molecular docking due to their Tanimoto coefficient’s value were larger than a cutoff of 0.08. The molecular mechanics-generalized born surface area was used to evaluate the binding free energies, and the top 10 ligands with free energies below an energy threshold of -35.22 kcal/mol were selected. ZINC13783511 formed the most stable complex with BlAXBP and its recognition mechanism were further explored by microsecond MD simulations in explicit solvent. Free energy landscapes were used to evaluate conformational changes of BlAXBP in its ligand free and binding states. Collectively, this work identified potential novel sugar mimics to BlAXBP, providing novel atomic-level understanding of the binding mechanism.
A UPLC–MS/MS method for simultaneous determination of 1-deoxynojirimycin and N-methyl-1-deoxynojirimycin in rat plasma and its application in pharmacokinetic and absolute bioavailability studies
2018, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Citation Excerpt :
DNJ (> 98.0%) was supplied by Shanghai Yuanye Bio-Technology Co. Ltd. (Shanghai, China). N-CH3-DNJ (>98.0%) was prepared according to the method of Yan [26]. Miglitol (IS, >98.0%) was obtained from the National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China).
A specific, sensitive, rapid, precise, and reliable UPLC–MS/MS-based method was designed for the first time for the simultaneous determination of 1-deoxynojirimycin (DNJ) and N-methyl-1-deoxynojirimycin (N-CH₃-DNJ) in rat plasma. Miglitol was served as the internal standard (IS). An MN-NUCLEODUR HILIC column was assessed to separate the two compounds by isocratic elution using acetonitrile: water with 0.05% formic acid and 6.5 mM ammonium acetate (72:28, v/v) at a flow rate of 0.4 mL/min. A triple quadrupole mass spectrometer was operated in the positive ionization mode using multiple reaction monitoring (MRM), and it was employed to determine transitions of m/z 164.1 → 110.1, 178.1 → 100.1, and 208.1 → 146.1 for DNJ, N-CH₃-DNJ, and IS, respectively. The method of the two constituents was validated and the results were acceptable. The absolute bioavailability of DNJ and N-CH₃-DNJ in rats was 50 ± 9% and 62 ± 24%, respectively. The method was then successfully used for the first time to study the pharmacokinetic behavior and absolute bioavailability of DNJ and N-CH₃-DNJ in rats after intravenous (10 mg/kg) and oral administration (80 mg/kg). The results of this study might provide more information on preclinical pharmacokinetics and a solid basis for assessing the clinical efficacy of DNJ and N-CH₃-DNJ.
Re-exploring promising α-glucosidase inhibitors for potential development into oral anti-diabetic drugs: Finding needle in the haystack
2015, European Journal of Medicinal Chemistry
Citation Excerpt :
Denmark and Hurd (1999) [60c] reported first synthesis of casuarine. Further work on its biological activities revealed that it also potently inhibits the N-terminal domain of human intestinal maltase-glucoamylase (ntMGAM) (Ki = 0.45 μM) [60d]. Salacia reticulata has been used in Ayurvedic traditional medicine for the treatment of diabetes mellitus.
Treatment of diabetes mellitus by oral α-glucosidase inhibitors is currently confined to acarbose, miglitol and voglibose marred by efficacy problems and unwanted side effects. Since the discovery of the drugs more than three decades ago, no significant progress has been made in the drug development area of anti-diabetic α-glucosidase inhibitors. Despite existence of a wide chemical diversity of α-glucosidase inhibitors identified to date, majority of them are simply piled up in publications and reports thus creating a haystack destined to be forgotten in the scientific literature without given consideration for further development into drugs. This review finds those “needles” in that haystack and lays groundwork for highlighting promising α-glucosidase inhibitors from the literature that may potentially become suitable candidates for pre-clinical or clinical trials while drawing attention of the drug development community to consider and take already-identified promising α-glucosidase inhibitors into the next stage of drug development.
A divergent, short, and stereoselective approach to pyrrolidine iminosugars: Synthesis of 1,4-dideoxy-1,4-imino-derivatives of d-allitol, d-ribitol, ethyl-erythritol, and (-)-2,3-trans-3-4-cis-dihydroxyproline
2015, Tetrahedron Letters
Glycosidase inhibitors from the roots of Glyphaea brevis
2015, Phytochemistry
Citation Excerpt :
Broussonetines are polyhydroxy-pyrrolidines (5-membered iminosugars) featuring a 13-carbon substituent vicinal to nitrogen (Fig. 1) and to date, about twenty compounds of the broussonetine family have been isolated from Broussonetia kazinoki (Moraceae), which differ in configuration and in the substitution pattern of the alkyl chain (Asano et al., 2004; Kato et al., 2010). Recently, new pyrrolidine derivatives with long side chain at the C-1 position were isolated from Adenophora triphylla and Suregada glomerulata (Kato et al., 2010; Yan et al., 2013). Interestingly, six-membered iminosugars (piperidine derivatives) possessing additional alkyl substitution (n > 4) are rare and are limited to the three batzellasides A–C isolated from a marine source and a few related analogs (Segraves and Crews, 2005) (Fig. 1).
Ten phenylalkyl-substituted iminosugars (1–10) and a cinnamic acid derived glucoside (11) were isolated from the roots of Glyphaea brevis (Malvaceae). Their structures were elucidated by 1D and 2D NMR analysis, as well as by HR-ESIMS. Compounds 1–10 retain an unprecedented structure composed of an iminosugar-like core identified as 1-deoxyfuconojirimycin in glyphaeaside A₁–A₄ (1, 2, 5, 6), 1-deoxygalactonojirimycin in glyphaeaside B₁–B₅ (3, 4, 7–9) or 1-deoxynojirimycin in glyphaeaside C (10), substituted by a β-d-glucopyranose in compounds 2, 4, 6 and 9. These compounds feature a di-, tri- or tetra-hydroxylated nine-carbon chain at the pseudo-anomeric position, substituted by a terminal phenyl group. All alkyl C-iminosugars displayed potent and selective inhibition towards β-glucosidase with IC₅₀ values ranging from 0.15 to 68 μM. Compound 10 with an 1-deoxynojirimycin backbone was the most active and was found to act as a competitive inhibitor with K_i = 31 nM, therefore emerging as one of the most potent inhibitor of β-glucosidase reported to date. Inhibition of β-mannosidase was observed with compounds 1, 3, 7 and 10, but only weak inhibition could be detected with the alkyl-C-iminosugars on the other tested glycosidases (α-glucosidase, α-fucosidase, α- and β-galactosidase).

View all citing articles on Scopus

View full text

α-Glucosidase-inhibitory iminosugars from the leaves of Suregada glomerulata

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

General experimental procedures

Acknowledgments

Medicinal Use of Iminosugars

Phytochemistry

Phytochemistry

Eur. J. Biochem.

Chem. Pharm. Bull.

J. Nat. Prod.

J. Nat. Prod.

J. Agric. Food Chem.

J. Nat. Prod.

J. Nat. Prod.

J. Nat. Prod.

Phytochemistry

Phytochem. Lett.

Phytochem. Lett.

Phytochem. Lett.

J. Agric. Food Chem.

J. Chin. Med. Mater.