Benzophenones from Mango Leaves Exhibit α-Glucosidase and NO

Article pubs.acs.org/JAFC

Benzophenones from Mango Leaves Exhibit α‑Glucosidase and NO Inhibitory Activities Jing Pan,† Xiaomin Yi,† Yihai Wang,*,† Guisi Chen,† and Xiangjiu He*,†,§ †

School of Pharmacy, Guangdong Pharmaceutical University, 280 East Outer Ring Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, China § Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica, State Administration of TCM, Guangzhou 510006, China S Supporting Information *

ABSTRACT: Mango (Mangifera indica L.) is a succulent tropical fruit. Bioactive phytochemical investigation has been carried out to the leaves of mango. Three new benzophenone glycosides, along with 14 known compounds, were purified and identified. The novel benzophenones were elucidated to be 2,4,4′,6-tetrahydroxy-3′-methoxybenzophenone-3-C-β-D-glucopyranoside (1), 4,4′,6-trihydroxybenzophenone-2-O-α-L-arabinofuranoside (7), and 4′,6-dihydroxy-4-methoxybenzophenone-2-O-(2″),3-C-(1″)1″-desoxy-α-L-fructofuranoside (11). The α-glucosidase inhibitory, NO production inhibitory, and antioxidant activities were assessed for the purified benzophenones and triterpenoids. Some benzophenones showed moderate α-glucosidase and NO inhibitory activities. The IC50 value of the α-glucosidase inhibitory of isolated compounds 1, 13, and 14 were 284.93 ± 20.29, 239.60 ± 25.00, and 297.37 ± 8.12 μM, respectively. Most compounds showed moderate effects to reduce the NO content in 50 and 100 μM. The above results of bioactivity powerfully demonstrated the phytochemicals from mango, especially benzophenones, probably partially rational for its antidiabetes and anti-inflammatory. KEYWORDS: mango, Mangifera indica, benzophenones, α-glucosidase inhibitory, antioxidant, anti-inflammatory

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INTRODUCTION Mango (Mangifera indica L.), which is one of the most significant tropical fruits, belongs to the family Anacardiaceae. Mango is widely distributed in the world and its origin is South Asia. In traditional medicine, mango was widely used as herbal drugs, such as its kernel applied to cure for asthma, anthelmintic, dysentery, laxatives, aphrodisiacs, and tonics, while its juice applied to treat sinuses, its dry seed was used to remove dandruff by power to the head, it and was also used as an antidiarrheal.1 Mango byproducts, especially bark, kernel, peel of mango, and leaves, have high capacity of phenolic compounds containing phenolic acids, xanthones, flavonoids, benzophenones, and gallotannins.2−4 The polyphenols present in mango have showed kinds of bioactivity, such as antioxidant capacity,5,6 antifungal,7 antimicrobial, antidiabetic,8,9 antiinflammatory,10 antipyretic, analgesic activity, and immunomodulatory.11 The enzyme of α-glucosidase plays an important role in lower of dietetic saccharides in human, and several antidiabetics have been used to improve postprandial glucose control in type II diabetic sickness in clinic such as miglitol and acarbose.12 In previous studies, the utilization of mango has dealt with its peels, juices, kernel, and stem bark, and a little attention has been given to its leaves. In the present study, we reported the separation and structural assessment from mango and the biological evaluation of three novel benzophenones, together with known 14 compounds from mango leaves. This study also evaluated in vitro α-glucosidase inhibitory, NO production inhibitory, and antioxidant activities of phytochemicals from mango. © XXXX American Chemical Society

MATERIALS AND METHODS

General Apparatus and Chemicals. All the NMR spectra were achieved on an Avance III-400 NMR spectrometer (Bruker Inc., Falanden, Switzerland). ESI-MS analyses were obtained on a Waters AQUITY UPLC/Q-TOF mass spectrometer (Milford, MA, USA). HPLC analysis and preparation were performed on the Rainin chromatographic system comprising a pump and variable-wavelength absorbance detector model UV-D II (Woburn, MA, USA). A Cosmosil PHPLC column (5C18-MS-II, 10 ID × 250 mm, Nacalai Tesque, Kyoto, Japan) was used in isolation. Silica gel CC (300−400 and 200− 300 mesh) was a product of Anhui Liangchen Silicon Material Co. Ltd. (Lu′an, China). ODS (40−60 μm) for MPLC was obtained from Merck KGaA (Darastadt, Germany). Methanol for chromatography was product of Oceanpak Chemical Co. (Gothenburg, Sweden). Plant Material. The mango leaves were collected from the May 2014 from the campus of Guangdong Pharmaceutical University and tested by Prof. X. J. He at Guangdong Pharmaceutical University. The voucher sample (no. GDPU-NPR-201404) was deposited at the Lead Compounds Laboratory, School of Pharmacy, Guangdong Pharmaceutical University. Extraction and Isolation Procedure. Twenty kilograms of dried mango leaves were extracted three times with 70% ethanol at reflux. Evaporation of ethanol under lowered pressure gave an ethanol-free extract (25 L). The concentrated solution was successively extracted by cyclohexane, EtOAc, and normal butanol. The EtOAc fraction (239 g) was chromatographed by a silica gel CC using CHCl3−MeOH as eluent (100:1 to 0:1, v/v) to obtain 18 fractions (Frs. 1−18). Fraction 3 (2.7 g) was further isolated by silica gel CC eluted with cyclohexane−EtOAC (20:1 to 4:1, v/v) to give six fractions. Fr. 3-3 Received: May 29, 2016 Revised: August 22, 2016 Accepted: September 19, 2016

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DOI: 10.1021/acs.jafc.6b02404 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Journal of Agricultural and Food Chemistry

Figure 1. Structures of compounds isolated from M. indica leaves. °C for 5 min, then 20 μL of 2.5 mM PNPG (in 0.1 M PBS). After being preincubated at 37 °C for 15 min, 80 μL of 0.2 M Na2CO3 was mixed to terminate the reaction. Thereafter, the absorbance was measured at 405 nm by using microplate reader. Acarbose was dissolved in double-distilled water, filtered with filter paper, and diluted to various concentrations with methanol, which was selected as positive control. The inhibition (%) of compounds on the enzyme could be calculated as follows:

(93.5 mg) was isolated by HPLC to afford compound 16 (61.1 mg) using MeOH−H2O (85:15, v/v). Compound 17 (14.0 mg) was purified from fr. 3-6 (23.5 mg) by HPLC (MeOH−H2O, 80:20, v/v). Fraction 8 (10.2 g) was divided into 11 fractions by a silica gel (CHCl3−MeOH, 100:1 to 4:1, v/v). Fr. 8-7 (607.8 mg) was isolated by ODS (MeOH−H2O, 10:90 to 100:0, v/v) to give seven fractions, and fr. 8-7-5 (40.0 mg) was purified by HPLC (MeOH−H2O, 50:50, v/v) to yield compounds 13 (2.5 mg), 14 (5.0 mg), and 15 (6.1 mg). Fraction 11 (7.6 g) was subjected to a silica gel column eluted with chloroform−acetone (30:1 to 1:1, v/v) to give 11 fractions. Fr. 11-8 (2.2 g) was isolated by an ODS MPLC (MeOH−H2O, 10:90 to 70:30, v/v) to give seven fractions, and fr. 11-8-1 (20.3 mg) was separated by a Sephadex LH-20 using MeOH−H2O (70:30, v/v) to yield compound 11 (5.6 mg). Fraction 13 (19.9 g) was isolated using SiO2 CC (CHCl3−MeOH, 100:1 to 1:1, v/v) to give 13 fractions. Fr. 13-4 (10 mg) was separated using HPLC with MeOH−H2O (40:60, v/v) to afford compound 10 (5.2 mg). Fr. 13-7 (5.5 g) was isolated with an ODS MPLC (MeOH−H2O, 10:90 to 70:30, v/v) to give 13 fractions. Fr. 13-7-4 (190.2 mg) was separated by preparative HPLC with MeOH−H2O (30:70, v/v) to afford compounds 2 (27.6 mg), 6 (28.7 mg), and 12 (8.1 mg). Fr. 13-10 (911 mg) was separated by a Sephadex LH-20 column using MeOH−H2O (60:40, v/v) to yield compounds 3 (39.2 mg), 4 (27.6 mg), 5 (39.2 mg), 7 (9.7 mg), and 9 (15.1 mg). Fraction 14 (18.8 g) was isolated with an ODS column (MeOH−H2O, 10:90 to 50:50, v/v) to give 10 fractions. Fr. 14-2 (28.5 mg) was isolated by HPLC eluted with MeOH−H2O (20:80, v/ v) to give compound 1 (13.4 mg) and 8 (3.1 mg). α-Glucosidase Inhibitory Activity. α-Glucosidase inhibitory activity was determined by spectrophotometrically on 96-well plate of the reported protocol.12 Briefly, 20 μL of 0.1 M phosphate buffer solution (PBS), 20 μL of 0.2 U/mL α-glucosidase enzyme solution (enzyme in 0.01 M PBS including 0.2% of BSA), and 20 μL of test sample (the test concentration ranged from 10 to 1000 μM) in 50% water−methanol were mixed well. The mixture was preincubated at 37

inhibition(%) = [(A S − A SB)/(A C − A CB)] × 100 AS, ASB, AC, and ACB are the absorbance of sample, sample blank, control, and control blank, respectively. The result was expressed with the test concentration of inhibition on half of the α-glucosidase activity. The test was measured in triplicate. DPPH Radical Scavenging Activity. The radical scavenging ability was measured by using method of the DPPH assay of Silva.13 DPPH was dissolved in methanol at the concentration of 0.2 mmol/L, and 100 μL of this solution was mixed to 100 μL of the compound (dissolved in methanol) at the concentration of 2.5−400 μM. These solutions were mixed and incubated in the dark for half an hour at 25 °C. Finally, the OD value was measured at 510 nm, respectively. Superoxide Anion Radical Scavenging Capacity Activity. The superoxide radical scavenging capacities were assayed according to a described procedure.14 The 200 μL reaction mixture containing tested sample at the concentration of 2.5−700 μM, with 50 μL of NADH, NBT, and PMS, respectively. All tested samples were dissolved in methanol. The reaction was incubated for 5 min at 37 °C. The superoxide radical was calculated as follows:

scavenging activity(%) = [1 − (A S − A S − B)/(A C − A C − D)] × 100% B

DOI: 10.1021/acs.jafc.6b02404 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Journal of Agricultural and Food Chemistry AS, AS−B, AC, and AC−D represent the absorbance of samples, sample control, control, and vehicle control, respectively, at 546 nm. Ascorbic acid and gallic acid were selected as positive control. Anti-inflammatory Activity Assay. RAW 264.7 macrophage cells were seeded in 96-well plate with Dulbecco’s Modified Eagle’s Medium including 100 U/mL penicillin, 100 mg/mL streptomycin, and 10% fetal bovine serum at 37 °C with a moist atmosphere of 5% CO2. The release of NO in the supernatant was evaluated by Griess reaction to test the NO2− level. Statistical Analysis. Data were expressed as mean ± SD of at least triplicate assays. The statistic differences of the data were evaluated by using Prism 5 software with a one-way ANOVA for P-value of 1000) and 6 (IC50 > 1000). Previous studies on hydroxyl benzophenones have shown that adds the number of phenolic hydroxyl groups on the basic diphenyl ketone led to increase in α-glucosidase inhibitory activities.27 Thus, for compound 1, it has been shown that a 4-hydroxy group leads to increase inhibitory activity. For compounds 2, 3, and 5, the inhibitory rate is as follows: 2 (IC50 415.79 ± 34.98 μM), 3 (IC50 834.66 ± 51.94 μM), and 5 (IC50 > 1000 μM). Therefore, the phenolic functions (2 vs 3) offer the better activity.28 Compound 1, which lacks a methoxyl group, showed

compd

IC50 (μM)b

compd

IC50 (μM)b

1 2 3 4 5 6 7 8 9

284.93 ± 20.29 415.79 ± 34.98 834.66 ± 51.94 >1000 >1000 >1000 520.94 ± 36.79 >1000 >1000

10 11 12 13 14 15 16 17 acarbose

657.23 ± 64.72 >1000 >1000 239.6 ± 25.00 297.37 ± 8.12 >1000 NDc >1000 185.25 ± 6.00

Data were described as mean ± SD, n = 3. bTest concentrations ranged from 10 to 1000 μM. cND: not determined.

a

more inhibitory activity than compound 4. Thus, it was presumed that the methoxyl group connected to C-4 in benzophenones could cause a radical decrease in the inhibitory activity.29 Compound 7 (IC50 520.94 ± 36.79 μM) has shown moderate inhibitory activity compared with compounds 8 (IC50 > 1000 μM) and 9 (IC50 > 1000 μM). Therefore, the type of sugar may affect the inhibitory activity of the benzophenone glucosides. Furthermore, the triterpenoids also exhibit some activities, Compounds 13 (IC50 239.6 ± 25.00 μM) and 14 (IC50 297.37 ± 8.12 μM), which had a pentacyclic triterpenoid acid skeleton, showed potent inhibitory activity. Antioxidant Activity. DPPH radical scavenging and superoxide anion radical scavenging assays were used for evaluation antioxidant activities. In the present study, benzophenones have shown that the hydroxylation pattern on the phenyl rings was an important structural characteristic for the antioxidant activity and with more hydroxyl groups resulting in more activity.30 Thus, compound 10 showed D

DOI: 10.1021/acs.jafc.6b02404 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Journal of Agricultural and Food Chemistry

100 μM by comparing with the model group. The cytotoxicity was tested by MTT assay to evaluate the compounds in RAW 264.7 macrophage cells. The above results implied that most of the compounds had no cytotoxicity at their effective concentration (data not shown) except for compound 17. Taken together, the current study indicated that these benzophenons isolated from mango may serve as lead compounds with promising therapeutic potential as antiinflammatory agents. In conclusion, three new benzophenone glycosides, along with 14 known compounds, were isolated and elucidated from mango. The potent α-glucosidase inhibitory, NO inhibitory activity, and antioxidant capacity were revealed in some compounds. The above results strongly demonstrated that the phytochemicals from mango might be partially responsible for its antidiabetes and anti-inflammatory activities.

obvious antioxidant activity in the DPPH assays. Moreover, the dihydroxyl groups in 3′-hydroxy and 5′-hydroxy groups were able to give stability to the free radical form, which is significant for the antioxidant activity.11 Therefore, compounds 1−5, 7, and 12 showed some antioxidant activities in the DPPH assays and in the PMS/NADH-NBT assay, and 4-hydroxy group may lead to increase antioxidant activity. The triterpenoids showed weaker antioxidant activity in the assay. Ascorbic acid and gallic acid were selected as positive reagents (Table 3). Table 3. Antioxidant Activity of Compounds 1−17 IC50 (μM)b compd

DPPH

PMS/NADH-NBT

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 ascorbic acid gallic acid

180.61 ± 14.24 331.25 ± 9.08 259.72 ± 7.42 >400 171.89 ± 8.89 >400 275.79 ± 13.57 >400 >400 93.74 ± 1.89 >400 >400 >400 >400 >400 >400 >400 12.00 ± 2.55 8.61 ± 0.72

>700 323.63 ± 16.10 272.89 ± 21.27 428.42 ± 41.17 >700 >700 >700 >700 >700 >700 >700 428.42 ± 41.17 >700 >700 >700 >700 >700 146.5 ± 13.27 10.92 ± 0.39

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jafc.6b02404. HR-ESI-MS, 1H-NMR, 13C-NMR, HMQC, HMBC, NOESY, and DEPT spectra for compounds 1, 7, and 11 (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*Dr. X.H.: phone/fax, 86-20-3935-2132; E-mail, hexiangjiu@ 163.com. *Dr. Y.W.: phone, 86-20-3935-2140; E-mail, wangyih88@163. com. Funding

Data are described as mean ± SD, n = 3. bTest concentrations ranged from 2.5 to 700 μM. a

This research was supported by the project of Guangdong Provincial Department of Science and Technology (2015A020211027) and Guangdong Natural Science Foundation (2014A030313588).

Nitric Oxide Inhibitory Assay. The Griess reaction was used to evaluate the inhibitory activity. The purified compounds were tested on RAW 264.7 macrophage cells, which served as inflammatory model stimulated by LPS for releasing NO. Indomethacin (IC50 = 48.26 μM) was selected as the positive reagent. The tested samples showed moderate effect on NO release comparing with indomethacin. The results are shown in Figure 3. Compounds 1−3, 6−10, and 12−16 showed moderate effect to reduce the NO content in 50 and

Notes

The authors declare no competing financial interest.

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Figure 3. Effects of compounds 1−17 on NO production induced by LPS in RAW 264.7. Data were described as mean ± SD, n = 3. C: Control group; cells were cultured without LPS stimulation or any test sample. M: Model group; cells were cultured with 1 μg/mL LPS stimulation. *P < 0.05; **P < 0.01 versus model group. Compounds 5 and 9 not determined. E

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DOI: 10.1021/acs.jafc.6b02404 J. Agric. Food Chem. XXXX, XXX, XXX−XXX