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Oct 27, 2016 - Department of Chemistry, Faculty of Science, Chiang Mai University, Sutep, Muang, Chiang Mai 50200, Thailand. ∥. Departments of Chemi...
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New Benzophenones and Xanthones from Cratoxylum sumatranum ssp. neriifolium and Their Antibacterial and Antioxidant Activities Cholpisut Tantapakul,† Wisanu Maneerat,† Tawanun Sripisut,‡ Thunwadee Ritthiwigrom,§ Raymond J. Andersen,∥ Ping Cheng,∥ Sarot Cheenpracha,⊥ Achara Raksat,† and Surat Laphookhieo*,† †

Natural Products Research Laboratory, School of Science, Mae Fah Luang University, Tasud, Muang, Chiang Rai 57100, Thailand School of Cosmetic Science, Mae Fah Luang University, Tasud, Muang, Chiang Rai 57100, Thailand § Department of Chemistry, Faculty of Science, Chiang Mai University, Sutep, Muang, Chiang Mai 50200, Thailand ∥ Departments of Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia, 2036 Main Mall, Vancouver, BC, Canada V6T 1Z1 ⊥ School of Science, University of Phayao, Maeka, Muang, Phayao 56000, Thailand ‡

S Supporting Information *

ABSTRACT: Two new benzophenones (1 and 2) and four new xanthones (4−6 and 17) together with 24 known compounds (3, 7−16, and 18−30) were isolated from the roots and twigs of Cratoxylum sumatranum ssp. neriifolium. Their structures were elucidated by spectroscopic methods. Compounds 5 and 26 showed antibacterial activity against Micrococcus luteus, Bacillus cereus, and Staphylococcus epidermis with minimum inhibitory concentrations ranging from 4 to 8 μg/mL, whereas compounds 7, 20, and 26 displayed selective antibacterial activities against Staphylococcus aureus (8 μg/mL), Salmonella typhimurium (4 μg/ mL), and Pseudomonas aeruginosa (4 μg/mL), respectively. The radical scavenging effects of some isolated compounds were investigated. Compounds 11 and 21 exhibited potent activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) with IC50 values of 7.0 ± 1.0 and 6.0 ± 0.2 μM, respectively. KEYWORDS: Cratoxylum sumatranum ssp. neriifolium, benzophenone, xanthone, antibacterial activity, antioxidant activity

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nones,3 and some of them exhibited cytotoxicity.3 In the investigation presented here, we report the isolation and identification of two new benzophenones (1 and 2) (Figure 1), four new xanthones (4−6 and 17), and 24 known compounds (3, 7−16, and 18−30) (Figure 2) from C. sumatranum ssp. neriifolium roots and twigs. In addition, the antibacterial and antioxidant activities of some isolated compounds are reported.

INTRODUCTION Cratoxylum belongs to the Hypericaceae family1 that is widely distributed in South East Asian countries. In Thailand, only six species have been found,2 and some of them have been used as traditional medicines and cooking. The roots and stems of Cratoxylum cochinchinense have been used in folk medicine to treat diuretic, stomachic, and tonic effects and diarrhea,3−5 whereas the roots, bark, and leaves of Cratoxylum sumatranum ssp. neriifolium have been used for the treatment of rheumatoid arthritis and musculoskeletal pain and also used as a protective medicine for women after childbirth.6 Young leaves of C. sumatranum ssp. neriifolium as well as the flowers of Cratoxylum formosum ssp. formosum are chewed for relief of coughs.7,8 The latex of C. cochinchinense, C. formosum ssp. formosum, and C. formosum ssp. prunif lorum has been used to stop bleeding and to treat wound infections.9−11 The fresh shoots, young leaves, and flowers of some species of this genus, especially C. formosum ssp. formosum, are traditionally consumed as vegetables, and the taste is sour and slightly astringent because of the phenolic components.12 In addition, C. cochinchinense young leaves and fruits are commonly used as a spice for cooking and a substitute for tea, respectively.13 Cratoxylum species produce various types of secondary metabolites, including anthraquinones,14 benzophenones,15 flavonoids,16 xanthones,3,14,17 and triterpenoids,15 and many of them exhibited interesting biological activities as well as antioxidant activity.17,18 Previous phytochemical investigations of C. sumatranum leaves and stem bark resulted in the identification of xanthones17,19 and anthraquinonebenzophe© 2016 American Chemical Society

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MATERIALS AND METHODS

General Experimental Procedures. Melting points were determined on a Buchi B-540 visual thermometer. The [α]D values were measured with a Bellingham and Stanley ADP400 or Jasco P1010 polarimeter. UV−vis spectra were recorded with a PerkinElmer UV−vis or BMG LABTECH/SPECTROstar Nano spectrometer. The IR spectra were recorded using a PerkinElmer FTS FT-IR spectrometer. Electronic circular dichroism spectra were recorded on a JASCO J-815 CD spectrometer. The NMR spectra were recorded using a 400 or 600 MHz Bruker spectrometer. The HREIMS and ESITOF-MS data were measured on a MAT 95 XL or a Bruker-HewlettPackard 1100 Esquire-LC system mass spectrometer. Chiral HPLC was performed on a CHIRALPAK IA column (10 mm × 250 mm) attached to a Waters 2487 dual λ absorbance detector. Silica gel C60 (Silicycle, 0−20 μm) and silica gel G60 (Silicycle, 60−200 μm) were used to perform quick column chromatography (QCC) and column chromatography (CC), respectively. Analytical thin-layer chromatogReceived: Revised: Accepted: Published: 8755

August 15, 2016 October 24, 2016 October 27, 2016 October 27, 2016 DOI: 10.1021/acs.jafc.6b03643 J. Agric. Food Chem. 2016, 64, 8755−8762

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Journal of Agricultural and Food Chemistry

Figure 1. Compounds isolated from C. sumatranum roots.

Figure 2. Compounds isolated from C. sumatranum twigs. Extraction and Isolation. Air-dried roots of C. sumatranum ssp. neriifolium (2.75 kg) were macerated with CH2Cl2 and acetone, successively. The crude extract (47.88 g) was subjected to QCC over silica gel, eluting with an EtOAc/hexanes solvent gradient (100% hexanes to 100% EtOAc) to give compounds 6 (94.3 mg) and 10 (18.9 mg) and 13 fractions (1A−1M). Fraction 1B (1.84 g) was further separated by QCC (100% hexanes to 100% acetone) to give

raphy (TLC) was performed with the precoated plates of silica gel 60 F254. Plant Material. The roots and twigs of C. sumatranum ssp. neriifolium were collected from Mae Hong Son Province, Thailand, in June 2010. The plant was identified by J. Maxwell, and the voucher specimen (MFU-NPR0008) was deposited at the Natural Products Research Laboratory of Mae Fah Luang University. 8756

DOI: 10.1021/acs.jafc.6b03643 J. Agric. Food Chem. 2016, 64, 8755−8762

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Journal of Agricultural and Food Chemistry Table 1. 1H (400 MHz) and 13C (100 MHz) NMR Spectroscopic Data of 1 and 2 in CDCl3 cratosumatranone A (1) position

δC

1 2 3 4 5 6 7 1′ 2′ 3′ 4′ 5′ 6′ 1″ 2″ 3″ 4″ 5″ 6″ 7″ 8″ 9″ 10″ 1‴ 2‴ 3‴ 4‴ 5‴ OH-2 OH-6

104.5 161.0 93.0 163.8 108.8 158.7 197.9 140.2 127.9 129.0 132.0 129.0 127.9 65.4 118.9 141.5 39.4 26.0 123.7 131.8 25.8 16.6 17.7 21.6 122.2 132.6 17.8 25.6

δH [J (Hz)] − − 6.06 − − − − − 7.63 7.50 7.57 7.50 7.63 4.57 5.47 − 2.10 2.10 5.10 − 1.68 1.73 1.61 3.28 5.17 − 1.73 1.67 9.07 8.60

s

dd (7.2, dd (7.6, m dd (7.6, dd (7.2, d (6.4) t (6.4)

1.3) 7.2) 7.2) 1.3)

m m br t (6.8) s s s d (6.8) br t (6.8) s s br s br s

cratosumatranone B (2) HMBC

δC

δH [J (Hz)]

HMBC

− − 1, 2, 4, 5, 7, 1‴ − − − − − 7, 4′, 6′ 1′, 5′ 2′, 6′ 1′, 3′ 7, 4′, 2′ 4, 2″, 3″ 1″, 4″ − 5″, 9″ 4″ 4″, 5″, 8″ − 10″ 4″ 8″ 4, 5, 6, 2‴, 3‴ 1‴, 5‴ − 5‴ 4‴ 1, 2, 3 1, 5, 6

105.2 164.7 92.9 163.7 99.1 154.3 199.9 142.7 127.2 127.5 130.1 127.5 127.2 65.5 118.7 141.6 39.5 26.1 123.6 131.9 25.8 16.7 25.7 17.7 68.6 76.7 20.9 23.9 − −

− − 6.12 s − − − − − 7.45 br d (6.8) 7.39 br d (6.8) 7.44 m 7.39 br d (6.8) 7.45 br d (6.8) 4.58 d (6.4) 5.45 t (6.4) − 2.10 m 2.10 m 5.10 br t (6.4) − 1.68 s 1.73 s 1.61 s 2.76 dd (17.2, 5.2), 2.55 dd (17.2, 5.2) 3.58 t (5.2) − 0.85 s 0.92 s 12.37 br s −

− − 1, 2, 5, 7, 1‴ − − − − − 7, 4′ 1′ 4′, 6′ 1′ 7, 4′ 4, 2″, 3″ 1″, 4″, 9″ − 2″, 3″, 4″, 5″, 9″ 3″, 4″, 6″, 7″ 4″, 5″, 8″ − 6″, 7″, 10″ 2″, 3″, 4″ 6″, 8″ 4, 5, 6, 2‴, 3‴ 5, 4‴ − 2‴, 3‴ 2‴, 3‴ 1, 2, 3 −

five fractions (1BA−1BE). Compound 4 (8.1 mg) was obtained from subfraction 1BA (737.1 mg) by Sephadex LH-20 (10% CH2Cl2/ MeOH). Fraction 1C (4.39 g) was obtained by repeated QCC (15% acetone/hexanes) to yield four subfractions (1CA−1CD). Subfraction 1CA (126.6 mg) was purified by CC (15% acetone/hexanes), yielding compound 1 (79.6 mg). Compounds 2 (29.2 mg) and 3 (4.0 mg) were obtained from subfraction 1CD (220.0 mg) by CC (10% EtOAc/ hexanes). Purification of fraction 1D (838.0 mg) by repeated CC (10% acetone/hexanes) yielded compound 13 (10.5 mg). Fraction 1F (5.47 g) was further subjected to QCC (100% hexanes to 100% acetone) giving six fractions (1FA−1FF). Compounds 11 (11.6 mg) and 12 (168.6 mg) were obtained from subfraction 1FB (1.37 g) by repeated CC (20% acetone/hexanes) followed by Sephadex LH-20 (100% MeOH). The separation of subfractions 1FE (537.4 mg) and 1FF (471.4 mg) by Sephadex LH-20 (10% CH2Cl2/MeOH) afforded compounds 9 (13.2 mg) and 16 (76.4 mg), respectively. Fraction 1G (1.60 g) was chromatrographed by CC (25% acetone/hexanes) to produce five subfractions (1GA−1GE). Subfraction 1GD (657.1 mg) was obtained by repeated CC (20% acetone/hexanes), giving compounds 7 (150.7 mg) and 8 (82.3 mg). Purification of subfraction 1K (1.66 g) by CC (20% acetone/hexanes) produced compound 14 (80.4 mg). Fraction 1L (1.93 g) was subjected to CC (20% acetone/ hexanes) followed by Sephadex LH-20 (100% MeOH) to afford compound 5 (11.9 mg). Fraction 1M (1.44 g) was subjected to Sephadex LH-20 (10% CH2Cl2/MeOH) followed by repeated CC (40% acetone/hexanes), yielding compound 15 (22.5 mg). The air-dried twigs of C. sumatranum ssp. neriifolium (6.57 kg) were macerated with methanol. The MeOH extract (192.99 g) was subjected to QCC (100% hexanes to 100% EtOAc), providing 13 fractions (2A−2M). Fraction 2G (4.48 g) was subjected to CC (15% acetone/hexanes) to afford two subfractions (2GA and 2GB).

Purification of subfraction 2GB (57.1 mg) by CC (10% acetone/ hexanes) gave compound 26 (6.0 mg). Fraction 2H (3.51 g) was further separated by QCC (100% hexanes to 100% CH2Cl2) to give compounds 22 (9.8 mg) and 25 (7.7 mg) and eight subfractions (2HA−2HH). Compound 29 (8.1 mg) was obtained from subfraction 2HD (79.9 mg) by Sephadex LH-20 (100% MeOH). Subfraction 2HG (72.7 mg) was obtained by repeated CC (10% acetone/hexanes), yielding compounds 13 (4.0 mg), 23 (1.5 mg), and 28 (11.2 mg). Purification of subfraction 2HH (99.9 mg) was achieved by CC (10% acetone/hexanes) to give a mixture of compounds 27 and 30 that was further purified by CC (25% EtOAc/hexanes) to afford compounds 27 (1.7 mg) and 30 (3.3 mg). Fraction 2I (27.32 g) was subjected to QCC (100% hexanes to 100% acetone) to give six subfractions (2IA− 2IF). Compounds 19 (7.3 mg) and 24 (6.9 mg) were obtained from subfraction 2ID (2.06 g) by CC (10% acetone/hexanes). Fraction 2K (5.64 g) was further separated by Sephadex LH-20 (100% MeOH) to give nine subfractions (1KA−1KI). Subfractions 1KA (151.5 mg), 1KB (58.9 mg), and 1KC (35.5 mg) were combined and further purified by CC (10% EtOAc/hexanes), yielding compounds 17 (1.0 mg) and 18 (6.1 mg). Subfractions 2KG (60.7 mg) and 2KF (66.1 mg) were combined and purified by CC (7% EtOAc/CH2Cl2), yielding an additional amount of compounds 5 (11.2 mg) and 7 (11.3 mg). Compound 20 (2.0 mg) was obtained from subfraction 2KI (27.8 mg) by CC (10% acetone/hexanes), whereas compound 21 (11.7 mg) was isolated from fraction 2M (4.36 mg) by Sephadex LH-20 (10% CH2Cl2/hexanes). Cratosumatranone A (1). Yellow solid: mp 69−71 °C; UV (MeOH) λmax (log ε) 233 (4.33), 289 (4.54) nm; IR (neat) νmax 3328, 2915, 1626, 1591, 1421, 1171, 1081, 1001, 953, 817, 699 cm−1; see Table 1 for 1H NMR (CDCl3, 400 MHz) and 13C NMR (CDCl3, 100 MHz); HREIMS m/z 434.2452 [M]+ (calcd for C28H34O4, 434.2452). 8757

DOI: 10.1021/acs.jafc.6b03643 J. Agric. Food Chem. 2016, 64, 8755−8762

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Journal of Agricultural and Food Chemistry Cratosumatranone B (2). Yellow viscous oil: UV (MeOH) λmax (log ε) 201 (4.43), 233 (3.98), 285 (4.23) nm; IR (neat) νmax 3440, 2925, 1705, 1621, 1588, 1447, 1333, 1127, 1126, 1101, 815 cm−1; see Table 1 for 1H NMR (CDCl3, 400 MHz) and 13C NMR (CDCl3, 100 MHz); HREIMS m/z 450.2406 [M]+ (calcd for C28H34O5, 450.2401). Chiral HPLC Separation of (−)-2 and (+)-2. Separation of two enantiomers of 2 (3.3 mg) was performed by semipreparative HPLC on an enantioselective column [CHIRALPACK IA, 15 μL, 10 mm × 25 mm, 98:2 (v/v) n-hexane/i-PrOH eluent, 2 mL/min]. Compounds (−)-2 (tR = 53 min) [0.8 mg; [α]23D − 5.70 (c 0.4, CHCl3)] and (+)-2 (tR = 72 min) [1.2 mg; [α]23D + 3.7 (c 0.4, CHCl3)] were obtained. Cratosumatranone C (4). Yellow solid: mp 142−144 °C; [α]26D 0.0 (c 0.06, MeOH); UV (MeOH) λmax (log ε) 243 (4.48), 314 (4.49), 373 (3.75) nm; IR (neat) νmax 3441, 2968, 1648, 1627, 1587, 1497, 1416, 1255, 889, 757 cm−1; see Table 2 for 1H NMR (CDCl3, 400 MHz) and 13C NMR (CDCl3, 100 MHz); ESITOFMS m/z 447.2174 [M + H]+ (calcd for C28H31O5, 477.2171). Cratosumatranone D (5). Yellow solid: mp 211−213 °C; [α]26D 0.0 (c 0.08, acetone); UV (MeOH) λmax (log ε) 224 (4.48), 296 (3.12) nm; IR (neat) νmax 3387, 1649, 1578, 1169, 1092 cm−1; see Table 3 for 1 H NMR (CDCl3, 400 MHz) and 13C NMR (CDCl3, 100 MHz); HREIMS m/z 358.1048 [M]+ (calcd for C19H18O7, 358.1047). Cratosumatranone E (6). Yellow solid: mp 242−244 °C; [α]26D 0.0 (c 0.05, acetone); UV (MeOH) λmax (log ε) 231 (4.58), 264 (4.00), 306 (4.17) nm; IR (neat) νmax 3294, 2913, 1701, 1649, 1578, 1417, 1306, 1201, 1169, 1092, 1050, 812, 797 cm−1; see Table 3 for 1H NMR (CDCl3, 400 MHz) and 13C NMR (CDCl3, 100 MHz); HREIMS m/z 344.0891 [M]+ (calcd for C18H16O7, 344.0891). Cratosumatranone F (17). Yellow amorphous solid: UV (MeOH) λmax (log ε) 243 (4.42), 274 (4.37), 321 (4.10), 368 (4.00) nm; IR (neat) νmax 3343, 1728, 1670, 1597, 1505, 1446, 1264, 1214, 1114, 817, 756 cm−1; see Table 3 for 1H NMR (CD2Cl2, 600 MHz) and 13C NMR (CD2Cl2, 150 MHz); ESITOFMS m/z 319.0817 [M + H]+ (calcd for C16H15O7, 319.0817). Antibacterial Assay. Micrococcus luteus TISTR 884, Bacillus cereus TISTR 688, Bacillus subtilis TISTR 008, Staphylococcus aureus TISTR 1466, Staphylococcus epidermidis ATCC 12228, Escherichia coli TISTR 780, Salmonella typhimurium TISTR 292, and Pseudomonas aeruginosa TISTR 781 were obtained from the Microbiological Resources Center of the Thailand Institute of Scientific and Technological Research. The antibacterial assay and the minimum inhibitory concentrations (MICs) were determined by a 2-fold serial dilution method using Nutrient broth (NB).20 In brief, serial 2-fold dilutions of samples in DMSO were mixed with MHB in a 96-well microplate, and then 50 μL of bacteria was added to each well (final concentration of 1 × 104 colonyforming units/well). The plates were incubated at 35−37 °C for 16− 18 h followed by the addition of 10 μL of resazurin. The MIC was determined after added resazurin for 2−3 h. All of the antimicrobial assays were tested in duplicate, and the standard compounds were vancomycin and gentamycin. Antioxidant Assay. Briefly, serial dilutions of samples (100 μL) in EtOH were mixed with 100 μL of DPPH for 30 min. The mixture was recorded at 517 nm using a microplate reader (SPECTROstar Nano).21,22 The following equation was used for the calculation of the DPPH radical scavenging capacity: percent inhibition = [(AB − AS)/ AB] × 100, where AB and AS are the absorbance of the blank sample and sample, respectively. All experiments were performed in triplicate; ascorbic acid was used as the positive compound, and the calibration curve of ascorbic acid was r2 > 0.9836. The IC50 value of DPPH scavenging activity was calculated by plotting inhibition percentages against concentrations of the sample.

Table 2. 1H and 13C NMR Spectroscopic Data of 4 and 17 cratosumatranone C (4) position

δCa

1 2 3 4

156.6 105.2 159.7 112.8

5 6

145.3 119.6

7

124.2

8

116.0

9 4a 4b 8a 9a 1′

181.2 154.0 144.1 120.5 103.5 116.6

2′

125.7

3′ 4′a 4′b 5′ 6′

81.2 41.8 41.8 23.2 123.6

7′ 8′ 9′ 10′ 1″ 2″

132.1 25.7 26.9 17.6 41.3 155.8

3″a

104.0

3″b

104.0

4″ 5″ OH-1 OH-5 OMe-2 OMe-3 OMe-8

28.1 28.5

δH [J (Hz)]b

cratosumatranone F (17)

HMBC

δ Cc 156.5 137.8 152.7 99.0

7.25 dd (7.6, 2.4) 7.22 t (7.6)

5

149.6 120.6

5, 8, 8a

105.0

7.75 dd (7.6, 2.4)

4b, 6, 9

143.1

δH [J (Hz)]d

HMBC

6.74 s

2, 3, 4a, 9, 9a

7.24 d (9.0) 6.80 d (9.0)

4b, 5, 8 5, 8, 8a, 9

182.4 155.5 151.4 109.6 109.0 6.83 d (10.0) 5.58 d (10.0)

1, 2, 3, 3′ 2, 3′, 4′, 9′

1.91 m 1.74 m 2.14 m 5.12 br t (7.2)

5′, 9′ 4′ 5′, 8′

1.67 s 1.46 s 1.59 s

10′ 4′ 8′

6.70 dd (17.6, 10.4) 5.24 dd (10.4, 0.8) 5.07 dd (17.6, 0.8) 1.65 s 1.65 s 13.44 s

4, 1″, 5″ 1″, 2″ 1″ 1″, 5″ 4″ 1, 2, 9a 62.2 62.2 57.5

13.27 s 6.67 br s 3.97 s 4.01 s 3.89 s

2 3 8

a c

Measured at 100 MHz in CDCl3. bMeasured at 400 MHz in CDCl3. Measured at 150 MHz in CD2Cl2. dMeasured at 600 MHz in CD2Cl2.

non-4-O-geranyl ether (3),23 pruniflorone N (7),24 neriifolone B (8),19 isocudraniaxanthone B (9),14 10-O-methylmacluraxanthone (10),14 macluraxanthone (11),14 5-O-methyl-2-deprenylrheediaxanthone B (12),25 pancixanthone B (13),26 pruniflorone M (14),24 5′-demethoxycadensin G (15),27 cochinchinoxanthone (16),28 1,5-dihydroxy-8-methoxyxanthone (18),29 1,5-dihydroxy-6,7-dimethoxyxanthone (19),30 1,3,6-trihydroxy-7-methoxyxanthone (20),31 1,3,5,6-tetrahydroxyxanthone (21),27 1,2,8-trihydroxyxanthone (22),32 2,8dihydroxy-1-methoxyxanthone (23),33 cratoxyarborenone F (24),3 1,7-dihydroxyxanthone (25),34 trapezifolixanthone

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RESULTS AND DISCUSSION Isolation and Identification of Compounds. The crude extracts of C. sumatranum ssp. neriifolium (roots and twigs) were separated by repeated silica gel column chromatography and Sephadex LH-20 column chromatography to obtain six new compounds (1, 2, 4−6, and 17) along with 24 known compounds that were identified as 2,4,6-trihydroxybenzophe8758

DOI: 10.1021/acs.jafc.6b03643 J. Agric. Food Chem. 2016, 64, 8755−8762

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Journal of Agricultural and Food Chemistry

carbon at δC 104.5 (C-1), OH-2 was ortho to the methine carbon at δC 93.0 (C-3), and OH-6 was ortho to the quaternary carbon at δC 108.8 (C-5). The remaining signals in the NMR data of 1 were assigned to an oxygeranyl unit [δH 5.47 (1H, t, J = 6.4 Hz, H-2″), 5.10 (1H, br t, J = 6.8 Hz, H-6″), 4.57 (2H, d, J = 6.4 Hz, H-1″), 2.10 (4H, m, H-4″/H-5″), 1.73 (3H, s, H9″), 1.68 (3H, s, H-8″), 1.61 (3H, s, H-10″)] and a dimethylallyl group [δH 5.17 (1H, br t, J = 6.8 Hz, H-2‴), 3.28 (2H, d, J = 6.8 Hz, H-1‴), 1.73 (3H, s, H-4‴), 1.67 (3H, s, H-5‴)]. The oxygeranyl and dimethylallyl units were placed at C-4 and C-5, respectively, because H-3 (δH 6.06), H-1″ (δH 4.57), and H-1‴ (δH 3.28) showed HMBC correlations with C4 (δC 163.8). Once the oxygeranyl and dimethylallyl units had been situated, the remaining benzoyl fragment had to be attached to C-1. This location for the benzolyl fragment was consistent with the observation of a 4J HMBC correlation (Supporting Information and Table 1) between H-3 (δH 6.06) and the carbonyl carbon (δC 197.9), and the chemical shifts and sharpness of the two hydrogen-bonded hydroxy signals at δH 9.07 (1H, br s, OH-2) and 8.60 (1H, br s, OH-6),39 which implied they were hydrogen bonded to the benzoyl carbonyl group. Completed assignment of 1H and 13C NMR spectral data and additional HMBC correlations of cratosumatranone A (1) are summarized in Table 1. Cratosumatranone B (2) gave a molecular ion peak at m/z 450.2406 [M]+ (calcd, 450.2401) in its HREIMS spectrum, suggesting a molecular formula of C28H34O5. The UV and IR spectra displayed the same pattern as those of benzophenones 1 and 3.23 The 1H and 13C NMR data of 2 were also similar to those of 1 (Table 1), except that compound 2 displayed a 2hydroxy-3,3-dimethylchromane unit [δH 3.58 (1H, t, J = 5.2 Hz, H-2‴), 2.76 (1H, dd, J = 17.2, 5.2 Hz, H-1‴), 2.55 (1H, dd, J = 17.2, 5.2 Hz, H-1‴), 0.92 (3H, s, H-5‴), 0.85 (3H, s, H-4‴)] instead of the dimethylallyl and hydroxy groups at C-5 and C-6 in 1. Completed assignment of 1H and 13C NMR spectral data and additional HMBC correlations of cratosumatranone B (2) are summarized in Table 1. Attempts to identify the absolute configuration at C-2‴ by applied Mosher’s method were not successful. After the treatment of compound 2 with either (R)MTPA-Cl or (S)-MTPA-Cl, a mixture of two diastereomers was formed. Therefore, the mixture of (±)-2 was further analyzed with using a chiral HPLC column. The HPLC chromatogram of (±)-2 showed well-resolved peaks for the two enantiomers, (−)-2 and (+)-2. Pure compounds (−)-2 and (+)-2 displayed specific rotations with [α]23D − 5.7 (c 0.4, CHCl3) and [α]23D + 3.7 (c 0.4, CHCl3), respectively. The absolute configuration at C-2‴ of (+)-2 was assumed to be R because it displayed the same sign of specific rotation [α]23D + 3.7 (c 0.4, CHCl3) with those of lomatin [[α]22D + 12.4 (c 0.10, CHCl3)],40,41 while compound (−)-2 was proposed to be S because its specific rotation ([α]23D − 5.7) was the opposite of that of (+)-2. Cratosumatranone C (4) displayed a pseudomolecular ion peak at m/z 447.2174 [M + H]+ (calcd, 447.2171) in its ESITOFMS spectrum, suggesting a molecular formula of C28H31O5. The UV and IR spectra showed the same pattern as that of xanthone core structures.14,24,26 The 1H NMR spectroscopic data (Table 2) of 4 exhibited a hydrogen-bonded hydroxy proton at δH 13.44 (1H, s, OH-1) and a set of AMX splitting pattern of aromatic protons at δH 7.75 (1H, dd, J = 7.6, 2.4 Hz, H-8), 7.25 (1H, dd, J = 7.6, 2.4 Hz, H-6), and 7.22 (1H, t, J = 7.6 Hz, H-7). The presence of a 2-methyl-2-(4methylpent-3-en-1-yl)-2H-chromene unit was suggested by 1H

Table 3. 1H (400 MHz) and 13C (100 MHz) NMR Spectroscopic Data of 5 and 6 in CDCl3 cratosumatranone D (5) position

δC

1 2 3 4 5 6 7

161.2 99.1 160.2 109.4 135.0 156.4 113.9

8

121.1

9 4a 4b 8a 9a 2′

180.2 155.7 150.5 113.9 103.5 92.9

3′

45.7

4′ 5′

δH [J (Hz)]

HMBC

cratosumatranone E (6) δC

δH [J (Hz)]

HMBC

6.14 s

1, 4, 9a

7.04 d (8.8) 7.81 d (8.8)

5, 6, 8a

162.0 98.8 160.9 110.3 133.0 150.9 112.6

4b, 6, 9

116.1

7.60 d (8.8)

4b, 6, 9

181.5 156.7 147.0 114.8 104.2 92.9

5.52 br d (8.0)

3′, 4′

2.00 dd (13.6, 2.0), 1.91 br d (8.0)

4, 2′, 4′, 5′, 6′ 4, 3′, 6′ 4, 3′, 5′ 1, 2, 9a

6.12 s

3, 4, 9a

7.02 d (8.8)

5, 7, 8a

5.55 d (8.0) 2.03 m, 1.92 m

3, 3′, 4′ 4, 2′, 4′, 5′

31.7 28.4

1.73 s

4, 3′

32.7 28.2

1.73 s

6′

28.3

1.62 s

4, 3′

28.1

1.62 s

OH-1 OMe-5

61.1

13.09 s 4.02 s

1, 2, 9a 5

45.9

13.16 s

(26),35 5-O-methylisojacareubin (27),23 2,4,6-trimethoxybenzophenone (28),36 4-hydroxy-2,6-dimethoxybenzophenone (29),37 and annulatomarin (30).38 Cratosumatranone A (1) showed a molecular ion peak at m/ z 434.2452 (calcd, 434.2452) [M]+ in its HREIMS spectrum, corresponding to a molecular formula of C28H34O4. The UV and IR spectra displayed the same pattern as those of benzophenone 3.23 The 1H and 13C NMR spectra of 1 (Table 1) had signals for a monosubstituted aromatic ring at δH 7.63 (2H, dd, J = 7.2, 1.3 Hz, H-2′ and H-6′), 7.57 (1H, m, H4′), and 7.50 (2H, dd, J = 7.6, 7.2 Hz, H-3′ and H-5′) and δC 127.9 (C-2′ and C-6′), 132.0 (C-4′) 129.0 (C-3′ and C-5′), and 140.2 (C-1′). H-2′ (and H-6′) showed 3J HMBC correlations with C-7 (δC 197.9) connecting this unit to the carbonyl group to give a benzoyl fragment. An EIMS fragment observed at m/z 105 [C7H5O+] supported the presence of a benzoyl group. A second major structural unit of the molecule was identified as a phloroglucinol unit similar to those of benzophenone 3.23 Three downfield carbon resonances at δC 163.8 (C-4), 161.0 (C-2), and 158.7 (C-6) indicated trioxygenation.17,39 Quaternary carbon resonances at δC 108.8 (C-5) and 104.5 (C-1) and methine carbon resonances at δC 93.0 (C-3; δH 6.06, s) were also assigned to the phloroglucinol ring. 1H NMR resonances at δH 9.07 (1H, br s, OH-2) and 8.60 (1H, br s, OH-6)39 were assigned to hydroxy groups. The hydroxy resonances at δH 9.07 (OH-2) showed HMBC correlations to the carbon resonances at δC 161.0 (C-2), 104.5 (C-1), and 93.0 (C-3), while the hydroxy resonances at δH 8.60 (OH-6) showed HMBC correlations to the carbon resonances at δC 158.7 (C-6), 108.8 (C-5), and 104.5 (C-1), indicating that OH-2 and OH-6 were meta to each other and both ortho to the quaternary 8759

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Journal of Agricultural and Food Chemistry Table 4. Antibacterial Activity of Some Isolated Compounds antibacterial activity (MIC, μg/mL) Gram-positive bacteria

a

Gram-negative bacteria

compound

M. luteus

B. cereus

B. subtilis

S. aureus

S. epidermidis

E. coli

Sa. typhimurium

P. aeruginosa

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 23 24 25 26 28 29 vancomycin gentamycin

>128 a >128 >128 8 >128 16 >128 >128 >128 >128 >128 32 >128 >128 >128 128 32 32 128 128 64 64 32 4 128 128 0.25 −

>128 32 >128 >128 8 >128 32 >128 >128 >128 >128 >128 16 >128 >128 >128 64 64 16 128 64 64 64 64 4 64 64 0.25 −

a 32 a a 16 a 32 a a a a a 128 a a a 128 128 64 128 64 128 128 128 64 128 128 0.25 −

>128 8 >128 >128 32 >128 8 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 128 128 >128 128 128 128 >128 16 >128 >128 0.25 −

>128 16 >128 >128 8 >128 16 >128 >128 >128 >128 >128 32 >128 >128 >128 128 32 16 128 128 64 64 32 4 64 64 0.25 −

>128 >128 >128 >128 64 >128 32 >128 >128 >128 >128 >128 32 >128 >128 >128 64 32 64 64 64 16 32 16 32 64 32 − 0.25

>128 >128 >128 >128 32 >128 32 >128 >128 >128 >128 >128 32 >128 >128 >128 32 32 32 4 32 32 64 32 32 32 32 − 0.125

>128 128 >128 >128 16 >128 16 >128 >128 >128 >128 >128 16 >128 >128 >128 128 16 16 128 128 64 128 16 4 128 128 − 2

Not tested. Inactive with a MIC of >128 μg/mL.

resonance at δC 175.0 in the 13C NMR spectrum of compound 8.19 However, compound 5 showed an additional 1H NMR signal at δH 5.55 (1H, d, J = 8.0 Hz) that was correlated with a carbon resonance at δC 92.9 in the HMQC spectrum. These results implied that a carbonyl carbon of lactone at C-2′ of 8 was reduced to a hemiacetal moiety in 5. All assignments of 1H and 13C NMR and HMBC correlations of cratosumatranone D (5) are given in Table 3. Compound 5 also tried to determine the absolute configuration at C-2′ by the applied Mosher’s method. Unfortunately, the NMR data of the Mosher esters of compound 5 showed a mixture of two diastereomers similar to that of compound 2. Therefore, compound 5 is also a mixture of the enantiomers. The specific rotation of compound 5, [α]26D 0.0 (c 0.08, acetone), was also supported by this information. Cratosumatranone E (6) gave a molecular ion peak at m/z 344.0891 [M]+ (calcd, 344.0891) in its HREIMS spectrum, suggesting a molecular formula of C18H16O7. The 1H and 13C NMR spectra (Table 3) of 6 were closely related to those of 5, except that the OMe group at C-5 of 5 was replaced with an OH group. This change was confirmed by the 3J HMBC correlation observed between H-7 (δH 7.02, d, J = 8.8 Hz) and C-5 (δC 133.0). All 1H and 13C NMR assignments as well as HMBC correlations of cratosumatranone E (6) are listed in Table 3. The configuration at C-2′ of 6 was also racemic

NMR signals at δH 6.83 (1H, d, J = 10.0 Hz, H-1′), 5.58 (1H, d, J = 10.0 Hz, H-2′), 5.12 (1H, br t, J = 7.2 Hz, H-6′), 2.14 (2H, m, H-5′), 1.91 (1H, m, H-4′a), 1.74 (1H, m, H-4′b), 1.67 (3H, s, H-8′), 1.59 (3H, s, H-10′), and 1.46 (3H, s, H-9′).14 Moreover, the 1H NMR spectrum of 4 also showed the characteristic signals of the 1,1-dimethylallyl group at δH 6.70 (1H, dd, J = 17.6, 10.4 Hz, H-2″), 5.24 (1H, dd, J = 10.4, 0.8 Hz, H-3″a), 5.07 (1H, dd, J = 17.6, 0.8 Hz, H-3″b), and 1.65 (6H, s, H-4″ and H-5″). The location of the linear chromene ring at C-2 and C-3 was confirmed by HMBC correlations in which H-1′ (δH 6.83) showed cross peaks with C-1 (δC 156.6), C-2 (δC 105.2), and C-3 (δC 159.7), while a hydrogen-bonded hydroxy group at δH 13.44 (OH-1) was also correlated with C-1 (δC 156.6), C-2 (δC 105.2), and C-9a (δC 103.5). The attachment of a 1,1-dimethylallyl side chain at C-4 was confirmed by 3J HMBC correlation of the H-2″ methine proton (δH 6.70) with C-4 (δC 112.8). Detailed assignment of the proton and carbon resonanaces and a listing of HMBC correlations observed in the NMR data of 4 are given in Table 2. Cratosumatranone D (5) gave a molecular ion peak at m/z 358.1048 [M]+ (calcd, 358.1047) in its HREIMS spectrum, suggesting a molecular formula of C19H18O7. The 1H and 13C NMR data of 5 (Table 3) were similar to those of 8, neriifolone B.19 The main difference was the absence of a 13C NMR signal in the spectrum of 5 corresponding to the lactone carbonyl 8760

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Journal of Agricultural and Food Chemistry

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because of its specific rotation, [α]26D 0.0 (c 0.05, acetone), as well as the same pattern of NMR data for the Mosher esters. Cratosumatranone F (17) gave a pseudomolecular ion peak at m/z 319.0817 [M + H]+ (calcd, 319.0817) in its ESITOFMS spectrum, suggesting a molecular formula of C16H15O7. The 1H NMR spectrum (Table 2) of 17 showed the character of a xanthone skeleton that displayed a hydrogen-bonded hydroxy proton (δH 13.27, 1H, s, OH-1), an AB splitting pattern of aromatic protons [δH 7.24 (1H, d, J = 9.0 Hz, H-6), 6.80 (1H, d, J = 9.0 Hz, H-7)], and a singlet aromatic proton [δH 6.74 (1H, s, H-4)]. The remaining signals at δH 4.01 (3H, s, OMe3), 3.97 (3H, s, OMe-2), and 3.89 (3H, s, OMe-8) indicated three methoxyl groups, which were placed at C-3, C-2, and C-8, respectively, due to the 3J HMBC correlations of Ome-3 (δH 4.01) with C-3 (δC 152.7), of Ome-2 (δH 3.97) with C-2 (δC 137.8), and of Ome-8 (δH 3.89) with C-8 (δC 143.1). The full assignments of 1H and 13C NMR spectral data and HMBC correlations of cratosumatranone F (17) are given in Table 2. Antibacterial Activity. All isolated compounds except compounds 22, 27, and 30 were evaluated for their antibacterial activity against Gram-positive (M. luteus TISTR 884, B. cereus TISTR 688, B. subtilis TISTR 008, S. aureus TISTR 1466, and S. epidermidis ATCC 12228) and Gram-negative (E. coli TISTR 780, Sa. typhimurium TISTR 292, and P. aeruginosa TISTR 781) (Table 4) bacteria. Compounds 5 and 26 showed good activity against M. luteus, B. cereus, and S. epidermis with MIC values of 8 and 4 μg/mL, respectively. Compound 26 also exhibited antibacterial activity against P. aeruginosa with a MIC value of 4 μg/mL. In addition, compound 7 displayed activity against S. aureus (MIC of 8 μg/mL), while compound 20 exhibited activity against Sa. typhimurium with a MIC value of 4 μg/mL. The remaining compounds displayed moderate to weak activity against all bacteria tested (MICs of 16 to >128 μg/mL).10,42−44 Antioxidant Activity. Compounds 1, 4, 5, 7−12, 14−16, 21, and 24 were evaluated for their antioxidant activity using the DPPH assay. The results showed that compounds 11 and 21 exhibited potent antioxidant activity in a DPPH assay45,46 with IC50 values of 7.0 ± 1.0 and 6.0 ± 0.2 μM, respectively, which were better than that of ascorbic acid (10.5 ± 05 μM). The remaining tested compounds displayed weak antioxidant activity. In summary, six new compounds, including four xanthones and two benzophenones, along with 24 known compounds were isolated from C. sumatranum ssp. neriifolium roots and twigs. The occurrence of xanthones and benzophenone derivatives from C. sumatranum ssp. neriifolium is in agreement with the previous findings.3 Thus, the isolation of these compounds might be a useful chemotaxonomic marker of the Cratoxylum genus. The results of preliminary antibactrial and antioxidant assays suggested that xanthone 26 may be a good candidate for further evaluation as a new antibacterial agent and xanthones 11 and 21 may have potential as lead compounds for the development of antioxidant agents.

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Article

AUTHOR INFORMATION

Corresponding Author

*Phone: +66-5391-6238. Fax: +66-5391-6776. E-mail: surat. [email protected]. Funding

This work was supported by the Higher Education Research Promotion (HERP), the Thailand Research Fund through the TRF-NSFC collaborative project grant (Grant DBG5980001), the NSFC-TRF coproject (Grant 8156114801), and Mae Fah Luang University through the graduate student research grant. A full Ph.D. scholarship (to C.T.) from the Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program (Grant PHD/0109/2554) is also acknowledged. Mae Fah Luang University and the University of British Columbia are also acknowledged for laboratory facilities. Notes

The authors declare no competing financial interest.

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REFERENCES

(1) The Plant List, version 1. http://www.theplantlist.org/, 2010 (accessed January 1, 2016). (2) Smitinand, T. Thai Plant Names (Revised edition); Prachachon Co.: Bangkok, 2001. (3) Seo, E. K.; Kim, N. C.; Wani, M. C.; Wall, M. E.; Navarro, H. A.; Burgess, J. P.; Kawanishi, K.; Kardono, L. B. S.; Riswan, S.; Rose, W. C.; Fairchild, C. R.; Farnsworth, N. R.; Kinghorn, A. D. Cytotoxic prenylated xanthones and the unusual compounds anthraquinobenzophenones from Cratoxylum sumatranum. J. Nat. Prod. 2002, 65, 299− 305. (4) Laphookhieo, S.; Maneerat, W.; Koysomboon, S. Antimalarial and cytotoxic phenolic compounds from Cratoxylum maingayi and Cratoxylum cochinchinense. Molecules 2009, 14, 1389−1395. (5) Duan, Y. H.; Dai, Y.; Wang, G. H.; Chen, L. Y.; Chen, H. F.; Zeng, D. Q.; Li, Y. L.; Yao, X. S. Bioactive prenylated xanthones from the stems of Cratoxylum cochinchinense. J. Asian Nat. Prod. Res. 2015, 17, 519−531. (6) http://www.sisaket.go.th/samunprai/samunpai6.html (accessed May 13, 2016). (7) Buana, M. B. B.; Iqbal, M.; Barus, T. F.; Al-Fatony, Z.; Sudrajat, H.; Khairi, S. Isolation and structural elucidation of new xanthone from rot bark of Cratoxylum sumatranum. Bot. Res. Int. 2009, 2, 233− 234. (8) Choi, S. J.; Tai, B. H.; Cuong, N. M.; Kim, Y. H.; Jang, H. D. Antioxidative and anti-inflammatory effect of quercetin and its glycosides isolated from mampat (Cratoxylum formosum). Food Sci. Biotechnol. 2012, 21, 587−595. (9) Laphookhieo, S.; Maneerat, W.; Buatip, T.; Syers, J. K. New xanthones from Cratoxylum cochinchinense. Can. J. Chem. 2008, 86, 757−760. (10) Boonsri, S.; Karalai, C.; Ponglimanont, C.; Kanjana-opas, A.; Chantrapromma, K. Antibacterial and cytotoxic xanthones from the roots of Cratoxylum formosum. Phytochemistry 2006, 67, 723−727. (11) Srithi, K.; Balslev, H.; Wangpakapattanawong, P.; Srisanga, P.; Trisonthi, C. Medicinal plant knowledge and its erosion among the Mien (Yao) in northern Thailand. J. Ethnopharmacol. 2009, 123, 335− 342. (12) Yingngam, B.; Supaka, N.; Rungseevijitprapa, W. Optimization of process parameters for phenolics extraction of Cratoxylum formosum ssp. formosum leaves by response surface methodology. J. Food Sci. Technol. 2015, 52, 129−140. (13) Dai, D. N.; Thang, T. D.; Ogunwande, I. A. Volatile constituents of the leaf oil of Cratoxylum cochinchinense from Vietnam. Chem. Nat. Compd. 2014, 50, 158−160. (14) Boonnak, N.; Karalai, C.; Chantrapromma, S.; Ponglimanont, C.; Fun, H. K.; Kanjana-Opas, A.; Laphookhieo, S. Bioactive

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jafc.6b03643. NMR and MS spectra of compounds 1, 2, 4−6, and 17 (PDF) 8761

DOI: 10.1021/acs.jafc.6b03643 J. Agric. Food Chem. 2016, 64, 8755−8762

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Journal of Agricultural and Food Chemistry prenylated xanthones and anthraquinones from Cratoxylum formosum ssp. prunif lorum. Tetrahedron 2006, 62, 8850−8859. (15) Bennett, G. J.; Harrison, L. J.; Sia, G. L.; Sim, K. Y. Triterpenoids, tocotrienols and xanthones from the bark of Cratoxylum Cochinchinense. Phytochemistry 1993, 32, 1245−1251. (16) Iinuma, M.; Tosa, H.; Ito, T.; Tanaka, T.; Madulid, D. A. Two xanthones from roots of Cratoxylum formosanum. Phytochemistry 1996, 42, 1195−1198. (17) Buana, M. B. B.; Iqbal, M.; Barus, T. F.; Al-Fatony, Z.; Sudrajat, H.; Khairi, S. Isolation and structural elucidation of new xanthone from rot bark of Cratoxylum sumatranum. Bot. Res. Int. 2009, 2, 233− 234. (18) Mahabusarakam, W.; Nuangnaowarat, W.; Taylor, W. C. Xanthone derivatives from Cratoxylum cochinchinense roots. Phytochemistry 2006, 67, 470−474. (19) Nuangnaowarat, W. Ph.D. Dissertation, Walailak University, Nakhon Si, Thailand, 2010. (20) Wikler, M. A.; Cockerill, F. R.; Craig, W. A.; Dudley, M. N.; Eliopoulos, G. M.; Hecht, D. W.; Hindlar, J. F.; Low, D. E.; Sheehan, D. J.; Tenover, F. C.; Turnidge, J. D.; Weinstein, M. P.; Zimmer, B. L.; Ferraro, M. J.; Swenson, J. M. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. Approved Standard M7-A7; Clinical and Laboratory Standards Institute: Wayne, PA, 2006; Vol. 2, No. 2. (21) Kanlayavattanakul, M.; Lourith, N. Sapodilla seed coat as a multifunctional ingredient for cosmetic applications. Process Biochem. 2011, 46, 2215−2218. (22) Lourith, N.; Kanlayavattanakul, M. Appraisal of Thai glutinous rice husk for health promotion products. J. Cereal Sci. 2013, 57, 343− 347. (23) Bohlmann, F.; Suwita, A. Neue phloroglucin-derivate aus Leontonyx-arten sowie weitere verbindungen aus vertretern der tribus inuleae. Phytochemistry 1978, 17, 1929−1934. (24) Boonnak, N.; Khamthip, A.; Karalai, C.; Chantrapromma, S.; Ponglimanont, C.; Kanjana-Opas, A.; Tewtrakul, S.; Chantrapromma, K.; Fun, H. K.; Kato, S. Nitric oxide inhibitory activity of xanthones from the green fruits of Cratoxylum formosum ssp. prunif lorum. Aust. J. Chem. 2010, 63, 1550−1556. (25) Rath, G.; Potterat, O.; Mavi, S.; Hostettmann, K. Xanthones from Hypericum roeperanum. Phytochemistry 1996, 43, 513−520. (26) Ito, C.; Miyamoto, Y.; Rao, K. S.; Furukawa, H. A novel dibenzofuran and two new xanthones from Calophyllum pancif lorum. Chem. Pharm. Bull. 1996, 44, 441−443. (27) Sia, G. L.; Bennett, G. J.; Harrison, L. J.; Sim, K. Y. Minor xanthones from the bark of Cratoxylum cochinchinense. Phytochemistry 1995, 38, 1521−1528. (28) Ren, Y.; Matthew, S.; Lantvit, D. D.; Ninh, T. N.; Chai, H.; Fuchs, J. R.; Soejarto, D. D.; Carcache de Blanco, E. J.; Swanson, S. M.; Kinghorn, A. D. Cytotoxic and NF-κB inhibitory constituents of the stems of Cratoxylum cochinchinense and their semisynthetic analogues. J. Nat. Prod. 2011, 74, 1117−1125. (29) delle Monache, F.; Marquina Mac-Quhae, M.; delle Monache, G.; Marini Bettolo, G. B.; Alves de Lima, R. Xanthones, xanthonolignoids and other constituents of the roots of vismia guaramirangae. Phytochemistry 1983, 22, 227−232. (30) Alves de Lima, R.; Gottlieb, O. R.; Lins Mesquita, A. A. Xanthones from Caraipa densiflora. Phytochemistry 1972, 11, 2307− 2309. (31) Iinuma, M.; Tosa, H.; Ito, T.; Tanaka, T.; Riswan, S. Three new benzophenone-xanthone dimers from the root of Garcinia dulcis. Chem. Pharm. Bull. 1996, 44, 1744−1747. (32) Li, W.; Chan, C. L.; Leung, H. W.; Yeung, H. W.; Xiao, P. Xanthones from Polygala caudate. Phytochemistry 1999, 51, 953−958. (33) Gottlieb, O. R.; Taveira Magalhaes, M.; Stefani, G. M. The chemistry of Brazilian Guttiferae−VI: 1,2,8-trioxygenated xanthones from Kielmeyera petiolaris. Tetrahedron 1966, 22, 1785−1788. (34) Nagem, T. J.; Faustino de Oliveira, F. Xanthones and other constituents of Vismia parvif lora. J. Braz. Chem. Soc. 1997, 8, 505−508.

(35) Daud, S. B.; Ee, G. C. L.; Malek, E. A.; Teh, S. S.; See, I. A new coumarin from Calophyllum hosei. Nat. Prod. Res. 2014, 28, 1534− 1538. (36) Leary, G.; Oliver, J. A. Photochemical demethylation of 2methoxybenzophenones. Tetrahedron Lett. 1968, 9, 299−302. (37) Canter, F. W.; Curd, F. H.; Robertson, A. Hydroxy-carbonyl compounds. II. Benzoylation of ketones derived from phloroglucinol. J. Chem. Soc. 1931, 0, 1245−1255. (38) Nedialkov, P. T.; Zheleva-Dimitrova, D.; Girreser, U.; Kitanov, G. M. A new isocoumarin from Hypericum annulatum. Nat. Prod. Res. 2007, 21, 1056−1060. (39) Schmidt, S.; Jurgenliemk, G.; Skaltsa, H.; Heilmann, J. Phloroglucinol derivatives from Hypericum empetrifolium with antiproliferative activity on endothelial cells. Phytochemistry 2012, 77, 218−225. (40) Lemmich, J.; Eichstedt Neilsen, B. Stereochemistry of natural coumarins containing the 3-hydroxy-2,2-dimethylchroman system (1). Tetrahedron Lett. 1969, 10, 3−4. (41) Buendia-Trujillo, A. I.; Torrres-Valencia, J. M.; Joseph-Nathan, P.; Burgueno-Tapia, E. The absolute configuration of angular 3′acyloxypyranocoumarins by vibrational circular dichroism exciton chirality. Tetrahedron: Asymmetry 2014, 25, 1418−1423. (42) Baggett, S.; Protiva, P.; Mazzola, E. P.; Yang, H.; Ressler, E. T.; Basile, M. J.; Weinstein, I. B.; Kennelly, E. J. Bioactive benzophenones from Garcinia xanthochymus fruits. J. Nat. Prod. 2005, 68, 354−360. (43) Dharmaratne, H. R. W.; Wijesinghe, W. M. N. M.; Thevanasem, V. Antimicrobial activity of xanthones from Calophyllum species, against methicillin-resistant Staphylococcus aureus (MRSA). J. Ethnopharmacol. 1999, 66, 339−342. (44) Mahabusarakam, W.; Rattanaburi, S.; Phongpaichit, S.; KanjanaOpas, A. Antibacterial and cytotoxic xanthones from Cratoxylum cochinchinense. Phytochem. Lett. 2008, 1, 211−214. (45) Li, W.; Sun, Y. N.; Yan, X. T.; Yang, S. Y.; Choi, C. W.; Hyun, J. W.; Kang, H. K.; Paek, K. Y.; Kim, Y. H. Isolation of xanthones from adventitious roots of St. John’s Wort (Hypericum perforatum L.) and their antioxidant and cytotoxic activities. Food Sci. Biotechnol. 2013, 22, 945−949. (46) Li, W.; Sun, Y. N.; Yan, X. T.; Yang, S. Y.; Kim, S.; Chae, D.; Hyun, J. W.; Kang, H. K.; Koh, Y. S.; Kim, Y. H. Anti-inflammatory and antioxidant activities of phenolic compounds from Desmodium caudatum leaves and stems. Arch. Pharmacal Res. 2014, 37, 721−727.

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