Note Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
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Prenylated Acylphloroglucinols from Hypericum faberi Xin-Wen Zhang,†,§ Shao-Qiang Fan,‡ Fan Xia,†,§ Yan-Song Ye,†,§ Xing-Wei Yang,*,† Xian-Wen Yang,*,‡ and Gang Xu*,† †
State Key Laboratory of Phytochemistry and Plant Resources in West China, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People’s Republic of China ‡ Key Laboratory of Marine Biogenetic Resources, Third Institute of Oceanography, 184 Daxue Road, Xiamen 361005, People’s Republic of China § University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China J. Nat. Prod. Downloaded from pubs.acs.org by BUFFALO STATE on 05/01/19. For personal use only.
S Supporting Information *
ABSTRACT: The isolation and structure elucidation of six new prenylated acylphloroglucinols, faberiones A−F, from the whole plant of Hypericum faberi is reported. Faberiones A−D (1−4) share a rare styrene substituent and may be biosynthetically generated via further acylation of the acylphloroglucinols. By analyzing the MS and NMR data, the structures of the new isolates were established. Faberiones B (2) and C (3) showed moderate cytotoxicity against the pancreatic cell line (PANC-1) with IC50 values of 6.2 and 9.0 μM, respectively.
biosynthetic discussion, and cytotoxicity of the isolates are described herein. Faberione A (1) was purified as a yellow gum and exhibited a deprotonated molecular ion [M − H]− at m/z 431.2227 (calcd for C28H31O4, 431.2222) in the HRESIMS data. The UV absorptions [λmax 306 and 348 nm] were attributed to conjugated groups, and the IR absorptions implied the presence of hydroxyl (3424 cm−1) and carbonyl (1623 cm−1) functionalities. Its 1H NMR spectrum illustrated one monosubstituted benzene ring (δH7.73, 2H, d; 7.43, 2H, t; 7.32, 1H, t, J = 7.6 Hz), an isopropyl group (δH 1.35, 6H, d; 4.06, sept., J = 6.8 Hz), two olefinic protons (δH 5.04 and 5.34), three methyl singlets (δH1.59, 1.68, and 1.84), and three proton singlets (δH 7.01 and 6.68 and a deshielded proton at δH 14.26) (Table 1). The 13C NMR and HSQC spectra showed the presence of 28 carbon signals attributable to a phenyl group (δC 130.2, C-14; 124.1, C-15/19; 129.0, C-16/ 18; 128.1, C-17), an isobutyryl (δC 207.6, C-7; 38.9, C-8; and 19.0, C-9/10), a geranyl (δC 22.0, C-20; 121.5, C-21; 140.5, C22; 16.3, C-23; 39.7, C-24; 26.2, C-25; 123.6, C-26; 132.5, C27; 25.8, C-28; 17.8, C-29), eight sp2 resonances assignable to a phloroglucinol core (δC 101.1, C-1; 153.5, C-2; 111.8, C-3; 155.3, C-4; 108.3, C-5; and 163.2, C-6), and a ringlic group (δC 98.6 and 153.4) (Table 1). These observations implied that faberione A might be a geranylated acylphloroglucinol derivative.
Hypericum, comprising approximately 500 species, is subdivided into 36 taxonomic sections and is the largest genus of the Hypericaceae family.1 Chemical constituents of this genus involve abundant simple acylphloroglucinols, prenylated acylphloroglucinols, acylphloroglucinol-terpene adducts, xanthones, chromanes and chromenes, and dimeric acylphloroglucinols.2−5 Previous investigations have demonstrated that the structural types of compounds isolated from Hypericum species are diverse among different taxonomic sections.2 For example, dimeric acylphloroglucinols are present in plants of sections Brathys and Trigynobrathys,2 while polycyclic polyprenylated acylphloroglucinols (PPAPs) widely exist in plants of the sections Hypericum, Sampsonia, and Ascyreia (including the previously studied species H. cohaerens, H. henryi, H. uralum, H. subsessile, H. hookerianum, and H. pseudohenryi).2,5,6 Particularly, filicinic acid-terpene adducts (meroterpenoids) are exclusively isolated from H. japonicum of the section Trigynobrathys.7 In order to further explore the types and bioactivities of metabolites from different sections of Hypericum species, H. faberi (section Hypericum), a species never researched before, was selected for this study. Nine prenylated acylphloroglucinols, including the new faberiones A−F (1−6), were characterized. Compounds 1−4 seem to possess a stilbene core, but their styrene substituent is more likely to be biosynthetically generated via a second acylation of the acylphloroglucinols, which enriched the chemical diversity of acylphloroglucinol-type metabolites. These findings may present a new clue to the chemotaxonomic research of Hypericum species. The isolation, structure determinations, © XXXX American Chemical Society and American Society of Pharmacognosy
Received: November 28, 2018
A
DOI: 10.1021/acs.jnatprod.8b01006 J. Nat. Prod. XXXX, XXX, XXX−XXX
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Chart 1
Table 1. 1H and
13
C NMR Data of 1−4 (in CDCl3) 1
no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15, 19 16, 18 17 20 21 22 23 24 25 26 27 28 29 OH-6a OH-4a
δC, type 101.1, C 153.5, C 111.8, C 155.3, C 108.3, C 163.2, C 207.6, C 38.9, CH 19.0, CH3 19.0, CH3
98.6, CH 153.4, C 130.2, C 124.1, CH 129.0, CH 128.1, CH 22.0, CH2 121.5, CH 140.5, C 16.3, CH3 39.7, CH2 26.2, CH2 123.6, CH 132.5, C 25.8, CH3 17.8, CH3
2 δH (J in Hz)
δC, type
4.06, sept (6.8) 1.35, d (6.8) 1.35, d (6.8)
101.6, C 153.5, C 111.8, C 155.3, C 108.3, C 163.2, C 207.5, C 45.5, CH 16.6, CH3 26.6, CH2
7.01, s
7.73, 7.43, 7.32, 3.52, 5.34,
d (7.6) t (7.6) t (7.6) brd (7.2) t (7.2)
1.84, 2.11, 2.13, 5.04,
s overlap m t (6.1)
1.68, s 1.59, s 14.26, s 6.68, brs
12.0, CH3 98.6, CH 153.5, C 130.2, C 124.1, CH 129.0, CH 128.1, CH 22.0, CH2 121.5, CH 140.5, C 16.3, CH3 39.7, CH2 26.2, CH2 123.5, CH 132.5, C 25.8, CH3 17.8, CH3
3 δH (J in Hz)
3.95, 1.32, 1.97, 1.57, 1.00, 7.01,
m d (6.8) m m t (7.2) s
7.74, 7.43, 7.32, 3.52, 5.35,
d (7.6) t (7.6) t (7.6) brd (7.2) t (7.2)
1.84, 2.11, 2.14, 5.04,
s overlap m t (6.7)
1.68, s 1.61, s 14.37, s 6.69, brs
δC, type 101.3, C 153.4, C 112.1, C 155.3, C 108.4, C 162.9, C 207.8, C 39.0, CH 19.2, CH3 19.2, CH3
97.0, CH 153.8, C 123.5, C 126.0, CH 116.1, CH 155.9, C 22.2, CH2 121.8, CH 140.6, C 16.5, CH3 39.9, CH2 26.4, CH2 123.8, CH 132.6, C 25.9, CH3 17.9, CH3
4 δH (J in Hz)
δC, type
4.04, sept (6.8) 1.34, d (6.8) 1.34, d (6.8)
101.4, C 153.2, C 111.7, C 154.9, C 108.0, C 162.6, C 207.2, C 45.3, CH 16.4, CH3 26.4, CH2
6.86, s
7.61, d (8.6) 6.90, d (8.6) 3.51, brd (7.2) 5.34, t (7.2) 1.84, 2.10, 2.12, 5.04,
s overlap m t (6.1)
1.68, s 1.59, s 14.19, s 6.66, brs
11.8, CH3 96.7, CH 153.4, C 123.2, C 125.7, CH 115.7, CH 155.5, C 21.8, CH2 121.4, CH 140.2, C 16.1, CH3 39.5, CH2 26.0, CH2 123.4, CH 132.2, C 25.5, CH3 17.6, CH3
δH (J in Hz)
3.93, m 1.31, d (6.8) 1.96 m 1.57 m 0.99, t (7.4) 6.85, s
7.62, d (8.7) 6.91, d (8.7) 3.51, brd (7.2) 5.34, t (7.2) 1.84, 2.10, 2.12, 5.04,
s overlap m t (7.9)
1.68, s 1.59, s 14.30, s 6.85, brs
a
The positions of the hydroxy groups were determined by the HMBC correlations.
The HMBC cross-peaks of the deshielded hydroxy proton (δH 14.26, HO-6)/C-1, C-5, and C-6, of a second hydroxy proton (δH 6.68, HO-4)/C-3, C-4, and C-5, and of a methine singlet at δH 7.01 (H-12)/C-2, C-3, and C-4 confirmed the phloroglucinol core (Figure 1). The HMBC cross-peak of HO6/C-7 located the acyl group at C-1 and indicated the presence of an intramolecular hydrogen bond between the hydroxy and the carbonyl group. The HMBC cross-peaks of H2-20 (δH 3.52)/C-4, C-5, and C-6 showed the location of the geranyl group at C-5. The HMBC cross-peaks of H-12 (δH 7.01)/C-13 (δC 153.4) and C-14 and H-15/19 (δH 7.73)/C-13 indicated a styrene fragment at C-3 (Figure 1). Finally, an oxygen bridge between C-2 and C-13 to form a furan ring was deduced by the downfield chemical shifts of C-2 and C-13 and the indices of hydrogen deficiency. The NOESY correlations of Me-23/H2-
Figure 1. Key COSY and HMBC correlations of faberione A (1).
B
DOI: 10.1021/acs.jnatprod.8b01006 J. Nat. Prod. XXXX, XXX, XXX−XXX
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Table 2. 1H and 13C NMR Data of 5 (in CDCl3)
20 confirmed the (21E)-configured double bond of the geranyl moiety. Thus, the structure of faberione A (1) was elucidated. The molecular formula of faberione B (2) was deduced as C29H34O4 based on its 13C NMR (Table 1) and (−)-HRESIMS data, which suggested that it had one more carbon atom than 1. The 1D and 2D NMR spectra of 2 and 1 implied the presence of a sec-butyl (s-Bu) group (C-8, δC 45.5; C-9, δC 16.6; C-10, δC 26.6; and C-11, δC 12.0) in 2 instead of an isopropyl group in 1. Based on the MS and NMR data of faberiones C (3) and D (4) (Table 1), they had the same carbon skeletons and configurations as those of 1 and 2, respectively. The increased molecular weight by 16 mass units (m/z 447.2187 for 3 and 461.2343 for 4, [M − H]−) observed in the HRESIMS and the 1H NMR spectra of 3 and 4 showing signals of a para-disubstituted benzene ring (for 3: δH 7.61, 2H, d; 6.90, 2H, d, J = 8.6 Hz; δC 123.5, C-14; 126.0, C-15/19; 116.1, C-16/18; 155.9, C-17) suggested the presence of a phydroxyphenyl moiety in their structures. Faberione E (5) was obtained as a yellow gum and showed a deprotonated molecular ion [M − H]− at m/z 465.3010 (calcd for C30H41O4, 465.3010) in the (−)-HREIMS data. The structure of compound 5 was elucidated to possess a similar geranylated acylphloroglucinol scaffold to empetrikarinen A,8 by detailed comparison of its MS and 1D and 2D NMR data. An extra (E)-geranyl group substituted at C-5 was evidenced by the HMBC cross-peaks of H2-21 (δH3.39)/C-4 (δC 157.4), C-5 (δC 105.2), and C-6 (δC 163.4). The NOESY cross-peak of Me-24/H2-21 proved the (22E)-configured double bond of the geranyl moiety (Figure 2).
no.
δC, type
1 2 3 4 5 6 7 8 9 10 11 12 13 14
104.7, C 154.9, C 101.7, C 157.4, C 105.2, C 163.4, C 210.7, C 39.3, CH 19.4, CH3 19.7, CH3 117.3, CH 123.2, CH 80.5, C 41.6, CH2
15
26.5, CH3
δH (J in Hz)
3.86, 1.17, 1.16, 6.58, 5.37,
sept (6.8) d (6.8) d (6.8) d (10.0) d (10.0)
1.85, m 1.65, overlap 1.40, s
δC, type
δH (J in Hz)
16
23.2, CH2
17 18 19 20 21 22 23 24 25 26 27 28 29 30 OH-6 OH-4
123.8, CH 132.1, C 25.8, CH3 17.6, CH3 21.6, CH2 121.9, CH 140.3, C 16.2, CH3 39.7, CH2 26.1, CH2 123.5, CH 132.4, C 25.7, CH3 17.8, CH3
2.12, overlap 2.04, overlap 5.08, t (7.1)
no.
1.65, 1.55, 3.39, 5.25,
s s m t (6.9)
1.79, 2.07, 2.10, 5.02,
s m overlap t (6.3)
1.67, s 1.58, s 14.28, s 6.33, brs
Table 3. 1H and 13C NMR Data of 6 (in CDCl3) no.
δC, type
1 2 3 4 5 6 7 8 9 10
105.7, C 163.0, C 101.4, C 154.6, C 102.0, C 163.4, C 204.8, C 45.4, CH2 30.4, CH2 141.5, C
δH (J in Hz)
3.44, t (7.9) 3.04, t (7.9)
no.
δC, type
11, 15 12, 14 13 16 17 18 19, 20 21 OH-6 OH-4
128.2, CH 128.4, CH 125.9, CH 116.5, CH 125.1, CH 77.8, C 27.7, CH3 7.0, CH3
δH (J in Hz) 7.25, 7.30, 7.20, 6.56, 5.45,
d (7.5) t (7.5) t (7.5) d (9.9) d (9.9)
1.44, s 2.05, s 14.06, s 5.37, brs
the benzene rings in stilbenes.11 The two types of natural products arise from different biosynthetic pathways, and a secondary acylation of the acylphloroglucinols may lead to the formation of compounds 1−4 (Scheme 1). Detailed biosynthetic pathways to the formation of compounds 1−4, 6, and 7 are shown in Scheme 1. Compounds 1−9 were tested for their cytotoxic activities against four human tumor cell lines (ECA-109, PANC-1, BIU87, and BEL-7402) with Taxol as the positive control (IC50 values of 1.2, 3.5, 2.1, and 1.9 μM, respectively) using the MTT method (Biological Assay, Supporting Information).12 Compounds 2 and 3 showed moderate cytotoxicity against the pancreatic tumor cell line (PANC-1), with IC50 values of 6.2 and 9.0 μM, respectively.
Figure 2. Key COSY and HMBC correlations of faberione E (5).
The structure of faberione F (6) was deduced as C21H22O4 based on its (−)-HRESIMS ion with m/z 337.1454 [M − H]−. Compound 6 had the same backbone as that of 7,9 a prenylated chalcone also obtained in this study, by comparing the MS and NMR data (Table 3). These 1D NMR data suggested the Δ8(9) double bond in 7 was reduced (δC 45.4, C8, δH 3.44, 2H, t; δC 30.4, C-9, δH 3.04, 2H, t, J = 7.9 Hz) in 6. The COSY correlation for H2-8/H2-9 and the HMBC crosspeaks of H2-8/C-1 (δC 105.7) and C-10 (δC 141.5) and H2-9/ C-7 (δC 204.8) confirmed this deduction. Compounds 8 and 9 were isolated as two main constituents and have been reported from H. empetrifolium, and their structures were identified by matching their NMR and MS data.10 Acylphloroglucinols are widely found in plants of the Hypericaceae and Clusiaceae families,2−5 and most of the complex secondary metabolites, such as PPAPs and acylphloroglucinol-terpene adducts, are biosynthetically derived from further functionalization of the acylphloroglucinol core.5,6 Although the structures of faberiones A−D (1−4) appear to be stilbene derivatives, the substitution pattern of the acylphloroglucinol moiety of these compounds is distinct from any of
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EXPERIMENTAL SECTION
General Experimental Procedures. The general procedures were in accordance with the reported procedures with minor modification (General Experimental Procedures, Supporting Information).6c,13 Plant Material. The whole plants of Hypericum faberi were collected in Yiliang County, Zhaotong City, Yunnan Province, China. It was identified by Dr. Yong-Zeng Zhang in Kunming Institute of Botany. A voucher specimen (no. 201707H01) has been deposited at the Kunming Institute of Botany. Extraction and Isolation. The dried whole plants of H. faberi (15.0 kg) were powdered and soaked with MeOH (3 × 30 L), and the crude extract (3.2 kg) was applied silica gel column chromatography (CC) with successive elution using CHCl3 and EtOAc to give a C
DOI: 10.1021/acs.jnatprod.8b01006 J. Nat. Prod. XXXX, XXX, XXX−XXX
Journal of Natural Products
Note
Scheme 1. Putative Biosynthetic Pathways to 1−4, 6, and 7
C NMR data, see Table 2; HREIMS m/z 465.3010 [M − H]−(calcd for C30H41O4, 465.3010). Faberione F (6) [(E)-1-{5,7-Dihydroxy-2,2,6-trimethyl-2H-chromen-8-yl}-3-phenylpropan-1-one]. yellow gum; UV (MeOH) λmax (log ε) 343 (3.44), 286 (4.25), 204 (4.30) nm; IR (KBr) νmax 3422, 2974, 2971, 1608, 1424, 1132 cm−1; 1H and 13C NMR data, Table 3; HRESIMS m/z 337.1454 [M − H]−(calcd for C21H21O4, 337.1445). 13
nonpolar fraction (163.0 g) and a polar fraction (192 g). The CHCl3 fraction was fractionated by MCI-gel CC (MeOH/H2O, 70−100%) to yield Fr. 1−6 (polarity from small to large). Fr. 1 (49.0 g) was subsequently refined by silica gel CC using ether/acetone (1:2 to 0:1, v/v) to afford Fr. 1-1 to Fr. 1-6. Fr. 1-2 (5.0 g) was further purified by separation over an Rp-C18 column (MeOH/H2O, 85−100%) to give Fr. 1-2-1 to Fr. 1-2-8. Compounds 1 (4.1 mg, tR = 12.2 min) and 2 (5.8 mg, tR = 13.9 min) from Fr. 1-2-4 (940 mg) and compound 5 (4.4 mg, tR = 13.5 min) from Fr. 1-2-3 (784 mg) were obtained by preparative HPLC (SunFire OBD-C18, 19 × 250 mm, 95% aqueous MeOH). Similarly, compounds 3 (1.6 mg, tR = 21.2 min) and 4 (3.7 mg, tR = 23.5 min), 6 (10.4 mg, tR = 12.8 min) and 7 (29.3 mg, tR = 11.2 min) were afforded from Frs. 2−9 (1.8 g) and 3−10 (190 mg), respectively, by silica gel CC, followed by semipreparative HPLC (Zorbax SB-C18, 9.4 × 250 mm, 85% aqueous MeOH). The EtOAc fraction (192 g) was fractioned by MCI-gel CC (MeOH/H2O, 45− 90%) to give Fr. E1−E5 (polarity from small to large). In order to quickly separate the main components, part of Fr. E1 (10 g) was purified by an Rp-18 column (49 × 460 mm, MeOH/H2O, 75%) to afford compounds 8 (2.7 g) and 9 (3.3 g). Faberione A [(E)-1-{5-(3,7-dimethylocta-2,6-dien-1-yl)-4,6-dihydroxy-2-phenylbenzofuran-7-yl}-2-methylpropan-1-one] (1): yellow gum; UV (MeOH) λmax (log ε) 203 (4.42) nm, 306 (4.46) nm, 348 (3.81) nm; IR (KBr) νmax 3424, 2971, 2967, 1623, 1412, 1229, 1148, 1118 cm−1; 1H and 13C NMR data, Table 1; HRESIMS m/z 431.2227 [M − H]− (calcd for C28H31O4, 431.2222). Faberione B [(E)-1-{5-(3,7-dimethylocta-2,6-dien-1-yl)-4,6-dihydroxy-2-phenylbenzofuran-7-yl}-2-methylbutan-1-one] (2): yellow gum; [α]22D −16 (c 0.1, MeOH); UV (MeOH) λmax (log ε) 203 (4.53), 211 (4.47), 307 (4.56), 345 (3.91) nm; IR (KBr) νmax 3424, 2967, 2930, 1620, 1412, 1383, 1299, 1148, 1117 cm−1; 1H and 13C NMR data, Table 1; HRESIMS m/z 445.2386 [M − H]− (calcd for C29H33O4, 445.2379). Faberione C [(E)-1-{5-(3,7-dimethylocta-2,6-dien-1-yl)-4,6-dihydroxy-2-(4-hydroxyphenyl)benzofuran-7-yl}-2-methylpropan-1one] (3): yellow gum; UV (MeOH) λmax (log ε) 203 (4.63), 307 (4.59), 353 (3.83) nm; IR (KBr) νmax 3398, 2968, 2925, 1617, 1509,1416, 1385, 1233, 1171, 1116 cm−1; 1H and 13C NMR data, Table 1; HRESIMS m/z 447.2187 [M − H]− (calcd for C28H31O4, 447.2177). Faberione D [(E)-1-{5-(3,7-dimethylocta-2,6-dien-1-yl)-4,6-dihydroxy-2-(4-hydroxyphenyl)benzofuran-7-yl}-2-methylbutan-1-one] (4): yellow gum; [α]26D −16 (c 0.1, MeOH); UV (MeOH) λmax (log ε) 203 (4.63), 307 (4.60), 352 (3.83) nm; IR (KBr) νmax 3416, 2967, 2927, 1617, 1509, 1416, 1383, 1229, 1456, 1171, 1116 cm−1; 1H and 13 C NMR data, Table 1; HRESIMS m/z 461.2343 [M − H]−(calcd for C29H33O5, 461.2333). Faberione E [(E)-1-{6-(3,7-dimethylocta-2,6-dien-1-yl)-5,7-dihydroxy-2-methyl-2-(4-methylpent-3-enyl}-2H-chromen-8-yl)-2methylpropan-1-one] (5): yellow gum; [α]22D −16 (c 0.1, MeOH); UV (MeOH) λmax (log ε) 203 (4.44), 286 (4.30), 343 (3.44) nm; IR (KBr) νmax 3424, 2969, 2931, 1617, 1424, 1382, 1148 cm−1; 1H and
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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.jnatprod.8b01006. General experimental procedures, biological assay, and original MS and NMR spectra of 1−6 (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*Tel and Fax: +86-871-65217971. E-mail: xugang008@mail. kib.ac.cn. *E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Xing-Wei Yang: 0000-0002-9578-2986 Gang Xu: 0000-0001-7561-104X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The work was financially supported by the National Natural Sciences Foundation of China (31800296), the Natural Sciences Foundation of Yunnan Province (No. 2016FB017), foundations from Kunming Institute of Botany (KIB2017001) and Southeast Asia Biodiversity Research Institute (2017CASSEABRIQG003), CAS, Yunnan Key Laboratory of Natural Medicinal Chemistry (No. S2017-ZZ11), Youth Innovation Promotion Association CAS (No. 2016350), and West Light Foundation of the Chinese Academy of Sciences to X.W.Y. The authors thank Prof. J.-G. Dai for his valuable suggestions.
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REFERENCES
(1) Ccana-Ccapatinta, G. V.; Correa de Barros, F. M.; Bridi, H.; von Poser, G. L. Phytochem. Rev. 2015, 14, 25−50. (2) Bridi, H.; Meirelles, G. C.; von Poser, G. L. Phytochemistry 2018, 155, 203−232. (3) Singh, I. P.; Bharate, S. B. Nat. Prod. Rep. 2006, 23, 558−591.
D
DOI: 10.1021/acs.jnatprod.8b01006 J. Nat. Prod. XXXX, XXX, XXX−XXX
Journal of Natural Products
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DOI: 10.1021/acs.jnatprod.8b01006 J. Nat. Prod. XXXX, XXX, XXX−XXX
