Article pubs.acs.org/jnp
Catechin-Bound Ceanothane-Type Triterpenoid Derivatives from the Roots of Zizyphus jujuba Kyo Bin Kang, Hyun Woo Kim, Jung Wha Kim, Won Keun Oh, Jinwoong Kim, and Sang Hyun Sung* College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea S Supporting Information *
ABSTRACT: Three unprecedented ceanothane-type triterpenoids, ent-epicatechinoceanothic acid A (1), ent-epicatechinoceanothic acid B (2), and epicatechino-3-deoxyceanothetric acid A (3), containing C−C bond linkages with catechin moieties, were isolated from the roots of Zizyphus jujuba. Their chemical structures, including absolute configurations, were established by spectroscopic analysis and calculation of their ECD spectra. A possible biogenetic pathway for C−C bond formation between the catechin and the triterpenoid moieties is presented. Compound 1 was evaluated for its antiproliferative activity on HSC-T6 hepatic stellate cells.
Z
ent-epicatechinoceanothic acid B (2), and epicatechino-3deoxyceanothetric acid A (3), respectively, were isolated and structurally characterized. To the best of our knowledge, this is the first report of plant triterpenoid constituents in which the catechin moieties are bound to form C−C bonds.
izyphus jujuba Mill., a deciduous tree of the Rhamnaceae family, is cultivated widely in East Asia.1 In Korea, the fruits are eaten as a food, and their seeds have been used in traditional medicine for the treatment of insomnia and hepatic diseases. Numerous chemical constituents have been reported from Z. jujuba, including triterpenoids,2 flavonoids,3 phenolic acids,4 and alkaloids.5 Among these compounds, ceanothane-type triterpenoids are well-known for their characteristic fivemembered A-ring structures, which are observed only rarely among the triterpenoids. Most compounds of this structural type have been isolated from species of the Rhamnaceae, with some exceptions.6,7 In continuing research on the discovery of structurally novel bioactive secondary metabolites from Z. jujuba roots,8,9 three novel epicatechin-subunit containing ceanothanetype triterpenoids, named ent-epicatechinoceanothic acid A (1),
■
RESULTS AND DISCUSSION Compound 1 was obtained as brownish amorphous solid, for which the molecular formula was established as C45H56O9 by the HRESIMS deprotonated molecular ion peak at m/z 739.3857 ([M − H]−, calcd for C45H55O9, 739.3846). The 1H NMR spectrum of 1 (Table 1) showed a characteristic isopropenyl group [δH 5.10 (1H, br s, H-29a), 5.02 (1H, br s, H-29b), and 2.00 (3H, s, H-30)], suggesting that 1 is a lupane- or ceanothanetype triterpenoid derivative. Five additional tertiary methyl groups [δH 1.21 (H-23), 1.02 (H-26), 0.97 (H-27), 0.93 (H-25), and 0.86 (H-24)] and two methine protons [δH 4.05 (1H, s, H-1) and 3.93 (1H, s, H-3)] were also observed in the 1H NMR spectrum. The 1H−1H COSY correlation between these two methine protons and the HMBC correlations of H-23/H-24 with C-3 (δC 87.4) and of H-25 with C-1 (δC 54.1) were used to establish the pentacyclic A-ring structure of a ceanothane-type triterpenoid (Figure 1). The 1H NMR spectrum of 1 also exhibited four aromatic protons [δH 7.75 (1H, s, H-2″), 7.25 (2H, s, H-5″ and H-6″), and 6.43 (1H, s, H-6′)], two hydroxylated methine protons [δH 5.58 (1H, s, H-2′) and 4.76 (1H, br s, H-3′)], and a methylene group [δH 3.51 (2H, d, J = 4.4 Hz, H-4′)], which were similar to the characteristic 1H NMR signals of a catechin-type unit. The substructure of the catechin moiety was established using the HMBC spectrum, which Received: November 29, 2016 Published: March 3, 2017
© 2017 American Chemical Society and American Society of Pharmacognosy
1048
DOI: 10.1021/acs.jnatprod.6b01103 J. Nat. Prod. 2017, 80, 1048−1054
Journal of Natural Products
Article
Table 1. NMR Spectroscopic Data (δ in ppm and J Values in (Hz) in Parentheses) of Compounds 1−3a 1b position
a
δC mult.
1 2 3
54.1, CH 208.9, C 87.4, CH
4 5 6
45.2, C 46.6, CH 18.4, CH2
7
34.6, CH2
8 9 10 11
42.1, C 43.0, CH 50.3, C 23.1, CH2
12
26.9, CH2
13 14 15
39.0, CH 43.5, C 30.3, CH2
16
33.0, CH2
17 18 19 20 21
56.6, C 49.7, CH 47.3, CH 151.2, C 31.5, CH2
22
37.5, CH2
23 24 25 26 27 28 29
28.7, CH3 19.7, CH3 17.0, CH3 17.0, CH3 14.9, CH3 178.9, C 109.7, CH2
30 2′ 3′ 4′
20.5, CH3 80.6, CH 66.6, CH 28.7, CH2
4a′ 5′ 6′ 7′ 8′ 8a′ 1″ 2″ 3″ 4″ 5″ 6″
101.2, C 157.8, C 94.8, CH 155.3, C 99.6, C 154.6, C 131.6, C 115.5, CH 146.8, C 146.8, C 116.0, CH 118.9, CH
2c δH mult. (J in Hz) 4.05, s 3.93, s
1.89, m 1.48, m 1.33, m 1.41, m 1.37, m 2.01, m 2.20, m 1.06, m 1.90, m 1.41, m 2.70, dt (3.0, 11.0) 1.79, m 1.15, m 2.55, m 1.48, m 1.82, m 3.45, dt (3.8, 10.0) 2.22, m 1.52, m 2.20, m 1.55, m 1.21, s 0.86, s 0.93, s 1.02, s 0.97, s 5.10, s 5.02, s 2.00, s 5.58, s 4.76, br s 3.51, d (4.4)
6.43, s
7.75, s
7.25, s 7.25, s
δC mult. 146.0, C 107.8, CH 85.6, CH 40.7, C 62.6, CH 18.2, CH2 34.8, CH2 42.5, C 46.7, CH 45.5, C 24.3, CH2 26.0, CH2 38.7, CH 43.1, C 30.5, CH2 31.3, CH2 56.6, C 49.6, CH 47.7, CH 151.2, C 32.9, CH2 37.6, CH2 25.8, CH3 14.9, CH3 17.4, CH3 25.4, CH3 17.1, CH3 179.0, C 110.1, CH2 19.5, CH3 80.1, CH 66.9, CH 29.7, CH2 106.4, C 156.2, C 96.7, CH 146.0, C 103.1, C 153.6, C 131.8, C 116.5, CH 150.0, C 146.9, C 116.3, CH 119.3, CH
3c δH mult. (J in Hz) 6.99, s 4.86, s
1.47, m 1.39, m 1.30, m 1.42, m 1.36, m 2.11, m 1.63, m 1.36, m 1.96, m 1.27, m 2.72, m 1.93, m 1.23, m 2.23, m 1.50, m 1.72, m 3.47, m 2.63, m 1.55, m 2.24, m 1.57, m 1.25, s 1.06, s 0.90, s 1.05, s 1.03, s 4.88, s 4.72, s 1.75, s 5.38, s 4.69, br s 3.45, m 3.36, dd (4.2, 16.6)
6.67, s
7.88, s
7.28, d (8.1) 7.31, d (8.1)
δC mult. 156.8, C 109.7, CH 45.4, CH2 35.9, C 61.5, CH 19.0, CH2 38.4, CH2 42.0, C 47.2, CH 49.1, C 22.6, CH2 25.1, CH2 40.8, CH 60.8, C 29.4, CH2 35.7, CH2 57.0, C 52.6, CH 48.3, CH 151.4, C 31.5, CH2 38.0, CH2 32.7, CH3 26.3, CH3 18.0, CH3 18.7, CH3 178.9, C 179.7, C 110.7, CH2 19.7, CH3 80.4, CH 67.2, CH 30.5, CH2 108.5, C 156.0, C 96.4, CH 156.0, C 155.1, C 156.0, C 132.4, C 116.4, CH 147.2, C 147.2, C 116.7, CH 119.9, CH
δH mult. (J in Hz) 6.71, br s 2.72, m 2.42, m 1.32, m 1.34, m 2.11, m 1.92, m 3.00, m 1.73, m 2.24, m 1.69, m 3.12, dt (4.4, 12.1) 2.60, m 1.95, m 2.93, m 1.95, m 2.31, m 3.73, m 2.30, m 1.55, m 2.32, m 1.55, m 0.70, s 0.96, s 1.06, s 1.27, s
5.09, s 4.80, s 1.93, s 5.34, s 4.73, br s 3.47, m
6.68, s
7.91, br s
7.28, d (8.1) 7.33, d (8.1)
Spectra were measured in pyridine-d5. bRecorded at 400/100 MHz. cRecorded at 600/150 MHz.
(δC 155.3)/C-4a′/C-8′ (δC 99.6) (Figure 1). The 1H−1H COSY spin system of H-2′/H-3′/H-4′ also confirmed the presence of a catechin moiety. The linkage between the triterpene and catechin
showed correlations of H-2″/H-6″ with C-2′ (δC 80.6), of H-2′ with C-1″ (δC 131.6), of H-4′ with C-5′ (δC 157.8)/C-8a′ (δC 154.6)/C-4a′ (δC 101.2), and of H-6′ with C-5′/C-7′ 1049
DOI: 10.1021/acs.jnatprod.6b01103 J. Nat. Prod. 2017, 80, 1048−1054
Journal of Natural Products
Article
conformers were selected with an expected population above 50.0% (Table S1, Supporting Information). Although unconsidered conformers could possibly contribute to the ECD spectra, it was not possible to analyze every possible conformer because of a limitation of time and resources. Furthermore, four calculated ECD spectra showed similar patterns (Figure S3, Supporting Information), so it was assumed that other unconsidersed conformers would not affect the ECD spectra significantly. The geometry of these selected conformers was optimized with DFT at the B3LYP/def-SV(P) level in the gas phase followed by the calculation of the ECD spectra at the B3LYP/def-TZVP level. The Boltzmann-averaged computed ECD spectra of 1a and 1b are shown in Figure 2, and the latter
Figure 1. Selected 2D NMR correlations for compound 1.
moieties was established by the HMBC spectrum. A keto carbonyl carbon (δC 208.9) was observed in the 13C NMR spectrum and assigned as the carbonyl C-2 of a ceanothane-type triterpenoid by its HMBC correlations with H-1 and H-3. The HMBC correlations of H-1 with C-7′/C-8′/C-8a′ indicated that C-8′ is bound to the ketone carbonyl C-2. In addition, the ether bond between C-3 and C-7′ was determined by the HMBC correlation between H-3 and C-7′. The configuration of 1 was characterized by NMR and ECD spectroscopic analysis. The H-1 and H-3 exhibited singlet resonances in the 1H NMR spectrum, although they are vicinal protons. A literature citation revealed that 1β,3α-trans-oriented hydrogens represent the only possible configuration to exhibit singlet resonances in the 1H NMR spectra of ceanothane-type triterpenoids,10 and this was also supported by spectroscopic data acquired in a previous study.9 The 1H NMR resonances of H-2′ and H-3′ were also observed as singlets, which indicated that these protons are cis-oriented as in (+)- or (−)-epicatechin.11 The relative configurations of H-1 and H-3 were also confirmed by the ROESY spectrum, in which NOE correlations of H-1 with H-11a (δH 2.20)/H-25 and of H-3 with H-5 (δH 1.89)/H-23/H-24 were observed. The ROESY spectrum also exhibited many NOE correlations within the triterpenoidal moiety, which confirmed that the relative configuration of the latter was the same as in other reported ceanothane-type triterpenoids (Figure 1). In the ROESY spectrum, characteristic NOE correlations between the catechin B-ring protons (H-2″, 5″, and 6″) and the isopropenyl protons of the triterpenoid subunit (H-29a, 29b, and 30) were observed, suggesting that the catechin B-ring is proximal to the isopropenyl group on the most stable conformer of 1. In addition, the isopropenyl protons exhibited significantly more downfield chemical shifts in the 1 H NMR spectrum compared to the isopropenyl protons from other ceanothane- or lupane-type triterpenoids. These spectroscopic data suggested that the aromatic ring of the catechin B-ring provides a deshielding effect to the isopropenyl protons through its close spatial proximity. The absolute configuration at C-2′ and C-3′ in 1 was elucidated by comparing the experimental ECD spectrum with density functional theory (DFT) calculated spectra. The absolute configurations of natural pentacyclic triterpenoids have been established clearly, so the absolute configuration of the triterpenoidal moiety in 1 was inferred by analogy to those reported for common ceanothane-type triterpenoids. Molecular mechanics force field (MMFF) based conformational searches for two possible diastereomers, 1a (2′R,3′R) and 1b (2′S,3′S) (Figure S1, Supporting Information), generated more than 20 possible conformers for each diastereomer. This is because compound 1 has many flexible aliphatic and heterocyclic rings, such as the pentacyclic A-ring of the triterpene moiety and the C-ring of the catechin moiety, and it also has rotatable points such as C-2′. Among these, up to four of the most stable
Figure 2. Experimental and calculated ECD spectra of 1, 1a, and 1b.
was found to be similar to the experimental spectrum. Interestingly, this 2′S,3′S configuration is identical to (+)-epicatechin, which is also known as ent-epicatechin, and has been less commonly observed in Nature than its enantiomer, (−)-epicatechin. Although ent-epicatechin has not been reported in Z. jujuba or any phylogenetically close species, natural occurences of these atypical enantiomeric flavan-3-ol constituents have been reported in some plant species.12,13 In addition, it was reported that atypical ent-epicatechin and ent-catechin moieties could be induced by enzymatic action, especially in the biosynthesis of condensed tannins.14 Considering these, it could be supposed that the ent-epicatechin moiety of 1 is formed by the action of an epimerase enzyme during its biosynthesis. The DFTcalculated 3D structure of 1 shows that the spatial distance between H-29 or H-30 and H-5″ is close enough to cause the NOE correlation (3−4 Å). This could explain the NOE correlation between H-2″/H-5″/H-6″ and H-29s/H-30, and the downfield chemical shift of the H-29s and H-30 (Figure 3). Thus, the structure of 1 was assigned as shown and this compound was given the trivial name ent-epicatechinoceanothic acid A. The HRESIMS of 2 gave a deprotonated molecular ion peak at m/z 723. 3895 ([M − H]−, calcd for C45H55O8, 723.3897), corresponding to the molecular formula C45H56O9. The 1H NMR spectrum of 2 was similar to that of 1; however, the methine resonance of H-1 was absent, and instead, the resonance of a conjugated olefinic proton [δH 6.99 (1H, s, H-2)] was observed. The 13C NMR spectrum of 2 was not obtained because of the very limited amount of the compound obtained (0.8 mg); thus, the chemical shifts of the carbon resonances were assigned from 1050
DOI: 10.1021/acs.jnatprod.6b01103 J. Nat. Prod. 2017, 80, 1048−1054
Journal of Natural Products
Article
Figure 3. NOE correlations between H-2″/H-5″/H-6″ and H-29/H-30, which showed close distance in the DFT optimized 3D structural model of 1. Figure 5. Experimental and calculated ECD spectra of 2, 2a, and 2b.
the HSQC and HMBC spectra. The HMBC spectrum showed that two conjugated olefinic carbons [δC 146.0 (C-1) and 107.8 (C-2)] are present in the A-ring spin system of 2, which indicated that compound 2 has a double bond between C-1 and C-2 instead of the C-1 ketone functionality found in 1 (Figure 4).
that the configuration of 2 is identical to the configuration of 2b. Thus, the absolute configuration of 2, ent-epicatechinoceanothic acid B, was defined as 2′S,3′S. Compound 3 gave a molecular formula of C45H56O10, as indicated by the deprotonated molecular ion at m/z 755.3807 ([M − H]−, calcd for C45H55O10, 755.3795) in the HRESIMS. The 1H and 13C NMR spectra were similar to those of 2; however, only five methyl group signals [δH 1.93 (H-30), 1.27 (H-26), 1.06 (H-25), 0.96 (H-24), and 0.70 (H-23) (each 3H, s)] were observed while six methyl resonances were observed in the 1H NMR spectra of 1 and 2. Instead of lacking a methyl group, an additional carboxylic acid carbon resonance (δC 178.9, C-27) was observed, which suggested one of the methyl groups is substituted by a carboxylic acid function in compound 3. Downfield shifts of H-9 (δH 3.00), H-13 (δH 3.12), H-15a (δH 2.60), and H-16a (δH 2.93) showed that C-27 is substituted as a carboxylic acid group, which was supported also by the HMBC correlations of H-13 and H-15 with C-27 (Figure 4). The oxygenated methine proton resonance of H-3 was also absent in the 1H NMR spectrum of 3, and, instead, a downfield-shifted methylene group (δH 2.72 and 2.42) was observed. These protons exhibited HMBC correlations with C-1 (δC 156.8), C-2 (δC 109.7), C-23 (δC 32.7), and C-24 (δC 26.3), which indicated this methylene group to be located at C-3. Thus, the triterpene unit of 3 was determined as being identical to 3-deoxyceanothetric acid.9 The proton resonances of H-2′ and H-3′ were also observed as singlets, indicating the cis-orientation of these protons. The Boltzmann-averaged computed ECD spectra of two possible stereoisomers, 3a (2′R,3′R) and 3b (2′S,3′S), were calculated as shown in Figure 6, and the former was found to be similar to the experimental one, indicating a 2′R,3′R configuration for the epicatechin moiety. Thus, the structure of 3, epicatechino-3-deoxyceanothetric acid A, was defined as shown. As described above, compounds 1−3 are the first natural products with C−C bonds between triterpenoid and flavonoid moieties to have been discovered. Triterpenoids and flavonoids are among the most commonly isolated plant secondary metabolite types, but combined structures of these have not been reported before. The carbonyl C-2 is a structural characteristic of ceanothane-type triterpenoids, and is observed rarely in other types of triterpenoids. This characteristic substructure is thought to be responsible for the formation of the uncommon
Figure 4. Selected 2D NMR correlations for compounds 2 and 3.
The downfield chemical shift of H-3 [δH 4.86 (1H, s)] also supported the presence of a conjugated alkene at C-1 and C-2. The HMBC spectrum showed correlations of H-2 with C-8′a, and of H-3 with C-7′, indicating a C−C linkage between C-2 and C-8′ and an ester bond between C-3 and C-7′, respectively. In the ROESY spectrum of 2, H-3 exhibited NOE correlations with the β-oriented H-24 (δH 1.06) and H-25 (δH 0.90), which suggested the β-orientation of H-3. The cis-orientation of H-2′ and H-3′ was suggested by their singlet proton resonances, in the same manner as observed for compound 1. The Boltzmannaveraged computed ECD spectra of two possible stereoisomers, 2a (2′R,3′R) and 2b (2′S,3′S), were calculated as shown in Figure 5. The calculated spectrum of 2b showed a similar fit to the experimental one, with a negative Cotton effect at 236 nm and a positive Cotton effect at 287 nm. However, the calculated spectrum of 2a was also partially similar to the experimental one shown in Figure 5. Therefore, their calculated molecular structures were also considered for the determination of the absolute configuration of 2. In the calculated molecular model of 2b, catechin B-ring protons are far from the isopropenyl group (>4.5 Å) while they are very close in the model for 2a (95.0%, SigmaAldrich) was used as the positive control.
■
ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.6b01103. Chemical structures, DFT optimized 3D structural models, relative energies, populations, and calculated ECD spectra for possible conformers of diastereomeric compounds 1a, 1b, 2a, 2b, 3a, and 3b; raw HRESIMS, NMR, UV, and CD data of compounds 1−3 (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*Tel (S. H. Sung): (+82)-2-880-7859. E-mail:
[email protected]. kr. ORCID
Kyo Bin Kang: 0000-0003-3290-1017 Jinwoong Kim: 0000-0001-9579-738X Sang Hyun Sung: 0000-0002-0527-4815 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), which was funded by the Ministry of Science, ICT and Future Planning (NRF-2015M3A9A5030733). We would like to thank B. G. Jeong and E. J. Jeong (Gyeongnam National University of Science and Technology, Jinju, Republic of Korea) for kindly providing the plant material. We also would like to thank Y.-J. Ko of the National Centre for Interuniversity Research Facilities for her assistance with the NMR experiments.
■
REFERENCES
(1) Outlaw, W. H.; Zhang, S. Q.; Riddle, K. A.; Womble, A. K.; Anderson, L. C.; Outlaw, W. M.; Outlaw, N. N.; Outlaw, E. C.; Thistle, A. B. Econ. Bot. 2002, 56, 198−200. (2) Guo, S.; Duan, J. A.; Tang, Y. P.; Yang, N. Y.; Qian, D. W.; Su, S. L.; Shang, E. X. J. Agric. Food Chem. 2010, 58, 6285−6289. (3) Pawlowska, A. M.; Camangi, F.; Bader, A.; Braca, A. Food Chem. 2009, 112, 858−862. (4) Gao, Q. H.; Wu, P. T.; Liu, J. R.; Wu, C. S.; Parry, J. W.; Wang, M. Sci. Hortic. 2011, 130, 67−72. (5) Tripathi, M.; Pandey, M. B.; Jha, R. N.; Pandey, V. B.; Tripathi, P. N.; Singh, J. P. Fitoterapia 2001, 72, 507−10. (6) Guo, S.; Duan, J. A.; Tang, Y. P.; Qian, Y. F.; Zhao, J. L.; Qian, D. W. Biochem. Syst. Ecol. 2011, 39, 880−882. (7) Grishko, V. V.; Tolmacheva, I. A.; Pereslavtseva, A. V. Chem. Nat. Compd. 2015, 51, 1−21. (8) Kang, K. B.; Ming, G.; Kim, G. J.; Ha, T. K.; Choi, H.; Oh, W. K.; Sung, S. H. Phytochemistry 2015, 119, 90−95. (9) Kang, K. B.; Kim, J. W.; Oh, W. K.; Kim, J.; Sung, S. H. J. Nat. Prod. 2016, 79, 2364−2375. (10) Eade, R. A.; Grand, P. K.; McGrath, M. J. A.; Simes, J. J. H.; Wootton, M. Chem. Commun. 1967, 23, 1204−1206.
1053
DOI: 10.1021/acs.jnatprod.6b01103 J. Nat. Prod. 2017, 80, 1048−1054
Journal of Natural Products
Article
(11) Davis, A. L.; Cai, Y.; Davies, A. P.; Lewis, J. R. Magn. Reson. Chem. 1996, 34, 887−890. (12) Blair, A. C.; Nissen, S. J.; Brunk, G. R.; Hufbauer, R. A. J. Chem. Ecol. 2006, 32, 2327−2331. (13) Kofink, M.; Papagiannopoulos, M.; Galensa, R. Eur. Food Res. Technol. 2007, 225, 569−577. (14) Ellis, C. J.; Foo, L. Y.; Porter, L. J. Phytochemistry 1983, 22, 483− 487. (15) Nam, J.; Phansalkar, R. S.; Lankin, D. C.; Bisson, J.; McAlpine, J. B.; Leme, A. A.; Vidal, C. M. P.; Ramirez, B.; Niemitz, M.; Bedran-Russo, A.; Chen, S.; Pauli, G. F. J. Org. Chem. 2015, 80, 7495−7507. (16) Kundu, A. B.; Barik, B. R.; Mondal, D. N.; Dey, A. K.; Banerji, A. Phytochemistry 1989, 28, 3155−3158. (17) Lee, S. S.; Shy, S. N.; Liu, K. C. S. Phytochemistry 1997, 46, 549− 554. (18) Roitman, J. N.; Jurd, L. Phytochemistry 1978, 17, 491−494. (19) Shen, X.; Tang, Y.; Yang, R.; Yu, L.; Fang, T.; Duan, J. A. J. Ethnopharmacol. 2009, 122, 555−560. (20) Chen, J.; Lam, C. T.; Kong, A. Y.; Zhang, W. L.; Zhan, J. Y.; Bi, C. W.; Chan, G. K.; Lam, K. Y.; Yao, P.; Dong, T. T.; Tsim, K. W. Planta Med. 2014, 80, 1622−1627. (21) Kandimalla, R.; Dash, S.; Kalita, S.; Choundhury, B.; Malampati, S.; Kalita, K.; Kalita, B.; Devi, R.; Kotoky, J. Front. Pharmacol. 2016, 7, 298.
1054
DOI: 10.1021/acs.jnatprod.6b01103 J. Nat. Prod. 2017, 80, 1048−1054
