Ervadivamines A and B, Two Unusual Trimeric Monoterpenoid Indole

Jul 17, 2018 - Ervadivamines A (1) and B (2), two unprecedented trimeric monoterpenoid indole alkaloids, were isolated from Ervatamia divaricata. They...
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Ervadivamines A and B, Two Unusual Trimeric Monoterpenoid Indole Alkaloids from Ervatamia divaricata Zhi-Wen Liu,†,§ Jian Zhang,†,‡,§ Song-Tao Li,† Ming-Qun Liu,† Xiao-Jun Huang,† Yun-Lin Ao,† Chun-Lin Fan,† Dong-Mei Zhang,† Qing-Wen Zhang,‡ Wen-Cai Ye,*,† and Xiao-Qi Zhang*,†

J. Org. Chem. 2018.83:10613-10618. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 09/07/18. For personal use only.

†

Institute of Traditional Chinese Medicine and Natural Products, and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, P. R. China ‡ State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao SAR, P. R. China S Supporting Information *

ABSTRACT: Ervadivamines A (1) and B (2), two unprecedented trimeric monoterpenoid indole alkaloids, were isolated from Ervatamia divaricata. They are the first examples of vobasine-iboga-vobasine-type alkaloid with both C−C and C−N linkage patterns. Their structures including absolute configurations were fully accomplished by extensive spectroscopic analysis, single-crystal X-ray diffraction, and electric circular dichroism methods. The plausible biogenetic pathways of these trimeric alkaloids were also proposed. In addition, compound 1 exhibited significant cytotoxicity against four cancer cells.

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which are connected through C-3−C-11′ and N-1′−C-3′′ linkages, respectively. In addition, compound 1 showed significant cytotoxicity against four human cancer cell lines. Herein, we describe the isolation, structural elucidation, plausible biosynthesis pathways, and cytotoxic activities of 1 and 2. The molecular formula C61H76N6O4 of 1 was determined by HRESIMS data (m/z 957.6002 [M + H]+, calcd for C61H77N6O4: 957.6001), corresponding to 27 degrees of unsaturation. The UV absorption bands at 234 and 287 nm suggested the presence of an indole chromophore. The IR spectrum displayed the characteristic absorptions for amino (3372 cm−1) and carbonyl (1721 cm−1) functionalities. The 1H NMR spectrum of 1 (Table 1) showed the presence of two NH protons [δH 7.70 (1H, s), 7.35 (1H, s)], an ortho-disubstituted benzene ring [δH 7.58 (1H, d, J = 7.2 Hz), 7.16 (1H, t, J = 7.2 Hz), 7.13 (1H, t, J = 7.2 Hz), 7.09 (1H, d, J = 7.2 Hz)], seven aromatic protons [δH 7.58 (1H, d, J = 7.2 Hz), 7.40 (1H, d, J = 8.0 Hz), 7.07− 7.01 (4H, overlapped), 6.47 (1H, s)], two nitrogen methyls [δH 2.38 (1H, s), 1.97 (3H, s)], two methyl ester groups [δH 2.44 (3H, s), 2.34 (3H, s)], and three methyls [δH 0.94 (3H, t, J = 7.4 Hz), 0.83 (3H, t, J = 7.4 Hz), 0.82 (3H, t, J = 7.4 Hz)]. Moreover, three bridgehead nitrogen methines [δH 3.77 (1H, m), 3.72 (1H, m), 2.90 (1H, br s)] were characteristic for two vobasine-type and an iboga-type scaffolds, respectively. The 13C NMR and DEPT spectra of 1 (Table 1) established the presence of 61 carbons, including 2 carbonyl,

onoterpenoid indole alkaloids (MIAs) have long played an essential role in the development of new drugs due to their structural diversity and wide range of bioactivities.1 Vincristine derivatives, as distinct bisindole alkaloids, are well-known for their effective treatment for cancer.2 In recent years, exploration for novel and bioactive MIA oligomers lead to the discovery of more than 120 various dimers,3 whereas only a trimeric and a tetrakis MIAs were discovered from plant extracts so far.4 Compared with monomeric MIAs, oligomers provide new insight into the structural complexity of MIAs, while determination of the absolute configurations on MIA oligomers have faced more challenges. The genus Ervatamia (synonym: Tabernaemontana), belongs to the Apocynaceae family, is widely distributed in the tropical and subtropical areas of Asia and Australia.5 Plants of this genus have proven to be rich sources of MIAs, especially varied bisindole alkaloids.6 The roots of Ervatamia divaricata (L.) Burk. are traditionally used for treating hypertension, headache, and scabies in Guangdong and Guangxi provinces of China.7 Our previous study on MIAs from medicinal plants had reported a series of structurally attractive MIAs with notable cytotoxic or neuroprotective activities.8 In our continuing research, two unusual trimeric MIAs, ervadivamines A (1) and B (2), together with the dimeric intermediate 19,20-dihydroervahanine A (3),9 as well as their monomeric precursors bogamine (4)10 and ibogaine (5)11 were isolated from the roots of E. divaricate (Figure 1). Structurally, compounds 1 and 2 are the first examples of vobasine-iboga-vobasine-type trimeric MIAs. To the best of our knowledge, they are unprecedented trimeric MIAs containing two different types of constitutional units, © 2018 American Chemical Society

Received: June 7, 2018 Published: July 17, 2018 10613

DOI: 10.1021/acs.joc.8b01371 J. Org. Chem. 2018, 83, 10613−10618

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The Journal of Organic Chemistry

Figure 1. Chemical structures of 1−5.

Table 1. 1H (600 MHz) and 13C (150 MHz) NMR Data of 1 (CDCl3, δ in ppm, J in Hz)a δH

no. 2 3 5 6 7 8 9 10 11 12 13 14 15 16 18 19 20 21 22 23 24 1 (NH) a

α β

4.38 dd (13.0, 2.9) 3.77 m 2.28 2.62 dd (15.0, 8.2)

7.58 d (7.2) 7.07 7.04 7.02 α β

a b α β

1.85 1.52 2.39 2.68 d (2.8) 0.82 t (7.4) 1.53 1.30 0.94 2.18 2.05 d (12.7) 2.34 s 2.38 s 7.35 s

δC

no.

136.8 45.3 59.3 17.1

2′ 3′ 5′ 6′

111.3 130.0 118.1 119.0 121.8 109.7 136.2 42.6 34.6 43.9 12.9 25.6

7′ 8′ 9′ 10′ 11′ 12′ 13′ 14′ 15′ 16′ 17′

42.7 46.5

18′ 19′

172.6 49.8 43.0

20′ 21′

δH

α β α β

δC 143.5 51.0 54.5

3.05 m 3.35 m 3.20 m 2.72 3.34

21.1

7.40 d (8.0) 7.02 6.47 s

α β α β a b

1.89 1.24 1.88 3.20 m 1.62 2.15 0.94 t (7.4) 1.58 1.52 1.74 2.90 br s

110.8 128.0 118.0 120.0 140.2 109.5 135.5 26.8 31.8

δH

no. 2′′ 3′′ 5′′ 6′′ 7′′ 8′′ 9′′ 10′′ 11′′ 12′′ 13′′ 14′′

39.0 34.5

15′′ 16′′ 18′′ 19′′

12.0 28.3

20′′ 21′′

42.4 58.0

22′′ 23′′ 24′′ 1′′ (NH)

α β

5.95 d (12.0) 3.72 m 2.26 2.38

7.58 7.16 7.13 7.09 α β

a b α β

2.72 1.46 2.38 2.76 0.82 1.51 1.33 1.03 2.10 1.96

d (7.2) t (7.2) t (7.2) d (7.2)

δC 132.0 52.1 58.4 16.7 112.8 129.3 118.7 119.6 122.6 110.3 136.1 37.3

m t (2.8) t (7.4)

33.3 44.0 12.8 25.5

m dd (12.7, 3.8)

42.5 46.1

2.44 s 1.97 s 7.70 s

173.3 50.3 42.8

Overlapped signals were reported without designating multiplicity.

24 aromatic, or olefinic carbons, 14 methines, 14 methylenes, and 7 methyls. All the above spectral data indicated that 1 might be a trimeric MIA. Detailed analysis of the 1D and 2D NMR data allowed the assignment of three substructures (units A, B, and C) of 1. The 1 H−1H COSY spectrum of 1 exhibited nine spin systems, as shown in bold blue lines in Figure 2. In the HMBC spectrum, the correlations between H-9 and C-7/C-11/C-13, between H-6β and C-2/C-8, between H-24 and C-5/C-21, and between H-19a and C-15/C-21 as well as between H-3 and C-7 led to the establishment of the substructure unit A (Figure 2). In unit B, the iboga-type framework was verified by the HMBC correlations between H-9′ and C-7′/C-11′/C-13′, between H-21′ and C-2′/C-3′/C-5′/C-15′/C-17′/C-19′, as well as

Figure 2. 1H−1H COSY and key HMBC correlations of 1. 10614

DOI: 10.1021/acs.joc.8b01371 J. Org. Chem. 2018, 83, 10613−10618

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The Journal of Organic Chemistry between H-6′ and C-2′/C-8′. The planner structure of unit C was also deduced by the similar ways to unit A. Furthermore, the HMBC cross peaks between H-3 and C-11′, between H-12′ and C-3, as well as between H-3′′ and C-13′ indicated that units A and B as well as units B and C were connected via C-3− C-11′ and N-1′−C-3′′ bonds, respectively. The relative configuration of 1 could be elucidated by analysis of its ROESY and 1 H NMR spectra. In unit A, the ROE correlations between H-14α and H-6α/H-21α suggested that these protons were cofacial, while the correlations between H-3 and H-14β/H-15 as well as between H-21β and H-18/H-19a indicated a 3R*20S* configuration. The 16S* configuration was deduced from the shielded methyl ester groups [δH 2.34 (3H, s), H-23].12 A similar analysis strategy was taken on the determination of unit C. In addition, the ROE correlations between H-16′ and H-20′, between H-15′α and H-17′α, as well as between H-19′ and H-21′ revealed the relative configuration of unit B. Finally, the key ROE correlations between H-3 and H-10′, between H-12′ and H-14α/H-6′′α/H-14′′α, as well as between H-3′′ and H-16′/H-15′′ confirmed the stereochemistry of each unit of 1 (Figure 3). Crystals of 1 suitable for single-crystal X-ray Figure 4. X-ray ORTEP drawing of 1.

defined based on a good agreement of electric circular dichroism (ECD) spectra (Figure 5) by comparing with those of 1.

Figure 5. Experimental ECD spectra of 1 and 2.

Compounds 1 and 2 represent the first examples of vobasineiboga-vobasine-type trimeric alkaloids, which contribute a new type of complex and fascinating structure. Given that pericyclivine,13 bogamine (4), and ibogaine (5) were common constituents in Ervatamia plants, the biogenetic routes (Scheme 1) of 1 and 2 could be plausibly traced back to these analogous precursors. First, pericyclivine could be hydrogenated and methylated to afford an active intermediate B, which triggered a nucleophilic attack reaction from the C-11 of 4 and 5 to the C-3 of intermediate B to produce dimeric 19,20-dihydroervahanine A (3) and 16′-decarbomethoxydihydrovoacamine (6), respectively. Furthermore, the N-1 of 3 and 4 further attacked the C-3 of another intermediate B to form 1 and 2, respectively. The inhibitory effects of compounds 1−3 on the viability of A-549, MCF-7, HT-29, and HepG2/ADM cancer cells were evaluated by the MTT assay.14 The results showed that 1 exhibited significant cytotoxic effects against all the cancer cells, including adriamycin-resistant HepG2 with IC50 value of 12.55 ± 0.54 μm (Table 2). Whereas, compound 2 was inactive against the MCF-7 and HepG2/ADM cell lines.

Figure 3. Key ROESY correlations of 1.

diffraction analysis were obtained from MeOH/CHCl 3 solution. The final refinement of the Cu Kα data of 1 resulted in a small Flack parameter [0.078(8)], allowing unambiguous assignment of the absolute configuration as 3R,5S,15S, 16S,20S,14′R,16′R,20′S,21′S,3′′S,5′′S,15′′S,16′′S,20′′S (Figure 4). Compound 2 displayed C62H78N6O5 as the molecular formula based on its HRESIMS data (m/z 987.6104 [M + H]+, calcd for C62H79N6O5: 987.6106). The UV spectrum of 2 showed absorption maxima at 231, 287, and 294 nm. The NMR spectra of 2 (Table S2) were very similar to that of 1. The main difference was the appearance of resonances for an aromatic methyl group [δH 3.91 (3H, s), δC 55.9] and upfield shift for H-9 and C-9 as well as the absence of an aromatic proton, suggesting that 2 may be a 10′-methoxyl-substituted derivative of 1. Comprehensive analysis of the 1H−1H COSY, HSQC, HMBC, and ROESY data allowed full construction of 2. The HMBC correlations between H-22′ and C-10′ further verified the positon of methoxyl in 2. As expected, X-ray diffraction analysis of 2 established its relative configuration as shown in Figure S2. The absolute configuration of 2 was

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EXPERIMENTAL SECTION

General Procedures. Melting points were obtained on an X-5 micro melting point apparatus (Fukai Instrument, Beijing, China). 10615

DOI: 10.1021/acs.joc.8b01371 J. Org. Chem. 2018, 83, 10613−10618

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The Journal of Organic Chemistry Scheme 1. Plausible Biosynthetic Pathways of 1 and 2

Table 2. Cytotoxic Activities of Compounds 1−3 IC50 (μM) compd 1 2 3 ADMa a

A549 10.25 31.73 8.74 0.97

± ± ± ±

0.4 0.94 0.56 0.02

HT-29

MCF-7

HepG2/ADM

± ± ± ±

11.27 ± 0.34 >50 19.49 ± 0.68 1.51 ± 0.04

12.55 ± 0.54 >50 16.63 ± 0.74 45.70 ± 2.15

11.37 15.78 3.44 1.48

0.90 0.36 0.12 0.06

adriamycin as positive control.

Optical rotations were measured using CH3OH solutions on a Jasco P-1020 digital polarimeter (Jasco, Tokyo, Japan) at room temperature. UV data were recorded using CH3OH solutions on a Jasco V-550 UV−vis spectrometer (Jasco, Tokyo, Japan). IR spectra were obtained by a JASCO FT/IR-480 Plus Fourier transform infrared spectrometer (Jasco, Tokyo, Japan) using KBr pellets. CD spectra were obtained on Jasco J-810 spectropolarimeter (Jasco, Tokyo, Japan) at room temperature. HRESIMS were recorded on an Agilent 6210 ESI-TOF mass spectrometer (Agilent Technologies, CA, USA). NMR spectra were obtained on Bruker AV-300, AV-400 and AV-600 spectrometers (Bruker, Fällanden, Switzerland). Single-crystal data were performed using a Rigaku Oxford diffraction and Cu Kα radiation. Column chromatography was carried out on silica gel (200−300 mesh and 300− 400 mesh, Qingdao Marine Chemical Plant, Qingdao, P. R. China), Sephadex LH-20 (Pharmacia Biotech AB, Uppsala, Sweden), MCI GEL (Mitsubishi Chemical Corporation, Tokyo, Japan) and ODS (Merck, Darmstadt, Germany). Preparative HPLC was performed on an Agilent 1260 system equipped with a DAD detector, accompanied by a semi-preparative Waters Xbridge C18 reversed-phase column (10 × 250 mm) column. All solvents used in chromatography column and HPLC were of analytical (Tianjin Damao Chemical Plant, Tianjin, China) grade and chromatographic grade (Oceanpak, Sweden), respectively. Plant Material. The roots of Ervatamia divaricata (L.) Burk. were collected in Guangzhou City of China, in November of 2015 and

authenticated by associate Prof. Ying Zhang (Jinan University). A voucher specimen (no. 2015111301) was deposited in the Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, P. R. China. Extraction and Isolation. The air-dried and powdered roots of E. divaricata (51.6 kg) were percolated at room temperature with 95% EtOH (24 h × 6). The alcoholic extract was evaporated under reduced pressure to give a crude extract (3.7 kg), which was then suspended in H2O and treated with 0.5% hydrochloric acid to adjust the pH to 3. After extracted with CHCl3, the acidic aqueous phase was basified with aqueous ammonia to pH 9−10 and partitioned with CHCl3 to obtain a total alkaloid residue (659.0 g), which was subjected to a silica gel column eluted with gradient mixtures of CHCl3/CH3OH (100:0 to 0:100, v/v). Fifteen fractions (Frs. A−O) were collected and examined by TLC and HPLC analyses. Fr. K (22.5 g) was rechromatographed on a MCI GEL column (CH3OH/H2O, 0:100 to 100:0, v/v) to give nine subfractions (Frs. K1−K9). Fr. K2 (504.5 mg) was purified by a Sephadex LH-20 column (CHCl3/CH3OH, 1:1, v/v) and reversedphase semipreparative HPLC (MeOH/H2O/Et2NH, 84:16:0.0001, v/v) to afford 1 (6.0 mg, tR 44.0 min) and 2 (5.0 mg, tR 41.0 min). Fr. K4 (12.0 g) was separated by repeated Sephadex LH-20 columns (CHCl3/CH3OH, 1:1 and 0:1, v/v) and purified by pHPLC (CH3CN/H2O/Et2NH, 76:24:0.0001, v/v) to obtain 3 (36.0 mg, tR 26.0 min). Fr. C (4.8 g) was chromatographed on ODS column 10616

DOI: 10.1021/acs.joc.8b01371 J. Org. Chem. 2018, 83, 10613−10618

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The Journal of Organic Chemistry *E-mail: [email protected].

using CH3OH/H2O (2:8 to 10:0, v/v) as the eluent, followed by pHPLC using CH3CN−H2O−Et2NH (70:30:0.0001, v/v) as the mobile phase to afford 4 (27.0 mg, tR 27.3 min) and 5 (44.0 mg, tR 32.0 min). Ervadivamine A (1). Colorless blocks (CH3OH/CHCl3), mp 258− 259 °C; [α]25 D +63.2 (c 0.78, CHCl3); UV (CH3OH) λmax (log ε) 234 (4.72), 287 (4.30) nm; IR (KBr) vmax 3372, 3054, 2925, 2869, 1721, 1617, 1459, 1312, 1231, 1196, 1148, 1013 cm−1; HR-ESI-MS m/z: 957.6002 [M + H]+, calcd for C61H77N6O4, 957.6001; ECD (CH3OH) λmax (Δε) 226 (−101.6), 241 (+155.3), 297 (+27.4) nm; 1H (600 MHz, CDCl3) and 13C NMR (150 MHz, CDCl3) data, see Table S1. Ervadivamine B (2). Colorless blocks (CH3OH/CHCl3), mp 264− 265 °C; [α]25 D +69.2 (c 0.86, CHCl3); UV (CH3OH) λmax (log ε) 231 (4.59), 287 (4.17), 294 (4.15) nm; IR (KBr) vmax 3415, 3055, 2927, 2870, 1723, 1621, 1465, 1367, 1332, 1312, 1229, 1150, 1055, 1012 cm−1; HR-ESI-MS m/z: 987.6104 [M + H]+, calcd for C62H79N6O5, 987.6106; ECD (CH3OH) λmax (Δε) 226 (−80.6), 241 (+95.6), 296 (+26.1) nm; 1H (600 MHz, CDCl3) and 13C NMR (150 MHz, CDCl3) data, see Table S2. 19,20-Dihydroervahanine A (3).9 Yellow oil; [α]25 D −35.5 (c 0.82, CH3OH); UV (CH3OH) λmax (log ε) 237 (4.57), 286 (4.22) nm; IR (KBr) vmax 3390, 2926, 2871, 1718, 1653, 1622, 1560, 1462, 1363, 1337, 1316, 1235, 1158, 1103, 1059, 1011 cm−1; HR-ESI-MS m/z: 619.4007 [M + H]+, calcd for C40H51N4O2, 619.4007; ECD (CH3OH) λmax (Δε) 224 (−14.1), 243 (+32.7), 278 (−4.1), 302 (−8.0) nm; 1H (300 MHz, CDCl3) and 13C NMR (75 MHz, CDCl3) data, see Table S3. Ibogamine (4).10 Yellow oil; [α]25 D −18.2 (c 0.71, CH3OH); UV (CH3OH) λmax (log ε) 206 (4.17), 228 (4.14), 282 (3.35) nm; HR-ESI-MS m/z: 281.2016 [M + H]+, calcd for C19H25N2, 281.2012; 1 H (400 MHz, CDCl3) and 13C NMR (125 MHz, CDCl3) data, see Table S4. Ibogaine (5).11 Yellow oil; [α]25 D −34.7 (c 0.75, CH3OH); UV (CH3OH) λmax (log ε) 205 (4.27), 225 (4.22), 280 (3.56) nm; HR-ESI-MS m/z: 311.2118 [M + H]+, calcd for C20H27N2O, 311.2134. 1 H (400 MHz, CD3OD) and 13C NMR (125 MHz, CD3OD) data, see Table S4. Cytotoxicity Assay. The human lung cancer cell line A549, human colon cell line HT-29, human breast adenocarcinoma cell line MCF-7, and human hepatocellular carcinoma cell line HepG2 were obtained from the American Type Culture Collection (ATCC). The HepG2/ ADM cell line was obtained from adriamycin-selected multidrugresistant HepG2. All of the cell lines were cultured in RPMI 1640 medium, supplemented with 10% FBS (v/v) at 37 °C in a humidified atmosphere of 5% CO2 (v/v). Cells were cultured in 96-well plates for 24 h. Then the cells were treated with compounds 1−3 at various concentrations for 72 h. After incubation for another 4 h with a 30 μL aliquot of MTT solution (5 mg/mL in PBS), the medium was discarded, and 100 μL of DMSO was added to dissolve the produced formazan. The absorbance was measured at 570 nm using a microplate Reader (Thermo scientific multiskan MK3, USA). Each well was performed in triplicate in three independent experiments. The concentration giving 50% inhibition (IC50) was determined from the dose− response curves using Prism software and presented as the mean ± SD.

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ORCID

Xiao-Jun Huang: 0000-0002-3636-4813 Wen-Cai Ye: 0000-0002-2810-1001 Author Contributions §

Z.-W.L. and J. Z. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial supported was provided by the National Key R&D Program of China (no. 2017YFC1703802), the National Natural Science Foundation of China (nos. 81630095, 81373935), the State Administration of TCM of China (no. ZYBZH-Y-GD-12), the Science and Technology Planning Project of Guangdong Province (nos. 2013A022100028, 2016B030301004), and the Science and Technology Development Fund of Macau (no. 042-2014-A1).

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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.joc.8b01371. Detailed descriptions of the experimental procedure; UV, IR, MS, and NMR spectra for compounds 1−5; ECD spectra for 1−3 (PDF) X-ray crystallographic analyses of 1 (CIF) X-ray crystallographic analyses of 2 (CIF)

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REFERENCES

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. 10617

DOI: 10.1021/acs.joc.8b01371 J. Org. Chem. 2018, 83, 10613−10618

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DOI: 10.1021/acs.joc.8b01371 J. Org. Chem. 2018, 83, 10613−10618