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University, Guangzhou 510632, People's Republic of China. ‡ ... five novel MBAs with unprecedented carbon skeletons, gelsecorydines A-E (1-5) (Figur...
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Article Cite This: J. Org. Chem. 2018, 83, 5707−5714

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Gelsecorydines A−E, Five Gelsedine−Corynanthe-Type Bisindole Alkaloids from the Fruits of Gelsemium elegans Ni-Ping Li,†,‡ Miao Liu,†,‡ Xiao-Jun Huang,†,‡ Xue-Ying Gong,†,‡ Wei Zhang,†,‡ Min-Jing Cheng,†,‡ Wen-Cai Ye,*,†,‡ and Lei Wang*,†,‡ †

Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, People’s Republic of China ‡ Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, People’s Republic of China S Supporting Information *

ABSTRACT: Five monoterpenoid bisindole alkaloids with new carbon skeletons, gelsecorydines A−E (1−5), together with their biogenetic precursors were isolated from the fruits of Gelsemium elegans. Compounds 1−5 represent the first examples of heterodimeric frameworks composed of a gelsedine-type alkaloid and a modified corynanthe-type one. Notably, compound 2 featured an unprecedented caged skeleton with a 6/5/7/6/5/6 heterohexacyclic ring system, which possessed a pyridine ring that linked the two monomers. Their structures and absolute configurations were elucidated by spectroscopic analysis, X-ray diffraction, and electronic circular dichroism (ECD) calculation. A plausible biosynthetic pathway for compounds 1−5 is proposed. Compounds 1, 3, 4, and 5 exhibited a significant inhibitory effect against nitric oxide (NO) production in macrophages.

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INTRODUCTION Monoterpenoid bisindole alkaloids (MBAs) are an important class of natural products with diverse biological activities and unique chemical structures.1,2 To date, more than 16 classes of MBAs with different monomers and linkage modes have been reported.2 For example, goniomedines A and B are quebrachamine−pleioarpamine-type MBAs, which showed antimalarial activities.3 Tabercorymines A and B are vobasinyl−ibogan-type alkaloids with antiproliferative effects.4 Gelsemium elegans (Gardn. & Champ.) Benth. is a famous toxic plant in China.5 Phytochemical studies on the leaves and roots of this plant had resulted in the isolation of about 130 monoterpenoid indole alkaloids including five MBAs.6,7 Their highly complex structures and diverse biological activities8,9 make them interesting targets for organic chemists and pharmacologists.10 With an aim to explore the structurally interesting and bioactive alkaloids from G. elegans,7 five novel MBAs with unprecedented carbon skeletons, gelsecorydines A−E (1−5) (Figure 1), along with their biogenetic precursors (6−10) were isolated from the fruits of G. elegans. Compounds 1−5 are the first examples of heterodimeric frameworks composed of a gelsedine-type alkaloid and a modified corynanthe-type one. Furthermore, compound 2 features an unprecedented caged © 2018 American Chemical Society

skeleton with a 6/5/7/6/5/6 heterohexacyclic ring system, possessing a pyridine ring (ring F) that linked the two monomers. In addition, the corynanthe-type alkaloids (9 and 10) were isolated from genus Gelsemium for the first time. Compared with the known MBAs from G. elegans,6,7c compounds 1−5 are the first examples that possess corynanthe-type alkaloid building blocks. Moreover, the unprecedented ring system of 2 was formed through unique cyclization and aromatization processes in its proposed biosynthetic pathway. Herein, we describe the isolation, structural elucidation, and inhibitory activities against NO production in macrophages of these compounds. A plausible biosynthetic pathway for compounds 1−5 is also proposed on the basis of the coexisted biogenetic precursors (6−10).

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RESULTS AND DISCUSSION Gelsecorydine A (1) was obtained as colorless crystals from MeOH. The molecular formula of 1 was established to be C40H42N4O6 by its HR-ESI-MS data (m/z 675.3196 [M + H]+, Received: March 23, 2018 Published: May 3, 2018 5707

DOI: 10.1021/acs.joc.8b00736 J. Org. Chem. 2018, 83, 5707−5714

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The Journal of Organic Chemistry

Figure 1. Chemical structures of gelsecorydines A−E (1−5) and known compounds (6−10).

19−C-21′ and C-19′−C-20′ double bonds were in E and Z configurations, respectively. The NOE correlation between H18 and H-19′ suggested that the intervening single bond (C20′−C-21′) in 1 was in the s-cis configuration (Figure 3). The complete structure and stereochemistry of 1 were finally determined by single crystal X-ray diffraction analysis (Figure 4). The final refinement on the Cu Kα data resulted in a small Flack parameter of −0.04(11), allowing the unambiguous assignment of the absolute configuration of 1 as 3S, 5S, 7S, 14R, 15R, 16S, 3′S, and 15′S. The molecular formula of gelsecorydine B (2) was determined as C40H41N4O6 on the basis of its HR-ESI-MS at m/z 673.3033 [M]+ (calcd for C40H41N4O6 673.3021). The UV spectrum of 2 revealed the absorption maxima at 209 and 282 nm. The IR spectrum displayed the characteristic absorptions for a hydroxyl (3403 cm−1), aromatic ring (1613, 1462 cm−1), and carbonyl group (1716 cm−1). Comparison of the NMR data of 2 with those of 1 revealed that both structures had the same 14-hydroxygelsenicine (6) and vallesiachotamine (9) cores. The main differences between 1 and 2 involved resonances for C-19 ∼ C-20 and C-18′ ∼ C-21′, which suggested that the two compounds varied only in the linkage position and pattern. The HMBC correlations between H-18 and C-20/C-19′ as well as between H-18′ and C-19/C-20′ in 2 indicated the presence of a C−C linkage between C-19 and C-19′. Furthermore, the HMBC cross peaks between H-21′ and C5/C-20/C-15′/C-19′ as well as the NOESY correlations between H-21′ and H-5/H-6β (Figure 3) revealed the connection between N-4 and CH-21′. Thus, a 3,4-dimethylpyridin-1-ium moiety that fused the two monomer cores was established, forming an unprecedented 6/5/7/6/5/6 hexacyclic ring system. This was further confirmed by the major fragment ion peaks at m/z 362.1641 [C22H22N2O3+•], 281.1294 [C17H17N2O2+], and 642.2872 [C39H38N4O5+•] in the QTOF-MS/MS, which originated from the fragmentation of C-

calcd for C40H43N4O6 675.3177). The UV spectrum displayed absorption maxima at 211 and 282 nm, characteristic of indole and β-N-acrylate chromophores.11 The IR spectrum revealed the existence of a hydroxyl (3412 cm−1), aromatic ring (1616, 1463 cm−1), and carbonyl (1720 cm−1). The 1H NMR spectrum of 1 showed signals for eight aromatic protons, an amino group [δH 8.48 (1H, br s)], two methoxy groups [δH 3.68 (3H, s), 2.89 (3H, s)], and an ethylidene unit [δH 5.65 (1H, q, J = 6.9 Hz, H-19′) and 1.97 (3H, d, J = 6.9 Hz, H-18′)]. The 13C NMR and DEPT spectra indicated the presence of 40 carbons including four methyls, five methylenes, 18 methines, and 13 quaternary carbons. The above spectral data implied that 1 could be a MBA.7b,c With the aid of 1H−1H COSY, HSQC, HMBC, and NOESY experiments, the NMR signals of 1 could be assigned as shown in Tables 1 and 2. A comparison of the NMR data of 1 with those of known alkaloids revealed that the signals of 1 could be attributed to 14-hydroxygelsenicine (6)12 and vallesiachotamine (9) moieties,13 except for a methylene (CH2-19) in 14hydroxygelsenicine and the aldehyde group (C-21′) in vallesiachotamine were replaced by a couple of olefinic carbons (δC 138.7, 131.4) in 1 (Figure 2). The HMBC correlations between H-21′ and C-18/C-20/C-15′/C-19′ indicated that the two monomeric units were linked via the C-19−C-21′ double bond to form a conjugated diene moiety (Figure 2). The relative configuration of 1 was elucidated by the NOESY experiment and proton coupling constant. The NOE correlations between H-5 and H-16, between H-15 and H17β/H-21′, between H-15′ and H-14′β/H-18′, as well as between H-3′ and H-14/H-14′α indicated that the relative configurations of C-5, C-15, C-16, C-3′, and C-15′ in 1 are identical to those of 14-hydroxygelsenicine (6)12 and vallesiachotamine (9).13 The small coupling constant of H14/H-15 (J14,15 ≈ 0 Hz) indicated that the hydroxyl at C-14 was β oriented.14 Furthermore, the NOE correlations between H-15 and H-21′ and between H-15′ and H-18′ revealed that the C5708

DOI: 10.1021/acs.joc.8b00736 J. Org. Chem. 2018, 83, 5707−5714

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The Journal of Organic Chemistry Table 1. 13C NMR Data for Compounds 1−5 in CDCl3 no. 2 3 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 2′ 3′ 5′ 6′ 7′ 8′ 9′ 10′ 11′ 12′ 13′ 14′ 15′ 16′ 17′ 18′ 19′ 20′ 21′ 22′ N-OMe OMe Ar-OMe a

1

2

3

4

5

δ Ca 170.7 79.5 72.6 37.8 54.0 131.8 124.9 123.6 128.4 106.9 138.1 67.3 49.5 38.4 62.0 15.6 131.4 177.7 133.7 48.8 51.4 22.2 108.3 127.0 118.0 119.7 122.0 111.2 136.6 35.7 31.8 93.9 148.0 13.8 126.7 140.4 138.7 169.5 62.2 51.1

δ Cb 170.0 80.0 71.1 37.9 53.5 130.2 124.6 124.2 129.1 107.3 138.0 67.2 47.0 36.0 60.6 15.7 134.9 154.1 132.6 47.4 51.5 22.2 107.4 126.6 117.8 119.0 121.5 111.6 136.9 33.7 33.2 91.7 149.3 16.6 155.9 144.1 135.0 168.1 63.4 50.7

δ Cb 171.2 79.6 72.8 38.0 53.8 131.7 124.8 123.8 128.6 107.1 138.3 67.8 49.8 38.1 62.0 15.5 134.1 177.1 133.2 48.5 51.1 22.2 108.2 127.0 118.1 119.6 121.9 111.3 136.6 33.2 37.6 94.9 147.2 15.5 125.8 139.3 135.3 169.3 63.3 51.0

δ Cb 171.6 80.0 72.8 38.2 53.5 123.5 125.6 108.3 160.6 94.4 139.5 67.8 49.8 38.1 62.1 15.5 134.1 177.0 133.2 48.6 51.1 22.2 108.2 127.0 118.1 119.6 121.9 111.3 136.6 33.2 37.6 94.9 147.2 15.5 125.8 139.3 135.3 169.3 63.4 51.0 55.8

δ Ca 171.9 75.1 73.1 38.4 56.2 132.4 124.8 123.6 128.3 106.9 138.3 28.4 39.9 40.0 62.3 16.2 133.9 180.5 133.3 48.6 51.1 22.2 108.2 127.0 118.0 119.7 122.0 111.5 136.6 33.0 37.5 94.7 147.1 15.7 126.1 139.6 134.3 169.0 63.1 50.9

one at 211 nm, which were similar to those of the calculated spectrum for the stereoisomer with 3S, 5S, 7S, 14R, 15R, 16S, 3′S, and 15′S configurations (Figure 5). Hence, the absolute configuration of 2 was elucidated. Gelsecorydine C (3) showed the same molecular formula (C40H42N4O6) as 1 by its HR-ESI-MS data (m/z 675.3192 [M + H]+, calcd for C40H43N4O6 675.3177). The UV and IR spectra of 3 displayed signals similar to those of 1. Comparison of the NMR data of 3 with those of 1 (Tables 1 and 2) revealed that their NMR data were very similar except for the signals assigned to C-15′, C-18′, and C-21′, suggesting that 3 might be a geometric isomer of 1. The HMBC correlations between H21′ and C-18/C-20/C-15′/C-19′ confirmed that the two monomers were connected through the C-19−C-21′ bond (Figure S6). In the NOESY spectrum, the correlation between H-21′ and H-15 as well as the lack of correlation signal between H-21′ and H-18 implied that the C-19−C-21′ double bond was in an E configuration. Moreover, the NOE correlations between H-19′ and H-15′ and between H-21′ and H-18′ suggested that the geometries of the double bond (C-19′−C-20′) and intervening single bond (C-20′−C-21′) in 3 were in E and strans configurations, respectively (Figure 3). The ECD spectrum of 3 was in good agreement with that of 1 (Figure 6), indicating that the absolute configuration of 3 was identical with that of 1. Therefore, the complete structure of 3 was constructed. The molecular formula of gelsecorydine D (4) was determined to be C41H44N4O7 on the basis of its HR-ESI-MS data (m/z 705.3297 [M + H]+, calcd for C 41 H45 N4 O7 705.3283). The NMR spectra of 4 showed similar resonances to that of 3 (Tables 1 and 2), except for the lack of an aromatic proton signal and the presence of an additional methoxyl signal (δC 55.8) in 4. The above observations indicated that the 14hydroxygelsenicine unit (gelsedine part) in 3 was replaced by a 11-methoxyl-14-hydroxygelsenicine (7)17 unit in 4, which was further confirmed by an extensive analysis of the 1H−1H COSY, HSQC, HMBC, and NOESY spectra. The ECD spectrum of 4 showed similar Cotton effects to those of 1 (Figure 6), which revealed that they had the same absolute configurations. Hence, the structure of 4 was elucidated as shown in Figure 1. Gelsecorydine E (5) displayed a molecular formula C40H42N4O5 as determined by its HR-ESI-MS data (m/z 659.3229 [M + H]+, calcd for C40H43N4O5 659.3228). The NMR data of 5 were in good agreement with those of 3 (Table 1), except for the absence of signals for CH-14 and the presence of a methylene signal (δC 28.4), suggesting that the 14-hydroxygelsenicine unit in 3 was replaced by a gelsenicine (8) unit in 5.18 This conclusion was further confirmed by the 1 H−1H COSY correlations between H-14β and H-3/H-15, and the HMBC correlations between H-14α and C-7/C-16 (Figure S6). The NOE correlations between H-21′ and H-15 and between H-19′ and H-15′ indicated that the two double bonds (C-19−C-21′ and C-19′−C-20′) were both in E configurations. Furthermore, the NOE correlation between H-21′ and H-18′ was observed, which suggested that the intervening single bond (C-20′−C-21′) was in the s-trans configuration (Figure S7). Comparison of the ECD spectrum of 5 with that of 1 indicated that they had the same absolute configurations (Figure 6). Thus, the structure of 5 was determined (Figure 1). The known compounds 14-hydroxygelsenicine (6),12 11methoxyl-14-hydroxygelsenicine (7),17 gelsenicine (8),18 vallesiachotamine (9),13 and isovallesiachotamine (10)13 were

Data were measured at 150 MHz. bData were measured at 125 MHz.

20′−C-15′ bond and C-22′−OCH3 unit (Supporting Information). The relative configuration of 2 could be elucidated by the NOESY experiment (Figure 3), which suggested that the relative configurations of 2 are identical to those of 1. The calculation of 13C NMR chemical shifts of 2 at the mPW1PW91/6-311G(d,p) level with the PCM in CDCl3 agreed well with the experimental data, a correlation coefficient (R2) of 0.9987 (Figure S4) with the largest outlier Δδ = 4.6 ppm (C-19′) and the average error (CMAD) = 1.29 ppm (Table S5), which further confirmed the structure of 2.15,16 The absolute configuration of 2 was confirmed by comparing the experimental and the time-dependent DFT calculated electronic circular dichroism (ECD) spectra (Supporting Information). The experimental ECD spectrum of 2 exhibited positive Cotton effects at 286 and 228 nm as well as a negative 5709

DOI: 10.1021/acs.joc.8b00736 J. Org. Chem. 2018, 83, 5707−5714

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The Journal of Organic Chemistry Table 2. 1H NMR Data for Compounds 1−5 in CDCl3 (δ in ppm, J in Hz) no. 3 5 6 9 10 11 12 14 15 16 17 18 3′ 5′ 6′ 9′ 10′ 11′ 12′ 14′ 15′ 17′ 18′ 19′ 21′ N-OMe OMe Ar-OMe N-H a

1

2

3

4

5

δHa,c

δHb,c

δHb,c

δHb,c

δHa,c

3.55 4.52 m α 2.38 dd (15.7, 4.6) β 2.21 7.45 d (7.7) 7.01 dd (7.7, 7.7) 7.16 dd (7.7, 7.7) 6.66 4.23 br s 3.28 d (8.6) 2.54 β 4.43 dd (10.8, 3.0) α 4.28 d (10.8) 2.23 4.72 d (12.0) β 3.57 α 3.41 ddd (12.3, 12.2, 3.2) β 2.78 ddd (14.3, 12.2, 4.2) α 2.57 7.34 d (7.7) 7.02 dd (7.7, 7.7) 7.10 dd (7.7, 7.7) 7.30 d (7.7) α 2.26 d (11.2) β 1.86 m 4.09 d (5.3) 7.73 s 1.97 d (6.9) 5.65 q (6.9) 6.65 2.89 s 3.68 s

3.75 5.44 m α 2.70 β 2.22 d (15.4) 7.45 d (7.7) 7.05 dd (7.7, 7.7) 7.23 6.80 d (7.7) 4.38 br s 4.02 d (7.8) 3.33 m β 4.47 d (11.3) α 4.28 d (11.3) 2.53 s 4.40 d (12.0) β 3.64 α 3.64 β 2.87 m α 2.76 7.39 d (7.7) 7.00 dd (7.7, 7.7) 7.05 dd (7.7, 7.7) 7.26 α 2.49 d (12.1) β 1.87 m 4.33 d (5.5) 7.82 s 2.61 s 8.03 s 3.73 3.45 s

3.70, s 4.59 m α 2.47 dd (15.6, 4.7) β 2.36 d (15.6) 7.51 d (7.7) 7.07 dd (7.7, 7.7) 7.24 6.84 d (7.7) 4.57 br s 3.46 d (8.5) 2.66 m β 4.50 α 4.36 d (11.1) 2.12 s 4.50 β 3.55 ddd (12.4, 12.2, 3.8) α 3.63, d (5.2) β 2.86 m α 2.72 m 7.41 d (7.7) 7.03 dd (7.7, 7.7) 7.07 dd (7.7, 7.7) 7.26 α 2.41 d (13.0) β 1.68 m 3.66 d (4.5) 7.66 s 1.65 d (6.7) 5.46 q (6.7) 6.81 s 3.68 s 3.67 s

8.48 br s

10.54 br s

8.75 br s

3.67 4.58 m α 2.45 β 2.35 m 7.39 d (8.3) 6.57 dd (8.4, 2.4) 6.44 d (2.4) 4.55 d (2.1) 3.46 m 2.66 m β 4.51 α 4.37 d (11.0) 2.13 s 4.49 β 3.64 m α 3.56 ddd (12.6, 12.6, 3.8) β 2.87 m α 2.73 m 7.41 d (7.7) 7.04 ddd (7.7, 7.7, 1.0) 7.08 ddd (7.7, 7.7, 1.0) 7.26 d (7.7) α 2.40 β 1.63 m 3.66 7.66 s 1.66 d (6.8) 5.46 q (6.8) 6.81 s 3.69 s 3.68 s 3.79 s 8.70 br s

3.74 m 4.58 m α 2.47 β 2.32 d (15.3) 7.53 d (7.7) 7.06 dd (7.7, 7.7) 7.23 dd (7.7, 7.7) 6.85 d (7.7) α 2.45, β 2.24 m 3.40 t (9.2) 2.65 t (7.9) β 4.34 d (11.0) α 4.29 d (11.0) 2.11 s 4.51 d (11.6) β 3.64 m α 3.54 ddd (12.4, 12.2, 3.6) β 2.87 m α 2.73 d (12.9) 7.42 d (7.7) 7.04 dd (7.7, 7.7) 7.10 dd (7.7, 7.7) 7.33 d (7.7) α 2.40 d (12.6) β 1.66 m 3.61 7.67 s 1.69 d (6.8) 5.49 q (6.8) 6.64 s 3.62 s 3.68 s 8.48 br s

Data were measured at 600 MHz. bData were measured at 500 MHz. cOverlapped signals are reported without designating multiplicity.

Figure 2. Key 1H−1H COSY and HMBC correlations of 1 and 2.

other hand, the Michael addition between C-19 in 6 and the α,β-unsaturated ketone group in 9 (path ii) could lead to the formation of C-19−C-19′ linkage (iia). Furthermore, compound 2 could be yielded via the double bond migration, iminium formation, and oxidation processes.20 The crude methanol extract of the fresh fruits of G. elegans was analyzed by HPLC-ESI-MS (Supporting Information). The ion peaks in accordance with those of 1−5 were detected, which confirmed the natural occurrence of 1−5. Compounds 1−5 were evaluated for their inhibitory activities against NO production in RAW 264.7 macrophage cells. The

identified by comparison of their physical and spectroscopic data with those reported in the literatures. A biogenetic pathway of 1−5 was proposed as shown in Scheme 1. The gelsedine-type alkaloids (6−8) and corynanthetype alkaloids (9 and 10) were both generated from amino acid tryptophan and monoterpene precursor secologanin by strictosidine synthase- and strictosidine glucosidase-catalyzed condensation.19 The Knoevenagel reaction between C-19 in the gelsedine-type alkaloid and the aldehyde group in the corynanthe-type one (path i) could yield the intermediates ia−id, which could be dehydrated to afford 1 and 3−5. On the 5710

DOI: 10.1021/acs.joc.8b00736 J. Org. Chem. 2018, 83, 5707−5714

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Figure 3. Optimized structures and key NOESY correlations of 1−3.

Figure 4. X-ray ORTEP drawing of 1 (with the thermal ellipsoid scaled to the 30% probability level).

Figure 5. Calculated and experimental CD spectra of 2.

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CONCLUSION In summary, the first phytochemical investigation on the fruits of Gelsemium elegans led to the isolation of five monoterpenoid bisindole alkaloids with new carbon skeletons (1−5). Gelsecorydines A−E (1−5) represent a new class of MBAs named gelsedine−corynanthe-type alkaloids, which are constructed through different monomers (gelsedine-type and modified corynanthe-type) with unusual linkage modes. The

result revealed that compounds 1−5 exhibited concentrationdependent inhibition on lipopolysaccharide induced NO production with an IC50 value of 14.7 ± 1.8, 78.2 ± 2.8, 16.2 ± 1.5, 13.7 ± 1.7, and 4.2 ± 2.8 μM, respectively, and no obvious cytotoxicities were found at 50 μM. The IC50 value of the positive control indomethacin was 21.0 ± 1.4 μM (Table S6). 5711

DOI: 10.1021/acs.joc.8b00736 J. Org. Chem. 2018, 83, 5707−5714

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(Framingham, U.S.A.). NMR spectra were obtained on Bruker AV500 and AV-600 spectrometers (Bruker, Fällanden, Switzerland). Column chromatography (CC) were carried out on silica gel (200− 300 mesh, Qingdao Marine Chemical Plant, Qingdao, P. R. China), Sephadex LH-20 (Pharmacia Biotec AB, Uppsala, Sweden), and ODS (Merck, Darmstadt, Germany). Preparative HPLC was carried out on an Agilent 1260 Chromatograph equipped with a G1311C pump and a G1315D photodiode array detector (Agilent Technologies, CA, USA) with a semipreparative Waters XBridge BEH C18 OBD reversed-phase column (10 mm × 250 mm, 5 μm). All solvents used in CC and HPLC were of analytical (Shanghai Chemical Plant, Shanghai, China) grade and chromatographic grade (Fisher Scientific, NJ, USA), respectively. Plant Material. The fruits of G. elegans were collected from Zhangzhou city, Fujian province of China in February 2016, and authenticated by Professor Guang-Xiong Zhou (Jinan University, Guangzhou, China). A voucher specimen (no. 2016022505) was deposited in the Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou, P. R. China. Extraction and Isolation. The air-dried fruits of G. elegans (26.5 kg) were pulverized and extracted with 95% EtOH at room temperature. The extract (5.1 kg) was suspended in H2O and acidified with 5% HCl to pH 3. The acidic suspension was partitioned with CHCl3 to remove the neutral components. The aqueous layer was then basified with NH3·H2O to pH 9 and extracted with CHCl3 to obtain the total alkaloids (110 g). The alkaloid extract was subjected to silica gel column chromatography using CHCl3−MeOH (100:0 to 0:100, v/v) as an eluent to afford 10 fractions (Fr.A−J). Fr.C (6.9 g) was subjected to an ODS column using MeOH−H2O (10:90 to 100:0, v/v) as an eluent to afford eight subfractions (Fr.C1−C8). Fr.C4 (0.18 g) was purified by reversed-phase semipreparative HPLC (CH3CN− H2O−Et2NH, 45:55:0.01) to afford 9 (10 mg) and 10 (10 mg). Fr.C6 (0.21 g) was purified by reversed-phase semipreparative HPLC (CH3CN−H2O−Et2NH, 45:55:0.01) to afford 1 (4 mg), 3 (20 mg), and 5 (4 mg). Fr.C8 (0.01 g) was purified by reversed-phase semipreparative HPLC (CH3CN−H2O−Et2NH, 55:45:0.01) to afford 4 (5 mg). Fr.J (19 g) was subjected to an ODS column using MeOH− H2O (10:90 to 100:0, v/v) as an eluent to afford ten subfractions (Fr.J1−J10). Fr.J3 (0.3 g) was purified by reversed-phase semipreparative HPLC using CH3CN−H2O−Et2NH (25:75:0.01) as the mobile phase to obtain 6 (25 mg), 7 (20 mg), and 8 (15 mg). Fr.J10 (3.1 g) was chromatographed on Sephadex LH-20 (CHCl3−MeOH, 1:1) and purified by reversed-phase semipreparative HPLC using

Figure 6. Experimental CD spectra of 1, 3, 4, and 5.

6/5/7/6/5/6 hexacyclic ring system in 2 has never previously been found in natural products. Furthermore, compounds 1, 3, 4, and 5 were found to have a significant inhibitory effect against NO production in macrophages.

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EXPERIMENTAL SECTION

General Experimental Procedures. UV spectra were determined on a Jasco V-550 UV/vis spectrometer (Jasco, Tokyo, Japan). IR spectra (KBr disks, in cm−1) were recorded on a Jasco FT/IR-480 Plus Fourier Transform spectrometer (Jasco, Tokyo, Japan) using KBr pellets. Optical rotations were measured on a Jasco P-1020 polarimeter (Jasco, Tokyo, Japan) with a 1 cm cell at room temperature. Melting points were obtained on an X-5 micromelting point apparatus (Fukai Instrument, Beijing, China) without correction. CD spectra were obtained on a Jasco J-810 spectropolarimeter (Jasco, Tokyo, Japan) at room temperature. Single crystal data were performed using an Oxford-Diffraction SuperNova diffractometer and Cu Kα radiation. HR-ESI-MS and Q-TOF-MS/MS were carried out on an Agilent 6210 LC/MSD TOF mass spectrometer (Agilent Technologies, CA, USA) and a Waters Q TOF SYNAPT G2 mass spectrometer (Waters MS Technologies, Manchester, U.K.), respectively. HPLC-ESI-MS was carried out on a SCIEX X500R Q-TOF mass spectrometer

Scheme 1. Plausible Biosynthetic Pathways of 1−5

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DOI: 10.1021/acs.joc.8b00736 J. Org. Chem. 2018, 83, 5707−5714

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The Journal of Organic Chemistry

= 15.6 Hz, H-6β), 1.25 (3H, t, J = 7.4 Hz, H-18); 13C NMR (150 MHz, CDCl3) δ 181.4 (C-20), 171.6 (C-2), 160.5 (C-11), 139.3 (C13), 125.6 (C-9), 123.6 (C-8), 108.2 (C-10), 94.3 (C-12), 79.8 (C-3), 72.0 (C-5), 66.5 (C-14), 63.7 (N-OCH3), 62.0 (C-17), 55.8 (ArOCH3), 53.5 (C-7), 52.4 (C-15), 38.5 (C-16), 37.9 (C-6), 26.2 (C19), 10.2 (C-18); HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H25N2O5 373.1758, found 373.1755. Gelsenicine (8): colorless blocks (CH3OH); mp 168−169 °C; [α]25 D −144.5 (c 0.83, CH3OH); UV (CH3OH) λmax (log ε) 210 (3.36), 258 (2.76) nm; ECD (MeCN, Δε) λmax 210 (−15.7), 237 (+9.8), 262 (−6.6); IR (KBr) νmax 2918, 2867, 1726, 1643, 1616, 1464, 1428, 1369, 1309, 1295, 1217, 1110, 1035, 759 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.50 (1H, d, J = 7.7 Hz, H-9), 7.22 (1H, ddd, J = 7.7, 7.7, 1.1 Hz, H-11), 7.03 (1H, ddd, J = 7.7, 7.7, 1.1 Hz, H-10), 6.84 (1H, d, J = 7.7 Hz, H-12), 4.38 (1H, m, H-5), 4.26 (1H, dd, J = 11.1, 2.9 Hz, H17β), 4.23 (1H, dd, J = 11.1, 1.7 Hz, H-17α), 3.91 (3H, s, N-OCH3), 3.69 (1H, dd, J = 4.6, 1.9 Hz, H-3), 2.83 (1H, t, J = 9.3 Hz, H-15), 2.68 (1H, dq, J = 14.8, 7.4, H-19α), 2.54 (1H, t, J = 8.2 Hz, H-16), 2.39 (1H, overlapped, H-6α), 2.35 (1H, overlapped, H-19β), 2.32 (1H, overlapped, H-14α), 2.25 (1H, dd, J = 15.4, 2.3, H-6β), 2.10 (1H, ddd, J = 14.8, 10.0, 4.7 Hz, H-14β), 1.25 (3H, t, J = 7.4 Hz, H-18); 13C NMR (150 MHz, CDCl3) δ 184.5 (C-20), 171.5 (C-2), 138.2 (C-13), 132.4 (C-8), 128.2 (C-11), 124.9 (C-9), 123.5 (C-10), 106.7 (C-12), 75.1 (C-3), 72.7 (C-5), 63.5 (N-OCH3), 62.3 (C-17), 56.0 (C-7), 42.7 (C-15), 40.0 (C-16), 37.9 (C-6), 27.2 (C-14), 25.9 (C-19), 10.2 (C18); HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H23N2O3 327.1703, found 327.1709. Vallesiachotamine (9): colorless blocks (CHCl3); mp 230−231 °C; [α]25 D +36.1 (c 0.67, CH3OH); UV (CH3OH) λmax (log ε) 223 (3.19), 292 (3.09) nm; ECD (MeCN, Δε) λmax 203 (−9.4), 230 (−13.2), 266 (−3.1), 295 (+19.0); IR (KBr) νmax 3261, 2944, 2903, 2843, 1680, 1655, 1619, 1423, 1352, 1303, 1224, 1189, 1113, 1065, 1039, 748 cm−1; 1H NMR (600 MHz, CDCl3) δ 9.35 (1H, s, H-21), 8.00 (1H, br s, H-1), 7.66 (1H, s, H-17), 7.46 (1H, d, J = 7.7 Hz, H-9), 7.28 (1H, d, J = 7.7 Hz, H-12), 7.15 (1H, dd, J = 7.7, 7.7 Hz, H-11), 7.09 (1H, dd, J = 7.7, 7.7 Hz, H-10), 6.65 (1H, q, J = 7.2 Hz, H-19), 4.46 (1H, d, J = 11.2 Hz, H-3), 4.00 (1H, d, J = 5.8 Hz, H-15), 3.73 (1H, overlapped, H-5β), 3.69 (1H, overlapped, H-5α), 3.62 (3H, s, OCH3), 2.91 (1H, m, H-6β), 2.79 (1H, d, J = 13.3 Hz, H-6α), 2.15 (1H, d, J = 13.4 Hz, H-14α), 2.08 (3H, d, J = 7.2 Hz, H-18), 1.91 (1H, m, H-14β); 13C NMR (150 MHz, CDCl3) δ 196.1 (C-21), 168.6 (C-22), 153.0 (C19), 147.7 (C-17), 146.6 (C-20), 136.5 (C-13), 132.7 (C-2), 127.0 (C8), 122.3 (C-11), 120.0 (C-10), 118.4 (C-9), 111.2 (C-12), 108.7 (C7), 94.4 (C-16), 51.3 (C-5), 50.9 (OCH3), 49.5 (C-3), 34.3 (C-14), 28.6 (C-15), 22.3 (C-6), 15.3 (C-18); HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H23N2O3 351.1703, found 351.1709. Isovallesiachotamine (10): colorless blocks (CHCl3); mp 207−208 °C; [α]25 D −18.4 (c 0.83, CH3OH); UV (CH3OH) λmax (log ε) 224 (3.13), 291 (3.12) nm; ECD (MeCN, Δε) λmax 202 (−12.2), 241 (−9.8), 266 (−9.5), 291 (+15.6); IR (KBr) νmax 3267, 2924, 2854, 1669, 1652, 1604, 1590, 1439, 1418, 1359, 1325, 1296, 1209, 1182, 1158, 1101, 737 cm−1; 1H NMR (600 MHz, CDCl3) δ 10.27 (1H, s, H-21), 8.18 (1H, br s, H-1), 7.74 (1H, s, H-17), 7.45 (1H, d, J = 7.7 Hz, H-9), 7.28 (1H, d, J = 7.7 Hz, H-12), 7.14 (1H, ddd, J = 7.7, 7.7, 1.0 Hz, H-11), 7.08 (1H, ddd, J = 7.7, 7.7, 1.0 Hz, H-10), 6.54 (1H, qd, J = 7.2. 1.0 Hz, H-19), 4.23 (1H, d, J = 12.0 Hz, H-3), 4.01 (1H, d, J = 4.3 Hz, H-15), 3.68 (1H, dd, J = 12.9, 4.7 Hz, H-5β), 3.62 (3H, s, OCH3), 3.57 (1H, ddd, J = 12.9, 11.6, 4.0 Hz, H-5α), 2.90 (1H, m, H6β), 2.77 (1H, m, H-6α), 2.23 (1H, m, H-14α), 2.17 (3H, dd, J = 7.2. 1.0 Hz, H-18), 1.78 (1H, m, H-14β); 13C NMR (150 MHz, CDCl3) δ 190.9 (C-21), 168.4 (C-22), 148.0 (C-19), 147.2 (C-17), 143.4 (C20), 136.5 (C-13), 132.3 (C-2), 126.9 (C-8), 122.3 (C-11), 119.9 (C10), 118.2 (C-9), 111.3 (C-12), 108.7 (C-7), 93.9 (C-16), 51.1 (C-5), 50.9 (OCH3), 47.9 (C-3), 33.0 (C-14), 31.1 (C-15), 22.2 (C-6), 13.3 (C-18); HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H23N2O3 351.1703, found 351.1711. Biological Assay. The macrophage RAW 264.7 cells were cultivated in DMEM containing 10% FBS (v/v) with penicillin (100 U/mL) and streptomycin (100 U/mL) at 37 °C in a humidified atmosphere with 5% CO2 (v/v). The cells were allowed to grow in 96-

CH3CN−H2O (45:55; 5 mmol/L of CH3COONH4) as the mobile phase to obtain 2 (40 mg). Gelsecorydine A (1): colorless blocks (CH3OH); mp 205−206 °C; [α]25 D −62.2 (c 0.42, CH3OH); UV (CH3OH) λmax (log ε) 211 (3.36), 282 (3.29) nm; ECD (MeCN, Δε) λmax 210 (−57.8), 231 (+18.3), 266 (−33.2), 292 (+22.9); IR (KBr) νmax 3412, 2918, 2856, 1720, 1662, 1616, 1463, 1440, 1321, 1300, 1208, 1184, 1105, 1039, 749 cm−1; 1H and 13C NMR data (CDCl3) in Tables 1 and 2; HRMS (ESITOF) m/z [M + H]+ calcd for C40H43N4O6 675.3177, found 675.3196. Gelsecorydine B (2): colorless gums (CH3OH); [α]25 D +175.7 (c 0.54, CH3OH); UV (CH3OH) λmax (log ε) 209 (3.21), 282 (2.91) nm; ECD (MeCN, Δε) λmax 211 (−47.1), 228 (+23.4), 286 (+26.0); IR (KBr) νmax 3403, 2924, 2856, 1716, 1665, 1613, 1462, 1437, 1327, 1310, 1240, 1163, 1113, 1042, 749 cm−1; 1H and 13C NMR data (CDCl3) in Tables 1 and 2; HRMS (ESI-TOF) m/z [M]+ calcd for C40H41N4O6 673.3021, found 673.3033. Gelsecorydine C (3): amorphous powder (CH3OH); [α]25 D −9.2 (c 0.89, CH3OH); UV (CH3OH) λmax (log ε) 212 (3.36), 287 (3.20) nm; ECD (MeCN, Δε) λmax 211 (−57.6), 233 (+14.3), 261 (−9.8), 294 (+20.2); IR (KBr) νmax 3340, 2914, 2870, 1722, 1665, 1611, 1462, 1436, 1354, 1321, 1301, 1201, 1181, 1102, 1039, 745 cm−1; 1H and 13 C NMR data (CDCl3) in Tables 1 and 2; HRMS (ESI-TOF) m/z [M + H]+ calcd for C40H43N4O6 675.3177, found 675.3192. Gelsecorydine D (4): amorphous powder (CH3OH); [α]25 D −25.2 (c 0.71, CH3OH); UV (CH3OH) λmax (log ε) 218 (3.47), 287 (3.22) nm; ECD (MeCN, Δε) λmax 216 (−52.0), 234 (+17.7), 264 (−11.7), 292 (+17.2); IR (KBr) νmax 3414, 2921, 2851, 1719, 1664, 1613, 1494, 1455, 1439, 1385, 1359, 1322, 1303, 1214, 1183, 1108, 1038, 744 cm−1; 1H and 13C NMR data (CDCl3) in Tables 1 and 2; HRMS (ESITOF) m/z [M + H]+ calcd for C41H45N4O7 705.3283, found 705.3297. Gelsecorydine E (5): amorphous powder (CH3OH); [α]25 D −14.7 (c 0.73, CH3OH); UV (CH3OH) λmax (log ε) 212 (3.59), 287 (3.33) nm; ECD (MeCN, Δε) λmax 213 (−54.8), 233 (+19.0), 264 (−12.7), 293 (+22.0); IR (KBr) νmax 3363, 2918, 2853, 1723, 1670, 1610, 1463, 1438, 1357, 1321, 1300, 1201, 1183, 1164, 1103, 1038, 745 cm−1; 1H and 13C NMR data (CDCl3) in Tables 1 and 2; HRMS (ESI-TOF) m/ z [M + H]+ calcd for C40H43N4O5 659.3228, found 659.3229. 14-Hydroxygelsenicine (6): colorless gums (CH3OH); [α]D25 −110.9 (c 1.00, CH3OH); UV (CH3OH) λmax (log ε) 211 (3.28), 258 (2.67) nm; ECD (MeCN, Δε) λmax 211 (−14.8), 237 (+9.3), 262 (−5.8); IR (KBr) νmax 3370, 2935, 2878, 1719, 1670, 1644, 1616, 1467, 1323, 1234, 1113, 1041, 1012, 751 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.50 (1H, d, J = 7.7 Hz, H-9), 7.27 (1H, ddd, J = 7.7, 7.7, 1.0 Hz, H-11), 7.07 (1H, ddd, J = 7.7, 7.7, 1.0 Hz, H-10), 6.87 (1H, d, J = 7.7 Hz, H-12), 4.46 (1H, d, J = 2.3 Hz, H-14), 4.44 (1H, overlapped, H-5), 4.42 (1H, overlapped, H-17β), 4.32 (1H, d, J = 11.1 Hz, H-17α), 3.93 (3H, s, N-OCH3), 3.68 (1H, m, H-3), 2.92 (1H, d, J = 8.5 Hz, H15), 2.79 (1H, dq, J = 14.8, 7.4, H-19α), 2.60 (1H, m, H-16), 2.51 (1H, m, H-19β), 2.42 (1H, dd, J = 15.6, 4.6 Hz, H-6α), 2.33 (1H, dd, J = 15.6, 1.8 Hz, H-6β), 1.30 (3H, t, J = 7.4 Hz, H-18); 13C NMR (125 MHz, CDCl3) δ 181.6 (C-20), 171.0 (C-2), 137.9 (C-13), 131.7 (C8), 128.3 (C-11), 124.6 (C-9), 123.5 (C-10), 106.7 (C-12), 79.2 (C3), 71.8 (C-5), 66.0 (C-14), 63.4 (N-OCH3), 61.6 (C-17), 53.8 (C-7), 52.1 (C-15), 38.4 (C-16), 37.5 (C-6), 26.0 (C-19), 10.1 (C-18); HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H23N2O4 343.1652, found 343.1653. 11-Methoxyl-14-hydroxygelsenicine (7): colorless blocks (CH3OH); mp 87−88 °C; [α]25 D −115.8 (c 0.77, CH3OH); UV (CH3OH) λmax (log ε) 218 (3.24), 287 (2.32) nm; ECD (MeCN, Δε) λmax 217 (−11.3), 238 (+8.6), 266 (−3.7); IR (KBr) νmax 3380, 2924, 2837, 1724, 1630, 1496, 1459, 1443, 1361, 1238, 1218, 1177, 1111, 1038, 677 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.35 (1H, d, J = 8.3 Hz, H-9), 6.54 (1H, d, J = 8.3 Hz, H-10), 6.43 (1H, s, H-12), 4.40 (1H, overlapped, H-17β), 4.39 (1H, overlapped, H-14), 4.34 (1H, m, H-5), 4.27 (1H, d, J = 11.0 Hz, H-17α), 3.89 (3H, s, N-OCH3), 3.78 (3H, s, Ar-OCH3), 3.61 (1H, s, H-3), 2.85 (1H, d, J = 8.6 Hz, H-15), 2.72 (1H, m, H-19α), 2.54 (1H, ddd, J = 8.1, 8.1, 2.6 Hz, H-16), 2.45 (1H, m, H-19β), 2.35 (1H, dd, J = 15.6, 4.6 Hz, H-6α), 2.24 (1H, d, J 5713

DOI: 10.1021/acs.joc.8b00736 J. Org. Chem. 2018, 83, 5707−5714

Article

The Journal of Organic Chemistry well plates with 1 × 104 cells to treat test compounds. Cells were preincubated for 1 h in the absence or presence of compounds before the addition of LPS for 24 h. Then, the culture supernatant (100 μL) was incubated with a Griess reagent (100 μL, Sigma) at room temperature for 10 min. The absorbance was measured at 550 nm against a calibration curve with sodium nitrite standards. All experiments were performed in three independent replicates.

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Huang, X. J.; Zhang, S. Y.; Zhang, D. M.; Jiang, R. W.; Hu, J. Y.; Zhang, X. Q.; Wang, L.; Ye, W. C. Geleganidines A−C, Unusual Monoterpenoid Indole Alkaloids from Gelsemium elegans. J. Nat. Prod. 2015, 78, 2036−2044. (c) Zhang, W.; Xu, W.; Wang, G. Y.; Gong, X. Y.; Li, N. P.; Wang, L.; Ye, W. C. Gelsekoumidines A and B: Two Pairs of Atropisomeric Bisindole Alkaloids from the Roots of Gelsemium elegans. Org. Lett. 2017, 19, 5194−5197. (8) Jin, G. L.; Su, Y. P.; Liu, M.; Xu, Y.; Yang, J.; Liao, K. J.; Yu, C. X. Medicinal plants of the genus Gelsemium (Gelsemiaceae, Gentianales)A review of their phytochemistry, pharmacology, toxicology and traditional use. J. Ethnopharmacol. 2014, 152, 33−52. (9) Zhang, J. Y.; Gong, N.; Huang, J. L.; Guo, L. C.; Wang, Y. X. Gelsemine, a principal alkaloid from Gelsemium sempervirens Ait., exhibits potent and specific antinociception in chronic pain by acting at spinal α3 glycine receptors. Pain 2013, 154, 2452−2462. (10) (a) Shimokawa, J.; Harada, T.; Yokoshima, S.; Fukuyama, T. Total Synthesis of Gelsemoxonine. J. Am. Chem. Soc. 2011, 133, 17634−17637. (b) Zhou, X.; Xiao, T.; Iwama, Y.; Qin, Y. Biomimetic Total Synthesis of (+)-Gelsemine. Angew. Chem., Int. Ed. 2012, 51, 4909−4912. (c) Diethelm, S.; Carreira, E. M. Total Synthesis of Gelsemoxonine through a Spirocyclopropane Isoxazolidine Ring Contraction. J. Am. Chem. Soc. 2015, 137, 6084−6096. (11) Djerassi, C.; Monteiro, H. J.; Walser, A.; Durham, L. J. Alkaloid Studies. LVI. The Constitution of Vallesiachotamine. J. Am. Chem. Soc. 1966, 88, 1792−1798. (12) Ponglux, D.; Wongseripipatana, S.; Subhadhirasakul, S.; Takayama, H.; Yokota, M.; Ogata, K.; Phisalaphong, C.; Aimi, N.; Sakai, S. I. Studies on the indole alkaloids of Gelsemium elegans (Thailand): Structure elucidation and proposal of a biogenetic route. Tetrahedron 1988, 44, 5075−5094. (13) Waterman, P. G.; Zhong, S. M. Vallesiachotamine and Isovallesiachotamine from the Seeds of Strychnos tricalysioides. Planta Med. 1982, 45, 28−30. (14) Kitajima, M.; Nakamura, T.; Kogure, N.; Ogawa, M.; Mitsuno, Y.; Ono, K.; Yano, S.; Aimi, N.; Takayama, H. Isolation of GelsedineType Indole Alkaloids from Gelsemium elegans and Evaluation of the Cytotoxic Activity of Gelsemium Alkaloids for A431 Epidermoid Carcinoma Cells. J. Nat. Prod. 2006, 69, 715−718. (15) Dong, L. B.; Yang, J.; He, J.; Luo, H. R.; Wu, X. D.; Deng, X.; Peng, L. Y.; Cheng, X.; Zhao, Q. S. Lycopalhine A, a novel sterically congested Lycopodium alkaloid with an unprecedented skeleton from Palhinhaea cernua. Chem. Commun. 2012, 48, 9038−9040. (16) Zeng, J.; Zhang, D. B.; Zhou, P. P.; Zhang, Q. L.; Zhao, L.; Chen, J. J.; Gao, K. Rauvomines A and B, Two Monoterpenoid Indole Alkaloids from Rauvolf ia vomitoria. Org. Lett. 2017, 19, 3998−4001. (17) Kitajima, M.; Urano, A.; Kogure, N.; Takayama, H.; Aimi, N. New Oxindole Alkaloids and Iridoid from Carolina jasmine (Gelsemium sempervirens AIT. f.). Chem. Pharm. Bull. 2003, 51, 1211−1214. (18) Lin, L. Z.; Cordell, G. A. Gelsamydine, an Indole Alkaloid from Gelsemium elegans with Two Monoterpene Units. J. Org. Chem. 1989, 54, 3199−3202. (19) O′Connor, S. E.; Maresh, J. J. Chemistry and biology of monoterpene indole alkaloid biosynthesis. Nat. Prod. Rep. 2006, 23, 532−547. (20) Dewick, P. M. Medicinal natural products: a biosynthetic approach, 3rd ed.; Wiley: Hoboken, NJ, 2009; pp 371.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00736. UV, IR, HR-ESI-MS, NMR spectra of 1−5; Q-TOF-MS/ MS analysis of 2; chemical calculation details for 2; 1D NMR and CD spectra of 6−10; HPLC-MS analyses of the methanol extract for the fresh fruits of G. elegans (PDF) X-ray data for 1 (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Xiao-Jun Huang: 0000-0002-3636-4813 Wen-Cai Ye: 0000-0002-2810-1001 Lei Wang: 0000-0001-9242-1109 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Program for National Natural Science Foundation of China (U1401225, 81573307, and 81273391), the Science and Technology Planning Project of Guangdong Province (2016B030301004), the Guangdong Natural Science Foundation for Distinguished Young Scholar (2015A030306022), and the high-performance computing platform of Jinan University.

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REFERENCES

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DOI: 10.1021/acs.joc.8b00736 J. Org. Chem. 2018, 83, 5707−5714