Dimeric Cadinane Sesquiterpenoid Derivatives from Artemisia annua

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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Dimeric Cadinane Sesquiterpenoid Derivatives from Artemisia annua Da-Peng Qin,†,‡ Da-Bo Pan,†,‡ Wei Xiao,§ Hai-Bo Li,§ Biao Yang,§ Xiao-Jun Yao,∥ Yi Dai,†,‡ Yang Yu,*,†,‡ and Xin-Sheng Yao*,†,‡ †

Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy and ‡Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, People’s Republic of China § Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222001, People’s Republic of China ∥ State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, AvenidaWailong, Taipa, Macau S Supporting Information *

ABSTRACT: Arteannoide A (1), an unusual cadinane dimer featuring a rare fused 6,8-dioxabicyclo[3.2.l]octan-7-one ring system, arteannoides B and C (2 and 3), two novel heterodimers incorporating a rearranged cadinene sesquiterpenoid and a phenylpropanoid, together with two new rearranged cadinene sesquiterpenoids 4 and 5, were isolated from Artemisia annua L. Their structures were determined by a combination of NMR spectroscopy, electronic circular dichroism calculations, and X-ray diffraction analyses. Compounds 2 and 3 showed inhibition of nitric oxide production in lipopolysaccharide-induced RAW 264.7 mouse macrophage cell lines with IC50 values of 4.5 and 2.9 μM, respectively.

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esquiterpenes from the medicinal plant Artemisia annua L. (Qinghao) attracted the attention of chemists and biologists due to their diverse structures1−6 and interesting bioactivities.7−11 Among them, artemisinin possessing a peroxide bridge and potent antimalarial activity is the most famous sesquiterpenoid reported from this plant: the 2015 Nobel Prize in Physiology or Medicine was shared by Professor Youyou Tu for her impactful research work on the development of artemisinin in collaboration with other Chinese scientists.12 In our continuous efforts to discover new bioactive terpenes from medicinal plants, the extract from A. annua was found to contain potentially new sesquiterpenes by HPLC−MS analysis. Chemistry-guided investigation on the extract led to the isolation of three novel compounds, arteannoides A−C (1−3, respectively), along with two new compounds arteannoides D and E (4 and 5) from A. annua (Figure 1). To the best of our knowledge, compound 1 is the first sesquiterpenoid dimmer composed of two cadinene sesquiterpenoid units linked by an unusual fused ring system of 6,8-dioxabicyclo[3.2.l]octan-7-one.13 Compounds 2 and 3, two novel heterodimers incorporating a rearranged cadinene sesquiterpene and one phenylpropanoid unit, represent the first examples of cadinene sesquiterpene−phenylpropanoid conjugates. Compound 4 is a new rearranged cadinane-type sesquiterpenoid; only three compounds possessing this rearranged cadinane-type skeleton were isolated from brown alga Dictyopteris divaricate.14 Herein, we report the isolation, structural elucidation, possible biogenetic pathway, and antiinflammatory activities of 1−5. Arteannoide A (1) was obtained as colorless block crystals. The molecular formula was deduced to be C30H40O6 based on the pseudomolecular ion at m/z 497.2899 [M + H]+ (calcd for © XXXX American Chemical Society

Figure 1. Chemical structures of compounds 1−5.

C30H41O6, 497.2903) from the HRESIMS analysis. The 1H NMR spectrum of 1 (Table S1-1) showed signals assignable to three methyls [δH 2.40 (s), 0.91 (d, J = 6.5 Hz), 0.90 (d, J = 5.8 Hz)], one olefinic methylene [δH 5.96 (br s) and 5.50 (d, J = 1.5 Hz)], and one olefinic methine proton [δH 7.13 (s)]. Its 13C NMR displayed 30 carbon resonances including seven quaternary carbons (including one keto-carbonyl, one ester carbonyl, one carboxylic carbonyl, two olefinic carbons, and two oxygenated ones), 10 methines (including an olefinic one), 10 methylenes (including an olefinic carbon), and three methyls. Received: December 5, 2017

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DOI: 10.1021/acs.orglett.7b03796 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters The analysis of the 1H−1H COSY spectrum revealed the spin systems [C-5−C-6−C-7−C-8−C-9−C-10−C-1−C-2, C-1−C6, and C-10−C-14 (Figure 2)], combined with the main HMBC

C-6′ as well as the 1H−1H COSY correlation of H-7′/H-8′/H-9′ suggested the connections of the s-trans-1,3 diene substituent and C-1′. Nevertheless, a methoxy group was located at C-3′ (δC 149.4), due to the obvious HMBC correlation of δH 3.94/C-3′. The aforementioned data indicate the presence of a 9-substituted (E)-isoeugenol moiety. The 1H−1H COSY correlations of H-7/H2-8/H2-9/H-10/H314 revealed a five-membered chain (C-7−C-8−C-9−C-10−C14) as shown in Figure 2. The methylene protons H2-13 showed HMBC correlations with carboxylic acid carbons C-12 and C-7, confirming an acrylic acid positioned at C-7. The correlations from H-2 to C-1/C-3/C-5/C-6 and H3-15 to C-3/C-4 indicated the presence of a five-membered ring (C-1−C-2−C-3−C-5−C6−C-1) with an acetyl group. Furthermore, the associations of H-7/C-1 and H-10, H3-14/C-1 indicated the presence of a rearranged cadinane-type sesquiterpene moiety. Finally, the 9substituted (E)-isoeugenol moiety and the sesquiterpene moiety were connected by the HMBC correlations of H-9′/C-3, C-5, C6. Therefore, the deduced planar structure of 2 is shown in Figure 1. The relative configuration of 2 was determined on the basis of a NOESY experiment (Figure S2). The correlations of H-9a/H13b and H-9b/H3-14 suggested that H2-13 and H3-14 were situated on the opposite side. NOESY cross-peaks of H-7/H-8′ disclosed the H-8′ orientation. The absolute stereochemistry of 2 was elucidated by comparison of the experimental ECD spectrum of 2 with the calculated spectra of (7R, 10R)-2 and (7S, 10S)-2. The TDDFTcalculated ECD spectrum of the enantiomer (7R,10R)-2 was almost consistent with the experimental spectrum, indicating the 7R,10R configuration of 2. Thus, the structure of arteannoide B was assigned. Arteannoide C (3) was obtained as a reddish-brown powder. The molecular formula was determined to be C26H28O6 by the positive HRESIMS ion peak at m/z 437.1966 [M + H]+ (calcd for 437.1964). The similar UV, IR, and ECD spectra inferred that its structure was similar to that of 2. The differences between 2 and 3 were found by the presence of an additional methoxy group (δC 57.1) located at C-5′ in the (E)-isoeugenol moiety. The ECD data of 3 well matched that of 2 (Figure 4), indicating that they shared the same absolute configuration (7R, 10R). Thus, the structure of 3 was determined. Arteannoide D (4),14 a colorless gum, exhibited a molecular formula of C15H20O4 as determined by the HRESIMS (m/z 265.1442 [M + H]+, calcd for C15H21O4, 265.1440) and 13C NMR data, requiring six indices of hydrogen deficiency. The 1H NMR spectrum of 4 showed three methyl groups at δH 2.37 (s, H3-15), 1.15 (d, J = 7.1 Hz, H3-13), and 1.01 (d, J = 6.6 Hz, H3-

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

correlations (Figure 2) from H3-15 to C-3/C-4, from H-5 to C1/C-2/C-3/C-6, from H-7 to C-12/C-13, and from H2-13 to C7/C-12, led to the assignment of a rearranged cadinane-type sesquiterpene moiety. Similarly, the 1H−1H COSY correlations of H-6′/H-7′/H2-8′/H2-9′/H-10′/H-1′/H2-2′/H2-3′/H-4′/H215′, H-6′/H-1′ and H-10′/H3-14′, as well as HMBC correlations (Figure 2) from H2-13′ to C-7′/C-11′/C-12′, and from H2-15′ to C-3′/C-5′, from H-1′ to C-5′, completed the cadinane-type sesquiterpene moiety. The linkage of the above two moieties were confirmed by the 1H−1H COSY correlations of H2-13/H215′ and HMBC correlations from H2-13 to C-4′, and from H215′ to C-11. Therefore, the gross structure of arteannoide A was established as 1. The relative stereochemistry of 1 was assigned by X-ray crystallographic analysis and NOESY correlations between H-1 and H-7/H3-14, between H-6 and H-10, between H-1′ and H7′/H3-14′, and between H-6′ and H-4′/H-10′ (Figure 3). The absolute configuration was certified by the Flack absolute structure parameter 0.0(2).

Figure 3. Key NOESY correlations and X-ray crystallographic analysis of 1.

Arteannoide B (2) was obtained as a reddish brown powder. Its molecular formula was determined to be C25H26O5 by HRESIMS (m/z 407.1855 [M + H]+, calcd for C25H27O5, 407.1858), indicating 13 degrees of unsaturation. The 1H NMR spectrum of 2 (Table S1-2) contains one typical ABX proton coupling pattern (δH 7.11, d, J = 1.8 Hz, H-2′; δH 6.77, d, J = 8.0 Hz, H-5′; δH 6.97, dd, J = 8.0, 1.8 Hz, H-6′) and one s-trans-1,3 diene substituent (δH 6.94, d, J = 14.9 Hz, H-7′; δH 7.17, dd, J = 14.9, 12.5 Hz, H-8′; δH 8.08, d, J = 12.5 Hz, H-9′). Moreover, the HMBC correlations from H-8′ to C-1′, and from H-7′ to C-2′/

Figure 4. Experimental ECD spectra of 2 and 3 and calculated ECD spectra of (7R,10R)-2 and (7S,10S)-2. B

DOI: 10.1021/acs.orglett.7b03796 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 1. Plausible Biogenetic Pathway of Compounds 1−5

14), an olefinic proton at δH 7.20 (H-5), as well as signals with complex coupling patterns attributed to methylene and methane protons (Table S1-3). The 13C NMR and DEPT spectra of 4 showed 15 carbon signals for three methyls, three methylenes, four methines (one olefinic), and five quaternary carbons (one oxygen bearing, one olefinic, one keto-carbonyl, and one carboxylic carbonyl). The 1H−1H COSY correlations of H-1/H2-2, H-1/H-10/H29/H2-8, H-10/H3-14, revealed the main structural sequences (C2−C-1−C-10−C-14 and C-8−C-9−C-10) as shown in Figure S1. In the HMBC spectrum, long-range correlations (Figure S1) from H2-2 to C-1/C-3 and from H-5 to C-3/C-6/C-7 confirmed the presence of the bicyclo[4.3.0]nonane ring system in 4. In addition, the HMBC correlations from H2-2/H3-15 to C-4 and C-3 demonstrated the location of the acetyl at C-3, while correlations from H3-13 to C-7/C-12 confirmed the locations of the isopropyl acid at C-7. Apart from these characteristic signals, resonances for an epoxy group were also observed in the 1D NMR spectra, its position was assigned to C-6 and C-7 from the HMBC correlations of H-1/C-7 and H-2/C-6 (Figure S1). Thus, the structure of 4 was established as shown. The relative configuration of 4 was established by analyzing NOESY correlations (Figure S2). The correlations of H-1/H314, H-9b/H3-14, and H-9a/H3-13 suggested that H-1 and H3-14 were on the same side, H3-13 on the opposite side, whereas the lack of effective correlation makes it impossible to assign the relative configuration at C-11 by using NOESY observations. As a result, the conformers of (1S,6S,7R,10R,11R)-4 and (1S,6S,7R,10R,11S)-4 were calculated by using the Gaussian 09 software. It was found that the calculated weighted ECD spectra of (1S,6S,7R,10R,11R)-4 are in good accordance with the experimental CD spectrum of 4 (Figure S6). Consequently, the absolute configuration of 4 was unambiguously assigned. Arteannoide E (5)15 was obtained as colorless block crystals. The molecular formula of 5 was established to be C13H16O3 (6 degrees of unsaturation) from its HRESIMS (m/z 221.1178 [M + H]+, calcd for C13H17O3, 221.1178). The 1H NMR spectrum of 5 showed one methyl group at δH 1.04 (d, J = 6.4 Hz, H3-14), an olefinic methylene at δH 6.53 (s, H-13a) and 5.73 (s, H-13b), an olefinic proton at δH 5.63 (s, H-5), as well as several complex multiplets from δH 1.00 to 2.60 (see Table S1-3). The 13C NMR and DEPT spectra showed 13 carbon signals including one methyl, four methylenes (one olefinic), four methines (one olefinic), and four quaternary carbons (two olefinic, one ketone, and one carboxylic acid group) (Table S1-3). The planar bicycle

carbon skeleton of 5 was established by 2D NMR experiments. The 1H−1H COSY relationships of 5 exhibited the main structural sequences, C-2−C-1−C-10−C-14 and C-7−C-8−C9−C-10. In combination with the HMBC correlations between H2-13 and C-7/C-11/C-12, H-7 and C-1/C-6 revealed the presence of one six-membered ring moiety with a methyl at C-10 and an isopropyl at C-7. The HMBC correlations between H-1 and C-2, C-6, and C-10 and between H2-2 and C-1, C-6, and C10 clearly indicated that the C-1 was directly connected with C-2, C-6, and C-10, while correlations between H-5 and C-1, C-7 and between H-8 and C-6 established the connection between C-6 and C-7 to form the right six-membered ring. In addition, the HMBC correlations of H2-2/H-5 with the carbonyl carbon (C3), and H2-2 with C-5, revealed that the carbonyl was located between C-2 and C-5 to form the left five-membered ring. The relative stereochemistry of 5 was elucidated on the basis of NOESY analyses (Figure S2). The NOE correlations of H-1/H-7 and H-1/H3-14 suggested that H-1, H-7, H3-14 were situated on the same side. Finally, the absolute configuration of 5 was established as 1S,7R,10R by single-crystal X-ray diffraction using Cu Kα radiation (Figure S8). The discovery of rearranged cadinane-type sesquiterpenoid derivatives in A. annua is rather unusual from the viewpoint of chemotaxonomy. The putative biosynthetic route of 1−5 was proposed as shown in Scheme 1, in which oxidative cleavage and hetero-Diels−Alder cycloaddition were the key reactions.13,16−19 This plausible biogenetic pathway might be a useful inspiration for the total synthesis of 1−5. To evaluate the biological properties of the isolates with such a new chemical skeleton, all of the isolated compounds were evaluated for anti-inflammatory activities on NO production in LPS-activated RAW 264.7 cells. Compounds 2 and 3 could reduce NO levels in LPS-activated RAW 264.7 macrophages with an IC50 of 4.5 and 2.9 μM (hydrocortisone was used as a positive control, IC50 = 48.7 μM). Additionally, 1−5 did not show cytotoxic activities against the human tumor cell lines MCF-7, MDA-MB-231, and U937 (IC50 > 40 μM). In our research for new bioactive sesquiterpenes from traditional Chinese medicine, five rearranged cadinane-type sesquiterpenoid derivatives, arteannoides A−E (1−5), were isolated from A. annua. Compound 1 is an unusual sesquiterpenoid dimmer incorporating a rearranged cadinene sesquiterpene and a cadinene sesquiterpene through a rare fused 6,8-dioxabicyclo[3.2.l]octan-7-one ring system, which was postulated to be biosynthesized by a hetero-Diels−Alder C

DOI: 10.1021/acs.orglett.7b03796 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters cycloaddition. Compounds 2 and 3 represent the first two unprecedented cadinene sesquiterpene−phenylpropanoid conjugates, while compound 4 is a new rearranged cadinane-type sesquiterpene, increasing the structural diversity of sesquiterpenes in nature. The remarkable anti-inflammatory activities of 2 and 3, combined with their unique architectures, provide valuable inspiration for relevant drug discovery.

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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.orglett.7b03796. General experimental procedures, chemicals, extraction and isolation methods, anti-inflammatory activities of 1− 5, quantum chemical ECD calculations of 2 and 4, and MS, UV, IR, 1D and 2D NMR data, assignments, and spectra for compounds 1−5 (PDF) Accession Codes

CCDC 1547891 and 1547898 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

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

Xiao-Jun Yao: 0000-0002-8974-0173 Xin-Sheng Yao: 0000-0003-1603-4873 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by grants from the National Natural Science Foundation of China (Key Program No. 81630097). We are grateful to the State Key Laboratory of Biotherapy, Sichuan University, and Beijing Institute of Pharmacology and Toxicology for their assistance of activity test.

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REFERENCES

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DOI: 10.1021/acs.orglett.7b03796 Org. Lett. XXXX, XXX, XXX−XXX