Cassiabudanols A and B, Immunostimulative Diterpenoids with a

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

pubs.acs.org/OrgLett

Cassiabudanols A and B, Immunostimulative Diterpenoids with a Cassiabudane Carbon Skeleton Featuring a 3‑Oxatetracyclo[6.6.1.02,6.010,14]pentadecane Scaffold from Cassia Buds Haofeng Zhou,† Yindengzhi Guoruoluo,†,‡ Yali Tuo,† Junfei Zhou,† Hanqi Zhang,† Wei Wang,† Ming Xiang,† Haji Akber Aisa,‡ and Guangmin Yao*,† Downloaded via MCMASTER UNIV on January 2, 2019 at 16:56:18 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

†

Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China ‡ State Key Laboratory of Xinjiang Indigenous Medicinal Plants Resource Utilization, Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China S Supporting Information *

ABSTRACT: Two novel diterpenoids, cassiabudanols A (1) and B (2), were isolated from cassia buds. Their structures were determined by comprehensive spectroscopic analysis and singlecrystal X-ray diffraction. Compounds 1 and 2 possess an unprecedented 11,14-cyclo-8,14:12,13-di-seco-isoryanodane (cassiabudane) carbon skeleton featuring a unique 3-oxatetracyclo[6.6.1.02,6.010,14]pentadecane bridged system, and their biosynthetic pathways are proposed. Compounds 1 and 2 exhibited significant immunostimulative activity, and the mode of action of 2 involves upregulating CD4+ and CD8+ T cells and downregulating Tregs.

D

Scheme 1. Representative Diterpene Carbon Skeletons from Cinnamomum cassia and Their Biogenetic Relationships

iterpenoids with complex, highly oxygenated, polycyclic carbon skeletons from medicinal plants have been proved to be a potent resource for new drug discovery. A representative example is taxol, which was approved for treatment of cancers in the clinic by the U.S. FDA in 1992.1 Ryanodane diterpenoids possessing a complex polyoxygenated 6/5/5/6/5 pentacyclic skeleton have been found in the plants of Ryania speciosa (Flacourtiaceae),2 Cinnamomum zeylanicum (Lauraceae),3 Cinnamomum cassia (Lauraceae),4 Persea indica (Lauraceae),5 Spigelia anthelmia (Loganiaceae),6 and Erythroxylum passerinum and Erythroxylum nummularia (Erythroxylaceae),7 and some of them showed significant anticomplement,4a,b antifeedant,5 anti-inflammatory,4d cardiac,6 channelmodulatory,8 immunomodulatory,4c and insecticidal activities.5 Because of their complex structures and potent bioactivities, the total synthesis of ryanodane diterpenoids9 has attracted growing attention from organic chemists, and ryanodine,9a ryanodol,9b (+)-ryanodol,9c−e cinnzeylanol, cinnacasol, and cinncassiols A and B9f have been synthesized. C. cassia Presl (Lauraceae), a versatile evergreen tree, is a potent source of ryanodane and related diterpenoids. To date, a total of 29 diterpenoids have been reported from its bark,4a−d,10 twigs,4e and leaves.11 The representative diterpenoids are cinncassiols A−G and cinnamomanol A, and they belong to eight biogenetically related diterpene carbon skeletons (Scheme 1): ryanodane (cinncassiol B type),4a © XXXX American Chemical Society

11,12-seco-ryanodane (cinncassiol A type),4b 7,8-seco-ryanodane (cinncassiol C type),10a,b isoryanodane (cinncassiol D Received: December 5, 2018

A

DOI: 10.1021/acs.orglett.8b03883 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters type),10c−e 10,13-cyclo-12,13-seco-isoryanodane (cinncassiol E type),10f 12,13-seco-isoryanodane (cinncassiol F type),4c 11,12seco-isoryanodane (cinncassiol G type),4c and 6,10-cyclo-12,13seco-isoryanodane (cinnamomane).11 The dried immature fruits of C. cassia are known as cassia buds and are widely used not only as food spice and flavoring agents but also as a traditional Chinese medicine (Rou-Gui-Zi in Chinese) and a traditional Uighur medicine (Dahl’s Pro in Uyghur) to treat cardiothoracic pains, cold pain in the stomach and abdomen, nausea, vomiting, belch, hiccup, cough, and dyspnea.12 Previous phytochemical investigations of cassia buds revealed that their major components are essential oils, sesquiterpenoids, and phenolic compounds.13 However, there has been no report of diterpenoids from cassia buds. To search for structurally novel diterpenoids with significant immunomodulatory activity, cassia buds extract was further investigated, leading to the isolation of two minor novel diterpenoids, named cassiabudanol A (1) and B (2) (Figure 1), and a known isoryanodane diterpenoid, 18-hydroxypersea-

degrees of unsaturation, and thus, a tetracyclic system in 1 was deduced from the remaining four degrees of unsaturation. Analysis of the HSQC and 1H−1H COSY spectra of 1 revealed the presence of two partial structures of (a) “HOCH215−CH-2−CH2-3−CH2-4” and (b) “CH3-17−CH-12” (bold lines) (Figure 2). HMBC correlations from H-2 to C-1/C-4/

Figure 2. 1H−1H COSY and key HMBC and NOESY correlations and the X-ray crystal structure of cassiabudanol A (1).

C-5, from H2-4 to C-1/C-5, and from H2-15 to C-1 established the five-membered ring A. The six-membered ring B was constructed by the HMBC correlations from H3-16 to C-9/C8/C-5, from H-8 to C-6/C-7, and from H-2 to C-6. HMBC correlations from H3-16 to C-8/C-9/C-10, from H3-17 to C-7/ C-11/C-12, from H-8 to C-7/C-9/C-12, and from H-10 to C9/C-11/C-12 suggested the presence of the six-membered ring C and the locations of CH3-16 and CH3-17 at C-9 and C-12, respectively. In consideration of the six degrees of unsaturation as well as the HMBC correlations from H2-14 to C-10/C-11/ C-13/C-18 and from H-10 to C-13/C-14/C-11, an ether linkage between C-10 and C-13 was proposed, forming the five-membered ring D. The HMBC correlations from H3-19/ H3-20 to C-13/C-18 and from H3-21 to C-13 suggested that both the oxygenated isopropyl group and the methoxy group are located at the C-13 ketal carbon (δC 111.4). Consequently, the planar structure of 1 was determined. To meet the minimum-energy rule, H-12 in 1 was assigned to be an axial β orientation (Figure 2). The NOESY correlations of H-12β and H-14β, H-14β and H3-19/H3-20, and H-14α and 13-OCH3 suggested the α orientation of 13OCH3. Because of the lack of useful NOESY information, it was difficult to completely define the relative configuration of 1. Finally, the structure of 1 was confirmed by single-crystal Xray diffraction using Cu Kα radiation (Figure 2), and the calculated Flack parameter of 0.03(3)14 assigned its absolute configuration to be 2R,7R,8S,9S,10R,11R,12S,13R. Cassiabudanol B (2), a colorless oil, possesses a molecular formula of C20H30O8 as determined by the HR-ESI-MS ion at m/z 421.1836 [M + Na]+ (calcd for C20H30O8Na, 421.1838). During the purification of 2, there were two discrete peaks 2a and 2b in a ratio of ca. 3:2 in the HPLC chromatogram (Figure S1). To our surprise, the 1H NMR spectra of 2a and 2b were exactly same, displaying two set of signals in a ratio of ca. 3:2. Thus, compound 2 consists of two epimers that can easily convert to each other, indicating the presence of a hemiketal group.15 The NMR data of 2 were similar to those of 1, with the major difference of the absence of 13-OCH3 in 2. In addition, C-13 (δC 107.4, 2a; 107.6, 2b) was shielded

Figure 1. Chemical structures of cassiabudanol A (1) and B (2) and the nomenclature of the unique bridged system.

nol (3), which was previously isolated from the bark of C. cassia.4c Compounds 1 and 2 possess an unprecedented 5/6/ 6/5 tetracyclic 11,14-cyclo-8,14:12,13-di-seco-isoryanodane diterpene carbon skeleton derived from the isoryanodane diterpene carbon skeleton via 11,14-carbon−carbon bond reformation and 8,14:12,13-carbon−carbon bond cleavage (Scheme 1) and featuring a unique 3-oxatetracyclo[6.6.1.02,6.010,14]pentadecane bridged system. More importantly, 1 and 2 exhibited significant immunostimulative activity in vitro. Herein we report the isolation, structure elucidation, plausible biosynthetic pathways, and immunostimulative activities of 1 and 2 as well as the mode of action of 2. Cassiabudanol A (1) was obtained as cubic crystals (mp 134−136 °C, MeOH). Its molecular formula was determined to be C21H32O8 by the HR-ESI-MS ion at m/z 435.1992 [M + Na]+ (calcd for C21H32O8Na, 435.1995), indicating six degrees of unsaturation. The characteristic IR absorptions at 1666 and 1630 cm−1 and a maximum UV absorption at 260 nm suggested the presence of an α,β-unsaturated ketone functionality in 1. The 1H NMR spectrum of 1 (Table S1) showed resonances for one secondary methyl, three tertiary methyls, a methylene, an oxygenated methylene, and two oxygenated methines. The 13C NMR spectrum of 1 (Table S1) exhibited 21 carbon resonances assignable by DEPT and HSQC spectra to be four methyls, an oxygenated methyl (δC 50.7), four methylenes (one oxygenated), four methines (two oxygenated), a quaternary carbon, three oxygenated tertiary carbons, a ketal carbon (δC 111.4, C-13), two sp2 tertiary carbons (δC 138.9, C-1; 171.1, C-5), and a ketone carbonyl (δC 198.9, C-6). The double bond and carbonyl account for two B


Letter

Organic Letters

enzyme-mediated methylation. The detailed biosynthetic pathway is shown in Scheme S1. Since diterpenoids from the bark4c and leaves11 of C. cassia have been reported to exhibit immunomodulatory activity, 1 and 2 were evaluated for their in vitro immunomodulatory activity using a concanavalin A (ConA)- and lipopolysaccharide (LPS)-induced splenocyte proliferation assay (Table S2 and Figure 3).4c,17 Compounds 1 and 2 significantly promoted

compared with that in 1 (δC 111.4). Thus, compound 2 is a 13-de-OCH3 derivative of 1 bearing a 13-hemiketal functionality. 2D NMR data confirmed the structure and relative configuration of 2. The absolute configuration of 2, ignoring C13, was determined to be the same as 1 on the basis of their similar ECD spectra (Figure S2) and their biogenetic relationship. To date, a total of eight diterpene carbon skeletons, named cinncassiols A−G and cinnamomane,11 have been isolated from C. cassia (Scheme 1). Cassiabudanol A (1) and B (2) possess an unprecedented 5/6/6/5 tetracyclic 11,14-cyclo8,14:12,13-di-seco-isoryanodane diterpene skeleton featuring a unique 3-oxatetracyclo[6.6.1.02,6.010,14]pentadecane bridged system, and this new diterpene skeleton is named cassiabudane. In view of the biogenetic point, this new cassiabudane diterpene carbon skeleton may be derived from the isoryanodane diterpene carbon skeleton via 11,14-carbon− carbon bond reformation and 8,14:12,13-carbon−carbon bond cleavage. Thus, a plausible biosynthetic pathway for 1 and 2 involving carbon−carbon bond cleavage and reformation as well as ring formation is proposed (Scheme 2) starting from a likely biogenetic precursor, the known isoryanodane diterpenoid 3, which was coisolated in this study and previously isolated from the bark of C. cassia.4c Scheme 2. Proposed Biosynthetic Pathway for 1 and 2

Figure 3. Impacts of 1 and 2 on (A) ConA-induced T-cell and (B) LPS-induced B-cell proliferation. Control: spleen cells without LPS/ ConA. Other groups are stimulated by LPS/ConA. Mean ± SD of three replicates are shown; * indicates 0.01 < p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001 compared with Tp-5.

the proliferation of ConA-induced murine T cells with enhancement rates up to 39.99% at a concentration of 0.0015 μM and enhanced the proliferation of LPS-induced murine B cells with enhancement rates up to 92.36%. Interestingly, compound 2 showed more potent immunostimulative activity than 1 and the positive control, thymopentin (Tp-5).18 Thus, the hemiketal functionality in 2 may be the active group for the immunostimulative activity. More importantly, 1 and 2 did not show obvious general cytotoxity against the murine lymphocytes at concentrations from 0.0015 to 25 μM (Figure S3). T cells play an important role in the immune system and are classified into CD4+, CD8+, and CD4+CD25+Foxp3+ subsets. Among them, CD4+ T cells play a central role in immune protection, helping B cells produce antibodies.19 CD8+ T cells contribute to enhancing the immune function and improving the quality of T cell responses to antigenic stimulation.20 CD4+CD25+Foxp3+ T cells (Tregs) are related to immune tolerance21 and suppress immune responses.22 In order to study the effect of compound 2 on T cells, the spleen cells were treated with anti-CD3 plus anti-CD28 or not, and then the percentages of CD4+ T cells, CD8+ T cells, and Tregs in spleen T cells were detected using a flow cytometer. T cells were stimulated, activated, and purified by anti-CD3 plus antiCD28. The results (Figure 4) showed that compound 2 can increase the percentages of CD4+ T cells and CD8+ T cells in

First, the ether linkage between C-6 and C-11 of the hemiketal group in 3 is cleaved under the catalysis of acid to afford ketone 4, and then the bond between C-12 and C-13 in 4 is cleaved by a retro-aldol reaction16 to produce diketone 5. Under the catalysis of an alkaline enzyme, the bond between C-11 and C-14 is constructed by an aldol reaction in 5 to generate 6, which is the key step to form the new carbon skeleton. The bond between C-8 and C-14 in 6 is cleaved by a retro-aldol reaction to form the new diketone 7. Consequently, polyhydroxylated diketone 8 is produced by oxidation of 7. As a nucleophile, 10-OH in 8 attacks the C-13 carbonyl to form an oxygen bridge between C-10 and C-13, producing hemiketal 9. Dehydration of 9 under the catalysis of acid gives conjugated α,β-unsaturated ketone 10 (Scheme S1). Compound 2 is generated by selective reduction of the C-8 carbonyl in 10. Finally, compound 1 is generated from 2 by C


Letter

Organic Letters

via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

■

AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Haji Akber Aisa: 0000-0003-4652-6879 Guangmin Yao: 0000-0002-8893-8743 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was financially supported by the Foundation of the Key Laboratory of Plant Resources and Chemistry in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences (2008DP1730912016-01) and the Fundamental Research Funds for the Central Universities (HUST: 2016YXMS148). We thank the Analytical and Testing Center at Huazhong University of Science and Technology for spectroscopic data collection.

■

Figure 4. Effects of 2 and TP-5 at 0.3906 μM on spleen T cell subsets by FACS analysis. Spleen cells were stimulated by CD3CD28. (A) Representative FACS staining for CD3, CD4, or CD8 and the percentages of CD4+ and CD8+ T cells. (B) Cells were stained with CD4, CD25, and Foxp3, and the percentages of CD4+CD25+Foxp3+ Tregs are displayed.

normal spleen cells and spleen cells stimulated by anti-CD3 and anti-CD28, respectively. Intriguingly, compound 2 significantly decreased the percentage of Tregs in the stimulation group and is more potent than TP-5. Thus, compound 2 might enhance the immune function by upregulating CD4+ and CD8+ T cells and downregulating Tregs. In summary, two highly modified and functionalized diterpenoids with an unprecedented cassiabudane carbon skeleton, cassiabudanol A (1) and B (2), and their biogenetic precursor, 18-hydroxyperseanol (3), were isolated from cassia buds. Compounds 1 and 2 possess a 5/6/6/5 tetracyclic 11,14cyclo-8,14:12,13-di-seco-isoryanodane carbon skeleton featuring a unique 3-oxatetracyclo[6.6.1.02,6.010,14]pentadecane scaffold and exhibited in vitro immunostimulative activities. The mechanism study revealed that 2 can promote the expansion of CD4+ and CD8+ T cells and decrease Tregs. This finding provides a new structural class of immunostimulative agents.

■

REFERENCES

(1) Newman, J.; Cragg, G. M. J. Nat. Prod. 2016, 79, 629−661. (2) Rogers, E. F.; Koniuszy, F. R.; Shavel, J.; Folkers, K. J. Am. Chem. Soc. 1948, 70, 3086−3088. (3) (a) Isogai, A.; Suzuki, A.; Tamura, S.; Murakoshi, S.; Ohashi, Y.; Sasada, Y. Agric. Biol. Chem. 1976, 40, 2305−2306. (b) Isogai, A.; Murakoshi, S.; Suzuki, A.; Tamura, S. Agric. Biol. Chem. 1977, 41, 1779−1784. (4) (a) Nohara, T.; Tokubuchi, N.; Kuroiwa, M.; Nishioka, I. Chem. Pharm. Bull. 1980, 28, 2682−2686. (b) Yagi, A.; Tokubuchi, N.; Nohara, T.; Nonaka, G.; Nishioka, I.; Koda, A. Chem. Pharm. Bull. 1980, 28, 1432−1436. (c) Zeng, J.; Xue, Y.; Shu, P.; Qian, H.; Sa, R.; Xiang, M.; Li, X. N.; Luo, Z.; Yao, G.; Zhang, Y. J. Nat. Prod. 2014, 77, 1948−1954. (d) He, S.; Jiang, Y.; Tu, P. F. J. Asian Nat. Prod. Res. 2016, 18, 134−140. (e) Ngoc, T. M.; Ha, D. T.; Lee, I.-S.; Min, B. S.; Na, M. K.; Jung, H. J.; Lee, S. M.; Bae, K. H. Helv. Chim. Acta 2009, 92, 2058−2062. (5) (a) Fraga, B. M.; González-Coloma, A.; Gutiérrez, C.; Terrero, D. J. Nat. Prod. 1997, 60, 880−883. (b) Fraga, B. M.; Terrero, D.; Gutiérrez, C.; González-Coloma, A. Phytochemistry 2001, 56, 315− 320. (c) González-Coloma, A.; Hernández, M. G.; Perales, A.; Fraga, B. M. J. Chem. Ecol. 1990, 16, 2723−2733. (d) González-Coloma, A.; Cabrera, R.; Castañera, P.; Gutiérrez, C.; Fraga, B. M. Phytochemistry 1992, 31, 1549−1552. (e) González-Coloma, A.; Cabrera, R.; Socorro Monzón, A. R.; Frag, B. M. Phytochemistry 1993, 34, 397−400. (f) González-Coloma, A.; Terrero, D.; Perales, A.; Escoubas, P.; Fraga, B. M. J. Agric. Food Chem. 1996, 44, 296−300. (g) GonzálezColoma, A.; Gutiérrez, C.; Hübner, H.; Achenbach, H.; Terrero, D.; Fraga, B. M. J. Agric. Food Chem. 1999, 47, 4419−4424. (6) (a) Achenbach, H.; Huebner, H.; Vierling, W.; Brandt, W.; Reiter, M. J. Nat. Prod. 1995, 58, 1092−1096. (b) Hübner, H.; Vierling, W.; Brandt, W.; Reiter, M.; Achenbach, H. Phytochemistry 2001, 57, 285−296. (7) Barreiros, M. L.; David, J. P.; David, J. M.; Xavier Lopes, L. M.; de Sá, M. S.; Costa, J. F. O.; Almeida, M. Z.; de Queiróz, L. P.; Sant’Ana, A. E. G. Phytochemistry 2007, 68, 1735−1739. (8) Sutko, J. L.; Airey, J. A.; Welch, W.; Ruest, L. Pharmacol. Rev. 1997, 49, 53−98. (9) (a) Bélanger, A.; Berney, D. J. F.; Borschberg, H.-J.; Brousseau, R.; Doutheau, A.; Durand, R.; Katayama, H.; Lapalme, R.; Leturc, D. M.; Liao, C.-C.; MacLachlan, F. N.; Maffrand, J.-P.; Marazza, F.;

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03883. NMR spectroscopic data, detailed experimental procedures, and 1D and 2D NMR, IR, UV, ECD, and HRESI-MS spectra of 1 and 2 (PDF) Accession Codes

CCDC 1567064 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge D


Letter

Organic Letters Martino, R.; Moreau, C.; Saint-Laurent, L.; Saintonge, R.; Soucy, P.; Ruest, L.; Deslongchamps, P. Can. J. Chem. 1979, 57, 3348−3354. (b) Nagatomo, M.; Koshimizu, M.; Masuda, K.; Tabuchi, T.; Urabe, D.; Inoue, M. J. Am. Chem. Soc. 2014, 136, 5916−5919. (c) Nagatomo, M.; Hagiwara, K.; Masuda, K.; Koshimizu, M.; Kawamata, T.; Matsui, Y.; Urabe, D.; Inoue, M. Chem. - Eur. J. 2016, 22, 222−229. (d) Masuda, K.; Koshimizu, M.; Nagatomo, M.; Inoue, M. Chem. - Eur. J. 2016, 22, 230−236. (e) Chuang, K. V.; Xu, C.; Reisman, S. E. Science 2016, 353, 912−915. (f) Koshimizu, M.; Nagatomo, M.; Inoue, M. Angew. Chem., Int. Ed. 2016, 55, 2493− 2497. (10) (a) Nohara, T.; Nishioka, I.; Tokubuchi, N.; Miyahara, K.; Kawasaki, T. Chem. Pharm. Bull. 1980, 28, 1969−1970. (b) Kashiwada, Y.; Nohara, T.; Tomimatsu, T.; Nishioka, I. Chem. Pharm. Bull. 1981, 29, 2686−2688. (c) Nohara, T.; Kashiwada, Y.; Tomimatsu, T.; Kido, M.; Tokubuchi, N.; Nishioka, I. Tetrahedron Lett. 1980, 21, 2647−2648. (d) Nohara, T.; Kashiwada, Y.; Murakami, K.; Tomimatsu, T.; Kido, M.; Yagi, A.; Nishioka, I. Chem. Pharm. Bull. 1981, 29, 2451−2459. (e) Nohara, T.; Kashiwada, Y.; Tomimatsu, T.; Nishioka, I. Phytochemistry 1982, 21, 2130−2132. (f) Nohara, T.; Kashiwada, Y.; Nishioka, I. Phytochemistry 1985, 24, 1849−1850. (11) Zhou, L.; Tuo, Y.; Hao, Y.; Guo, X.; Tang, W.; Xue, Y.; Zeng, J.; Zhou, Y.; Xiang, M.; Zuo, J.; Yao, G.; Zhang, Y. Org. Lett. 2017, 19, 3029−3032. (12) Editorial Committee of Chinese Materia Medica. Chinese Materia Medica (Zhonghua bencao); Shanghai Science and Technology Publishing House: Shanghai, 1999; Vol. 7, pp 46. (13) (a) Guoruoluo, Y.; Zhou, H.; Zhou, J.; Zhao, H.; Aisa, H. A.; Yao, G. J. Agric. Food Chem. 2017, 65, 5614−5619. (b) Guoruoluo, Y.; Zhou, H.; Wang, W.; Zhou, J.; Aisa, H. A.; Yao, G. Biochem. Syst. Ecol. 2018, 78, 102−105. (14) Parsons, S.; Flack, H. D.; Wagner, T. Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng. Mater. 2013, 69, 249−259. (15) Lai, C. Z.; Liu, H. B.; Liu, J. X.; Ouyang, Q.; Pang, S. W.; Zhou, H.; Tian, H.; Liu, Y. L.; Yao, X. S.; Tang, J. S. RSC Adv. 2016, 6, 59257−59268. (16) Wang, L.; Yang, J.; Kong, L. M.; Deng, J.; Xiong, Z.; Huang, J.; Luo, J.; Yan, Y.; Hu, Y.; Li, X. N.; Li, Y.; Zhao, Y.; Huang, S. X. Org. Lett. 2017, 19, 3911−3914. (17) Fan, Y. Y.; Zhang, H.; Zhou, Y.; Liu, H. B.; Tang, W.; Zhou, B.; Zuo, J. P.; Yue, J. M. J. Am. Chem. Soc. 2015, 137, 138−141. (18) Ding, J. H.; Wang, L. L.; Chen, Z.; Wang, J.; Yu, Z. P.; Zhao, G.; Chen, B. A. Int. J. Hematol. 2013, 97, 280−283. (19) Zhu, S.; Xu, X.; Liu, K.; Gu, Q.; Yang, X. Pharmacol. Res. 2015, 102, 113−122. (20) Mannick, J. B.; Del Giudice, G.; Lattanzi, M.; Valiante, N. M.; Praestgaard, J.; Huang, B.; Lonetto, M. A.; Maecker, H. T.; Kovarik, J.; Carson, S.; Glass, D. J.; Klickstein, L. B. Sci. Transl. Med. 2014, 6, 268ra179. (21) Sakaguchi, S.; Yamaguchi, T.; Nomura, T.; Ono, M. Cell 2008, 133, 775−787. (22) Sakaguchi, S.; Wing, K.; Onishi, Y.; Prieto-Martin, P.; Yamaguchi, T. Int. Immunol. 2009, 21, 1105−1111.

E


Cassiabudanols A and B, Immunostimulative Diterpenoids with a

Recommend Documents