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Organic & Biomolecular Chemistry Organic & Biomolecular Chemistry Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/obc Page 1 of 10Organic & BiomolecularOrganic & Biomolecular Chemistry Dynamic Article Links ► Chemistry Cite this: DOI: 10.1039/c0xx00000x ARTICLE TYPE www.rsc.org/xxxxxx Structures, chemotaxonomic significance, cytotoxic and Na +,K +-ATPase inhibitory activities of new cardenolides from Asclepias curassavica Rong-Rong Zhang a, Hai-Yan Tian a, Ya-Fang Tan a, Tse-Yu Chung d, Xiao-Hui Sun a, Xue Xia a,Wen-Cai Yea, David A. Middleton b, Natalya Fedosova c, Mikael Esmann c* , Jason T.C. Tzen d* , Ren-Wang Jiang a* Manuscript 5 Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x Five new cardenolide lactates (1-5) and one new dioxane double linked cardenolide glycoside ( 17 ) along with 15 known compounds ( 6- 16 and 18 -21 ) were isolated from the ornamental milkweed Asclepias curassavica . Their structures were elucidated by extensive spectroscopic methods (IR, UV, MS, 1D- and 2D-NMR). The molecular structures and absolute configurations of 1-3 and 17 were further 10 confirmed by single-crystal X-ray diffraction analysis. Simultaneous isolation of dioxane double linked cardenolide glycosides ( 17 -21 ) and cardenolide lactates ( 1-5) provided unique chemotaxonomic markers for this genus. Compounds 1-21 were evaluated for the Accepted inhibitory activities against DU145 prostate cancer cells. The dioxane double linked cardenolide glycosides showed the most potent cytotoxic effect followed by normal cardenolides and cardenolide lactates, while the C21 steroids were non-cytotoxic. Enzymatic assay + + established a correlation between the cytotoxic effects in DU145 cancer cells and the K i for the inhibition of Na ,K -ATPase. Molecular 15 docking analysis revealed relatively strong H-bond interactions between the bottom of the binding cavity and compounds 18 or 20, and explained why the dioxane double linked cardenolide glycosides possessed higher inhibitory potency on Na +,K +-ATPase than the cardenolide lactate. calotropagenin ( 6), 8 5α-card-20( 22 )-enolide, 11β- Introduction hydroxycorotoxigenin ( 7), 9 frugoside ( 8), 10 ascleposide (9), 11 calactinic acid ( 10 ), 12 digitoxigenin ( 11 ), 13 sarcostin ( 12 ), 14 Cardenolides represent a class of steroids with a five-membered 12-O-benzoyldeacylmetaplexigenin ( 13 ), 15 curassavoside A 20 lactone ring at C-17. This class of compounds bind to the 15 15 15 50 (14 ), 12-O-benzoylsarcostin ( 15 ), curassavoside B ( 16 ), Chemistry extracellular surface of the housekeeping membrane protein calotropin ( 18 ), 16 16α-acetoxycalotropin ( 19 ), 17 calactin ( 20 )18 Na +,K +-ATPase. 1 In recent years, the anticancer effects of this and asclepin ( 21 )19 (Scheme 1), were isolated and structurally class of compounds received wide attention, and was found to be characterized by spectroscopic analysis in combination with related to the modifications in the Na +,K +-ATPase signalosome 2 single-crystal X-ray diffraction. Herein we report the structural 25 and the subsequent multiple downstream signaling pathways. 55 elucidation, chemotaxonomic significance and biological Asclepias curassavica L. (commonly called Mexican butterfly activities of these compounds. weed or tropical milkweed) is a species of flowering plant in the milkweed family Asclepiadaceae. This species is native to the Results and discussion American tropics. Currently, it is a common ornamental garden 30 plant and cultivated as a source of food for butterflies Compound 1 was isolated as colorless crystals. HRESIMS worldwide. 3 This species is a rich source of cardenolides. Early analysis of 1 showed a quasi-molecular ion peak at m/z 469.2563 + phytochemical studies on this herb collected from North America 60 [M+Na] , corresponding to a molecular formula C26 H38 O6.The IR was carried out 50 years ago, which resulted in the isolation of spectrum of 1 exhibited prominent absorption bands at 3430, -1 calotropin as a cytotoxic principle against the nasopharynx cancer 1733 and 1716 cm , indicating the presence of hydroxyl and Biomolecular 4 1 13 35 cells. Subsequent studies on this herb collected from Taiwan and carbonyl functionalities. H and C NMR spectra of 1 (Table 1) Yunnan provinces of China led to the identification of a series of showed the typical signals for a butenolactone ring [ δ 5.89 (1H, H & cardenolides and their glycosides with strong cytotoxicities 65 s, H-22), 4.99 (1H, dd, J = 18.4, 1.5 Hz, H-21 β), and 4.94 (1H, against human A549 (lung carcinoma cell), MCF-7 and MDA- dd, J = 18.4, 1.5 Hz, H-21 α), and δC 177.3, 178.5, 117.8 and 75.3], MB-231 (both breast carcinoma cells), and HepG2 (hepatoma two methyl singlets [ δH 0.85 (3H, s, H-19) and 0.88 (3H, s, H-18), 5-7 40 cell). In our continuous search for structurally unique and δC 12.5 and 16.4], one methyl doublet [ δH 1.35 (3H, d, J = 6.9 Hz, biologically interesting cardiotonic steroids from the plant H-3’), δC 20.6], resonances for two oxygenated carbons [ δH 4.18 kingdom, this plant cultivated in Guangdong province was 70 (1H,q, J = 6.9 Hz, H-2’) and 4.73 (1H, m, H-3), and δC 67.9 and 13 chosen for phytochemical investigation. Five new cardenolide 75.5], and an additional ester carbonyl at δ C 176.0. The CNMR lactates ( 1-5) and one dioxane double linked cardenolide chemical shifts of all the hydrogenated carbons could be assigned Organic 45 glycoside ( 17 ) along with 15 known compounds, i.e. unambiguously from the HSQC spectrum. Comparison of the This journal is © The Royal Society of Chemistry [year] [journal] , [year], [vol] , 00–00 | 1 Organic & Biomolecular Chemistry Page 2 of 10 NMR data for 1 with desglucouzarin 20 indicated that the 1H and 2(5H)-one unit could be formed by ring closure involving an 13 CNMR signals for the protons and carbons in the A, B, C, D and oxygen atom bridged to C-21 and C-23. Specially, HMBC E rings had similar chemical shifts. The maJor differences in the correlations from H 3-3’ (δH1.35) to C-2’ ( δC67.9) and C-1’ ( δC 13 20 C NMR spectral data between 1 and desglucouzarin were the 20 176.0), confirmed the presence of a lactate unit in compound 1, 5 presence of a lactate unit (one carbonyl, one oxygenated methine and the correlation between H-3 [ δH4.73 (1H, m)] and C-1’ and one methyl) in 1 instead of a sugar unit in desglucouzarin. 21 established location of the lactate unit at C-3. Taken together, The full NMR data assignments of 1 were determined by the compound 1 was determined as a new cardenolide with a lactate analyses of 1H-1H COSY, HSQC and HMBC spectroscopic data moiety at C-3 as shown in Fig. 1. 1 1 (Fig. 1). The H- H COSY spectrum showed three spin coupling 25 The relative configuration of 1 was determined by analysis of 10 systems (in bold face in Fig. 1): (i) H2-1→ H2-2→ H-3→ H2-4→ NOESY data, which showed correlations H 3-19 ↔ H-8, H-8↔ H-5→ H2-6→ H2-7→ H-8→ H-9→H2-11 → H2-12, (ii) H2-15 → H3-18, indicating that H 3-19, H-8 and H 3-18 were the same β- H2-16 → H-17, and (iii) H3-3’ → H-2’, which were consistent with oriented. Similarly, the NOESY correlations H-3 ↔ H-5, H-5 ↔ the cardenolide lactate skeleton. The HSQC spectrum revealed H-9, but absence of correlation H-3↔ H -18 suggested that H-3, 3 Manuscript that the proton at δH5.89 (H-22) was attached to the carbon at 30 H-5, H-9 were mutually oriented on the other side. 15 δC117.8 (C-22), and the HMBC spectrum showed that H-22 was correlated to C-20, C-21, and C-23, suggesting that the furan- O O O 23 O O OH O 22 E 21 O 2'' 19 20 1'' 3'' 12 17 11 13 C O 18 H 16 1 9 14 H D H 2 O 10 8 15 O H OH A H OH Accepted 5 7 H OH HO 2' HO B 1' 3 O O HO 4 H 6 3' H H 1 2 3 O OH O OR2 OH OH OH O 2'' O OH O 2'' O H OH H O H R1O R R O 6''' H OH 1 2 H OH 4''' 5''' O 12 H H HO HO O 2' H Chemistry O 3''' 2''' 1''' 13 H Bz H OH 5 4 OH 14 Rc Bz O O 23 O O 22 O OR 21 2 18 20 OH 12 11 17 R2 R OH R1 13 4 OH H 1 R3 H 14 R4 3' O 9 16 R H 4' 3 2' 2 10 8 15 R2 H OH H OH 5' 1' 3 7 H OH R1O O O 5 6' H H 4 H 6 R1 R R R R H R1 R2 1 2 3 4 15 H Bz 17 OH H OH H R1 R2 R3 R4 Rc Bz 6 OH OH CHO H 16 18 OH H CHO H 7 OH H CHO OH 19 OH H CHO OAc Biomolecular 8 Ra H CH2OH H 20 H OH CHO H 9 Ra H CH3 H 21 H OAc CHO OAc 10 Rb OH CHO H & 11 OH H CH3 H O O OH Me Me Me O O O O HO O O O Rb = Rc Bz = Ra = HO HO H = O OH OH OMe OH Scheme 1 Structural formulae of compounds 1-21 Organic 2 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 3 of 10 Organic & Biomolecular Chemistry obtained from methanol solution.
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