Dihydro-Î²-Agarofuran Sesquiterpene Pyridine Alkaloids from the Seeds Of

Journal of Saudi Chemical Society (2013) xxx, xxx–xxx

King Saud University Journal of Saudi Chemical Society

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ORIGINAL ARTICLE Dihydro-b-agarofuran sesquiterpene pyridine alkaloids from the seeds of Euonymus hamiltonianus

Mudasir A. Tantry a,b,c,*, Mohammad A. Khuroo b, Abdul S. Shawl c, Muzaﬀar H. Najar b, Ikhlas A. Khan a a National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, MS 38677, United States b Department of Chemistry, University of Kashmir, Srinagar 190006, Kashmir, India c Natural Product Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Srinagar 190005, Kashmir, India

KEYWORDS Abstract Plants of the Celastraceae family produce various dihydro-b-agarofuran sesquiterpene Euonymus hamiltonianus; pyridine alkaloids. Two dihydro-b-agarofuran sesquitepene pyridine alkaloids (1,2) apart from four Dihydro-b-agarofuran known compounds euojaponin C (3), wilforine (4), austronine (5) and O9-benzoyl-O9-deacetylevonine sesquiterpene pyridine (6), were isolated from the ripe seeds of Euonymus hamiltonianus. Their chemical structures were alkaloids; elucidated mainly by analysis of NMR and MS spectral data. All compounds were evaluated for Insecticidal activity insecticidal activity. ª 2012 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.

1. Introduction India. Over the years, a large variety of biologically-active secondary metabolites have been identiﬁed from the members Dihydro-b-agarofuran sesquiterpenoids are a structurally of Celastraceae. They include potent maytansinoids (Cordell diverse class of natural products based on the tricyclic and Farnsworth, 1977; Nakao et al., 2004; Cassady et al., 5,11-epoxy-5b,10a-eudesman-4-(14)-ene skeleton. The family 2004), macrocyclic spermidines (Seguineau et al., 1992; Schultz Celastraceae is the major source of dihydro-b-agarofuran et al., 1997), amphetamines (Al-Motarreb et al., 2002), sesquiterpenoids and comprises approximately 88 genera and terpenoids (Munoz et al., 1993; Li et al., 1997; Duan et al., 1300 plant species, which are widespread in tropical and 2001; Nakagawa et al., 2004; Ankli et al., 2000; Niampoka subtropical regions of the world including China and North et al., 2005), cardenolides (Kitanaka et al., 1996) and ﬂavonoids (Corsino et al., 2003). The Celastraceae are a source * Corresponding author at: National Center for Natural Products of several terpenoids such as triterpenes of a series friedlane Research, Research Institute of Pharmaceutical Sciences, School of (Figueiredo et al., 1998; Ohsaki et al., 2004), lupane (Kitanaka Pharmacy, The University of Mississippi, MS 38677, United States. et al., 1996; Nunez et al., 2005), oleanane (Corsino et al., 2003), Tel.: +1 662 607 9594; fax: +1 662 915 1708. several types of dimeric triterpenes (Gonzalez et al., 1996), and E-mail address: [email protected] (M.A. Tantry). sesquiterpenes (Bruning and Wagner, 1978). On the other Peer review under responsibility of the King Saud University. hand, in our previous work on branches and the stem bark of Euonymus hamiltonianus, we reported the isolation of coumarins (Tantray et al., 2008) and glutinane triterpenes (Tantray et al., 2009) respectively. However the most Production and hosting by Elsevier wide-spread and characteristic metabolites of this family are

Please cite this article in press as: Tantry, M.A. et al., Dihydro-b-agarofuran sesquiterpene pyridine alkaloids from the seeds of Euonymus hamiltonianus. Journal of Saudi Chemical Society (2013), http://dx.doi.org/10.1016/j.jscs.2012.11.012 2 M.A. Tantry et al. a large group of unusually highly oxygenated sesquiterpenoids, by the taxonomist at the center for Biodiversity and Taxonomy based on 5,11-epoxy-5b,10a-eudesman-4-(14)-ene skeleton known Biodiversity (CBT), University of Kashmir, Srinagar India. A as dihydro-b-agarofurans and are regarded as chemotaxonomic voucher specimen (No. EH-SS-09-004; dated 14/10/2009) of markers of the family (Bruning and Wagner, 1978). Moreover they the plant was deposited in the same center. are endowed with novel chemical diversity and complicated stereochemistry, and possess a broad spectrum of biological 2.3. Extraction and isolation activities such as immunosuppressive (Zheng et al., 1989), cytotoxic (Kuo et al., 1994), as insect antifeedant, insecticidal The dried and pulverized seeds (600 g) of E. hamiltonianus (Gonzalez et al., 1989), anti-HIV (Duan et al., 1999), reverse were extracted with hexanes (2.5 L) under reflux for 2 h. The multi-drug resistance (MDR) phenotype (Cortes-Selva et al., extracted material was re-extracted with acetone (4 l) twice. 2005) and antitumour activities (Ujita et al., 1993), suggesting The acetone extract was combined and concentrated to give the interactions of sesquiterpenoids with a variety of cellular a brown semisolid residue (98.5 g). This crude extract was targets. The exploitation of these molecules should allow rapid chromatographed on a silica gel (40 lm) column using discovery of biologically active compounds across a broad range EtOAc-petroleum ether (2:8 fi 8:2) as eluent to give 84 of therapeutic areas on a reasonable time scale. Taking this into fractions (each 500 ml). Fractions 50–62 were combined account, our work was switched to chemical investigation of (28 g) and chromatographed on Sephadex LH-20 by using seeds of E. hamiltonianus (Celastraceae), for this we already methanol to obtain 3 (22.5 mg) and 4 (13.2 mg). Fraction investigated some parts. The acetone extract of seeds of 65–71 (12 g) were chromatographed on Sephadex LH-40 under E. hamiltonianus led to the isolation of six dihydro-b-agarofuran vacuum (VLC) by using MeOH–H2O (9.5:0.5) to afford 5 sesquitepene pyridine alkaloids by including two new ones (1,2). (8.8 mg) and 6 (17.5 mg). Fractions 73–79 (8 g) were collected The known ones were identified as euojaponin C (3), and subjected to HPLC (RP-18, MeOH–H2O–CH3CN, wilforine (4)(Jinbo et al., 2002), austronine (5)(Sousa et al., 62:35:3) to afford compounds 1 (5.4 mg) and 2 (4.8 mg). 2006) and O9-benzoyl-O9-deacetylevonine (6)(Almeida et al., 2010). The chemical structures of all the isolated compounds, 2.3.1. Hamiltonianin A (1) were elucidated mainly by NMR and MS spectral data. All Amorphous powder [a] 25 = +12.5 (0.10, MeOH); UV compounds (1–6) were evaluated for insecticidal activity, some D (MeOH) k (loge): 232 (4.21), 268 (3.98) nm; IR (KBr) m : of them (2, 5, 6) showed considerable activity. max max 3424, 2921, 1744, 1726, 1612, 1596, 1439, 1371, 1224, 1176, 1073 cm1; HR-ESIMS: m/z 996.2753 [M + Na]+ (Calcd. 2. Experimental 1 13 for C49H51NO20Na); H and C NMR: (see Table 1).

2.1. General 2.3.2. Hamiltonianin B (2) 25 Amorphous powder [a]D = +8.2 (0.10, MeOH); UV NMR spectra were recorded on Bruker 400 and 600 NMR (MeOH) kmax (loge): 226 (4.25), 266 (3.99) nm; IR (KBr) mmax: spectrometer instruments using TMS as the internal standard. 3439, 2927, 1745, 1723, 1619, 1589, 1429, 1358, 1245, 1152, Chemical shifts were reported in d units and coupling 1039 cm1; HR-ESIMS: m/z 1036.3093 [M+H]+ (Calcd. for 1 13 constants (J) in Hz. ESIMS and HRESIMS were obtained on C54H53NO20H); H and C NMR: (see Table 1). Agilent Series 1100 SL mass spectrometer. IR spectra were recorded using KBr pellet on a Bruker Tensor 27 FT-IR 3. Results and discussion spectrometer. Optical rotations were measured on a Rudolph Research AutoPol IV polarimeter. Column chromatography Compound 1 was analyzed for C49H51NO20 by showing was performed by using silica gel (40 lm mesh, JT Baker), molecular ion peak at m/z 996.2753 [M+Na]+. IR absorption ODS silica gel and reversed-phase RP-C18, C-8 silica (Polarbond; displayed absorption at 1726 cm1 and 1744 cm1 indicating JT Baker). Medium Pressure Liquid Chromatography was the presence of ester groups by indicating a,b-unsaturated performed on Biotage Inc. Horizon MPLC System. TLC carbonyl system and a free hydroxyl absorption at analysis was carried out on silica gel 60 F254 plates (Merck) 3424 cm1. The NMR spectral data (Table 1) suggested the and spots on TLC plates were observed under UV light presence of ﬁve acetate esters and two benzoate esters and (254/365 nm). Spraying reagents vanillin-H2SO4 (Sigma–Aldrich), one evoninate ester. The 1H NMR spectrum of compound 1 p-anisaldehyde-H2SO4, 10% H2SO4 in ethanol and water, showed the presence of sec-methyl group at dH 1.39 (d, 6.8). followed by heating were used for the detection of The signals observed at dH 5.90 (d, 3.5), 5.42 (dd, 3.5, 2.8), spots. All HPLC experiments were carried out on a Shimadzu 4.82 (d, 2.8), 6.85 (d, 4.0), 2.51 (bs), 5.58 (dd, 3.7, 6.0) and SIL-10A with auto injector, SCL-10A System with Activation 5.48 (d, 6.0) were ascribable to H-1, H-2, H-3, H-6, H-7, H-8 GoldPak 100 5 lm ODS 250 · 10 mm or Waters C18 and H-9 protons, respectively, based on the 1H–1H 300 · 8mm5lm semi-preparative columns. All solvents used DQF-COSY spectrum of 1 and by comparing the chemical for extractions and chromatographic separations were of shifts and coupling constants of 1 with Euoverrine A and B analytical grade with the exception of HPLC grade solvents used (Jinbo et al., 2002). The signals dH 4.92 (d, 12.1), 5.30 for HPLC separations. (d, 12.1) and dH 3.88 (d, 11.8), 5.56 (d, 11.8) were ascribable to geminal coupled protons bearing ester moieties. The 13C 2.2. Plant material NMR spectrum of 1 depicted the chemical shift value completely in agreement with Euoverrine A (Jinbo et al., The seeds of E. hamiltonianus were collected from 2002), with one methyl substituted with acetate and these Wangath-Naranag Ganderbal (Kashmir Valley) and identiﬁed resonances were in agreement with b-dihydroagarofuran

1 13 Table 1 H-NMR (600 MHz, pyridine-d5, dH, J/Hz), C-NMR (150 MHz, pyridine-d5, dC) of 1 and 2. Position 1 2

dC dH dC dH 1 73.2 d 5.90 d (3.5) 74.1 d 5.92 d (3.5) 2 69.9 d 5.42 dd (3.5, 2.8) 69.8 d 5.40 dd (3.5, 2.8) 3 76.4 d 4.82 d (2.8) 75.8 d 4.85 d (2.5) 4 70.3 s 70.1 s 5 92.5 s 93.0 s 6 74.7 d 6.85 d (4.0) 74.6 d 6.89 d (4.0) 7 49.1 d 2.51 bs 48.9 d 2.54 bs 8 70.2 d 5.58 dd (3.7, 6.0) 70.1 d 5.60 dd (3.7, 6.0) 9 71.4 d 5.48 d (6.0) 70.9 d 5.50 d (6.0) 10 51.9 s 52.5 s 11 83.8 s 83.5 s 12 21.7 q 1.64 s 22.4 q 1.65 s 13 60.5 t 4.92 d (12.1), 5.30 d (12.1) 60.9 t 4.89 d, 5.33 d (12.1) 14 70.6 t 3.88 d (11.8), 5.56 d (11.8) 71.2 t 3.89 d, 5.58 d (11.8) 15 19.2 q 1.71 s 19.5 q 1.72 s 20 163.4 s 164.2 s 30 124.5 s 123.9 s 40 136.6 d 8.05 dd (7.8, 1.8) 135.5 d 8.03 dd (7.7, 1.8) 50 122.3 d 7.58 m 122.5 d 7.61 m 60 157.7 d 8.69 dd (4.8, 1.8) 157.8 d 8.69 dd (4.5, 1.8) 70 35.9 d 4.72 m 74.5 d 5.43 d (6.0) 80 69.7 d 5.59 d (6.2) 46.6 d 5.59 d (6.0) 90 175.6 s 174.5 s 100 168.2 s 167.6 s 110 15.2 q 1.39 d (6.8) 19.6 q 1.42 d (6.4) OAc (C-2) 20.1 q, 168.7 s 1.95 s 20.2 q, 168.9 s 1.91 s OAc (C-8) 21.1 q, 170.2 s 2.18 s 22.1 q, 170.1 s 2.17 s OAc (C-9) 20.2 q, 169.6 s 2.21 s 20.2 q, 169.9 s 2.28 s OAc (C-13) 20.3 q, 170.6 s 2.23 s 20.3 q, 172.2 s 2.21 s OAc (C-80) 19.1 q, 171.2 s 2.20 s OBz (C-1) 165.2 s, (CO) 165.2 s, (CO) 130.2 s, (C1) 130.3 s, (C1) 129.2 d, (C2), 129.8 d, (C6) 8.02 dd, 8.03 dd 129.2 d, (C2), 129.8 d, (C6) 8.05 dd, 8.07 dd 127.2 d, (C3), 127.8 d, (C5) 7.52 m, 7.53 m 127.2 d, (C3), 127.8 d, (C5) 7.49 m, 7.53 m 133.4 d, (C4) 7.60 m 133.5 d, (C4) 7.61 m OBz (C-6) 165.1 s, (CO) 165.1 s, (CO) 130.3 s, (C1) 130.5 s, (C1) 129.3 d, (C2), 128.9 d, (C6) 8.01 dd, 8.03 dd 129.8 d, (C2), 129.1 d, (C6) 8.10 dd, 8.08 dd 127.1 d, (C3), 127.3 d, (C5) 7.53 m, 7.51 m 127.2 d, (C3), 127.8 d, (C5) 7.52 m, 7.50 m 133.1 d, (C4) 7.59 m 133.1 d, (C4) 7.57 m OBz (C-70) 164.9 s, (CO) 130.3 s, (C1) 129.8 d, (C2), 129.0 d, (C6) 8.00 dd, 8.02 dd 127.2 d, (C3), 127.9 d, (C5) 7.55 m, 7.54 m 132.9 d, (C4) 7.58 m

sesquiterpene alkaloid (Schaneberg et al., 2001; Zhu et al., (J2,3 = 3.5) suggested that both protons had an equatorial 2008). Chemical shifts and coupling constants of protons orientation. The coupling constants (J7,8 = 3.7, J8,9 = H-1 (5.90, d, J = 3.5), H-2 (5.42, dd, J = 3.5, 2.8) and H-6 6.0 Hz) between the protons H-7, H-8 and H-9 suggested that (6.85, d, J = 4.0) have axial, equatorial and axial orientations the protons H-7, H-8 and H-9 are in equatorial, equatorial and respectively. The coupling constants between H-2 and H-3 axial orientations respectively which was conﬁrmed by cross

O O O O O O

13 13 O O O O 1 9 1 9 2 10 8 2 10 8

O 3 5 7 O O 3 5 7 O 4 6 4 6 O 15 O 15 11 O 11 O O HO O HO 12 9' 12 9' O 14 11' 14 O O O O 8' 8' O O O O 7' 7' 10' 2' 3' 10' 2' 3' 11' O

N N 4' O 4' O

6' 6' 5' 5' 1 2

Figure. 1 Structure of compounds 1 and 2.

O O O O O O

O O O O

O O O O O O O O O O HO HO O O O O O O O O O

N O N O

1 2

Figure. 2 1H–1H DQF-COSY ( ) and HSQC, HMBC ( ) correlations of compounds 1 and 2. peaks between H-1 and H-9 in the NOESY spectrum of 1 and that of 1. The 1H NMR spectrum convincingly supports same coupling constant patterns as in Euoverrine A (Jinbo b-dihydrogaro sesquiterpene core skeleton, with typical signals et al., 2002). at dH 5.92 (d, 3.5), 5.40 (dd, 3.5, 2.5), 4.85 (d, 2.5), 6.89 (d, 4.0), Chemical shift values of 1 with Euoverrine A showed the 2.54 (bs), 5.60 (dd, 3.7, 6.0) and 5.50 (d, 6.0) were ascribable to substituted methyl group with ester by showing the cross peak H-1, H-2, H-3, H-6, H-7, H-8 and H-9 protons respectively, 0 1 1 13 in HMBC spectra at dH 5.59 (H-8 )/dC 171.2 (C‚O), dH 5.58 supported by H– H DQF-COSY spectrum. The C NMR (H-8)/dC 170.2 (C‚O), dH 5.48 (H-9)/dC 169.6 (C‚O), dH spectrum of 2 depicted the additional signal of benzoate. 4.92 (H-3)/dC 170.6 (C‚O), dH 5.90 (H-1)/dC 165.2 (C‚O) Chemical shift and coupling constants are in quite agreement and dH 6.85 (H-6)/dC 165.1 (C‚O). The resonances of three with axial, equatorial and axial orientation of H-1, H-2 and aromatic protons at dH 8.05 (dd), dH 7.58 (m) and dH 8.69 H-6. The substitution of benzoyl moiety was conﬁrmed by 0 (dd) corresponds to the pyridine moiety of evorinic acid series interaction of dH 5.43 (d, 6.0, H-7 )/dC 164.9 (C‚O) in HMBC (Jinbo et al., 2002). The comparison of chemical shift values spectrum. The close agreement of NMR spectral data of 2 with and coupling constants of the compound 1 seems to be 1 and also with Euoverrine A, has allowed us to be elucidate substituted Euoverrine A as elucidated acetyl Euoverrine A compound 2 as benzoyl Euoverrine A and was named and was named hamiltonianin A (Fig. 1). hamiltonianin B (Fig. 1). The 1H–1H DQF-COSY, HSQC Compound 2 was determined to be C54H53NO20 by and, HMBC correlations of compounds 1 and 2 are shown HRESIMS, which displayed a molecular ion peak at m/z in Fig. 2. 1036.3093 [M+H]+. IR absorption again displayed Using previously published protocol (Wu et al., 1992), 1 1 absorption at 1723 cm and 1745 cm indicating the the KD50 (the dose required to knock down 50% of the presence of ester moieties and three benzoyl esters, indicating population of target insect larvae) determined for the one additional benzoates and one deﬁcient acetate as compounds 1–6 were 57.2, 121.6, 98.4, 108.9, 203.7 and

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