PHYTOCHEMISTRY Phytochemistry 68 (2007) 1799–1804 www.elsevier.com/locate/phytochem Iridoids from Scutellaria albida ssp. albida Chrysoula Gousiadou a, Anastasia Karioti a, Jörg Heilmann b, Helen Skaltsa a,* a b Department of Pharmacognosy and Chemistry of Natural Products, School of Pharmacy, University of Athens, Panepistimiopolis, Zografou, 15771 Athens, Greece Institute of Pharmacy, Department of Pharmaceutical Biology, University of Regensburg, Universitätsstrasse 31, D-93053 Regensburg, Germany Received 20 February 2007; received in revised form 16 April 2007 Available online 29 May 2007 Abstract Three iridoid glycosides, 6 0 -O-E-p-coumaroylgardoside (1), 6 0 -O-p-E-coumaroyl-8-epi-loganic acid (2) and scutelloside (3) were isolated from the aerial parts of Scutellaria albida subsp. albida, in addition to an anomeric mixture in equilibrium of one iridoid aglycone (4, 4a), nine iridoid glycosides (5–13), four known phenylethanoid glycosides (14–17), and six known phenolic derivatives (18–23).  2007 Elsevier Ltd. All rights reserved. Keywords: Scutellaria albida subsp. albida; Lamiaceae; Iridoids; Phenylethanoid glycosides; Phenolic derivatives 1. Introduction 2. Results and discussion Scutellaria albida L. ssp. albida (Lamiaceae) is an herbaceous perennial plant, often somewhat woody at the base. The plant has a general distribution from N. Italy to the Balkan peninsula and Crimea (Bothmer, 1985). Several species of the genus Scutellaria present antispasmodic, diaphoretic and febrifuge properties and are used in folk medicine (Duke, 1986). In previous research into S. albida L. ssp. albida, apigenin, hispidulin and luteolin glycosides have been isolated (Skaltsa et al., 1996). In further study, the essential oil of the plant has been investigated (Skaltsa et al., 2000). In this paper, we report on the isolation and structural elucidation of three new iridoid glycosides, 6 0 -O-E-p-coumaroylgardoside (1), 6 0 -O-p-E-coumaroyl-8-epi-loganic acid (2) and scutelloside (3) in addition to 10 known iridoid aglycones and glycosides (4–13), four known phenylethanoid glycosides (14–17), and six simple phenolic derivatives (18–23). The methanolic extract of the aerial parts of S. albida ssp. albida after being successively chromatographed on silica gel columns and RP-HPLC, yielded along with the three new iridoid glycosides, an anomeric mixture in equilibrium of one iridoid aglycone (4, 4a), namely dihydrocatalpogenine (C-1) a-epimer (4)/b-epimer (4a) (Gao et al., 1997), nine known iridoid glycosides, catalpol (5) (Çalis et al., 1993a; Chaudhuri and Sticher, 1981), albidoside (6) (Çalis et al., 1993a), picroside III (7) (Weinges and Künstler, 1977), dihydrocatalpol (8) (Huang et al., 2006), 10-descinnamoylglobularinin (9) (Chaudhuri et al., 1979), globularin (10) (Foderaro and Stermitz, 1992), (Çalis et al., 2002), gardoside (11) (Albach et al., 2004), 8-epiloganic acid (12) (Damtoft et al., 1984), macfadyenoside (13) (Bianco et al., 1974), four known phenylethanoid glycosides, martynoside (14) (Warashina et al., 1992), isomartynoside (15) (Çalis et al., 1984), deacyl-martynoside (16) (Çalis et al., 1984, 1993b), acteoside (17) (Andary et al., 1982) and six known phenolic derivatives, E-p-coumaric acid (18) (Harborne, 1984), E-caffeic acid (19) (Harborne, 1984), E-ferulic acid (20) (Harborne, 1984), E-p-coumaroylglucoside (21) (Harborne, 1984), vanilloloside (22) * Corresponding author. Tel./fax: +30 2107274593. E-mail address: skaltsa@pharm.uoa.gr (H. Skaltsa). 0031-9422/$ - see front matter  2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.phytochem.2007.04.014 1800 C. Gousiadou et al. / Phytochemistry 68 (2007) 1799–1804 (Ida et al., 1994) and benzyl-b-glucopyranoside (23) (Schwab and Schreier, 1988) were also isolated. The known compounds 4–23 were identified by spectral analysis and direct comparison of their physical properties with those reported previously for these compounds. Compound 1 was obtained as yellowish oil. 1D and 2D NMR spectra showed that 1 consisted of a gardoside moiety esterified to a p-coumaroyl group. In the 1H NMR spectrum, downfield shifts of sugar protons H-6a 0 and H6b 0 (at d 4.47 and 4.38 respectively) were observed, which indicated esterification at C-6 0 of the b-glucopyranosyl moiety. The HSQC spectrum offered further support for the proposed structure of 1. The C-6 0 resonance of the b-glucopyranose was typically deshielded by 2.3 ppm (a-effect) while the C-5 0 resonance was shifted upfield by 2.5 ppm (b-effect) due to the acylation of the primary hydroxyl function. HMBC confirmed the position of the p-coumaroyl residue by showing a clear long-range correlation peak between the carbonyl carbon (d 168.7) and both H-6a 0 and H-6b 0 (d 4.47 and 4.38) of the glucopyranosyl unit. Therefore 1 was assigned as 6 0 -O-E-p-coumaroylgardoside. Compound 2 was obtained as yellowish oil. 1D and 2D NMR spectra showed that 2 consisted of a 8-epi-loganic acid moiety esterified to a p-coumaroyl group at C-6 0 . Structure elucidation strategy was very similar compared Table 1 Spectral data of compounds 1–3 in CD3OD (1H 400 MHz, Position 1 3a 3b 4a 4b 5 6a 6b 7 8 9 10a 10b 11 10 20 30 40 50 60a 60b 100 200 and 600 300 and 500 400 700 800 900 1 to 1 and confirmed that 2 was the hitherto unknown 6 0 O-p-E-coumaroyl-8-epi-loganic acid. Compound 3 was obtained as amorphous substance. In the ESI-MS spectrum no molecular ion peak was observable and the dominating fragment showed a m/z at 200 [Mglucose; (calcd for C15H24O11: 380.13182)]. The 1H NMR, 13C NMR, HSQC and COSY spectral data suggested that 3 had a nine carbon catalpol-like iridoid structure, attached to a b-glucopyranosyl moiety at C1. An HMBC correlation peak between H-1 0 [d 4.68 (d, J = 7.8 Hz)] and C-1, confirmed the attachment of the sugar unit. The 1H NMR spectrum displayed two acetal protons [d 5.63 (d, J = 1.6 Hz, H-1), 5.27 (d, J = 2.7 Hz, H-3)], two oxygenated methine protons [d 4.04 (dd, J = 7.4, 0.9 Hz, H-7), 4.03 (dd, J = 7.4, 2.6 Hz, H-6)], two oxygenated methylene protons [d 3.98 (d, J = 12.4 Hz, H-10a), 3.60 (d, J = 12.4 Hz, H-10b)], two methine protons [d 2.53 (dd, J = 9.5, 1.6 Hz, H-9), 2.30 (ddd, J = 9.5, 7.8, 2.6 Hz, H-5)] and two methylene protons [d 2.44 (dd, J = 13.4, 7.8 Hz, H-4a (b)), 1.67 (dd, J = 13.4, 2.7 Hz, H-4b (a))]. The absence of signals of olefinic protons in the 1H NMR spectrum, showed that the double bond usually occurring between the positions 3 and 4 did not exist. There were also signals characteristic of the b-glucopyranosyl group (Table 1). 13 C 100 MHz) 2 3 dH dC dH dC dH dC 5.25 d (J = 4.2) 7.13 s – – – 3.19 d (J = 8.0) 1.90–2.10 m 96.5 147.2 95.6 150.4 5.63 d (J = 1.6) 5.27 d (J = 2.7) 93.6 96.0 113.5 115.6 72.8 150.9 45.9 112.0 – 4.65 3.25 3.40 3.33 3.50 4.47 4.38 – 7.57 6.80 – 7.63 6.36 – 171.2 99.5 73.5 77.0 70.9 74.8 63.8 2.44 dd (J = 13.4, 7.8) 1.67 dd (J = 13.4, 2.7) 2.30 ddd (J = 9.5, 7.8, 2.6) 4.03 dd (J = 7.4, 2.6) – 4.04 dd (J = 7.4, 0.9) – 2.53 dd (J = 9.5, 1.6) 3.98 d (J = 12.4) 3.60 d (J = 12.4) – 4.68 d (J = 7.8) 3.18 dd (J = 8.6, 7.8) 3.19–3.40 m 35.3 4.39 m – 2.9 m 5.19 brd (J = 7.5) 5.28 d (J = 5.0) 7.29 s – – – 3.03 m 1.9 m 1.78 m 3.78 m 2.05 m 2.46 m 1.02 d (J = 7.4) – – 4.68 d (J = 8.2) 3.24 dd (J = 8.0, 7.9) 3.40–3.34 m d (J = 8.0) dd (J = 9.5, 8.0) t (J = 9.5) t (J = 9.5) m dd (J = 12.0, 2.2) dd (J = 12.0, 6.2) d (J = 8.5) d (J = 8.5) d (J = 16.0) d (J = 15.7) 31.0 40.9 160.1 130.2 115.7 127.9 147.0 114.9 168.7 Assignments were made using HSQC and HMBC data. 3.55 4.50 4.39 – 7.46 6.80 – 7.64 6.36 – m dd (J = 12.1, 2.7) dd (J = 12.0, 6.2) d (J = 8.6) d (J = 8.5) d (J = 16.4) d (J = 16.4) 32.2 41.5 79.2 45.4 43.2 14.4 172.7 99.9 74.8 77.9 71.7 75.7 64.4 161.8 131.2 116.7 127.1 146.9 114.9 169.8 3.87 d (J = 12.4) 3.66 d (J = 12.4) – – – – – – – 35.7 86.0 74.7 79.9 48.0 62.0 – 99.1 75.1 78.3 72.0 78.1 62.9 – – – – – – – 1801 C. Gousiadou et al. / Phytochemistry 68 (2007) 1799–1804 The main products of the plant are catalpol (5) and albidoside (6), with catalpol being a useful taxonomic marker for the genus Scutellaria (Cole et al., 1991). The isolation of compounds 1, 2, 11 and 12 is important for biosynthetic reasons. It is known that 8-epi-loganic acid and consequently gardoside biosynthetically occur from 8-epi-deoxyloganic acid (Damtoft, 1994), while loganic acid is formed via different pathway and therefore the exact determination of the configuration at C-8 is of considerable taxonomic significance (Jensen et al., 1989; Naas and Rimpler, 1996). The C-1 epimers 4 and 4a were isolated as an inseparable mixture. This is the first time that these free iridoid aglycones have been isolated from the Lamiaceae family. Only once before they were isolated and identified from Pedicularis striata – Scrophulariaceae (Gao et al., 1997). Though similar iridoids possessing a rigid three ring skeleton have been previously reported (Iwagawa et al., 1991; Jia et al., 1999; Yoshikawa et al., 1986; Kim et al., 2006), scutelloside (3) is the first iridoid glucoside bearing such a skeleton to be isolated from the genus Scutellaria (see Fig. 2). The small coupling of H-1 (J = 1.6 Hz) with H-9 (d 2.53), confirmed the b-orientation of H-9, since H-1 is known to be a-orientated in naturally occurring iridoid glucosides (Tietze et al., 1980), and suggested a dihedral angle close to 60. The large coupling of H-9 (J = 10 Hz) with the adjacent proton H-5 (d 2.30) confirmed the b-orientation of H-5, indicating a dihedral angle near 0 and thus demonstrating that the stereochemistry of the catalpol ring fusion was cis. No other vicinal couplings to H-9 were observed, so it was concluded that C-8 (d 79.9) was quaternary. The COSY spectrum offered no coupling signals between H-5 and H-4a (d 1.67) as also between H-4b (d 2.44) and H-3, indicating that their dihedral angles were nearly 90. Furthermore, H-3 showed a small coupling with H-4a (J = 2.7) thus suggesting an equatorial position for H-3. The existence of a dihedral angle of 90 between H-4b and H-3 combined with the clear long-range correlation signals between H-10a and C-3 in the HMBC spectrum, gave evidence of an ether linkage between C-3 and C-10 (and not between C-3 and C-8) (Iwagawa et al., 1991), thus confirming that 3 had a rigid three ring skeleton. The NOESY spectrum exhibited correlation signals between H-7 and H-9, H-7 and H-5, confirming thus the b-orientation of H-7 and consequently the a-orientation of the hydroxyl group at C-7. Also, NOE signals occurred between H-6 and H-4a, leading to the conclusion that H6 had a-orientation. Finally, the signals between H-10b and H-1 revealed that the ether linkage between C-3 and C-10 had a-configuration. Based upon the data mentioned above, the proposed structure for scutelloside is that shown in Fig. 1. 3. Experimental 3.1. General 1 H, 13C and 2D NMR spectra were recorded in CD3OD on Bruker DRX-400 and Bruker AC-200 (50.3 MHz for 13 C NMR) instruments at 295 K. Chemical shifts are given in parts per million (ppm) and were referenced to the solvent signals at 3.31 ppm and 49.5 ppm for 1H and 13C 11 6 H COOH COOH H 4 5 3 HO O HO 7 8 6'' 1 H3C 10 O H 10 O 8 O 9 H O O 5'' 8'' 1'' 7'' 9'' O O O 6' HO 5' HO 4'' HO 1' 3'' 2'' HO 4' HO 2' 3' HO OH 1 2 HO H 6 4 3 5 10 HO O 7 O 9 8 H 1 HO HO HO O 6' O 5' 4' HO 3' 2' OH 1' 3 Fig. 1. Structures of compounds 1–3. OH O 1802 C. Gousiadou et al. / Phytochemistry 68 (2007) 1799–1804 11 COOH 11 COOH 6 6 5 7 1 2 8 2 3'' HO O H C 10 O 1 9 H C 10 HO 9 3 3 8 4 7 4 HO 3'' 5 HO 2'' O 4'' 2'' 8'' O O 4'' 8'' 1'' O 5'' 7'' 6'' 1'' 9'' O 4' 6' 7'' 5'' 6'' 9'' O 4' 6' 5' 5' O HO HO O HO HO 2' 3' 1' HO 2' 3' 1' HO Fig. 2. Selected HMBC correlations for 1 and 2. NMR, respectively. COSY, HSQC, HMBC and NOESY were performed using standard Bruker microprograms. IR spectra were obtained on a Perkin–Elmer PARAGON 500 FT-IR spectrophotometer. UV spectra were recorded on a Shimadzu UV-160A spectrophotometer. ESI mass spectra were measured on a TSQ 7000 spectrometer using a spray voltage of 4 kV and a heated capillary of 200 C (MeOH + 10 mmol/l NH4Ac). Optical rotations were measured on a Perkin–Elmer 341 polarimeter. Vacuum-liquid chromatography (VLC) was carried out on Silica Gel 60H (Merck, Art. 7736). Column chromatography (CC) was carried out on Silica Gel 60 (Merck, Art. 9385). Preparative HPLC was performed on Jasco system equipped with a PU 980 pump, RI-930 refractive index detector (Jasco Corporation, Tokyo, Japan) and a reversed phase column, Kromasil C18 250 · 10 mm column (see Fig. 3). 3.2. Plant material The aerial parts of S. albida ssp. albida were collected at Mount Pelion (Central Greece) in June 2001. The plant was authenticated by Dr. T. Constantinidis (Institute of Systematic Botany, Agricultural University of Athens) and a voucher specimen was deposited in the Herbarium (ACALazari & Gousiadou 001). NOESY HMBC HO H 6 Hâ 4 H Há 3 4 5 7 O 9 8 H HO HO HO 1 O H 9 8 H 7 HO OH OH O H HO O HO 2' 3 H 5 6 O 6' 5' 4' 3' O 10 HO 1 H 10 Ha 1' Fig. 3. Selected HMBC and NOESY correlations for 3. O Hb 3.3. Extraction and isolation Fresh aerial parts of S. albida ssp. albida (480 g) were successively extracted at room temperature with acetone, MeOH and MeOH–H2O 5:1 (2 L of each solvent, twice, 48 h). The dried MeOH extract (27.6 g) was subjected to VLC over silica gel (10 · 8 cm) using as eluent CH2Cl2– MeOH mixtures of increasing polarity to yield finally seven fractions (MA 0 –MR 0 ). Fraction MK 0 (110.0 mg; eluted with CH2Cl2–MeOH 50:50) was pure compound 5. Fraction MM 0 (8.7 g; eluted with CH2Cl2–MeOH 65:35– 60:40) was further applied to VLC over silica gel using EtOAc–MeOH and yielded 16 fractions (MM 0 A–MM 0 P). Fraction MM 0 E (370 mg; eluted with EtOAc–MeOH 90:10) was submitted to CC on silica gel (CH2Cl2–MeOH 95:5–50:50) and yielded three fractions, which were further subjected to RP-HPLC: fraction MM 0 EC (25.5 mg; MeOH–H2O 35:65) yielded compound 2 (1.4 mg); tR 11.0. Fraction MM 0 K (1.1 g; eluted with EtOAc–MeOH 76:24–75:25) was subjected to VLC over silica gel (10 · 8 cm) using H2O–MeOH as eluent and yielded five fractions (MM 0 KA–MM 0 KE). Further purification by TLC on silica gel of fraction MM 0 KA (eluted with H2O) yielded compound 5 (18.8 mg). Fraction MM 0 D was submitted to CC over Sephadex LH-20 (MeOH) and yielded six fractions (MM 0 DA–MM 0 DF). Fraction MM 0 DC after HPLC with MeOH–H2O 15:85 yielded compound 3 (2.2 mg); tR 9.5 min. Further purification by TLC on silica gel of fractions MM 0 DD and MM 0 DF yielded compounds 6 (19.1 mg) and 17 (5.9 mg), respectively. Fraction MM 0 E (370 mg; EtOAc–MeOH 90:10) was submitted to CC on silica gel (CH2Cl2–MeOH 95:5–50:50) and yielded three fractions, which were further subjected to RP-HPLC: fraction MM 0 EC (25.5 mg; MeOH–H2O 35:65) yielded compounds 1 (1.4 mg); tR 11.0 min, 18 (2.7 mg); tR 8.0 min, 19 (2.5 mg); tR 6.52 min and 22 (2.2 mg); tR 6.30 min. Fraction MM 0 ED (26.0 mg; MeOH–H2O 25:75) yielded compounds 16 (2.5 mg); tR 30.0 min and 20 (3.0 mg); tR 10.0 min. Fraction MM 0 EF (33.6 mg; MeOH–H2O 35:65) yielded 21 (1.5 mg); tR 16.8 min. Fraction MM 0 J C. Gousiadou et al. / Phytochemistry 68 (2007) 1799–1804 (904.5 mg; EtOAc–MeOH 80:20–77:23) was submitted to CC on silica gel (EtOAc–MeOH–H2O 90:10:1–70:30:3) and finally yielded three fractions: fraction MM 0 JE 0 (73.1 mg) was further purified by HPLC using as eluent MeOH–H2O 5:95 and yielded compounds 11 (3.2 mg); tR 20.0 min and 12 (2.7 mg); tR 31.0 min. Fractions MM 0 JK 0 (86.9 mg) and MM 0 JT 0 (160.2 mg) were further purified by HPLC with MeOH–H2O 10:90 and yielded compounds 9 (3 mg); tR 12.0 min,13 (2.5 mg); tR 10.83 min and 8 (3.3 mg); tR 9.76 min respectively. Finally, fraction MK 0 (3.6 g; CH2Cl2–MeOH 70:30) subjected to CC on silica gel with EtOAc–MeOH (97:3–70:30) yielded fraction MK 0 F (30 mg) which after HPLC with MeOH–H2O 9:11 yielded compounds 4 and 4a (5.5 mg); tR 7.2 min, 7 (1.5 mg); tR 10.2 min, 10 (1.6 mg); tR 22.0 min, 14 (4.7 mg); tR 26.4 min, 15 (1.3 mg); tR 38.0 min and 23 (1.6 mg); tR 10.7 min. 3.4. 6 0 -O-E-p-coumaroylgardoside (1) 20 Yellowish oil; ½aD  4:29 (c 0.12, MeOH); UV/vis (MeOH) kmax nm (log e): 300.5sh (4.42), 312 (4.89); IR (film): mmax cm1: 3352 (O–H), 2914 (CAH), 1644 (C@O), 1607 (C@C); for 1H and 13C NMR spectra, see Table 1; HR-ESI-MS m/z 519.1499 [MH] (calcd for C25H27O12: 519.1503). 3.5. 6 0 -O-E-p-coumaroyl-8-epi-loganic acid (2) 20 Yellowish oil; ½aD  50:67 (c 0.15, MeOH); UV/vis (MeOH) kmax nm (log e): 298sh (3.53), 309 (4.03); IR (film) mmax cm1: 3352 (O–H), 2914 (CAH), 1644 (C@O), 1607 (C@C); for 1H and 13C NMR spectra, see Table 1; HRESI-MS m/z 521.1670 [MH] (calcd for C25H29O12: 521.1659). 3.6. Scutelloside (3) Amorphous powder; ½a20 D  3:43 (c 0.22, MeOH); UV/ vis (MeOH) kmax nm (log e): 264sh (0.73) ; IR (film) mmax cm1: 3352 (O–H), 2914 (C–H); for 1H and 13C NMR spectra, see Table 1; ESI-MS and HR-ESI-MS no molecular or pseudomolecular ion observable. References Andary, C., Wylde, R., Laffite, C., Privat, G., Winternitz, F., 1982. Structures of verbascoside and orobanchoside, caffeic acid sugar esters from Orobanche rapum-genistae. Phytochemistry 21, 1123– 1127. Albach, D.C., Gotfredsen, C.H., Jensen, S.R., 2004. Iridoid glucosides of Paederota lutea and the relationships between Paederota and Veronica. Phytochemistry 65, 2129–2134. Bianco, A., Guiso, M., Iavarone, C., Trogolo, C., 1974. Iridoids. XV. Macfadienoside. Structure and configuration. Gazz. Chim. Ital. 104, 731–738. Bothmer, R., 1985. Differentiation patterns in the Scutellaria albida group (Lamiaceae) in the Aegean area. Nord. J. 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