Two new diterpenoids named 13-oxo-wollifoliane-10,15-olide (1) and 19-acetoxy-7,9,10-deacetyl-baccatin VI (2), along with 14 known taxanes (3-16), were isolated from Taxus baccata. The structures of these compounds were elucidated by 1-dimensional and 2-dimensional nuclear magnetic resonance spectra, high-resolution electrospray ionization-mass spectrometry, and infrared spectroscopy. Structurally, 13-oxo-wollifoliane-10,15-olide (1) is the first taxane diterpenoid possessing an unusual carbonyl group at the C-13 position of the 11(15→1),11(10→9)bis-abeo-taxane structure (5/6/6/6/4 skeleton), and 19-acetoxy-7,9,10-deacetyl-baccatin VI (2) is a new compound containing an acetoxy group at the C-19 position of 6/8/6/4-taxane. Among the 14 known taxane compounds 3-16, compounds 7 and 9 were first isolated and reported from T. baccata. Several compounds (3-16) were evaluated for cytotoxicity against MCF-7 and HCT116 human cancer cell lines, but none of them showed considerable cytotoxic activity.
Taxus species, distributed in the northern hemisphere, have attracted a great deal of attention as sources of anticancer agents since the first isolation of paclitaxel from the bark of the Pacific yew (Taxus brevifolia).1 The unique taxoid diterpene paclitaxel (Taxol) is one of the most reputable natural anticancer agents which currently serves widely in the clinic against breast cancer, ovarian cancer, nonsmall cell lung cancer, and prostate cancer among various of chemotherapeutic agents.2 However, there are multiple toxic side effects of paclitaxel, such as poor bioavailability, allergenicity, neurotoxicity, and ototoxicity, etc.3 Therefore, chemists have been researching into different Taxus species to find new lead compounds to replace paclitaxel. Until now, various types of chemical constituents have been isolated from Taxus species, such as taxanes possessing different skeleton systems, flavonoids, lignans, steroids, and sugar derivatives.4 According to the pharmacological studies, taxane diterpenoids are the major bioactive components of this species,5 and many taxane diterpenoids have anticancer activity against different cancer cell lines.6
European yew (Taxus baccata), a member of the Taxus species, is mainly distributed and cultivated in European countries, North Africa, and the Caucasus.7,8 In order to search for new and promisingly bioactive components, as a part of our efforts focused on studying the chemical composition of T. baccata, we present here the structural elucidation of 2 new diterpenoids 1 and 2, as well as 14 known taxane diterpenoids (Figure 1). Compound 1 is determined to be a C-13-carbonyl taxane diterpenoid with 11(15→1),11(10→9) bis-abeo-taxane skeleton. To our best knowledge, it was the first example with a C-13 carbonyl group in the natural products of this skeleton. Compound 2 is a new 6/8/6/4-taxane with a rare C-19-acetoxy group. Isolation of compounds 7 and 9 are first reported in T. baccata. Moreover, the cytotoxicity against MCF-7 and HCT116 human cancer cell lines of several compounds (3-16) was also investigated.
Structures of compounds 1-16 from Taxus baccata and wallifoliol and 7,9,10-deacetyl-accatin VI.
Results and Discussion
Multiple column chromatography separation of the dichloromethane extract of T. baccata afforded 2 new compounds 13-oxo-wollifoliane-10,15-olide (1) and 19-acetoxy-7,9,10-deacetyl-baccatin VI (2) as well as 14 known taxanes. The structures are shown in Figure 1.
Compound 1 was obtained as a white amorphous powder. The molecular formula was found to be C29H32O10 on the basis of high-resolution electrospray ionization-mass spectrometry (HR-ESI-MS) at m/z 563.1889 [M + Na]+ (calc. for 563.1893), suggesting the presence of 14 degrees of unsaturation. The infrared (IR) spectrum displayed absorption bands characterized as hydroxyl (3362 cm−1), phenyl (1633-1470 cm−1), and carbonyl groups (1715 cm−1). Its 1H nuclear magnetic resonance (NMR) spectrum (Table 1) indicated the presence of 5 methyl groups (δH 2.09, 1.79, 1.72, 1.44, and 1.19, each 3 H, s) and 5 downfield protons (δH 7.95, d, 2 H, J = 7.2 Hz, 2 H; 7.49, t, J = 7.8 Hz, 1 H and 7.64, t, J = 7.8 Hz, 2 H) pointing out a benzoyloxy substituent. Another remarkable feature of 1H NMR spectrum was 8 doublets (Table 1). The relationship of 6.07/2.56 (d, J = 12.6 Hz), 2.99/2.29 (d, J = 18.6/19.2 Hz), and 4.64/4.24 (d, J = 8.4/9.0 Hz) was also pointed out through the 1H-1H-correlation spectroscopy. There were 6 downfield quaternary signals in 13C NMR, 4 of them likely carbonyl carbons, including a keto carbonyl at δC 205.3, an acetoxy substituent at δC 169.4 (which indicated by the heteronuclear multiple bond correlation [HMBC] spectrum first contribution at δC 21.3-169.4), the benzoyloxy substituent at δC 164.3 and 173.6 without HMBC. One methyl (δH 2.09, corresponding δC 8.3) correlated with the remaining 2 carbonyl carbons (δC 162.2 and 138.5) and the keto group pointing out the presence of 1 double bond. Considering the molecular formula of compound 1 (C29H32O10) and subtracting the contribution of the 2 substituents (C7H5O2 and C2H3O2), 1 C=C and 2 C=O were in the remaining “parent” structure which is C20H32O4. Thus, the 5 degrees of unsaturation suggested a pentacyclic diterpene. Considering the molecular formulas of compound 1 (C29H32O10) and the known wallifoliol (C29H34O10, Figure 1),9 their structural similarity was observed from NMR data; the carbonyl group at δC 205.3 and 1 oxygenated methine less in compound 1 were the major differences but apparently, they shared the same scaffold. The different carbonyl carbon had HMBC with H-18 (δH 2.09, 3 H, s) and H-14 (δH 2.99, 2.29, both 1 H, doublet, J = 18.6/19.2 Hz). Moreover, the C-11 and C-14 in compound 1 were deshielded to δC 162.2 and 38.9 from δC 131.0 and 37.1 in wallifoliol,9 respectively, while C-18 was shielded from δC 10.9 in wallifoliol9 to δC 8.3 in compound 1. All the evidence implied the carbonyl δC 205.3 was at C-13 (Figure 2). The nuclear Overhauser effect spectroscopy (NOESY) correlations of H-2/H-20-β, H-2/H-19 suggested that H-2 and C-19-methyl groups were β-oriented. Therefore, the structure of compound 1 was confirmed as shown in Figure 1, named 13-oxo-wollifoliane-10,15-olide.
Selected 2-dimensional nuclear magnetic resonance correlations of 1. COSY, correlation spectroscopy; HMBC, heteronuclear multiple bond correlation; NOESY, nuclear Overhauser effect spectroscopy.
1H (600 MHz, δ in ppm, J in Hz) and 13C Nuclear Magnetic Resonance (150 MHz, δ in ppm) Data of Compounds 1, Wallifoliol, 2, and 7,9,10-Deacetyl-Baccatin VI in Deuterated Chloroform.
Compound 2 was obtained as a white amorphous powder. Its molecular formula C33H42O13 was established by the HR-ESI-MS that showed a pseudomolecular-ion peak at m/z 669.2517 [M + Na]+ (calc. for 669.2523), indicating the presence of 13 degrees of unsaturation. The IR spectrum demonstrated the presence of phenyl (1659-1469 cm−1), hydroxyl (3362 cm−1), and carbonyl (1741 cm−1) groups. The presence of 3 acetyl groups [δH 2.29 (3H, s), δC 169.4, 22.8; δH 2.18 (3H, s), δC 170.5, 21.3; δH 2.35 (3H, s), δC 172.8, 21.1] and a benzoate ester [δH 8.09 (2H, m), 7.47 (2H, m), 7.60 (1H, m); δC 167.1, 129.3, 128.6 × 2, 130.0 × 2, 133.6] was inferred according to the 1H-NMR, 13C-NMR, and heteronuclear multiple quantum coherence spectra. Moreover, 3 more methyl groups could be verified by the observation of 1H and 13C signals [δH 1.31 (3H, s), 1.71 (3H, s), 1.85 (3H, s), corresponding δC 28.3 (q), 21.9 (q), 15.0 (q)]. The 1H signals (δH 4.14 and 4.39, both doublet, J = 8.4 Hz) and a 13C signal (δC 76.0, C-20) suggested the presence of an oxetane ring. As per the above evidences, compound 2 was determined as a taxane diterpenoid with a typical 6/8/6/4 skeleton,1,10,11 which was further confirmed by the observation of characteristic 13C NMR signals (δC 46.6, 46.7, 43.2; Table 1) for C-3, C-8, and C-15 in a typical taxoid core. The spectroscopic data showed satisfactory agreement with the known 7,9,10-deacetyl-baccatin VI (Figure 1),10,11 except for an acetyl group [δH 2.35 (3H, s); δC 172.8, 21.1] which was at C-19 (δc 62.3) verified by the correlation of H19/carbonyl carbon signal at δC 172.8. Instead, the C-19 signal at δc 12.4 (q) was found in the known compound 7,9,10-deacetyl-baccatin VI. The relative configuration of compound 1 was confirmed by NOESY correlations (Figure 3). Thus, the structure of 2 was confirmed as shown in Figure 3, named 19-acetoxy-7,9,10-deacetyl-baccatin VI.
Selected 2-dimensional nuclear magnetic resonance correlations of compound 2. COSY, correlation spectroscopy; HMBC, heteronuclear multiple bond correlation; NOESY, nuclear Overhauser effect spectroscopy.
Structures of the 14 known taxanes were identified by spectral data and compared the values with reported literature as taxinine (3),12O-cinnamoyltaxicin I triacetate (4),12 5-cinnamoyl-9-acetyltaxicin I (5),12 taxinine B (6),13 decinnamoyltaxinine E (7),14 7-deacetoxytaxinine J (8),15 taxumairol K (9),16 baccatin IV (10),17 3,11-cyclotaxane (11),18 1-hydroxytaxuspine C (12),19 taxagifine (13),20 taxinine M (14),21 taxin B (15),22 and taxuspine W (16)23 (Figure 1).
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was carried out to evaluate the in vitro cytotoxicity of the known compounds (3-16) against MCF-7 and HCT116 human cancer cell lines. None of them showed inhibitory activity.
Experimental
Plant Materials
The plant material was the left scrap after industrial extraction of 10-deacetylbaccatin III and paclitaxel from T. baccata, which was provided by Beijing Norzer Biotechnology Co., Ltd. (Beijing, China) in 2018. A voucher specimen (DQ-01) was deposited at School of Life Science and Engineering, Southwest Jiaotong University, Sichuan Province, P. R. China.
General Experimental Procedures
Silica gel (200-300 mesh, Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) and RP-18 silica gel (40-60 μm, Merck, Darmstadt, Germany) were used for column chromatography. Optical rotations were measured by a PerkinElmer 341 polarimeter (PerkinElmer, Waltham, MA, USA). IR spectra were obtained using a Thermo Fisher Nicolet 6700 spectrometer (Thermo Fisher Scientific, MA, USA) and potassium bromide (KBr) pellets; in cm−1. 1H NMR spectra were recorded on a Bruker Avance-600 spectrometer (600 MHz, Bruker, Karlsruhe, Germany). Chemical shifts were recorded in ppm relative to tetramethylsilane as the internal standard. Data was reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet-doublet, dt = doublet-triplet, m = multiplet, br = broad), coupling constants (Hz), integration. 13C NMR data were collected on a Bruker Avance-600 spectrometer (150 MHz, Bruker, Karlsruhe, Germany) with complete proton decoupling. Chemical shifts were reported in ppm with the tetramethylsilane as the internal standard. HR-ESI-MS data were recorded using a Q-TOF micro mass spectrometer (Waters, Milford, MA, USA) in m/z. NP7000 serial pump and NU 3000 serial ultraviolet (UV)/Visible detector (Hanbon Science & Technology, Huaian, China) were used for preparative medium pressure column chromatography (MPLC). Waters quaternary gradient module 2545, UV/Visible detector 2489, and C18 column (7 µm, 19 × 300 cm, Waters, Milford, USA) were used for preparative high-performance liquid chromatography (HPLC). The thin-layer chromatographic (TLC) plates were precoated with silica gel GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China) and were visualized under a UV lamp (ZF-20C, Shanghai Jihui scientific analysis instrument Co. Ltd., Shanghai, China) at 254 nm.
Extraction and Isolation
The plant scrap (20 g) was suspended in water (H2O; 1.0 L) and successively partitioned with petroleum ether (PE; 0.5 L × 5), dichloromethane (CH2Cl2; 0.5 L × 5), and ethyl acetate (EtOAc; 0.5 L × 5) to afford PE (1.3 g), CH2Cl2 (7.3 g), EtOAc (2.9 g) fractions, respectively. Most of the taxane diterpenoids were enriched in CH2Cl2 fraction by TLC analysis. Therefore, the CH2Cl2 (7.3 g) fraction was subjected to preparative MPLC with methanol (MeOH)-H2O (40%-100% for MeOH) to give 7 fractions A-G. Fraction A (0.9 g) was subjected to silica gel column chromatography, eluted with PE-EtOAc gradient solvent system (starting from 30:1 to 1:10, v/v) to obtain 3 subfractions (A1-A3). Compound 16 (8.9 mg) was isolated from subfraction A2 with CH2Cl2-MeOH solvent system (starting from 80:1 to 10:1, v/v). Fraction C (1.6 g) was separated by silica gel column chromatography with the CH2Cl2-MeOH solvent system (starting from 80:1 to 1:10, v/v) to afford subfractions (C1-C5). These subfractions were further purified by RP-18 silica gel column with MeOH-H2O-formic acid solvent system (5:100:0.1 to 95:5:0.1, v/v/v) to obtain compounds 3 (15.2 mg), 5 (15.7 mg), 7 (12.8 mg), 8 (5.7 mg), and 13 (19.8 mg). Fraction E (1.4 g) was subjected to preparative MPLC with MeOH-H2O (40:60 to 100:1, v/v) to give 5 subfractions E1-E5. Then these subfractions were separated by silica gel column chromatography, eluted with PE-CH2Cl2-MeOH (30:70:1 to 30:70:50, v/v/v) to obtain compounds 6 (13.2 mg), 9 (8.0 mg), 14 (16.4 mg), and other subfractions (eg, E2a, E3d, E5b etc.). Subfractions E2a (50.7 mg), E3d (45.4 mg), and E5b (60.2 mg) were isolated via preparative HPLC (MeOH-H2O, 45:55 to 100:1, v/v) to yield compounds 1 (3.0 mg), 11 (6.9 mg), and 12 (9.7 mg), respectively. The isolation of fraction G (1.2 g) was performed according to the method depicted in the “isolation of fraction E” section. Fraction G was subjected to preparative MPLC with MeOH-H2O (40:60 to 100:1, v/v) to afford 3 subfractions G1-G3. Subfractions G1b, G2a, and G3a were further purified by preparative HPLC through different flow phases. Compound 2 (3.9 mg) was purified from subfraction G1b by preparative HPLC (MeOH-H2O, 11:9 to 9:1, v/v). Subfraction G2a (MeOH-H2O, 9:11 to 4:1, v/v) yielded compound 4 (10.5 mg) and other sub-subfractions. Further isolation of sub-subfraction G2a1 (MeOH-H2O, 2:3 to 4:1, v/v) and subfraction G3a (MeOH-H2O, 9:11 to 7:1, v/v) yielded compounds 10 (5.1 mg) and 15 (14.2 mg), respectively.
13-Oxo-wollifoliane-10,15-olide (1)
White amorphous powder; : −16.67 (c = 0.09, chloroform [CHCl3]). IR (KBr) νmax: 3362, 3199, 2921, 2851, 1715, 1660, 1633, 1470, 1375, 1272, 1244, 1171, 1098, 1069, 1026, 974, 891, 712, 639, 609, 531 and 479 cm−1; 1H and 13C-NMR data see Table 1; HR-ESI-MS data: m/z 563.1889 [M + Na]+ (calc. for C29H32O10Na, 563.1893).
19-Acetoxy-7,9,10-deacetyl-baccatin VI (2)
White amorphous powder; : −12.00 (c = 0.075, CHCl3). IR (KBr) νmax: 3362, 3197, 2956, 2921, 2851, 1741, 1659, 1633, 1469, 1373, 1260, 1239, 1112, 1066, 1024, 983, 943, 804, 712, 642, 605, and 472 cm−1; 1H and 13C-NMR data see Table 1; HR-ESI-MS data: m/z 669.2517 [M + Na]+ (calc. for C33H42O13Na, 669.2523).
Conclusion
Sixteen diterpenoids were obtained from T. baccata, including 2 new diterpenoids named 13-oxo-wollifoliane-10,15-olide (1) and 19-acetoxy-7,9,10-deacetyl-baccatin VI (2), along with 14 known taxanes (3-16). The new compound 1 possesses an 11(15→1),11(10→9) bis-abeo-taxane structure (5/6/6/6/4 skeleton) with an unusual carbonyl group at the C-13 position. Compound 2 was a new 6/8/6/4-taxane with a rare C-19-acetoxy group. Among the 14 known taxane compounds 3-16, compounds 7 (decinnamoyltaxinine E) and 9 (taxumairol K) were first isolated and reported from T. baccata. None of the tested compounds (3-16) showed cytotoxicity against MCF-7 and HCT116 human cancer cell lines.
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Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this work was financially supported by grants from NSFC (31570341 and 31870329). We are very grateful to Beijing Norzer Biotechnology Co. Ltd (Beijing, China) for providing the scrap of T. baccata.
ORCID iD
Feng Gao
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