Bioactive Terpenoids from Salvia plebeia: Structures, NO Inhibitory

Article pubs.acs.org/jnp

Bioactive Terpenoids from Salvia plebeia: Structures, NO Inhibitory Activities, and Interactions with iNOS Jing Xu,*,† Meicheng Wang,† Xiaocong Sun,† Quanhui Ren,† Xiangrong Cao,† Shen Li,† Guochen Su,† Muhetaer Tuerhong,‡ Dongho Lee,§ Yasushi Ohizumi,⊥ Mark Bartlam,∥ and Yuanqiang Guo*,† †

State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, and ∥State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin 300350, People’s Republic of China ‡ College of Chemistry and Environmental Sciences, Laboratory of Xinjiang Native Medicinal and Edible Plant Resources Chemistry, Kashgar University, Kashgar 844000, People’s Republic of China § Department of Biosystems and Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea ⊥ Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan S Supporting Information *

ABSTRACT: A phytochemical investigation to obtain new NO inhibitors resulted in the identification of six new (1−6) and four known (7−10) terpenoids from Salvia plebeia. Compounds 1 and 2 are new diterpenoids, 3−5 are new meroditerpenoids, 6−9 are sesquiterpenoids, and 10 is a known meroditerpenoid. The structures of these isolates were determined by routine NMR experiments and X-ray diffraction, as well as the electronic circular dichroism spectra. Compounds 1−4 are diterpenoids carrying an oxygen bridge, and 6 is a rare copane-type sesquiterpenoid with a bridged tricyclic framework. The isolates inhibited NO generation induced by lipopolysaccharide in BV-2 cells. The possible mechanism of NO inhibition of some bioactive compounds was also investigated using molecular docking, which revealed interactions of bioactive compounds with the iNOS protein. acids, steroids, and flavonoids,7−20 displaying extensive biological activities including antimicrobial, antioxidant, cytotoxic, and anti-HIV activities.7 Salvia plebeia R. Br. is a herbaceous plant distributed all over mainland China. The whole plants have been used for various medicinal purposes, such as removing toxic materials and heat, promoting urination to reduce edema, cooling blood, and reducing stasis.21 In an ongoing search for biologically active substances from plants,22−24 considerable attention has been focused on bioactive compounds inhibiting NO production, since these constituents have the possibility to be developed into therapeutical agents for inflammation and related neurodegenerative diseases.4,5 A continuous phytochemical investigation of S. plebeia to obtain new NO inhibitors afforded two new diterpenoids 1 and 2, three new meroditerpenoids 3−5, a new sesquiterpenoid 6, the known sesquiterpenoids 7−9, and the known meroditerpenoid 10. Using routine NMR experiments and X-ray diffraction, as well as electronic circular

N

itric oxide (NO) is a well-known biological signaling molecule exerting the regulation of multiple physiological functions.1,2 It has been confirmed that this signaling molecule participates in brain development, neuron growth, and synapse plasticity of the central nervous system (CNS).3 However, related studies of NO have also disclosed that NO is a notable inflammatory factor and excessive NO in the CNS is a significant sign indicating microglia activation and inflammatory response, which has been proven to be neurotoxic and can cause neuron degeneration and subsequent neurologic disorders.4 All of the studies referring to NO biological function and related diseases concluded that NO inhibitors have the possibility to be developed into therapeutical agents to treat inflammatory diseases and related disorders.5 The genus Salvia (Lamiaceae) contains more than 1000 different kinds of plants growing widely in the warmer and temperate areas.6 There are about 100 Salvia species in China, most of which are found in the southwestern region.6 Many species of the Salvia genus have been employed as folk herbal medicines to treat multiple diseases.6,7 The major constituents from this genus have been reported to be terpenoids, phenolic © 2016 American Chemical Society and American Society of Pharmacognosy

Received: August 8, 2016 Published: November 14, 2016 2924

DOI: 10.1021/acs.jnatprod.6b00733 J. Nat. Prod. 2016, 79, 2924−2932

Journal of Natural Products

Article

Chart 1

Table 1. 13C NMR Data for Compounds 1−5 (δ in ppm) position 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 OAc

1 36.3, 68.3, 46.5, 35.5, 49.7, 19.9, 41.7, 78.6, 134.9, 49.2, 142.4, 182.5, 136.8, 142.5, 26.9, 21.8, 21.4, 32.7, 22.6, 77.9, 170.6, 21.2,

2 CH2 CH CH2 C CH CH2 CH2 C C C C C C CH CH CH3 CH3 CH3 CH3 CH2 C CH3

40.2, 65.4, 50.6, 35.6, 49.5, 19.9, 41.7, 78.6, 135.2, 49.5, 142.4, 182.6, 136.8, 142.4, 26.9, 21.8, 21.2, 32.9, 23.0, 78.0,

3 CH2 CH CH2 C CH CH2 CH2 C C C C C C CH CH CH3 CH3 CH3 CH3 CH2

23.3, 22.8, 76.8, 36.7, 51.3, 21.0, 31.7, 128.5, 122.2, 40.2, 142.2, 142.7, 132.9, 118.3, 27.2, 22.5, 22.2, 29.5, 24.3, 103.5,

OCH3

4 CH2 CH2 CH C CH CH2 CH2 C C C C C C CH CH CH3 CH3 CH3 CH3 CH

35.9, 69.0, 46.2, 34.9, 42.7, 29.5, 71.2, 126.7, 132.9, 41.0, 140.0, 140.7, 132.9, 112.1, 27.1, 22.9, 22.7, 32.8, 21.6, 68.8, 171.3, 21.9,

5 CH2 CH CH2 C CH CH2 CH C C C C C C CH CH CH3 CH3 CH3 CH3 CH2 C CH3

34.3, 68.6, 42.2, 35.8, 141.5, 142.3, 180.1, 121.3, 135.8, 39.8, 141.6, 145.4, 133.3, 116.4, 27.2, 22.7, 22.4, 29.5, 28.5, 24.8, 171.3, 21.5,

CH2 CH CH2 C C C C C C C C C C CH CH CH3 CH3 CH3 CH3 CH3 C CH3

55.1, CH3

HRESIMS [M + H]+ ion at m/z 375.2174 (calcd for C22H31O5, 375.2171) and the 13C NMR data. Its 1H NMR spectrum displayed characteristic signals attributable to two aliphatic methyl singlets (δH 1.01 and 1.10), two aliphatic methyl doublets (δH 1.09 × 2, J = 6.8 Hz), and one acetyl methyl singlet (δH 2.04). Additionally, a set of oxymethylene protons [δH 3.78 (d, J = 8.0 Hz) and 4.52 (d, J = 8.0 Hz)] were also observed. The methyl singlet at δH 2.04, together with the corresponding carbon signals at δC 170.6 and 21.2, revealed the presence of an acetyl structural fragment. In addition to this acetyl group, the two methyl doublets [δH 1.09 × 2 (H3-16 and H3-17)] and the typical carbon signals at δC 26.9, 21.8, and 21.4 suggested the presence of an isopropyl moiety. Excluding the above five carbons forming the two moieties, there were a

dichroism (ECD) data, the structures of these isolates were identified. Herein, the structural identification and their propensity to suppress NO generation induced by lipopolysaccharide (LPS) of these isolates as well as their interactions with the iNOS protein are described.

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RESULTS AND DISCUSSION Fractionation of the petroleum ether-soluble portion of the MeOH extract of the whole plants of S. plebeia yielded two new diterpenoids 1 and 2, three new meroditerpenoids 3−5, a new sesquiterpenoid 6, the known sesquiterpenoids 7−9, and the known meroditerpenoid 10. Compound 1 was obtained as colorless quadrate crystals. The molecular formula C22H30O5 was derived from the 2925



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Figure 1. 1H−1H COSY and key HMBC correlations of compounds 1 and 3−6.

Figure 2. Conformations and key NOESY correlations of compounds 1 and 3−6.

further 17 resonances present in the 13C NMR spectrum. Utilizing DEPT and HMQC experiments, these 17 signals were sorted as one carbonyl, four olefinic carbons, and 12 aliphatic carbons comprising two methyls, five methylenes, two methines, two quaternary carbons, and one oxygenated tertiary carbon (Table 1). According to the aforementioned spectro-

scopic features, compound 1 should be a diterpenoid carrying an acetoxy group.25,26 The diterpenoid scaffold was elucidated by 1H−1H COSY and HMBC experiments. The HMBC signals observed for H3-18/19 to C-3, C-4, and C-5, H2-20 to C-1, C-5, C-9, and C-10, H-2 to C-1, C-3, C-4, and C-10, and H-5 to C-1, C-3, C-4, C-6, C-7, C-9, C-10, and C-20, together with the 2926



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1

H−1H COSY couplings (Figure 1), indicated the presence of two 6/6 fused rings A and B. In addition, another unsaturated six-membered ring carrying the isopropyl moiety at C-13 was also inferred from the 1H−1H COSY cross-peaks and the longrange couplings of H-14 (δH 6.79) with C-8, C-9, C-12, C-13, and C-15, and H-15 with C-14, C-16, C-17, C-12, and C-13 in the HMBC spectrum (Figure 1). The three 6/6/6 fused ring system, the isopropyl moiety at C-13, and the geminal methyls (Me-18 and Me-19) at C-4 suggested an abietane-type diterpenoid scaffold for 1.27−31 This skeletal type was established through analysis of 2D NMR spectroscopic data, where the oxygenated, olefinic, and carbonyl signals at δC 68.3, 78.6, 134.9, 136.8, 142.4, 142.5, and 182.5 were assigned to C2, C-8, C-9, C-13, C-11, C-14, and C-12, respectively. After establishing the abietane-type skeleton, the C-2 placement of the acetoxy group was done via the HMBC cross-peak of H-2 (δH 4.71) with the carbonyl (δC 170.6) of the acetoxy moiety. This analysis permitted assignment of the 2D structure of 1. However, the molecular formula of this 2D structure differed from that suggested by the HRESIMS data, indicating the presence of one more ring in 1. The HMBC cross-peaks of H220 to C-8 and HRESIMS data of compound 1 indicated a bridge connecting C-8−O−C-20.29−31 Hence, the 2D structure of 1 was defined unambiguously as illustrated in Figure 1. NOESY interactions and Chem3D modeling enabled the configuration of compound 1 to be assigned. The NOE effects between H3-19/H-2, H3-19/H-6β, H3-19/H-3β, H3-19/H-20b, H-20b/H-2, H-20b/H-6β, H-1β/H-20a (b), H3-18/H-5, H318/H-3α, and H-3α/H-1α (Figure 2), along with Chem3D modeling, implied the conformation of 1 as illustrated in Figure 2. According to this conformation, the unsaturated C-ring was almost planar, rings B and A were trans-fused with H-5 in an αaxial position and C-20 in a β-axial position, the C-2 acetoxy group occupied an α-equatorial position, and the oxygen bridge of C-20−O−C-8 extended above the plane of the B-ring. This conformation was subsequently corroborated by X-ray crystallographic analysis with Mo Kα radiation, and an ORTEP drawing is shown in Figure 3. The absolute

indicating a (2S, 5S, 8R, 10R) absolute configuration for 1. Thus, the structure of compound 1 was defined and the compound given the trivial name plebedipene A. Compound 2 (2-O-deacetylplebedipene A) had a molecular formula of C20H28O4 as shown by the HRESIMS [M + H]+ ion at m/z 333.2069 and the 13C NMR data. Its 1H and 13C NMR spectra showed a close resemblance to those of 1, except for the absence of signals for an acetyl moiety in 2. Comparison of the NMR data of 1 and 2 implied that 2 was the de-O-acetyl derivative of 1,29−31 which was verified by the 2D NMR experiments. NOESY correlations revealed that compound 2 had the same relative configuration as 1 and the C-2 hydroxy group was in an α-equatorial position. The absolute configuration of 2 was derived via comparison of the ECD spectra of compounds 2 and 1 (Figure 4B). The highly similar experimental ECD spectra and the same relative configurations implied a (2S, 5S, 8R, 10R) absolute configuration for compound 2 and the structure as shown in Figure 2. The 1H and 13C NMR data suggested that 3 (plebedipene B) was also an abietane-type diterpenoid bearing a methoxy group (δH 3.51, δC 55.1).27−31 In addition to the same fused rings A and B as in compounds 1 and 2, an aromatic ring carrying an isopropyl group at C-13 and two hydroxy groups at C-11 and C-12 was proposed according to the proton signal at δH 6.52 (1H, s) and the six-carbon resonances at δC 128.5, 122.2, 142.2, 142.7, 132.9, and 118.3. This aromatic ring and the two fused rings A and B constituted an abietane-type diterpenoid scaffold (Figure 1), and the skeletal proton and carbon signals were assigned by interpretation of the 2D NMR data.29,30 The methoxy group was located at C-20, which was confirmed by the HMBC cross-peak of H-20 to the methoxy carbon. Furthermore, a C-20−O−C-3 bridge similar to that of 1 was disclosed by the HMBC cross-peaks of H-3 to C-20 and H-20 to C-3. The above analysis enabled the 2D structure of 3 to be established. NOESY interactions shown in Figure 2 revealed the same trans-fusion of the A/B rings in 3 as in compounds 1 and 2. The 3,20-oxygen bridge extended above the plane of the A-ring, H-3 was assigned as α-oriented, and H-20 was βoriented and on the outside of the 3,20-oxygen bridge (Figure 2). After defining the relative configuration of 3, the ECD spectrum of 3 was simulated. The calculated and experimental ECD spectra were highly similar (Figure 4C), indicating a (3S, 5S, 10R, 20S) absolute configuration for compound 3. The 1H and 13C NMR spectra for compound 4 were indicative of an abietane-type diterpenoid, whose structure was found to be similar to that of compound 3. According to the NMR data, the main differences between 4 and 3 involved the presence of an acetyl group and an oxymethylene carbon (δC 68.8) in 4 instead of the acetal carbon (δC 103.5) of 3. The oxymethylene carbon (δC 68.8) was assignable to C-20, and the C-2 location of the acetoxy group was confirmative via interpretation of the HMBC data (Figure 1). Similarly, a C20−O−C-7 bridge was also confirmed by the corresponding HMBC cross-peaks. The definition of the relative configuration was based upon the NOESY interactions. The NOE effects as well as Chem3D modeling (Figure 2) revealed the trans-fusion of the A/B rings with C-20 and H-5 occupying β-axial and αaxial positions, respectively. In turn, the C-2 acetoxy group and H-7 were both assigned as α-oriented and the 7,20-oxygen bridge was above the plane of the B-ring (Figure 2). As in the case of 3, TDDFT ECD calculations enabled assignment of the absolute configuration of 4. The experimental and calculated ECD spectra of 4 were in good agreement (Figure 4D),

Figure 3. ORTEP drawing of 1.

configuration of 1 was established by comparing the experimental and calculated ECD data, a method applicable to assigning absolute configuration of natural products.32,33 Through systematic conformational search, geometry optimizations, and ECD calculations,34−36 the ECD spectra were obtained using SpecDis 1.62 software. The calculated ECD spectrum of 1 (Figure 4A) agrees with the experimental data, 2927



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Figure 4. Calculated and/or experimental ECD spectra for compounds 1 (A), 2 (B), 3 (C), 4 (D), 5 (E), and 6 (F) in acetonitrile.

20, H3-19/H-2, H3-20/H-2, H3-19/H-3β, H3-20/H-1β, H3-18/ H-3α, and H-3α/H-1α, as well as Chem3D modeling (Figure 2), indicated that H-2, Me-19, and Me-20 were all in β-axial positions. Using the same TDDFT ECD calculations and comparison (Figure 4E) as for compounds 1, 3, and 4, the (2S, 10R) absolute configuration of 5 was defined. The structure of compound 5, plebedipene D, was thus defined as shown in Figure 2. The molecular formula of compound 6 was derived as C15H24O from the HRESIMS [M + H]+ ion at m/z 221.1897 (calcd for C15H25O, 221.1905) and the 13C NMR data. The molecular formula required four indices of hydrogen deficiency. The 1H NMR spectrum of 6 showed the presence of one olefinic methyl [δH 1.71 (H3-15)], three aliphatic methyls [δH 0.82 (H3-12), 0.84 (H3-13), and 0.91 (H3-14)], one olefinic proton [δH 5.34 (H-3)], and one oxymethine proton [δH 4.24 (H-9)]. The 13C NMR spectrum displayed 15 carbon resonances. Using DEPT and HMQC experiments, these 15

suggesting a (2S, 5S, 7S, 10R) absolute configuration. Compound 4, plebedipene C, was therefore characterized as shown. The 1H and 13C NMR data implied that 5 is an abietane-type meroditerpenoid similar to compound 4.29,37 Upon comparison of their NMR data, the same acetyl group and aromatic C-ring with an isopropyl group attached at C-13 were apparent. Additionally, the presence of carbon signals at δC 141.5, 142.3, and 180.1 implied one more double bond and an additional conjugated carbonyl group in compound 5 compared to those of compound 4. The conjugated carbonyl carbon was assignable to C-7, and the C-5−C-6 placement of a double bond was verified by analysis of the 2D NMR spectra. The HMBC signal of H-2 to the corresponding carbonyl carbon was indicative of the C-2 placement of the acetoxy group. Further analysis of the 1D and 2D NMR spectra (Figure 1) enabled the proton and carbon signals to be assigned and the 2D structure to be established. NOESY interactions detected for H3-19/H32928



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Table 2. 1H NMR Data for Compounds 1−5 (δ in ppm, J in Hz) position 1α 1β 2 3α 3β 5 6α 6β 7α 7β 14 15 16 17 18 19 20 OAc OCH3 a

1 2.68, t (12.8) 2.15, dt (12.8, 3.7) 4.71, tt (12.8, 3.7) 1.80, 1.43, 1.64, 1.62, 1.83, 2.21, 1.30, 6.79, 2.95, 1.09, 1.09, 1.01, 1.10, a 4.52, b 3.78, 2.04,

ma t (12.8) dd (10.9, 6.8) m m dt (12.4, 3.7) m s sept (6.8) d (6.8) d (6.8) s s d (8.0) d (8.0) s

2 2.59, t (12.8) 2.14, dt (12.8, 3.2) 3.61, tt (12.8, 3.2) 1.81, 1.32, 1.62, 1.61, 1.81, 2.21, 1.31, 6.78, 2.95, 1.09, 1.09, 1.01, 1.05, a 4.46, b 3.74,

ma ma t (8.6) m m dt (12.5, 3.4) m s sept (6.9) d (6.9) d (6.9) s s d (7.8) d (7.8)

3 3.07, 3.04, 2.13, 1.96, 3.46,

dd (11.5, 1.7) dd (11.5, 1.7) m m t (2.6)

1.58, 1.55, 1.81, 2.80,

m m m m

6.52, 3.22, 1.22, 1.24, 1.05, 1.10, 4.93,

s sept (6.9) d (6.9) d (6.9) s s s

4

5

2.76, t (12.6) 2.37, d (12.6) 5.05, tt (12.6, 3.8)

1.45, ma 3.82, dd (13.5, 8.5) 5.43, m

1.89, 1.38, 1.47, 2.02, 1.58, 4.73,

2.38, dd (15.8, 6.4) 1.73, dd (15.8, 2.1)

br. d (12.6) t (12.6) dd (12.3, 5.1) dd (12.3, 5.1) t (12.3) s

6.58, s 3.09, sept (6.3) 1.22 d (6.3) 1.22, d (6.3) 0.90, s 1.20, s a 4.25, d (8.7) b 3.11, d (8.7) 2.08, s

7.73, 3.11, 1.27, 1.31, 1.52, 1.48, 1.63,

s sept (6.6) d (6.6) d (6.6) s s s

2.02, s

3.51, s

Signals were in overlapped regions of the spectra, and the multiplicities could not be discerned.

diseases.4,5 Compounds 1−10 were thus tested for their NO inhibitory effects.43 The NO inhibitor 2-methyl-2-thiopseudourea sulfate (SMT) was used as control (IC50 value of 2.9 μM).43 All the isolates suppressed NO generation induced by LPS in murine microglial BV-2 cells, and the IC50 values are collated in Table 3. The cytotoxic test (MTT assay) showed that all of the isolates had no impact on BV-2 cell survival at their effective concentrations (data not shown).

signals were assigned as two olefinic carbons, six methines (one oxygenated), two methylenes, four methlyls, and one quaternary carbon (Table 1). These spectroscopic features and the indices of hydrogen deficiency implied compound 6 is a tricyclic sesquiterpenoid,38,39 which was substantiated by the HMBC and 1H−1H COSY experiments. The analysis of 1D and 2D NMR data revealed the presence of the 6/6 fused bicyclic system composed of C-1−C-10 and the C-5−C-10 bridged connection. By further analyzing 1D and 2D NMR spectra, the assignments of the proton and carbon signals were accomplished, leading to the establishment of a sesquiterpenoid structure with a bridged tricyclic framework for 6.39 NOESY correlations combined with experimental and calculated ECD spectra permitted assignment of the absolute configuration of 6. NOESY interactions observed for H3-14/H9, H3-14/H-2β, H-2α/H-6, H-5/H-7, H-1/H-8α, and H3-15/ H-3, and Chem3D modeling (Figure 2) afforded a molecular conformation as illustrated in Figure 2. This conformation was suggestive of a cis-fusion of the two six-membered rings, where H-1 and H-6 were both in α-positions and Me-14 and the C-7 isopropyl group were required to be in α-positions. The C-9 hydroxy group, relative to the six-membered B-ring, was determined as β-oriented, which was supported by the coupling constants (J9,8β/8α = 1.4, 5.3 Hz) between H-9 and H2-8. Following the definition of the relative configuration, agreement of the experimental and calculated ECD spectra permitted assignment of a (1R, 5R, 6R, 7R, 9S, 10S) absolute configuration for 6. The structure of compound 6, plebesespene A, was, therefore, defined as a rare copane sesquiterpenoid with a bridged tricyclic framework.38 The known terpenoids, by comparison of the spectroscopic data with literature data, were identified as oplopanone (7),40 oplodiol (8),40 15-acetoxyaromadendrane-4β,10α-diol (9),41 and demethylsalvicanol (10).42 Studies on the relationship of NO and inflammation revealed that compounds inhibiting NO production may be developed into agents to treat inflammation and related neurodegenerative

Table 3. IC50 Values of Compounds 1−10 Inhibiting NO Production in BV-2 Cells compound

IC50 (μM)a

compound

IC50 (μM)

1 2 3 4 5 6

5.7 14.8 >30 >30 26.5 92.9

7 8 9 10 SMTa

38.9 63.5 47.6 10.6 2.9

a

SMT (2-methyl-2-thiopseudourea sulfate) was used as a positive control. Data are presented based on three experiments.

The NO amount was regulated by three types of NO synthase (NOS), namely, neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS), of which iNOS is critical and in charge of the amount of NO in the inflammatory process.44 The bioactive terpenoids with significant NO inhibitory effects prompted us to perform molecular docking to understand the interaction of compounds with the iNOS protein.44−46 The more bioactive compounds 1, 2, 5, 7, 9, and 10 (IC50 value 2σ(I). Final indices: R1 = 0.0723, wR2 = 0.1455 for observed reflections, and R1 = 0.1233, wR2 = 0.1659 for all reflections. The crystallographic data of

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.6b00733. NMR spectra of compounds 1−6 (PDF) X-ray diffraction of compound 1 (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*Tel/Fax (J. Xu): 86-22-23507760. E-mail: xujing611@nankai. edu.cn. *Tel/Fax (Y. Guo): 86-22-23502595. E-mail: victgyq@nankai. edu.cn. ORCID

Yuanqiang Guo: 0000-0002-5297-0223 2931



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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was financially supported by the National Natural Science Foundation of China (No. 21372125), the Ministry of Science & Technology 973 Project (No. 2014CB560709), the Natural Science Foundation of Tianjin, China (No. 16JCYBJC27700), and the State Key Laboratory of Medicinal Chemical Biology (No. 201602007).

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