Diterpenoids of the Cassane Type from Caesalpinia decapetala

Article pubs.acs.org/jnp

Diterpenoids of the Cassane Type from Caesalpinia decapetala Yuben Qiao,†,⊥ Qianqian Xu,†,⊥ Zhengxi Hu,† Xiao-Nian Li,‡ Ming Xiang,† Junjun Liu,† Jinfeng Huang,† Hucheng Zhu,† Jianping Wang,† Zengwei Luo,† Yongbo Xue,*,† and Yonghui Zhang*,† †

Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation and Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, People’s Republic of China ‡ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, Yunnan Province, People’s Republic of China S Supporting Information *

ABSTRACT: Eighteen compounds, including eight new cassane-type furanoditerpenoids, 3β-hydroxyphanginin H (1), 3β-acetoxyphanginin H (2), 7β-acetoxyphanginin H (3), 7βhydroxyphanginin H (4), 4-epi-3β-hydroxycaesalpinilinn (5), 4epi-3β-acetoxycaesalpinilinn (6), 20-acetoxytaepeenin D (7), and tomocin E (8), along with 10 known compounds (9−18) were isolated from the roots of Caesalpinia decapetala. Compounds 1−13 were isolated from C. decapetala for the first time. The new compounds with their absolute configurations were determined by extensive spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Compounds 1, 4, 5, 7, and 11 exhibited inhibitory activities against the SW1990 human pancreatic cancer cell line with IC50 values ranging from 2.9 to 8.9 μM.

T

he genus Caesalpinia (Fabaceae), comprising more than 100 species, is distributed widely in the tropical and subtropical regions of Southeast Asia, of which about 17 species are found in the People’s Republic of China.1 Caesalpinia decapetala (Roth) Alston, also known as “Yan-wang-ci”, is a thorny climbing shrub.2 The leaves and roots of C. decapetala are used in folk medicine to treat bronchitis, dysentery, diabetes, malaria, and pediatric infantile malnutrition and to prevent colds.3 Cassane-type furanoditerpenoids, consisting of three cyclohexane rings and a furan ring or an α,β-butenolide moiety,4 were reported as the characteristic and main metabolites of Caesalpinia species. Nearly 120 compounds of this type have been found of natural origin, only 12 of which possess an aromatic ring C.5 These naturally occurring cassanetype furanoditerpenoids display a broad spectrum of biological activities,6 including antimalarial,7 cytotoxic,8 and antiviral properties.9 As part of a continuing search for structurally interesting and biologically active natural products from Chinese traditional herbs,10 a chemical investigation on the EtOH extract of the roots of C. decapetala was performed. This led to the isolation of eight new cassane-type furanoditerpenoids, 3β-hydroxyphanginin H (1), 3β-acetoxyphanginin H (2), 7β-acetoxyphanginin H (3), 7β-hydroxyphanginin H (4), 4-epi-3β-hydroxycaesalpinilinn (5), 4-epi-3β-acetoxycaesalpinilinn (6), 20-acetoxytaepeenin D (7), and tomocin E (8), together with 10 known compounds (9−18). The absolute configurations of 1, 2, and 7 were secured unambiguously by single-crystal X-ray diffraction analysis, and those of 3−6 and 8 were established by experimental circular dichroism (CD) and electronic circular © XXXX American Chemical Society and American Society of Pharmacognosy

dichroism (ECD) data analysis. The known compounds were identified as caesaljapin C (9), 4b caesalacetal (10), 11 caesalpinista B (11),12 11E-labdadien-19-oic acid (12),13 henrilabdane C (13),14 trans-communic acid,15 ozoroalide,16 3-hydroxy-4-methoxycinnamaladehyde,17 4-hydroxy-3-methoxypropiophenone,18 and intricatinol,19 by comparing their 1H and 13C NMR spectroscopic data with literature values. Herein, the extraction, isolation, structure elucidation, and cytotoxic activities of these isolates are described.

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RESULTS AND DISCUSSION 3β-Hydroxyphanginin H (1) was isolated as colorless crystals from CH2Cl2, mp 232−234 °C. The HRESIMS analysis of 1 gave a sodiated molecular ion peak at m/z 383.1837 [M + Na]+, indicating a molecular formula of C21H28O5 (eight degrees of unsaturation). The IR spectrum of 1 showed absorption bands attributed to hydroxy group (3418 cm−1) and ester carbonyl (1724 cm−1) functionalities. The UV spectrum of 1 displayed an absorption band maximum at 229 nm, together with diagnostic proton signals of two olefinic methines at δH 7.31 (d, J = 1.8 Hz, H-16) and 6.22 (d, J = 1.8 Hz, H-15) in the 1H NMR spectrum (Table 1), and suggested the presence of a furan ring.20 Direct determination of 13C NMR and DEPT (Table 2) spectra, in combination with HSQC correlations, revealed the presence of 21 carbon signals, corresponding to two methyls [δC 14.8 (C-17) and 9.8 (CReceived: October 5, 2016

A

DOI: 10.1021/acs.jnatprod.6b00910 J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

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425.1943 [M + Na]+ (nine degrees of unsaturation), which differed from that of caesaldecin A (1) by 42 amu (C2H2O). This difference indicated the presence of an additional acetyl group (δC 170.0, 21.0 and δH 1.99, s) by analysis of its 1H and 13 C NMR spectra (Tables 1 and 2) and was supported by the absence of a hydroxy group absorption band in the IR spectrum. As a consequence, the hydroxy group at C-3 of 1 was proposed to be acetylated when compared with 2, which was confirmed by the HMBC correlation from H-3 to C-22 (Figure S16, Supporting Information). The relative configurations of all chiral centers of 2 were highly consistent with those of 1 on the basis of its NOESY spectrum (Figure S18, Supporting Information). Finally, the structure and the absolute configuration of 2 (3β-acetoxyphanginin H) was established unequivocally on the basis of a single X-ray diffraction experiment (Figure 3). 7β-Acetoxyphanginin H (3) was isolated as a white, amorphous powder, and its molecular formula was established as C23H30O6 by the positive HRESIMS ion at m/z 425.1941 [M + Na]+, according to nine degrees of unsaturation. Comparison of the 1H and 13C NMR spectroscopic data (Tables 1 and 2) of 3 with those of 2 indicated that both compounds share the same carbon framework. The main difference between them was the location of the acetyl group. The key HMBC correlations (Figure S25, Supporting Information) from H-7 (δH 5.05, d, J = 2.7 Hz) to C-8 and C-6 and from H-8 (δH 2.26, m) to C-7 suggested that the acetyl moiety is substituted at C7, which was further supported by the spin−spin coupling systems of H-6/H-7/H-8 disclosed in the 1H−1H COSY spectrum (Figure S26, Supporting Information). The relative configuration of 3 was established by analysis of the NOESY spectrum (Figure S27, Supporting Information) and by comparison of its chemical shifts and coupling constants with those of 1 and 2. The ROESY cross-peaks of H-5/H-7 and H7/H-9 revealed that those protons are α-oriented. As a consequence, the relative configuration of 3 was established. The absolute configuration of 3 was elucidated because its experimental ECD spectrum was closely comparable to those of 1 and 2 (Figure S74, Supporting Information). Additionally, the absolute configuration of 3 was further verified by comparing its experimental ECD curves with the calculated circular dichroism curves as 4R, 5R, 7S, 8S, 9S, 10R, 11R, and 14R (Figure S76, Supporting Information). 7β-Hydroxyphanginin H (4) was isolated as a white, amorphous powder, possessing the same molecular formula as that of 1 on the basis of its HRESIMS and NMR spectroscopic data. The IR spectrum of 4 showed an absorption band at 3442 cm−1 assignable to a hydroxy group. The 1H and 13 C NMR data (Tables 1 and 2) of 4 resembled those of 3, except for the absence of an acetyl group in 4. Inspection of the 1D and 2D NMR of 4 suggested that compound 4 is a deacetylated derivative of 3. In the same manner as those of compounds 1−3, the relative configuration of 4 was elucidated (Figure 1). Subsequently, the absolute configuration of 4 was assigned as 4R, 5R, 7S, 8S, 9S, 10R, 11R, and 14R according to the helicity rule with a negative Cotton effect at 229 nm (Δε −0.76) associated with a π−π* transition of the furan chromophore in the CD spectrum (Figure S74, Supporting Information).24 This matched well with those of 1−3, indicating that the absolute configurations at C-11 and C-14 of 4 are identical with those of 1−3. 4-epi-3β-Hydroxycaesalpinilinn (5) was isolated as a white, amorphous powder. Its molecular formula was determined to

19)], a methoxy group [δC 52.2 (C-21)], five methylenes including an oxygenated carbon [δC 34.6 (C-1), 27.0 (C-2), 24.6 (C-6), 30.0 (C-7), and 70.3 (C-20)], four sp2 quaternary carbon atoms [δC 109.1 (C-15), 142.9 (C-16), 148.0 (C-12), and 127.3 (C-13)], six methines including two oxygenated carbons [δC 75.1 (C-3), 47.5 (C-5), 36.8 (C-8), 49.2 (C-9), 68.8 (C-11), and 31.9 (C-14)], and two tertiary carbons [δC 53.7 (C-4) and 45.3 (C-10)]. The aforementioned spectroscopic data of 1 resembled those of phanginin H,21 indicating that compound 1 is a cassane-type furanoditerpenoid. Compared with phanginin H, the carbon chemical shift of C3 was shifted downfield from δC 36.8 to δC 75.1 in 1, indicating the presence of an additional hydroxy group at C-3 of 1, rather than a methylene group in phanginin H. This prediction was evidenced by the key HMBC correlations of H-3 (δH 4.10, dt, J = 11.5, 5.1 Hz) with C-2, C-4, and C-18 and assisted by the proton−proton coupling system of H2-1/H2-2/H-3 in the 1 H−1H COSY spectrum (Figure 1). Hence, the planar structure of 1 was established as shown in Figure 1. Biogenetically, cassane-type and clerodane-type diterpenoids have been reported to share parallel pathways, which arise from geranylgeranyl pyrophosphate (GGPP) and possess a ring A/B trans ring fusion.22 Structurally, the relative configuration of H5 and H3-17 of cassane-type furanoditerpenoids is found to be α-oriented.5,23 In the NOESY spectrum of 1, the NOESY interactions of H-5 with H-9 and H-3 and of H-9 with H-11 and H3-17 suggested that these protons are all on the same side of the molecule and, hence, were assigned as α-oriented. The cross-peak of H-8/H-14 indicated that they are on the opposite face of the ring system, and these were assigned as β-oriented. Thus, the relative configuration of 1 was determined (Figure 1). A single-crystal X-ray diffraction pattern analysis of 1 was obtained using Cu Kα radiation, which permitted the absolute configuration of 1 to be determined as 3S, 4S, 5R, 8S, 9S, 10R, 11R, and 14R (Figure 2). 3β-Acetoxyphanginin H (2) was isolated as colorless crystals from CH2Cl2, mp 149−150 °C. Its molecular formula was determined to be C23H30O6 from the HRESIMS peak at m/z B


a

C

dd (12.3, 3.1) m dd (12.5, 2.8) dd (12.5, 3.0) m dt (12.2, 3.8) dd (12.1, 3.9) d (3.9)

dq (7.1, 4.4) d (1.8) d (1.8) d (7.1) s d (8.2) dd (8.2, 1.8)

2.06, 1.26, 1.52, 1.40, 1.71, 1.93, 1.78, 4.82,

2.65, 6.22, 7.31, 0.96, 0.97, 3.87, 3.98,

3.74, s

m dt (13.3, 3.6) dd (12.6, 4.2) dd (8.9, 4.9) dt (11.5, 5.1)

1.34, 2.12, 1.65, 1.86, 4.10,

1a

dq (7.1, 4.3) d (1.6) d (1,6) d (7.1) s d (8.2) dd (8.2, 1.8)

m m dd (12.5, 2.7) m m m dd (12.1, 3.9) d (3.8)

dd (12.6, 3.0) m dd (13.2, 3.8) m dd (11.9, 4.7)

3.67, s 1.99, s

2.64, 6.21, 7.30, 0.95, 1.01, 3.88, 3.98,

2.16, 1.23, 1.50, 1.43, 1.70, 1.93, 1.78, 4.80,

1.37, 2.13, 1.68, 1.93, 5.22,

2a m d (12.9) m m m m d (2.4) m m d (2.7)

3a

dq (7.1, 4.5) d (1.7) d (1.7) d (7.1) s d (8.0) d (8.0)

2.02, s

3.69, s

2.60, 6.23, 7.33, 0.95, 1.14, 4.05, 4.47,

2.26, m 1.89, m 4.86, d (4.2)

1.20, 2.12, 1.72, 1.90, 1.64, 1.86, 2.30, 1.57, 1.59, 5.05,

Recorded at 400 MHz in CDCl3. bRecorded at 400 MHz in CD3OD.

1a 1b 2a 2b 3a 3b 5 6a 6b 7a 7b 8 9 11a 11b 14 15 16 17 19 20a 20b OCH3-12 OCH3-18 OCOCH3-3 OCOCH3-6 OCOCH3-7 OCOCH3-20

position m m m m m m m d (3.7) d (3.7) d (2.8)

4a

dq (7.1, 4.4) d (1.9) d (1.9) d (7.1) s d (7.9) dd (7.9, 2.0)

3.71, s

2.61, 6.23, 7.32, 0.96, 1.30, 4.00, 4.59,

2.52, dt (11.7, 5.4) 1.82, m 4.83, d (4.2)

1.20, 2.10, 1.69, 1.90, 1.68, 1.85, 2.12, 1.55, 1.58, 4.03,

Table 1. 1H NMR Spectroscopic Data for Compounds 1−8 (δ in ppm, J in Hz)

dq (7.1, 4.2) d (1.9) d (1.9) d (7.1) s

overlap overlap m dd (12.2, 2.6) m dd (12.0, 3.9) overlap d (3.7)

m dt (13.6, 3.4) m m dt (10.8, 5.3)

3.75, s

2.71, 6.26, 7.37, 1.01, 1.53,

2.10, 1.37, 1.61, 1.46, 1.71, 1.90, 2.07, 5.35,

1.59, 2.37, 1.75, 1.80, 3.98,

5a

dq (7.1, 4.1) d (1.9) d (1.9) d (7.1) s

m m m m m m m d (3.8)

m m m m m

3.68, s 2.00, s

2.73, 6.37, 7.48, 1.05, 1.54,

2.29, 1.47, 2.43, 1.35, 1.49, 1.81, 2.29, 5.47,

1.48, 1.76, 1.77, 1.84, 5.18,

6b m m m m m m br s dt (6.3, 1.7)

dd (2.2, 0.9) d (2.2) s s dd (11.7, 1.3) d (11.6)

2.04, s

2.06, s

3.71, s

6.74, 7.56, 2.33, 1.47, 4.59, 4.85,

2.95, d (18.4) 3.20, dd (18.4, 6.1)

1.42, 2.84, 1.78, 1.70, 1.65, 1.75, 2.69, 5.29,

7a

d (7.4) s d (13.6) d (13.6) s s

1.12, 1.57, 4.21, 4.82, 3.19, 3.69,

2.03, s

m t (3.8) m d (2.6) t (13.3) dd (13.7, 3.0) dd (7.4, 5.1) s

m d (13.3) d (3.8) m m td (13.3, 4.0) s m 1.49, 1.53, 2.10, 1.65, 1.34, 2.62, 2.92, 5.83,

0.99, 2.42, 1.44, 1.60, 1.62, 1.77, 2.01, 3.97,

8a

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Table 2. 13C NMR Spectroscopic Data for Compounds 1−8 (δ in ppm) position 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 OCH3-12 OCH3-18 OCOCH3-3 OCOCH3-3 OCOCH3-6 OCOCH3-6 OCOCH3-7 OCOCH3-7 OCOCH3-20 OCOCH3-20 a

1a 34.6, 27.0, 75.1, 53.7, 47.5, 24.6, 30.0, 36.8, 49.2, 45.3, 68.8, 148.0, 127.3, 31.9, 109.1, 142.9, 14.8, 177.1, 9.8, 70.3,

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

52.2, CH3

2a 34.2, 23.6, 76.5, 51.9, 47.3, 24.4, 29.9, 36.8, 49.0, 45.2, 68.8, 147.9, 127.2, 31.9, 109.1, 142.8, 14.7, 175.7, 11.0, 70.1,

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

52.3, CH3 170.0, C 21.0, CH3

3a 37.1, 18.3, 34.3, 47.5, 48.9, 38.7, 71.4, 30.0, 49.6, 46.1, 68.3, 148.1, 127.0, 31.5, 109.1, 143.0, 14.7, 177.7, 17.6, 72.1,

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

4a 37.2, 18.4, 38.5, 48.0, 49.8, 38.5, 69.3, 29.1, 49.9, 46.1, 68.8, 148.5, 126.9, 31.7, 109.1, 142.7, 14.9, 175.7, 18.2, 72.4,

52.2, CH3

5a

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

32.1, CH2 26.6, CH2 75.2, CH 53.5,C 46.6, CH 26.2, CH2 29.6, CH2 38.4, CH 47.2, CH 49.8, C 68.5, CH 144.5, C 130.6, C 31.7, CH 109.4, CH 144.1, CH 15.2, CH3 177.8, C 10.5, CH3 175.4, C

52.0, CH3

52.5, CH3

6b 30.6, 24.6, 77.8, 53.2, 47.8, 32.7, 27.3, 40.1, 48.4, 51.2, 70.2, 146.2, 132.2, 33.2, 110.5, 145.5, 15.5, 178.0, 12.2, 177.7,

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

53.0, CH3 171.8, C 20.8, CH3

7a 34.6, 18.4, 38.4, 47.7, 47.1, 70.2, 34.6, 124.0, 139.8, 41.0, 107.1, 153.0, 126.4, 128.7, 105.0, 144.7, 16.0, 178.1, 19.1, 66.0,

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

52.4, CH3

8a 34.1, 18.3, 38.4, 48.2, 51.1, 69.1, 39.2, 36.2, 44.5, 41.0, 38.1, 107.6, 170.7, 36.4, 115.7, 170.1, 12.0, 180.0, 18.8, 63.2, 50.8, 52.2,

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

170.3, C 21.1, CH3 170.1, C 21.6, CH3 170.8, C 21.7, CH3

170.8, C 21.1, CH3

Recorded at 100 MHz in CDCl3. bRecorded at 100 MHz in CD3OD.

Figure 1. Key COSY, HMBC, and NOESY correlations of compounds 1, 5, 7, and 8.

that they are α-oriented. In turn, the NOESY correlations of H8/H-14 showed that both H-8 and H-14 are β-oriented. Consequently, the relative configuration of 5 was assigned as shown in Figure 1. The absolute configuration of 5 was thus elucidated as 3S, 4S, 5R, 8S, 9S, 10R, 11R, and 14R, and the experimental ECD spectrum was in good agreement with the calculated ECD spectrum of 5 (Figures 4 and S75, Supporting Information). 4-epi-3β-Acetoxycaesalpinilinn (6) was isolated as colorless needle crystals from CH2Cl2, mp 214−216 °C, exhibiting an HRESIMS ion peak at m/z 439.1726 [M + Na] + ,

be C21H26O6 according to the positive ion peak at m/z 397.1640 [M + Na]+ in the HRESIMS, requiring nine degrees of unsaturation. Its IR spectrum showed the presence of a hydroxy group absorption band at 3442 cm−1. The 13C NMR data (Table 2) of 5 were very similar to those of 1, except for a carbonyl carbon atom that resonated at δC 175.4 in 5 (Table 2). In the HMBC spectrum, correlations from H-9/H-11 to C-20 and from H-1b to C-20 were observed (Figure 1). The configuration of compound 5 was established from its NOESY and ECD spectra. The NOESY correlations of H-5 with H-3 and H-9 and of H-9 with H-11 and H3-17 indicated D



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(1642, 1604, 1530, 1459, and 1435 cm −1 ) spectra.25 Comparison the 1H NMR spectrum (Table 1) of 7 with those of 1−6 showed the absence of a doublet methyl and the presence of a singlet methyl at δH 2.33 in the 1H NMR spectrum. Additionally, the 13C NMR data (Table 2) of 7 resembled those of the known taepeenin D.4a The main differences of 7 and taepeenin D were evident from the presence of an oxygenated methylene group (δC 66.0, C-20) and an acetyl moiety (δC 170.8, 21.7, OAc-20). Moreover, the chemical shift of C-20 together with the molecular formula of 7 indicated that H3-20 of taepeenin D is oxygenated in 7. This deduction was verified by the key HMBC correlations from H20 to C-10 and C-22 and from H3-23 to C-20 (Figure 1). The NOESY cross-peak of H-20 and H3-19 indicated that they are both on the same side of the molecule and were assigned as βoriented. In turn, the NOESY correlation of H-5 and H-6 suggested they are α-oriented. Thus, the relative configuration of 7 was elucidated as shown in Figure 1. To establish the absolute configuration of 7, a single-crystal X-ray diffraction experiment was performed using Cu Kα radiation. Figure 5 shows an ORTEP drawing, and the use of this technique unambiguously demonstrated the absolute configuration of 7 as 4R, 5R, 6R, and 10R.

Figure 2. X-ray ORTEP drawing of compound 1.



Tomocin E (8) was isolated as a white, amorphous powder. The HRESIMS analysis displayed a positive sodiated molecular ion peak at m/z 473.2153 [M + Na]+, revealing a molecular formula of C24H34O8 (eight degrees of unsaturation). The IR spectrum showed absorption bands at 3425, 1736, and 1717 cm−1 ascribed to a hydroxy group and two carbonyl groups, respectively. In addition, the presence of an α,β-butenolide ring was evidenced by the absorption band at 1757 cm−1 in the IR spectrum and by the absorption maximum at 228 nm in the UV spectrum.26 The 1D NMR spectroscopic data of 8 (Tables 1 and 2) were similar to those of tomocin A,4d except for the absence of an aldehyde group and the presence of three additional signals [a methoxy group (δC 50.8, δH 3.19, s), an oxygenated methylene (δC 63.2, δH 4.21, d, J = 13.6 Hz, 4.82, d, J = 13.6 Hz), and an oxygenated methine (δC 69.1, δH 3.97, m)] and one acetyl group (δC 170.8, 21.1, δH 2.03, s) in 8. The HMBC (Figure 1) correlations from H-20 to C-1, C-10, and C11 indicated that H3-20 of tomocin A is oxygenated in 8. The HMBC correlations from H-6 (δH 3.97, m) to C-5 and C-7 indicated that a hydroxy group is located at C-6. In addition, the HMBC correlation (Figure 1) from OCH3-12 to C-12 demonstrated that C-12 is linked directly with a methoxy group. The NOESY (Figure 1) correlations of H-5/H-6, H-5/

Figure 4. Calculated ECD spectra of 5 and its enantiomer and experimental ECD spectrum of 5 in MeOH.

corresponding to a molecular formula of C23H28O7 with 10 degrees of unsaturation. Close similarities were observed in the 13 C NMR data (Table 2) between compounds 5 and 6, except for the absence of evidence of a hydroxy group and the presence of an acetyl group in 6. This indicated that compound 6 is a C-3 acetylated derivative of 5. The relative configuration of 6 was established by analysis of the NOESY spectrum (Figure S54, Supporting Information) and was identical to that of 5. Additionally, the absolute configuration of 6 was elucidated as being the same as that of 5, according to the ECD spectrum (Figure S75, Supporting Information). 20-Acetoxytaepeenin D (7) was obtained as colorless crystals from CH2Cl2, mp 190−192 °C, and was designated with a molecular formula of C 25 H 30 O 7 , with 11 degrees of unsaturation, on the basis of its HRESIMS peak at m/z 465.1903 [M + Na]+. The absorption bands of a benzofuran moiety were displayed in the UV (227 and 253 nm) and IR E



Article

Plant Material. The roots of Caesalpinia decapetala were collected at the Dabie Mountains area, Hubei Province, People’s Republic of China, in October 2012 and identified by Prof. C. G. Zhang, School of Pharmacy, Tongji Medical College, Huzhong University of Science and Technology. A voucher specimen (No. 2012107B) was deposited in the herbarium of Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, Tongji Medical College, Huazhong University of Science and Technology. Extraction and Isolation. The air-dried and powdered roots of C. decapetala (10.0 kg) were extracted with 95% aqueous EtOH (50 L) three times at room temperature, and the solvent was evaporated under reduced pressure to give a brown syrup (740.2 g, 7.4%). The syrup was suspended in H2O and partitioned successively with EtOAc and n-BuOH to yield an EtOAc and an n-BuOH extract, respectively. The EtOAc extract (307.6 g) was chromatographed over silica gel (80−120 mesh) and eluted with a gradient system of petroleum ether−EtOAc (100:0 → 0:100, v/v) to give eight fractions. Fraction 5 was decolorized using MCI column chromatography (CC) [MeOH−H2O (80:20 → 90:10), v/v] followed by reversedphase ODS CC [7.2 g, MeOH−H2O (40:60 → 90:10) → MeOH] to afford seven fractions. Fr. 5-2 (241.3 mg) was then chromatographed over Sephadex LH-20 (MeOH) to afford seven fractions. Fr. 5-2-3 (27.8 mg) was purified by semipreparative HPLC (acetonitrile−H2O, 55:45, v/v) to yield 16 (2.8 mg) and 17 (4.4 mg). Fr. 5-3 (834.3 mg) was chromatographed over Sephadex LH-20 (MeOH) to afford five fractions. Fr. 5-3-2 (120.5 mg) was subjected to silica gel CC [petroleum ether−acetone (60:1 → 1:1)] to yield four fractions (p1− p4). Of these, p1 (87.7 mg) was purified by semipreparative HPLC (acetonitrile−H2O, 65:35, v/v) to yield 1 (3.7 mg), 2 (7.2 mg), 3 (3.1 mg), and 7 (4.6 mg). In turn, p2 (37.0 mg) was purified by semipreparative HPLC (MeOH−H2O, 80:20, v/v) to yield 12 (3.8 mg). Fr. 5-3-3 (382.5 mg) was subjected to silica gel CC [petroleum ether−acetone (50:1 → 1:1), v/v] to yield seven fractions (p5−p11). P8 (209.3 mg) was chromatographed over silica gel CC [petroleum ether−EtOAc (15:1 → 1:1), v/v] to yield three fractions (s1−s3). S2 (56.6 mg) was purified by semipreparative HPLC (MeOH−H2O, 70:30, v/v) to yield 10 (7.3 mg) and 11 (6.2 mg). P9 (37.3 mg) was purified by semipreparative HPLC (MeOH−H2O, 67:33, v/v) to afford 15 (2.3 mg). Fr. 5-3-4 (50.9 mg) was purified by semipreparative HPLC (MeOH−H2O, 80:20, v/v) to give 6 (2.3 mg) and 9 (7.7 mg). Fr. 5-4 (647.2 mg) was subjected to silica gel CC [petroleum ether−acetone (20:1 → 2:1), v/v] to yield five fractions. Fr. 5-4-3 (383.4 mg) was chromatographed over RP-C18 ODS [MeOH−H2O (70:30 → 90:10) → MeOH, v/v] to afford three fractions (p12−p14). P13 (40.3 mg) was purified by semipreparative HPLC (MeOH−H2O, 80:20, v/v) to yield 8 (5.7 mg). Fraction 6 was decolorized using MCI column chromatography (CC) [MeOH−H2O, (80:20 → 90:10), v/v], and, when followed by silica gel CC [4.9 g, petroleum ether−acetone (35:1 → 1:1), v/v], eight fractions were obtained. Fr. 6-2 (1.3 g, oil) was chromatographed using Sephadex LH-20 (MeOH) to give three fractions. Fr. 6-2-3 (89.4 mg) was purified by semipreparative HPLC (MeOH−H2O, 60:40, v/ v) to yield 4 (3.9 mg). Fraction 7 was decolorized using MCI CC [MeOH−H2O (80:20 → 90:10), v/v] and afforded five fractions by silica gel CC [2.2 g, petroleum ether−EtOAc (13:1 → 1:1), v/v]. Fr. 7-4 (1.0 g) was chromatographed by Sephadex LH-20 (MeOH) to give seven fractions. Fr. 7-4-5 (49.2 mg) and Fr. 7-4-6 (38.2 mg) were purified by semipreparative HPLC (MeOH−H2O, 60:40, v/v) to yield 5 (5.6 mg), 13 (4.4 mg), and 14 (6.9 mg), respectively. Finally, fraction 7-4-7 (23.7 mg) was purified by semipreparative HPLC (MeOH−H2O, 80:20, v/v) to yield 18 (6.7 mg). 3β-Hydroxyphanginin H (1): colorless crystals (CH2Cl2), mp 232− 234 °C, [α]25D +19 (c 0.4, CH2Cl2); UV (CH2Cl2) λmax (log ε) 229 (3.54) nm; CD (CH2Cl2) λmax (Δε) 229 (−1.12) nm; IR (KBr) νmax 3418, 2938, 2863, 1450, 1724, 1244 cm−1; 1H and 13C NMR data, see Tables 1 and 2; HRESIMS m/z 383.1837 [M + Na]+ (calcd for C21H28O5Na, 383.1834). 3β-Acetoxyphanginin H (2): colorless crystals (CH2Cl2), mp 108− 109 °C, [α]25D +17 (c 0.2, CH2Cl2); UV (CH2Cl2) λmax (log ε) 229

H-9, H-9/H3-17, and H3-17/OCH3-12 suggested that they are α-oriented. In contrast, the correlations of H2-20/H3-19, H220/H-8, and H-8/H-14 indicated that they are β-oriented. As a result, the relative configuration of all chiral centers of 8 was established as shown in Figure 1. The absolute configuration of 8 was elucidated as 4R, 5R, 6R, 8S, 9S, 10S, 12R, and 14R, because the experimental ECD spectrum of 8 was in good accordance with the calculated ECD spectrum (Figure 6).

Figure 6. Calculated ECD spectra of 8 and its enantiomer and experimental ECD spectrum of 8 in CH2Cl2.

Some of the isolates were evaluated for their in vitro cytotoxic activities against five cancer cell lines (SW1990, HepG2, A2780, Panc02, and B16) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method.27 Gemcitabine and cisplatin were used as positive controls. Compounds 1, 4, 5, 7, and 11 showed antiproliferative activities against SW1990 human pancreatic cells with IC50 values in the range 2.9−8.9 μM (Table S1, Supporting Information), which were comparable to the positive control gemcitabine (IC50 2.3 μM). In addition, compound 11 displayed inhibitory activity against HepG2 human hepatoma cells with an IC50 value of 3.9 μM. All 13 test compounds were inactive against the B16, Panc02, and A2780 tumor cell lines (IC50 > 10 μM). Also, these compounds were evaluated for their in vitro cytotoxic activities against T and B lymphocyte proliferation using the same method. Cyclosporin A and mycophenolate mofetil were used as positive controls. All test compounds were inactive (IC50 > 10 μM) in this assay.

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EXPERIMENTAL SECTION

General Experimental Procedures. Melting points were obtained using a Beijing Tech. X-5 microscopic melting point apparatus and are uncorrected. Optical rotations were determined with a PerkinElmer PE-341 polarimeter (PerkinElmer, Waltham, MA, USA). UV spectra were measured by a Varian Cary 50 UV/vis spectrophotometer (Varian, Salt Lake City, UT, USA). ECD data were obtained using a JASCO-810 spectrometer. IR spectra were recorded with a Bruker Vertex 70 FT-IR spectrophotometer (Bruker, Karlsruhe, Germany). NMR spectra were recorded on a Bruker AM-400 NMR spectrometer (Bruker, Karlsruhe, Germany). HRESIMS data were acquired using a Thermo Fisher LTQ XL LC/MS (Thermo Fisher, Palo Alto, CA, USA). Compounds were purified by a Dionex HPLC system semipreparative HPLC equipped with an Ultimate 3000 DAD detector (Thermo Fisher, Scientific, Germany). Chemical shifts are expressed in ppm with reference to the CDCl3 (δH 7.26/δC 77.0) and CD3OD (δH 3.31/δC 49.0) signals. The crystallographic data were obtained on a Bruker APEX DUO diffractometer equipped with graphite-monochromatized Cu Kα radiation (λ = 1.541 78 Å). Silica gel (80−120 mesh, 100−200 mesh, and 200−300 mesh, Qingdao Marine Chemical Inc., Qingdao, People’s Republic of China), ODS (50 μm, YMC, Japan), and Sephadex LH-20 (Pharmacia Biotech AB, Uppsala, Sweden) were used for column chromatography. F



Article

90°, β = 100.323(2)°, γ = 90°, V = 2121.41(19) Å3, T = 100(2) K, space group P21, Z = 4, μ(Cu Kα) = 0.738 mm−1, 21 866 reflections measured, 6446 independent reflections (Rint = 0.0373). The final R1 values were 0.0545 (I > 2σ(I)). The final wR(F2) values were 0.1412 (I > 2σ(I)). The final R1 values were 0.0553 (all data). The final wR(F2) values were 0.1422 (all data). The goodness of fit on F2 was 1.075. Flack parameter = 0.02(9). Crystal data for 20-acetoxytaepeenin D (7): C25H30O7, M = 442.49, a = 7.7215(6) Å, b = 16.2785(13) Å, c = 17.9730(15) Å, α = 90°, β = 90°, γ = 90°, V = 2259.1(3) Å3, T = 100(2) K, space group P212121, Z = 4, μ(Cu Kα) = 0.778 mm−1, 12 876 reflections measured, 4150 independent reflections (Rint = 0.0402). The final R1 values were 0.0556 (I > 2σ(I)). The final wR(F2) values were 0.1459 (I > 2σ(I)). The final R1 values were 0.0557 (all data). The final wR(F2) values were 0.1461 (all data). The goodness of fit on F2 was 1.187. Flack parameter = 0.02(5). Computational Section. The conformational analyses were carried out for all compounds by using both the programs BALLOON and Confab.29 The quantum chemical computations were conducted with Gaussian 09 software.30 The input geometries of 3, 5, 8, and their enantiomers were optimized with the DFT method at the B3LYP/631G* level. The B3LYP functional and the aug-cc-pVDZ basis set were employed for the TDDFT calculations. Calculation of ECD spectra was accomplished using the GaussSum 2.2.5 program.31 Electronic transitions were expanded as Gaussian curves, with a fwhm (full width at half-maximum) for each peak set to 0.4 eV, which gives a good fit with the experimental width of the bands. Rotational strengths computed for all transitions with dipole-velocity gauge formulation differed from dipole-length values by less than 5% for all compounds. Cytotoxicity against Cancer Cell Lines. Cytotoxicity of the isolated compounds against the five cancer cell lines (SW1990, HepG2, A2780, Panc02, and B16) was evaluated using the MTT method. Gemcitabine (Sigma, St. Louis, MO, USA) and cisplatin (Dalian Meilun Biology Technology Co., Ltd., Dalian, People’s Republic of China) were used as positive controls. The cells were maintained in an RRMI S7 1640 medium (Hyclone, Thermo Scientific, Logan, UT, USA) supplemented with 10% (v/v) fetal bovine serum (Gibco BRL, Rockville, MD, USA), 100 units/mL penicillin, and 100 μg/mL streptomycin (Invitrogen, Carlsbad, CA, USA). Cultures were incubated at 37 °C in a humidified atmosphere of 5% CO2. Tumor cells were seeded in 96-well microtiter plates at 5000 cells/well. After 24 h, test compounds were added to the wells. After incubation for 48 h, cell viability was determined by measuring the metabolic conversion of MTT (Sigma) into purple formazan crystals by viable cells. The MTT assay results were read using a microplate spectrophotometer (Thermo Scientific, Waltham, MA, USA) plate reader at 570 nm. All of the selected compounds were tested at five concentrations (50, 25, 10, 2.5, and 1 μM) in 100% DMSO with a final concentration of DMSO of 0.5% (v/v) in each well. Each concentration of the compounds was tested in three parallel experiments. IC50 values were expressed as the means ± SEM calculating by GraphPad Prism 5. Effects on T and B Lymphocyte Proliferation. Three male Balb/c (4−6 week old) mice (purchased from Beijing HFK BioTechnology Co., Ltd.) were sacrificed, and their spleens were removed under aseptic conditions. The animal experiments were approved by the Institutional Animal Care and Use Committee of Huazhong University of Science and Technology (approval number: SYXK20160057; approval date: March 2016). T and B cells were enriched with splenocytes from a nylon-wool column, as previously described,32 stimulated by 5 μg/mL ConA (Sigma) and 10 μg/mL LPS (Sigma), respectively, followed by identical procedures of cytotoxicity assays. Cyclosporin A (Sigma) and mycophenolate mofetil (Sigma) were used as positive controls.

(3.57) nm; CD (CH2Cl2) λmax (Δε) 228 (−1.31) nm; IR (KBr) νmax 2938, 2880, 2861, 1450, 1734, 1243 cm−1; 1H and 13C NMR data, see Tables 1 and 2; HRESIMS m/z 425.1940 [M + Na]+ (calcd for C23H30O6Na, 425.1943). 7β-Acetoxyphanginin H (3): white, amorphous powder, [α]25D −12 (c 0.3, CH2Cl2); UV (CH2Cl2) λmax (log ε) 229 (3.72) nm; CD (CH2Cl2) λmax (Δε) 229 (−0.59) nm; IR (KBr) νmax 2936, 2871, 1736, 1445, 1241 cm−1; 1H and 13C NMR data, see Tables 1 and 2; HRESIMS m/z 425.1940 [M + Na]+ (calcd for C23H30O6Na, 425.1943). 7β-Hydroxyphanginin H (4): white, amorphous powder, [α]25D +5 (c 0.4, CH2Cl2); UV (CH2Cl2) λmax (log ε) 229 (3.74) nm; CD (CH2Cl2) λmax (Δε) 229 (−0.76) nm; IR (KBr) νmax 3442, 2932, 2872, 1721, 1458, 1257 cm−1; 1H and 13C NMR data, see Tables 1 and 2; HRESIMS m/z 383.1844 [M + Na]+ (calcd for C21H28O5Na, 383.1834). 4-epi-3β-Hydroxycaesalpinilinn (5): white, amorphous powder, [α]26D +10 (c 0.1, MeOH); UV (MeOH) λmax (log ε) 219 (3.65) nm; CD (MeOH) λmax (Δε) 218 (−11.38), 235 (+3.29) nm; ECD (MeOH) λmax (Δε) 218 (−4.17), 235 (+4.04) nm; IR (KBr) νmax 3442, 2936, 2869, 1767, 1718, 1449, 1258 cm−1; 1H and 13C NMR data, see Tables 1 and 2; HRESIMS m/z 397.1640 [M + Na]+ (calcd for C21H26O6Na, 397.1627). 4-epi-3β-Acetoxycaesalpinilinn (6): colorless, tiny needle crystals (CH2Cl2), mp 214−216 °C, [α]25D +2 (c 0.2, CH2Cl2); UV (CH2Cl2) λmax (log ε) 229 (4.13) nm; CD (CH2Cl2) λmax (Δε) 229 (−0.78), 236 (+2.92) nm; IR (KBr) νmax 2944, 2821, 2860, 1773, 1734, 1451, 1268 cm−1; 1H and 13C NMR data, see Tables 1 and 2; HRESIMS m/z 439.1726 [M + Na]+ (calcd for C23H28O7Na, 439.1733). 20-Acetoxytaepeenin D (7): colorless, massive crystals (CH2Cl2), mp 190−192 °C, [α]25D −30 (c 0.1, CH2Cl2); UV (CH2Cl2) λmax (log ε) 227 (3.47) nm, 253 (3.77) nm; CD (CH2Cl2) λmax (Δε) 228 (−0.77), 253 (−1.92) nm; IR (KBr) νmax 2980, 2934, 2863, 1743, 1724, 1642, 1604, 1530, 1459, 1435, 1250, 1240, 1221 cm−1; 1H and 13 C NMR data, see Tables 1 and 2; HRESIMS m/z 465.1903 [M + Na]+ (calcd for C25H30O7Na, 465.1889). Tomocin E (8): white, amorphous powder, [α]25D −126 (c 0.3, CH2Cl2); UV (CH2Cl2) λmax (log ε) 228 (3.71) nm; CD (CH2Cl2) λmax (Δε) 228 (−17.73) nm; ECD (CH2Cl2) λmax (Δε) 234 (−20.55) nm; IR (KBr) νmax 3425, 2963, 2940, 2865, 1757, 1736, 1717, 1284, 1248 cm−1; 1H and 13C NMR data, see Tables 1 and 2; HRESIMS m/z 473.2153 [M + Na]+ (calcd for C24H34O8Na, 473.2151). X-ray Crystal Structure Analysis. Crystals of 1, 2, and 7 were obtained from CH2Cl2. The intensity data for 3β-hydroxyphanginin H (1), 3β-acetoxyphanginin H (2), and 20-acetoxytaepeenin D (7) were collected at 100 K on a Bruker APEX DUO diffractometer equipped with an APEX II CCD using Cu Kα radiation. Cell refinement and data reduction were performed with Bruker SAINT. The structures were solved by direct methods using SHELXS-97,28 expanded using difference Founier techniques, and refined by the program and fullmatrix least-squares calculations. The non-hydrogen atoms were refined anisotropically, and hydrogen atoms were fixed at calculated positions. Crystallographic data (excluding structure factor tables) for the reported structures have been deposited with the Cambridge Crystallographic Data Center (CCDC) as supplementary publication nos. CCDC 1493052 for 1, CCDC 1493054 for 2, and CCDC 1493053 for 7. Copies of the data can be obtained free of charge from the CCDC, 12 Union Road, Cambridge CB 1EZ, UK [fax: Int. +44(0) (1223) 336 033); e-mail: [email protected]]. Crystal data for 3β-hydroxyphanginin H (1): C21H28O5, M = 360.43, a = 7.8585(10) Å, b = 13.8457(17) Å, c = 8.4093(10) Å, α = 90°, β = 106.247(4)°, γ = 90°, V = 878.45(19) Å3, T = 100(2) K, space group P21, Z = 2, μ(Cu Kα) = 0.780 mm−1, 8276 reflections measured, 2843 independent reflections (Rint = 0.0872). The final R1 values were 0.0366 (I > 2σ(I)). The final wR(F2) values were 0.1015 (I > 2σ(I)). The final R1 values were 0.0660 (all data). The final wR(F2) values were 0.1041 (all data). The goodness of fit on F2 was 1.085. Flack parameter = 0.04(5). Crystal data for 3β-acetoxyphanginin H (2): C23H30O6, M = 402.47, a = 8.4070(4) Å, b = 23.1784(13) Å, c = 11.0659(6) Å, α = G



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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.6b00910. HRESIMS, IR, UV, 1D and 2D NMR, and CD spectra of 1−8; ECD computational details of 3, 5, and 8; bioassay data for 1−13 (PDF) X-ray crystallographic data of 1, 2, and 7 (CIF) (CIF) (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*Tel: 86-27-82609207. E-mail: [email protected]. (Y. Xue). *Tel: 86-27-83692311. Fax: 86-27-83691325. E-mail: [email protected]. (Y. Zhang). ORCID

Yongbo Xue: 0000-0001-9133-6439 Yonghui Zhang: 0000-0002-7222-2142 Author Contributions ⊥

Y. Qiao and Q. Xu contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Analytical and Testing Center at Huazhong University of Science and Technology for assistance in conducting CD, IR, and UV analyses. We greatly acknowledge the financial support from the Program for New Century Excellent Talents in University, State Education Ministry of China (NCET-2008-0224), the National Natural Science Foundation of China (Nos. 31370372, 81573316, and 81641129), the National Science and Technology Project of China (No. 2011ZX09102-004), and the Fundamental Research Fund for the Central Universities (No. 2016YXMS149).

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REFERENCES

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Article

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Diterpenoids of the Cassane Type from Caesalpinia decapetala

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