Veluflavanones AâP, Cytotoxic Geranylated Flavanones from

Article Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX

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Veluflavanones A−P, Cytotoxic Geranylated Flavanones from Dalbergia velutina Stems Sutin Kaennakam,*,† Edwin Risky Sukandar,† Pongpun Siripong,‡ Kitiya Rassamee,‡ and Santi Tip-pyang*,† †

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Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand, 10330 ‡ Natural Products Research Section, National Cancer Institute, Bangkok, Thailand, 10400 S Supporting Information *

ABSTRACT: Sixteen new geranylated flavanones, named veluflavanones A−P (1−16), and a known analogue (17), were isolated from Dalbergia velutina. The chemical structures of 1−17, as well as their absolute configurations, were determined by spectroscopic analysis and experimental ECD data. All isolated compounds were tested for their cytotoxicity against five human cancer cell lines. Compound 9 showed cytotoxicity toward KB, HeLa S3, and MCF-7 cells with IC50 values of 9.9, 8.1, and 10.0 μM, respectively. In addition, compounds 10, 11, 14, and 16 exhibited selective cytotoxicity against HeLa S3 cells with IC50 values of 6.6−9.9 μM. Dalbergia velutina Benth (Leguminosae) is a plant found in Thailand, and the cytotoxicity of pterocarpans,1 isoflavones,2 and isoflavans3 from its roots has been reported previously. The discovery of compounds with interesting structures and diverse bioactivities prompted further investigations of bioactive compounds from other parts of the plant. Herein, 16 new geranylated flavanones, named veluflavanones A−P (1−16), and the known analogue 17 are reported. The structures of these compounds were characterized by spectroscopic analyses, specifically 1D and 2D NMR spectroscopy. In addition, the 1D NMR data of the compounds were compared with literature data. The absolute configurations at C-2 of flavanones were assigned using experimental electronic circular dichroism (ECD) analysis. The cytotoxicities of geranylated flavanones 1−17 were tested in five human cancer cell lines.

Veluflavanone A (1) was determined to have the molecular formula C25H28O5 on the basis of the HRESIMS ion at m/z 407.1881 [M − H]− (calcd for C25H27O5−, 407.1858). Its IR data showed absorption bands for carbonyl and hydroxy groups at 1684 and 3180 cm−1, respectively. The UV data showed λmax peaks at 326, 315, 292, and 286 nm. The 1H NMR data of 1 (Table 1) indicated the presence of two protons of a methylene group at δH 2.71 (1H, dd, J = 2.7, 16.7 Hz, H-3β) and 3.01 (1H, dd, J = 12.8, 16.7 Hz, H-3α) and an oxymethine proton at δH 5.45 (1H, dd, J = 2.7, 12.8 Hz, H-2) in the C-ring, two aromatic protons at δH 6.63 (1H, d, J = 8.6 Hz, H-6) and 7.60 (1H, d, J = 8.6 Hz, H-5) in the A-ring, and four aromatic protons at δH 6.91 (2H, d, J = 8.5 Hz, H-3′, 5′) and 7.43 (2H, d, J = 8.5 Hz, H-2′, 6′) in the B-ring, suggesting the presence of a flavanone skeleton. In addition, the 1H NMR data indicate the presence of two hydroxy protons at δH 8.52 (1H, s, 4′-OH) and 9.31 (1H, s, 7-OH) in the B- and A-rings, an olefinic proton at δH 5.30 (1H, t, J = 7.0 Hz, H-2″), two olefinic resonances of trans double-bond protons at δH 5.56 (1H, m, H-5″) and 5.57 (1H, d, J = 13.4 Hz, H-6″), two

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RESULTS AND DISCUSSION The crude CH2Cl2 extract from the stems of D. velutina afforded 16 new geranylated flavanones, veluflavanones A−P (1−16), and a known analogue, prostratol F (17)4 (Figure 1). The structures of the flavanones were elucidated by comparison with reported 1D NMR and HRESIMS data. © XXXX American Chemical Society and American Society of Pharmacognosy

Received: August 15, 2018

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DOI: 10.1021/acs.jnatprod.8b00688 J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

Article

Figure 1. Chemical structures of compounds 1−17.

Table 1. 1H NMR Data for Compounds 1−8 in Acetone-d6 (δ in ppm, J in Hz) no. 2

1

2

3

4

5

6

7

5 6 2′ 3′ 5′ 6′ 1″ 2″

5.45 dd (2.7, 12.8) 3.01 dd (12.8, 16.7) 2.71 dd (2.7, 16.7) 7.60 d (8.6) 6.63 d (8.6) 7.43 d (8.5) 6.91 d (8.5) 6.91 d (8.5) 7.43 d (8.5) 3.37 d (7.0) 5.30 t (7.0)

5.45 dd (2.78, 12.8) 2.97 dd (12.80, 16.7) 2.71 dd (2.78, 16.7) 7.60 d (8.6) 6.63 d (8.6) 7.42 d (8.4) 6.91 d (8.4) 6.91 d (8.4) 7.42 d (8.4) 3.38 d (7.1) 5.31 t (7.3)

5.31 dd (2.7, 12.8) 2.89 dd (12.8, 16.7) 2.57 dd (2.7, 16.7) 7.46 d (8.6) 6.49 d (8.6) 7.29 d (8.5) 6.77 d (8.5) 6.77 d (8.5) 7.29 d (8.5) 3.22 d (7.1) 5.14 t (7.1)

5.43 dd (2.3, 13.0) 2.99 dd (13.0, 16.7) 2.70 dd (2.3, 16.7) 7.66 d (8.6) 6.59 d (8.6) 7.42 d (8.4) 6.91 d (8.4) 6.91 d (8.4) 7.42 d (8.4) 3.06 m 4.43 m

5.44 dd (2.9, 12.9) 2.99 dd (12.9, 16.8) 2.71 dd (2.9, 16.8) 7.60 d (8.6) 6.63 d (8.6) 7.43 d (8.5) 6.91 d (8.5) 6.91 d (8.5) 7.43 d (8.5) 3.34 d (7.4) 5.27 t (7.4)

5.50 dd (2.9, 12.4) 3.07 dd (12.4, 16.7) 2.70 dd (2.9, 16.7) 7.68 d (8.6) 6.47 d (8.6) 7.41 d (8.8) 6.89 d (8.8) 6.89 d (8.8) 7.41 d (8.8) 3.18 m 4.83 m

5.47 dd (2.9, 13.0) 3.03 dd (13.0, 16.7) 2.69 dd (2.9, 16.7) 7.62 d (8.6) 6.58 d (8.6) 7.45 d (8.5) 6.91 d (8.5) 6.91 d (8.5) 7.45 d (8.5) 2.91 m, 2.97 m 2.49 t (6.63)

4″ 5″ 6″

2.62 d (6.2) 5.56 m 5.57 d (13.4)

2.67 d (6.6) 5.50 m 5.39 d (15.9)

1.81 m 1.44 m 3.82 m

2.10 m 2.08 m 4.99 t (7.1)

2.21 m 3.94 m 4.89 d (9.4)

1.53 m 2.15 m 5.14 t (7.0)

8″ 9″ 10″ 7-OH 4′-OH 5″OCH3 7″OCH3

1.22 1.62 1.22 9.31 8.52

1.17 1.64 1.17 9.34 8.53

4.58 1.51 1.53 9.15 8.38

1.65 4.78 1.56 9.77 8.54

1.62 1.67 1.57 9.32 8.55 3.12

1.65 s 1.25 s 1.61 s

5.21 m 2.01 m, 2.19 m 3.45 dd (5.5, 9.9) 0.84 s 1.53 s 0.91 s 9.38 s 8.54 s

3α 3β

s s s s s

s s s s s

s, 4.71 s s s s s

s s, 5.02 s s s s

s s s s s s

8.54 s

8 5.49 dd (3.7, 13.5) 3.03 dd (13.5, 16.7) 2.73 dd (3.7, 16.7) 7.62 d (8.7) 6.50 d (8.7) 7.43 d (8.0) 6.91 d (8.0) 6.91 d (8.0) 7.43 d (8.0) 2.94 m 3.91 dd (7.1, 12.3) 1.70 m 2.19 m 5.12 t (7.1) 1.65 s 1.26 s 1.59 s 8.54 s

3.04 s

B



Article

Table 2. 1H NMR Data for Compounds 9−16 in Acetone-d6 (δ in ppm, J in Hz) no.

9

10

11

12

13

14

15

5.40 dd (2.7, 13.0) 2.95 dd (13.0, 16.7) 2.66 dd (2.7, 16.7) 7.57 d (8.8) 6.42 d (8.8) 7.36 d (8.5) 6.86 d (8.5) 6.86 d (8.5) 7.36 d (8.5) 2.59 t (6.7) 1.24 m, 1.77 m 1.56 m

5.47 dd (2.9, 13.0) 3.02 dd (13.0, 16.7) 2.71 dd (2.9, 16.7) 7.61 d (8.72) 6.47 d (8.72) 7.42 d (8.30) 6.90 d (8.30) 6.90 d (8.30) 7.42 d (8.30) 2.64 t (6.71) 1.73 m, 1.87 m 2.33 d (5.6)

5.49 dd (2.9, 13.0) 3.02 dd (13.0, 16.7) 2.71 dd (2.9, 16.7) 7.61 d (8.8) 6.46 d (8.8) 7.42 d (8.5) 6.90 d (8.5) 6.90 d (8.5) 7.42 d (8.5) 2.65 t (6.6) 1.29 m, 1.84 m 1.59 m, 1.78 m

5.48 dd (2.9, 13.0) 3.02 dd (13.0, 16.7) 2.72 dd (2.9, 16.7) 7.62 d (8.8) 6.49 d (8.8) 7.42 d (8.5) 6.91 d (8.5) 6.91 d (8.5) 7.42 d (8.5) 2.66 t (6.9) 1.29 m, 1.80 m 2.45 d (7.4)

5.49 dd (2.7, 13.0) 3.02 dd (13.0, 16.6) 2.74 dd (2.7, 16.6) 7.61 d (8.7) 6.47 d (8.7) 7.42 d (8.4) 6.90 d (8.4) 6.90 d (8.4) 7.42 d (8.4) 2.68 t (6.6) 1.29 m, 1.87 m 1.77 m

5.47 dd (2.9, 12.9) 3.01 dd (12.9, 16.7) 2.71 dd (2.9, 16.7) 7.61 d (8.7) 6.46 d (8.7) 7.42 d (8.5) 6.91 d (8.5) 6.91 d (8.5) 7.42 d (8.5) 2.65 t (6.5) 1.76 m, 1.90 m 1.61 m, 2.00 m

5″ 6″ 8″ 9″ 10″ 4′-OH 5-OH 7″OCH3

2.07 5.06 1.60 1.26 1.54 8.64

5.70 5.71 1.25 1.28 1.25 8.58

5.50 dd (3.0, 13.1) 3.03 dd (13.1, 16.7) 2.72 dd (3.0, 16.7) 7.26 d (8.7) 6.49 d (8.7) 7.43 d (8.5) 6.91 d (8.5) 6.91 d (8.5) 7.43 d (8.5) 2.67 t (6.8) 1.78 m, 1.90 m 2.40 dd (3.4, 6.9) 5.67 m 5.53 d (15.8) 1.22 s 1.32 s 1.22 s 8.55 s

1.62 4.01 4.75 1.31 1.69 8.52

5.76 6.26 4.92 1.31 1.84 8.59

1.66 6.67 1.22 1.32 1.20 8.53

1.42 3.26 1.15 1.32 1.15 8.54

Table 3.

13

2 3α 3β 5 6 2′ 3′ 5′ 6′ 1″ 2″ 4″

m t (7.1) s s s s

m d (15.6) s s s s

m m s, 4.90 s s s s

m d (15.6) s s s s

m m s s s s

16

m, 1.74 m t (11.2) s s s

5.50 dd (3.0, 12.9) 3.16 dd (12.9, 17.0) 2.77 dd (3.0, 17.0) 5.85 7.42 6.91 6.91 7.42 2.55 1.29 1.63

s d (8.4) d (8.4) d (8.4) d (8.4) t (6.8) m, 1.82 m m

2.10 m 5.12 t (6.9) 1.66 s 1.32 s 1.60 s 8.56 s 11.89 s

3.10 s

C NMR Data for Compounds 1−16 in Acetone-d6 (δ in ppm)

no.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

2 3 4 5 6 7 8 9 10 1’ 2’ 3’ 4’ 5’ 6’ 1″ 2″ 3″ 4″ 5″ 6″ 7″ 8″ 9″ 10″ 5″-OCH3 7″-OCH3

80.3 44.6 190.9 126.3 110.4 162.2 116.4 162.0 115.4 131.5 128.7 116.1 158.4 116.1 128.7 22.7 123.5 134.6 43.2 124.8 141.2 70.1 30.4 16.2 30.4

80.5 44.7 191.1 126.5 110.6 162.4 116.5 162.1 115.5 131.7 128.8 116.2 158.6 116.2 128.8 22.9 124.0 134.5 43.4 126.5 137.9 75.1 26.4 16.5 26.4

80.3 44.6 191.0 126.3 110.4 162.2 116.6 162.0 115.4 131.5 128.8 116.1 158.4 116.1 128.8 22.7 122.9 135.6 36.5 34.5 75.4 149.3 110.4 16.3 17.8

80.6 44.8 191.1 127.1 111.8 164.1 114.7 162.1 115.2 131.5 128.6 116.2 158.6 116.2 128.6 31.0 76.0 152.4 32.9 27.4 125.1 133.7 25.9 108.9 17.8

80.5 44.8 191.1 126.4 110.6 162.4 116.6 162.1 115.5 131.7 128.9 116.3 158.6 116.3 128.9 22.9 125.5 132.5 46.8 77.3 127.4 135.8 25.9 17.2 18.5 55.7

80.5 44.6 190.4 129.0 104.7 167.9 112.1 159.8 115.4 131.4 128.9 116.2 158.7 116.2 128.9 27.5 91.6 73.3 39.3 22.4 125.6 131.7 25.8 22.6 17.6

80.7 44.9 191.3 126.4 111.0 163.0 118.2 162.6 115.5 131.7 129.1 116.3 158.7 116.3 129.1 24.6 48.2 138.0 119.5 33.3 74.7 38.9 26.6 23.5 19.2

80.4 44.3 190.8 126.2 111.9 161.5 109.2 160.3 114.9 131.2 128.7 116.1 158.6 116.1 128.7 26.6 67.1 80.6 38.5 22.2 125.1 131.9 25.7 18.8 18.3

80.4 44.4 191.0 126.2 112.4 161.7 110.3 161.2 114.7 131.4 128.8 116.3 158.6 116.3 128.8 17.2 30.7 78.1 39.8 22.9 125.0 132.1 25.9 24.5 17.8

80.5 44.4 190.9 126.1 112.3 161.7 110.3 161.1 114.8 131.4 128.8 116.3 158.6 116.3 128.8 17.1 30.4 78.2 42.6 121.0 144.1 70.3 30.5 24.7 30.5

80.6 44.6 190.9 126.3 112.4 161.8 110.4 161.1 114.9 131.6 128.9 116.3 158.7 116.3 128.9 17.3 30.5 78.1 42.9 125.0 140.9 75.3 26.4 24.9 26.4

80.4 44.4 190.7 126.1 112.3 161.6 110.6 161.3 114.7 131.4 128.8 116.2 158.6 116.2 128.8 17.2 30.6 78.2 35.8 30.5 75.8 149.2 110.5 24.6 17.8

80.4 44.4 190.9 126.1 112.3 161.6 110.3 160.9 114.8 131.4 128.8 116.2 158.6 116.2 128.8 17.1 30.4 78.2 43.2 125.5 137.4 142.8 115.8 24.7 18.8

80.4 44.4 190.8 126.1 112.3 161.6 110.3 160.9 114.8 131.4 128.8 116.2 158.6 116.2 128.8 17.1 30.6 77.8 36.3 24.1 64.2 58.2 25.0 24.3 18.8

80.4 44.4 190.9 126.0 112.3 161.6 110.3 161.2 114.6 131.3 128.7 116.1 158.5 116.1 128.7 17.1 30.6 78.4 37.1 26.3 79.4 72.9 25.9 24.7 25.2

80.0 43.5 197.6 162.6 97.7 163.7 101.9 161.2 103.5 131.1 129.0 116.4 158.8 116.4 129.0 16.8 30.9 78.9 39.9 23.0 125.1 132.2 25.9 24.7 17.8

50.3

50.4

carbons at δC 16.2 (C-9″) and 30.4 (C-8″, C-10″); three methylene carbons at δC 22.7 (C-1″), 43.2 (C-4″), and 44.6 (C-3); 10 methine carbons at δC 80.3 (C-2), 110.4 (C-6), 116.1 (C-3′, 5′), 123.5 (C-2″), 124.8 (C-5″), 126.3 (C-5), 128.7 (C-2′, 6′), and 141.2 (C-6″); three oxygenated sp2 carbons at δC 158.4 (C-4′), 162.0 (C-9), and 162.2 (C-7); an

methylene protons at δH 2.62 (2H, d, J = 6.2 Hz, H-4″) and 3.37 (2H, d, J = 7.0 Hz, H-1″), and three methyl groups at δH 1.22 (6H, s, H3-8″, H3-10″) and 1.62 (3H, s, H3-9″), which are consistent with a (2E,5E)-7-hydroxy-3,7-dimethylocta-2,5dienyl fragment. The 13C NMR data for compound 1 (Table 3) displayed 25 carbon resonances, comprising three methyl C



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oxygenated sp3 carbon at δC 70.1 (C-7″); four quaternary carbons at δC 115.4 (C-10), 116.4 (C-8), 131.5 (C-1′), and 134.6 (C-3″); and a carbonyl carbon at δC 190.9 (C-4). The 1D NMR data were similar to those of prostratol F (17) except for the geranyl group of 17 being replaced by a (2E,5E)-7hydroxy-3,7-dimethylocta-2,5-dienyl group. The structure of the side chain was confirmed by the COSY correlations of H1″/H-2″, H-4″/H-5″, and H-5″/H-6″ and the HMBC correlations of H3-8″ and H3-10″ with C-6″ and C-7″ and of olefinic H-5″ with C-3″, C-4″, C-6″, and C-7″ (Figure S2, Supporting Information). In addition, the structure of the side chain was confirmed by comparison with reported NMR data.5 The configurations of the double bonds in the side chain were assigned as 2″E,5″E based on the coupling constant of H-6″ (J = 13.4 Hz) and the chemical shift of C-9″ (δC 16.2) [for E (δC ∼16.2) and Z (δC ∼23.3)].6 The experimental ECD spectrum of 1 (Figure S1, Supporting Information) showed a negative Cotton effect at 280−300 nm and a positive Cotton effect at 330−350 nm, which corresponded with the (2S) configuration.7 Thus, the structure of veluflavanone A (1) was assigned as shown in Figure 1. Veluflavanone B (2) was found to have the molecular formula C26H30O5 based on the HRESIMS ion at m/z 421.2045 [M − H]− (calcd for C26H29O5−, 421.2015). The 1D NMR and ECD data of 2 and 1 were nearly identical except for the side chain of 2, which showed a signal for an OCH3 group at C-7″. The presence of a methoxy group was confirmed by the HMBC correlation of the methoxy protons at δH 3.04 (3H, s, OCH3-7″) with C-7″ (δC 75.1) (Figure S2, Supporting Information). In addition, the structure of the side chain was confirmed by comparison with reported NMR data.8 Finally, the structure of veluflavanone B (2) was determined as shown in Figure 1. Veluflavanone C (3) was determined to have the molecular formula C25H28O5 based on the HRESIMS ion at m/z 407.1873 [M − H]− (calcd for C25H27O5−, 407.1858). The 1D NMR and ECD spectra of 3 were remarkably similar to those of 17, except that the geranyl group of 17 was replaced by a 6-hydroxy-3,7-dimethylocta-2,7-dienyl moiety [δH/δC 5.14 (1H, t, J = 7.1 Hz, H-2″)/122.9; 4.58, 4.71 (2H, each s, H-8″)/110.4; 3.82 (1H, m, H-6″)/75.4; 3.22 (2H, d, J = 7.1 Hz, H-1″)/22.7; 1.81 (2H, m, H-4″)/36.5; 1.53 (3H, s, H10″)/17.8; 1.51 (3H, s, H-9″)/16.3; 1.44 (2H, m, H-5″)/34.5; δC 135.6 (C-3″), 149.3 (C-7″)] in 3. The structure of the side chain was confirmed by the COSY correlations of H-1″/H-2″, H-4″/H-5″, and H5″/H-6″ as well as the HMBC correlations of two exomethylene protons (H2-8″) and a methyl proton (H3-10″) with C-6″ and C-7″ and of the oxymethine proton (H-6″) with C-4″, C-5″, C-7″, C-8″, and C-10″ (Figure S2, Supporting Information). Moreover, the structure of the side chain was confirmed by comparison with reported NMR data.9 Definition of the absolute configuration at C-6″ of compound 3 was attempted using Mosher’s method. However, the NMR data of the Mosher esters of 3 showed a mixture of compounds. Thus, the structure of veluflavanone C (3) was assigned as shown in Figure 1. Veluflavanone D (4) was determined to have the molecular formula C25H28O5 based on the HRESIMS ion at m/z 407.1891 [M − H]− (calcd for C25H27O5−, 407.1858). The 1D NMR and ECD data of 4 are similar to those of 3, except unlike 3, the side chain in 4 was a 2-hydroxy-7-methyl-3methylene-6-octaenyl group [δH/δC 5.02, 4.78 (2H, each s, H9″)/108.9; 4.99 (1H, t, J = 7.1 Hz, H-6″)/125.1; 4.43 (1H, m,

H-2″)/76.0; 3.06 (2H, m, H-1″)/31.0; 2.10 (2H, m, H-4″)/ 32.9; 2.08 (2H, m, H-5″)/27.4; 1.65 (3H, s, H-8″)/25.9; 1.56 (3H, s, H-10″)/17.8; δC 133.7 (C-7″), 152.4 (C-3″)]. The COSY correlation of H-1″/H-2″ and the HMBC correlations of an oxymethine proton (H-2″) with C-8 (δC 114.7), C-1″, C3″, C-4″, and C-9″ (Figure S2, Supporting Information) were used to determine the structure of the side chain. In addition, the structure of the side chain was confirmed by comparison with reported NMR data.10 The absolute configuration at C-2″ was not determined. Thus, the structure of veluflavanone D (4) was characterized as shown in Figure 1. Veluflavanone E (5) was determined to have the molecular formula C26H30O5 based on the HRESIMS ion at m/z 421.2033 [M − H]− (calcd for C26H29O5−, 421.2015). The similarities of the NMR and ECD data of 5 with those of 17 indicated that 5 differed from 17 by the presence of a methoxy group on a geranyl side chain at δH 3.12 (3H, s, 5″-OCH3), which showed an HSQC correlation with the carbon at δC 55.7. The position of the OCH3 moiety in the side chain was assigned based on the HMBC correlation between the protons of OCH3-5″ and C-5″ (δC 77.3) and between H-5″ (δH 3.12) and C-3″ (δC 132.5), C-7″ (δC 135.8), and OCH3-5″ (δC 55.7) (Figure S2, Supporting Information). The structure of the side chain was confirmed by comparison with reported NMR data.11 The absolute configuration at C-5″ was not assigned. Thus, the structure of veluflavanone E (5) was determined as shown in Figure 1. Veluflavanone F (6) was found to have the molecular formula C25H28O5 from the HRESIMS ion at m/z 407.1875 [M − H]− (calcd for C25H27O5−, 407.1858). The structure of 6 was assigned based on a combination of 1D and 2D NMR data. The carbon signals at δC 73.3 (C-3″) and 91.6 (C-2″) indicated the presence of an oxygen-containing substituent and a modification of the geranyl chain. The COSY and HMBC data suggested that C-2″ was linked to the oxygen present at C-7 (δC 167.9), forming a 1,2-dihydrofuran ring, and that C-3″ was substituted with hydroxy and methyl groups. The chemical shifts of carbon signals of C-5″ to C-10″ in the side chain were the same as those reported for geranyl chains in related structures. The structure of the side chain was assigned based on the COSY correlation between H-1″ (δH 3.18) and H-2″ (δH 4.83) as well as the HMBC correlations between H-2″ and C-7, C-8 (δC 112.1), C-1″ (δC 27.5), and C-3″ (Figure S2, Supporting Information). In addition, the data of the side chain were also compared with reported NMR data.12 The absolute configurations at C-2″ and C-3″ were not determined. Finally, the structure of veluflavanone F (6) was characterized as shown in Figure 1. Veluflavanone G (7) was determined to have the molecular formula C25H28O5 from the HRESIMS ion at m/z 407.1886 [M − H]− (calcd for C25H27O5−, 407.1858). The 1D NMR and ECD data of 7 clearly showed similarities to those of 17, except unlike 17, the signals of the geranyl side chain were replaced with signals for a 3,7,7-trimethylcyclohex-4-en-6-ol unit [δH/δC 5.21 (1H, m, H-4″)/119.5; 3.45 (1H, dd, J = 5.5, 9.9 Hz, H-6″)/74.7; 2.91, 2.97 (2H, each m, H-1″)/24.6; 2.49 (1H, t, J = 6.6 Hz, H-2″)/48.2; 2.01, 2.19 (2H, each m, H-5″)/ 33.3; 1.53 (3H, s, H-9″)/23.5; 0.91 (3H, s, H-10″)/19.2; 0.84 (3H, s, H-8″)/26.6; δC 38.9 (C-7″), 138.0 (C-3″)]. The structure of the new side chain was confirmed by the COSY correlations of H-1″/H-2″, H-4″/H-5″, and H5″/H-6″ as well as the HMBC correlations of a methylene proton (H-2″) with C-8, C-1″, C-3″, C-4″, C-6″, and C-7″ and of a methine D



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was not assigned. Accordingly, the structure of veluflavanone K (11) was determined as shown in Figure 1. Veluflavanone L (12) was determined to have the molecular formula C25H28O5 from the HRESIMS ion at m/z 407.1877 [M − H]− (calcd for C25H27O5−, 407.1858). The NMR and ECD data of 12 were similar to those of 9. The difference was the prenyl group in 9 had been exchanged for a 6-hydroxy-7methylbuten-7-yl group in 12. The structure of the side chain was confirmed based on the COSY correlation between H-6″ (δH 4.01) and H-5″ (δH 1.62) as well as the HMBC correlations between H2-8″ (δH 4.75 and 4.90) and C-6″ (δC 75.8), C-7″ (δC 149.2), and C-10″ (δC 17.8) (Figure S3, Supporting Information). The absolute configurations at C-3″ and C-6″ were not determined. Thus, the structure of veluflavanone L (12) was characterized as shown in Figure 1. Veluflavanone M (13) was found to have the molecular formula C25H26O4 based on the HRESIMS ion at m/z 389.1778 [M − H]− (calcd for C25H25O4−, 389.1753). The 1D NMR and ECD data of 13 were similar to those of 9, except that the prenyl unit in 9 was replaced with a (E)-7methylbuta-5,7-dienyl unit in 13. The 1H NMR data showed two olefinic resonances of trans double-bond protons at δH 6.26 (1H, d, J = 15.6 Hz, H-6″) and 5.76 (1H, m, H-5″). The COSY correlation at H-5″/H-6″ and the HMBC correlations between H-6″ and C-4″ (δC 43.2), C-5″ (δC 125.5), C-7″ (δC 142.8), C-8″ (δC 115.8), and C-10″ (δC 18.8) (Figure S3, Supporting Information) were used to determine the structure of the side chain. In addition, the structure of the side chain was compared with reported NMR data.13 The absolute configuration at C-3″ was not determined. Thus, the structure of veluflavanone M (13) was assigned as shown in Figure 1. Veluflavanone N (14) was found to have the molecular formula C25H28O5 based on the HRESIMS ion at m/z 407.1880 [M − H]− (calcd for C25H27O5−, 407.1858). The NMR and ECD data of 14 were similar to those of 12, except that the OH group at C-6″ of 12 was cyclized to an epoxide in 14. The structure of the side chain was assigned based on the COSY correlation between H-6″ (δH 6.67) and H-5″ (δH 1.66) and the HMBC correlations between H3-8″ (δH 1.22) and C6″ (δC 64.2), C-7″ (δC 58.2), and C-10″ (δC 18.8) and between H3-10″ (δH 1.20) and C-6″, C-7″, and C-8″ (δC 25.0) (Figure S3, Supporting Information). The absolute configurations at C-3″ and C-6″ were not assigned. Thus, the structure of veluflavanone N (14) was determined as shown in Figure 1. Veluflavanone O (15) was determined to have the molecular formula C25H30O6 based on the HRESIMS ion at m/z 425.2005 [M − H]− (calcd for C25H29O6−, 425.19640). The 1D NMR and ECD data of 15 were shown to be the same as those of 14, except that the epoxide ring of 14 was opened to afford two hydroxy groups in 15. The structure of the side chain was assigned based on the HMBC correlations between the two groups of methyl protons at δH 1.15 (6H, s, H3-8″, H310″) with C-6″ (δC 79.4) and C-7″ (δC 72.9) (Figure S3, Supporting Information) and based on a comparison with reported NMR data.7 The absolute configurations at C-3″ and C-6″ were not determined. Accordingly, the structure of veluflavanone O (15) was characterized as shown in Figure 1. Veluflavanone P (16) was found to have the molecular formula C25H28O5 based on the HRESIMS ion at m/z 407.1884 [M − H]− (calcd for C25H27O5−, 407.1858). The 1D NMR and ECD data of 16 were remarkably similar to those of 9, except for the absence of the aromatic H-5. The 1H

proton (H-6″) with C-4″, C-5″, C-7″, C-8″, and C-10″ (Figure S2, Supporting Information). The absolute configurations at C-2″ and C-6″ were not assigned. Thus, the structure of veluflavanone G (7) was determined as shown in Figure 1. Veluflavanone H (8) was found to have a molecular formula of C25H28O5 from the HRESIMS ion at m/z 407.1884 [M − H]− (calcd for C25H27O5−, 407.1858). The 1D NMR data of 8 indicated it had the same flavanone core as compounds 1−7 and suggested a structural modification at C-3″ of the geranyl moiety. The 13C NMR data (Table 3) of 8 showed new signals of an oxygenated tertiary carbon at δC 80.6 (C-3″) and an oxygenated secondary carbon at δC 67.1 (C-2″), which was associated with δH 3.91 (1H, dd, J = 7.1, 12.3 Hz, H-2″). In addition, the signal of one of the double bonds of the geranyl moiety and the signal of the hydroxy moiety at C-7 were absent. These data suggest that the geranyl chain was cyclized at C-3″ and C-7 via an oxygen atom to form a six-membered ring. The structure of the side chain was assigned based on the COSY correlation between H-1″ (δH 2.94, 2H, m) and H-2″ and the HMBC correlations between H-2″ and C-8 (δC 109.2), C-1″ (δC 26.6), C-3″, C-4″ (δC 38.5), and C-9″ (δC 18.8) (Figure S2, Supporting Information). In addition, the structure of the side chain was confirmed by comparison with reported NMR data.11 The absolute configurations at C-2″ and C-3″ were not determined. Thus, the structure of veluflavanone H (8) was defined as shown in Figure 1. Veluflavanone I (9) was found to have the molecular formula C25H28O4 based on the HRESIMS ion at m/z 391.1934 [M − H]− (calcd for C25H27O4−, 391.1909). The 1D NMR (Tables 2 and 3) and ECD data of 9 were similar to those of 8, except 9 lacked the OH group at C-2″. The structure of the side chain was assigned based on the COSY correlation between H-1″ (δH 2.59) and H-2″ (δH 1.24 and 1.77) as well as the HMBC correlations between H2-2″ and C8 (δC 110.3), C-1″ (δC 17.2), and C-3″ (δC 78.1) (Figure S3, Supporting Information). The absolute configuration at C-3″ was not determined. Thus, the structure of veluflavanone I (9) was characterized as shown in Figure 1. Veluflavanone J (10) was determined to have the molecular formula C25H28O5 from the HRESIMS ion at m/z 407.1855 [M − H]− (calcd for C25H27O5−, 407.1858). The NMR and ECD data of 10 were remarkably similar to those of 9, except for the substitution pattern of the double bond in the prenyl side chain and the presence of a hydroxy group at C-7″ in 10. The 1H NMR data showed two olefinic resonances of trans double-bond protons at δH 5.71 (1H, d, J = 15.6 Hz, H-6″) and 5.70 (1H, m, H-5″) and two methyl groups at δH 1.25 (6H, s, H-8″, 10″). The structure of the side chain was confirmed based on the COSY correlation of H-5″/H-6″ and the HMBC correlations of H3-8″ and H3-10″ with C-5″ (δC 121.0), C-6″ (δC 144.1), and C-7″ (δC 70.3) (Figure S3, Supporting Information). The absolute configuration at C-3″ was not determined. Thus, the structure of veluflavanone J (10) was assigned as shown in Figure 1. Veluflavanone K (11) was found to have the molecular formula C26H30O5 based on the HRESIMS ion at m/z 421.2047 [M − H]− (calcd for C26H29O5−, 421.2015). The 1D NMR data and ECD data of 11 were quite similar to those of 10. The difference was in C-7″ of the prenyl side chain; the OH group in 10 was replaced by a OCH3 group in 11. The HMBC data showed a cross-peak from the methoxy protons at δH 3.10 (3H, s, 7″-OCH3) to δC 75.3 (C-7″) (Figure S3, Supporting Information). The absolute configuration at C-3″ E



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Table 4. Cytotoxicity Dataa of Compounds 9−11, 14, and 16 IC50 (μM) ± SD compound

KB

HeLa S3

MCF-7

Hep G2

HT-29

9 10 11 14 16 doxorubicinb

9.9 ± 0.8 >10 >10 >10 >10 0.13 ± 0.01

8.1 ± 0.2 6.6 ± 0.2 8.6 ± 0.1 8.3 ± 0.3 9.9 ± 0.7 0.03 ± 0.01

9.9 ± 1.0 >10 >10 >10 >10 0.61 ± 0.06

>10 >10 >10 >10 >10 1.07 ± 0.16

>10 >10 >10 >10 >10 0.34 ± 0.07

Cytotoxicity was expressed as the mean values of three experiments ± SD; the other isolated compounds were inactive (IC50 > 10 μM). Doxorubicin was tested as positive control.

a

b

400 AVANCE spectrometer. The HRESIMS data were collected on a Bruker MICROTOF model mass spectrometer. Plant Material. D. velutina stems were collected from Kalasin Province, Thailand (16°43′35″ N 103°29′22″ E) in July 2016. The sample (voucher specimen: Khumkratok no. 4-12) was identified by Dr. Suttira Sedlak (botanist) at Mahasarakham University. Extraction and Isolation. The stems of D. velutina (10.0 kg) were macerated with CH2Cl2 for 7 days (2 × 30 L). The solvent was removed by a rotary evaporator to provide the crude CH2Cl2 extract (780.0 g), which was further purified by silica gel CC using a gradient of hexane/EtOAc (100% hexane, 85%, 65%, 45%, 25%, and 100% EtOAc, each 10 L) to provide eight fractions (Fr. A−H). Fr. D (122.5 g) was separated on a Sephadex LH-20 column (250 g) using 50% CH 2 Cl2 /MeOH (3.5 L) to yield six subfractions, D1−D6. Compounds 9 (5.2 mg) and 11 (3.5 mg) were isolated from Fr. D1 (10.5 mg) using radial chromatography (Chromatotron) eluted with 90% n-hexane/EtOAc (150 mL). Fr. D2 (8.5 mg) was subjected to a Chromatotron using 95% n-hexane/EtOAc (150 mL) to yield compounds 13 (4.5 mg) and 14 (2.2 mg). Compounds 6 (2.8 mg), 10 (3.3 mg), and 12 (3.0 mg) were isolated from Fr. D3 (10.0 mg) using a Chromatotron with 90% n-hexane/EtOAc (150 mL). Fr. D4 (20.0 g) was passed through a Sephadex column (250 g) using 50% CH2Cl2/MeOH (3.5 L) and further purified using a Chromatotron using 90% n-hexane/EtOAc (150 mL) to yield compounds 8 (2.5 mg), 16 (3.2 mg), and 17 (3.5 mg). Fr. E (75.0 mg) was separated on a Sephadex column (250 g) eluting with 40% CH2Cl2/MeOH (3.5 L) to give subfractions E1−E3. Compounds 2 (3.5 mg) and 5 (2.5 mg) were purified from Fr. E1 (6.5 mg) using a Chromatotron with 90% nhexane/EtOAc (150 mL). Fr. E2 (25.5 mg) was purified on a Sephadex (250 g) column using 50% CH2Cl2/MeOH (3.5 L) and purified on a Chromatotron with 90% n-hexane/EtOAc (150 mL) to yield compounds 1 (3.5 mg), 3 (5.2 mg), and 4 (2.2 mg). Finally, Fr. E3 (9.0 g) was separated using a Chromatotron with 90% n-hexane/ EtOAc (150 mL) to give compounds 7 (2.5 mg) and 15 (3.5 mg). Veluflavanone A (1): yellow gum; [α]20 D −11 (c 0.7, CHCl3); IR νmax 3180, 1684 cm−1; UV (CHCl3) λmax (log ε) 326 (3.2), 315 (2.2), 292 (2.4), 286 (3.1) nm; ECD (CHCl3) λmax (Δε) 339 (+70.5); 1D NMR data (Tables 1 and 3); negative HRESIMS m/z 407.1881 [M − H]− (calcd for C25H27O5−, 407.1858). Veluflavanone B (2): yellow gum; [α]20 D −11 (c 0.6, CHCl3); IR νmax 3184, 1682 cm−1; UV (CHCl3) λmax (log ε): 325 (3.0), 314 (2.5), 291 (2.3), 287 (3.2) nm; ECD (CHCl3) λmax (Δε) 341 (+43.1); 1D NMR data (Tables 1 and 3); negative HRESIMS m/z 421.2045 [M − H]− (calcd for C26H29O5−, 421.2015). Veluflavanone C (3): yellow gum; [α]20 D −0.6 (c 0.4, CHCl3); IR νmax 3181, 1683 cm−1; UV (CHCl3) λmax (log ε) 324 (3.2), 316 (2.1), 293 (2.2), 285 (3.0) nm; ECD (CHCl3) λmax (Δε) 342 (+6.5); 1D NMR data (Tables 1 and 3); negative HRESIMS m/z 407.1873 [M − H]− (calcd for C25H27O5−, 407.1858). Veluflavanone D (4): yellow gum; [α]20 D −0.3 (c 0.5, CHCl3); IR νmax 3178, 1679 cm−1; UV (CHCl3) λmax (log ε) 324 (2.9), 317 (2.5), 290 (2.2), 284 (2.8) nm; ECD (CHCl3) λmax (Δε) 336 (+36.6); 1D NMR data (Tables 1 and 3); negative HRESIMS m/z 407.1891 [M − H]− (calcd for C25H27O5−, 407.1858).

NMR spectrum displayed a hydroxy proton involved in hydrogen bonding at δH 11.89 (1H, s, 5-OH) and an aromatic proton at δH 5.85 (1H, s, H-6). The HMBC spectrum showed cross-peaks between HO-5 and C-5 (δC 162.6), C-6 (δC 97.7), and C-10 (δC 103.5) (Figure S3, Supporting Information). The absolute configuration at C-3″ was not determined. Finally, the structure of veluflavanone P (16) was assigned as shown in Figure 1. The absolute configuration at C-2 of each of the flavanones was determined as (2S) based on their experimental ECD spectra (Figure S1, Supporting Information). It is well known that flavanones with a (2S) configuration display a negative Cotton effect at ∼290 nm and a positive Cotton effect at ∼330 nm in their ECD spectra.7,14 Compounds 3−8, 12, 14, and 15 were determined to be racemic as far as the stereogenic center of the geranyl side chain is concerned based on the lack of Cotton effects near 200 nm in their experimental ECD curves.8,15 The applied Mosher’s method was also used in an attempt to assign the absolute configurations of the geranyl side chains of compounds 3, 4, 7, 8, 12, and 15. However, the 1D NMR data of the Mosher esters of these compounds showed mixtures of compounds. In previous reports, flavanones showed significant cytotoxicities.16,17 The effect of cytotoxic geranylated flavonoids is related to their significant ability to permeate the membranes of cells and to their lipophilicity.18 Therefore, all the isolated flavanones were tested for their cytotoxic activities against five human cancer cell lines using the modified MTT method, and doxorubicin was used as the positive control (Table 4). Veluflavanone I (9) showed cytotoxicity against KB, HeLa S3, and MCF-7 cells with IC50 values of 9.9, 8.1, and 10.0 μM, respectively. In addition, veluflavanones J (10), K (11), N (14), and P (16) selectively exhibited cytotoxicity against only HeLa S3 cells, with IC50 values of 6.6, 8.6, 8.3, and 9.9 μM, respectively. The other compounds were considered inactive, as their IC50 values exceeded 10 μM. These results suggest that the cyclization of the geranyl side chain at C-3″ and C-7 via an ether linkage to form a six-membered ring in the geranylated flavanones might improve the cytotoxicity, especially against HeLa S3 cells, as indicated by different activities of compounds 1, 2, 9, 10, 11, and 17.

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EXPERIMENTAL SECTION

General Experimental Procedures. The IR data were measured on a Nicolet 6700 spectrometer (FT-IR) using KBr discs. The UV− visible data were measured on a UV-2550 spectrometer. Optical rotations were determined on a Jasco P-1010 polarimeter. The experimental ECD data were measured on a Jasco J-815 circular dichroism spectropolarimeter. NMR data were acquired on a Bruker F



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Veluflavanone E (5): yellow gum; [α]20 D −0.3 (c 0.4, CHCl3); IR νmax 3183, 1685 cm−1; UV (CHCl3) λmax (log ε) 323 (3.0), 310 (2.3), 287 (2.1), 287 (3.2) nm; ECD (CHCl3) λmax (Δε) 342 (+33.5); 1D NMR data (Tables 1 and 3); negative HRESIMS m/z 421.2033 [M − H]− (calcd for C26H29O5−, 421.2015). Veluflavanone F (6): yellow gum; [α]20 D −0.8 (c 0.2, CHCl3); IR νmax 3183, 1687 cm−1; UV (CHCl3) λmax (log ε) 324 (2.9), 319 (2.3), 295 (2.1), 281 (3.2) nm; ECD (CHCl3) λmax (Δε) 346 (+27.1); 1D NMR data (Tables 1 and 3); negative HRESIMS m/z 407.1875 [M − H]− (calcd for C25H27O5−, 407.1858). Veluflavanone G (7): yellow gum; [α]20 D −0.2 (c 0.3, CHCl3); IR νmax 3181, 1684 cm−1; UV (CHCl3) λmax (log ε) 326 (3.2), 316 (2.3), 294 (2.4), 285 (3.0) nm; ECD (CHCl3) λmax (Δε) 341 (+1.4); 1D NMR data (Tables 1 and 3); negative HRESIMS m/z 407.1886 [M − H]− (calcd for C25H27O5−, 407.1858). Veluflavanone H (8): yellow gum; [α]20 D −0.5 (c 0.2, CHCl3); IR νmax 3183, 1681 cm−1; UV (CHCl3) λmax (log ε) 323 (3.3), 313 (2.3), 292 (2.2), 286 (3.4) nm; ECD (CHCl3) λmax (Δε) 340 (+14.7); 1D NMR data (Tables 1 and 3); negative HRESIMS m/z 407.1884 [M − H]− (calcd for C25H27O5−, 407.1858). Veluflavanone I (9): yellow gum; [α]20 D +5 (c 0.7, CHCl3); IR νmax 3182, 1685 cm−1; UV (CHCl3) λmax (log ε) 324 (3.2), 318 (2.4), 293 (2.2), 285 (3.2) nm; ECD (CHCl3) λmax (Δε) 346 (+29.4); 1D NMR data (Tables 2 and 3); negative HRESIMS m/z 391.1934 [M − H]− (calcd for C25H27O4−, 391.1909). Veluflavanone J (10): yellow gum; [α]20 D −1 (c 0.7, CHCl3); IR νmax 3182, 1679 cm−1; UV (CHCl3) λmax (log ε) 321 (3.0), 313 (2.3), 291 (2.2), 285 (3.2) nm; ECD (CHCl3) λmax (Δε) 345 (+27.5); 1D NMR data (Tables 2 and 3); negative HRESIMS m/z 407.1855 [M − H]− (calcd for C25H27O5−, 407.1858). Veluflavanone K (11): yellow gum; [α]20 D +4 (c 0.6, CHCl3); IR νmax 3176, 1689 cm−1; UV (CHCl3) λmax (log ε) 327 (3.2), 315 (2.2), 290 (2.3), 285 (3.1) nm; ECD (CHCl3) λmax (Δε) 343 (+69.0); 1D NMR data (Tables 2 and 3); negative HRESIMS m/z 421.2047 [M − H]− (calcd for C26H29O5−, 421.2015). Veluflavanone L (12): yellow gum; [α]20 D −0.4 (c 0.6, CHCl3); IR νmax 3183, 1682 cm−1; UV (CHCl3) λmax (log ε) 324 (3.1), 318 (2.5), 287 (2.2), 285 (2.8) nm; ECD (CHCl3) λmax (Δε) 342 (+55.9); 1D NMR data (Tables 2 and 3); negative HRESIMS m/z 407.1877 [M − H]− (calcd for C25H27O5−, 407.1858). Veluflavanone M (13): yellow gum; [α]20 D +10 (c 0.7, CHCl3); IR νmax 3184, 1682 cm−1; UV (CHCl3) λmax (log ε) 322 (3.0), 312 (2.0), 290 (2.1), 283 (3.0) nm; ECD (CHCl3) λmax (Δε) 345 (+36.2); 1D NMR data (Tables 2 and 3); negative HRESIMS m/z 389.1778 [M − H]− (calcd for C25H25O4−, 389.1753). Veluflavanone N (14): yellow gum; [α]20 D −0.9 (c 0.4, CHCl3); IR νmax 3181, 1682 cm−1; UV (CHCl3) λmax (log ε) 326 (3.2), 315 (2.2), 291 (2.4), 287 (3.1) nm; ECD (CHCl3) λmax (Δε) 343 (+10.7); 1D NMR data (Tables 2 and 3); negative HRESIMS m/z 407.1880 [M − H]− (calcd for C25H27O5−, 407.1858). Veluflavanone O (15): yellow gum; [α]20 D −0.7 (c 1.0, CHCl3); IR νmax 3192, 1694 cm−1; UV (CHCl3) λmax (log ε) 329 (3.1), 309 (1.9), 292 (2.0), 282 (2.8) nm; ECD (CHCl3) λmax (Δε) 344 (+50.1); 1D NMR data (Tables 2 and 3); negative HRESIMS m/z 425.2005 [M − H]− (calcd for C25H29O6−, 425.1964). Veluflavanone P (16): yellow gum; [α]20 D +10 (c 0.8, CHCl3); IR νmax 3220, 1704 cm−1; UV (CHCl3) λmax (log ε) 329 (3.5), 321 (2.3), 287 (2.0), 281 (2.8) nm; ECD (CHCl3) λmax (Δε) 338 (+38.8); 1D NMR data (Tables 2 and 3); negative HRESIMS m/z 407.1884 [M − H]− (calcd for C25H27O5−, 407.1858). Cytotoxicity Assay. All flavanones (1−17) were tested for their cytotoxicities toward five human cancer cell lines, namely, epidermoid carcinoma (KB), cervical adenocarcinoma (HeLa S3), breast adenocarcinoma (MCF-7), hepatocellular adenocarcinoma (Hep G2), and colon adenocarcinoma (HT-29), employing the colorimetric method.19 Doxorubicin was tested as a positive control, and it showed activity against the five human cancer cell lines.

Article

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.8b00688. NMR, HRESIMS, and experimental ECD spectra of 1− 16 (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail (S. Kaennakam): [email protected]. *E-mail (S. Tip-pyang): [email protected]. ORCID

Santi Tip-pyang: 0000-0003-4048-9544 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was fully funded by the Graduate School of Chulalongkorn University for a Postdoctoral Fellowship (Ratchadaphiseksomphot Endowment Fund).

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REFERENCES

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