Swinhoeisterols from the South China Sea Sponge ... - ACS Publications

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Cite This: J. Nat. Prod. 2018, 81, 1645−1650

Swinhoeisterols from the South China Sea Sponge Theonella swinhoei Jiao Li,†,‡ Hua Tang,†,‡ Tibor Kurtań ,§ Attila Mań di,§ Chun-Lin Zhuang,† Li Su,† Gui-Liang Zheng,*,⊥ and Wen Zhang*,† †

School of Pharmacy, Second Military Medical University, 325 Guo-He Road, Shanghai 200433, People’s Republic of China Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary ⊥ Department of Otorhinolaryngology, Head and Neck Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kong-Jiang Road, Shanghai 200092, People’s Republic of China Downloaded via TUFTS UNIV on July 27, 2018 at 06:35:44 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

§

S Supporting Information *

ABSTRACT: Swinhoeisterols C−F (1−4), four new steroids having a rearranged 6/6/5/7 ring system, were isolated from the Xisha sponge Theonella swinhoei, together with the known analogue swinhoeisterol A (5). Their structures were determined based on spectroscopic analysis, TDDFT-ECD and optical rotation calculations, and biogenetic correlations. In an in vitro assay, compound 1 showed an inhibitory effect on (h)p300 with an IC50 value of 8.8 μM, whereas compounds 2−4 were not active.

T

he marine sponge Theonella swinhoei has been found to produce structurally diverse metabolites, including cyclic peptides, depsipeptides, macrolides, steroids, alkaloids, and fatty acids.1−7 These substances have displayed a spectrum of biological activities, including cytotoxicity,4,8 chymotrypsin and protease inhibitory effects,2,3 and anti-inflammatory properties.9,10 Among these metabolites, sterols having a 4-methylene functionality are considered as taxonomic chemical markers of this genus.7,11,12 These steroids were reported to have significant cytotoxicity,12 and agonistic and antagonistic effects of nuclear receptors PXR and FXR, respectively.7,10,11 In the process of an ongoing search for bioactive compounds with unique structures from marine invertebrates and associated fungi,13−17 two new steroids, swinhoeisterols A (5) and B, were isolated from the Xisha sponge Theonella swinhoei.16 These steroids possess an intriguing 6/6/5/7 ring system and exhibited cytotoxicity against A549 and MG-63 cells. Swinhoeisterol A (5) was found to be a potential inhibitor of (h)p300 by the inverse virtual screening approach and corroborated by an in vitro bioassay.16 (H)p300 is the known member of the histone acetyltransferases (HATs) family. Dysfunction of (h)p300 may induce disorder in gene expression that correlated to some diseases, in particular cancer.18−20 Several small molecules have been reported as (h)p300 inhibitors, including Lys-CoA,20 garcinol,21 C646,22 curcumin,23 plumbagin,24 isothiazolone,25 cinnamoyl chloride,26 and epidithiodiketopiperazine.27 Epidithiodiketopiperazine was subjected to preclinical evaluation and later dropped due to potential side effects.27 The discovery of swinhoeisterol A (5) as a new kind of (h)p300 inhibitor has encouraged continuing work on the metabolites of this class. A reinvestigation of the sponge T. swinhoei led to the isolation of swinhoeisterol A (5) and four new analogues, swinhoeisterols C−F (1−4). Herein are reported the isolation, structure elucidation, and (h)p300 inhibitory activity of these new compounds. © 2018 American Chemical Society and American Society of Pharmacognosy

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RESULTS AND DISCUSSION Swinhoeisterol C (1) was obtained as an off-white noncrystalline solid (CH2Cl2). Its HRESIMS gave the molecular formula C29H46O3, requiring seven degrees of unsaturation. The IR spectrum of 1 indicated the presence of hydroxy groups (3436 cm−1), carbonyl groups (1711 cm−1), and terminal double bonds (1667, 899 cm−1). Twenty-nine carbon signals were observed in the 13C NMR and DEPT spectra (Table 1), including three sp2 carbon atoms (1 CO, 1 CCH2) and 26 sp3 carbon atoms (2 CO, 1 CHO, 2 C, 6 CH, 9 CH2, 6 CH3), taking into account the two degrees of unsaturation. The remaining unsaturations were due to the presence of five rings in Received: April 6, 2018 Published: July 10, 2018 1645

DOI: 10.1021/acs.jnatprod.8b00281 J. Nat. Prod. 2018, 81, 1645−1650

Journal of Natural Products

Article

Table 1. 1H and 13C NMR Data for Compounds 1 and 2 (in CDCl3) 1 position 1α 1β 2α 2β 3 4 5 6α 6β 7 8 9 10 11α 11β 12α 12β 13 14 15α

δC,a type 33.0, CH2 32.1, CH2 72.7, CH 151.9, C 38.7, CH 19.6, CH2 41.7, CH 72.4, C 75.8, C 36.7, C 23.6, CH2

36.3, CH2 47.5, C 209.3, C 44.2, CH2

15β 16α 16β 17 18 19 20 21 22 23 24 25 26 27 28 29 OH-7

19.6, CH2 54.6, CH 18.4, CH3 16.7, CH3 34.7, CH 21.3, CH3 30.3, CH2 33.3, CH2 39.1, CH 32.3, CH 20.4, CH3 18.2, CH3 15.6, CH3 103.7, CH2

δHb (J in Hz)

2 δC,a type

1.59, dd (13.5, 3.9) 32.9, CH2 1.64, ovd 2.02, ovd 32.0, CH2 1.41, ovd 3.98, dd (11.5, 5.5) 72.6, CH 150.8, C 2.04, ovd 37.7, CH 2.07, dd (13.5, 2.5) 30.6, CH2 1.24, m 3.22, d (7.4) 74.7, C 76.0, C 79.0, C 36.8, C 1.85, dd (13.8, 8.5) 24.2, CH2 1.79, ddd (13.9, 10.2, 8.4) 1.32, ovd 32.9, CH2 1.62, ovd 48.1, C 212.8, C 2.43, ddd (18.8, 38.4, CH2 11.6, 2.7) 2.72, ddd (18.8, 6.3, 1.9) 1.66, ovd 22.3, CH2 1.68, ovd 1.51, dd (10.9, 2.4) 46.8, CH 1.08, s 18.2, CH3 0.88, s 16.8, CH3 1.46, ovd 34.6, CH 0.94, d (6.9) 20.2, CH3 1.44, ovd 29.4, CH2 0.97, m 1.20, ovd 32.6, CH2 1.22, ovd 38.7, CH 1.54, m 32.3, CH 0.86, d (6.8) 20.2, CH3 0.80, d (6.9) 18.2, CH3 0.79, d (6.4) 15.5, CH3 5.13, s 104.2, CH2 4.71, s

δHc (J in Hz) 1.68−1.72, m 2.09, ovd 1.49, ovd 4.03, dd (11.0, 3.5) 2.06, d (13.5) 1.30, dd (14.0, 1.8) 1.96, t (13.5)

Figure 1. Key 1H−1H COSY and HMBC correlations of compounds 1−4.

Swinhoeisterol D (2) was obtained as a colorless noncrystalline solid (CH2Cl2). Its HRESIMS gave the molecular formula C29H46O4, showing 16 mass units more than 1. The NMR data (Table 1) of 2 were almost identical to those of 1, with the difference recognized being the replacement of the methine signal at C-7 (δC 41.7) in 1 by resonances for an oxygenated tertiary carbon (δC 74.7) in 2. This assignment was supported by the long-range correlations from OH-7 (δH 3.79) to C-7, C-8, and C-14 (Figure 1). The NOE effects of OH-7 with H-5, H15α, and H-17 (Figure 2) indicated the α-configuration of these protons. The assigned configuration of OH-7 was confirmed by the pyridine-induced solvent shifts for H-5 (Δδ 0.68) and H15α (Δδ 0.36) (Supporting Information, Table S1).28,29 The structure of 2 was established as shown. Swinhoeisterol E (3) was afforded as an off-white noncrystalline solid (CH2Cl2). Its HRESIMS gave the same molecular formula as that of swinhoeisterol A (5).16 However, the Δ8 double bond in 5 was translocated as a Δ7 double bond in 3 (Table 2), which was supported by the establishment of the proton connectivity from H-9 to H2-12 and the observation of the long-range correlations from H-9 to C-7 and C-8 and from both H2-6 and H3-18 to C-8 (Figure 1). The α-configuration of H-9 was identified by its NOE cross-peaks with H-1α, H-5, and H-12α (Figure 2), resulting in the determination of the structure and relative configuration of 3 as shown. Swinhoeisterol F (4) was afforded to be an off-white, noncrystalline solid (CH2Cl2). Its HRESIMS gave the molecular formula C29H46O3, being the same as that of compound 1. The NMR data of 4 (Table 2) closely resembled those of 1. However, the two oxygenated tertiary carbon signals of 4 were deshielded (δC 88.7 and 85.7) with respect to those of 1 (δC 75.8 and 72.4). The deshielded signals in 4 could be located at C-8 and C-17 rather than C-8 and C-9 in 1, as indicated by the proton connectivity from H-9 to H2-12 and the long-range correlations from both H2-12 and H3-18 to C-8 and C-17 (Figure 1). The presence of an 8,17-oxetane group in 4 was therefore determined. The similar NMR shift values for the oxetane unit published for mitrephorone A (δC 89.0 and 87.3)30 supported the presence of this structural unit. The α-configuration of H-9 was indicated by its NOE effects with H-1α, H-5, and H-12α. The distinct NOE correlations of H-7 with H-18 and H-19 suggested an α-ether bridge and a boat configuration of ring B in the molecule of 4 (Figure 2). The structure and relative configuration of compound 4 were thus established as shown. Due to their similar ECD spectra and shared biosynthetic origin, the absolute configuration of compounds 1−4 was

1.85, ovd 1.73, ovd 1.53, ovd 1.20, m

3.65, ddd (13.1, 11.6, 5.9) 2.39, dt (11.4, 4.2) 1.72, ovd 1.82, ovd 1.82, ovd 0.81, s 0.89, s 1.72, ovd 0.95, d (6.8) 1.26, m 1.01, m 1.13, m 1.21, m 1.51, ovd 0.84, d (6.9) 0.79, d (6.8) 0.76, d (6.5) 5.17, s 4.87, s 3.79, s

a

100 MHz. b600 MHz. c400 MHz. dov = overlapped signal.

the molecule. The NMR data of 1 (Table 1) demonstrated significant similarities to those of swinhoeisterol A (5),16 except for the signals for the Δ8,9 (δC 135.9 and 146.9) in 5 being replaced by those for oxygenated tertiary carbons (δC 72.4 and 75.8) in 1. The oxygenated carbons were determined as an epoxy group rather than two hydroxy groups due to the limited unsaturation in the molecule. This assignment was supported by the long-range correlations from H-6α, H-11α, and H3-18 to C-8 and those from 12β and H3-19 to C-9 (Figure 1). The distinct NOE effects of H3-18 with H3-19, H-6β, and H-7 (Figure 2) indicated an α-orientation of the epoxy ring. The structure of 1 was then assigned as shown, and its relative configuration was established as (3S*,5S*,7R*,8S*,9S*,10S*,13R*,17R*,20R*,24R*). 1646



Article

Figure 2. Key NOE correlations of compounds 1−4.

assumed to be consistent with that of swinhoeisterol A (5).16 Interestingly, compound 4 displayed a negative specific rotation, opposite those of the coisolated analogues 1−3 and 5. Therefore, the absolute configuration of 3 and 4 was determined independently by both TDDFT-ECD31,32 and optical rotation (OR)15,33 calculations. The Merck Molecular Force Field (MMFF) conformational search of (3S,5R,9R,10R,13R,17R,20R,24R)-3 and (3S,5R,7R,8S,9R,10S,13R,17S,20R,24R)4 resulted in 199 and 173 conformers in a 21 kJ/mol energy window, and these conformers were reoptimized at the B3LYP/ 6-31+G(d,p) and the CAM-B3LYP/TZVP34 PCM (both for CH3CN and CHCl3) levels. Electronic circular dichroism (ECD) and OR calculations were performed with various functionals (B3LYP, BH&HLYP, CAM-B3LYP, and PBE0) and the TZVP basis set applying the same solvent model as in the preceding optimization step or without a solvent model. ECD spectra computed at all applied combinations of levels for both 3 and 4 reproduced well the experimental ECD spectra, verifying the assumed homochirality with 5. Solvent model OR calculations for 3 and 4 were also in line with the experimental positive and negative specific rotation values, respectively (Supporting Information, Tables S2 and S3), confirming the absolute configuration of 4. These isolates were tested in vitro for the (h)p300 inhibitory activity, using garcinol as positive control (IC50 = 0.5 μM). Compounds 1 and 5 displayed a similar inhibitory effect toward (h)p300, with IC50 values of 8.8 and 3.3 μM, respectively. Compounds 2−4 were inactive (IC50 values >10 μM). The observations suggest a significant role of a double bond or an epoxy group substitution for the C-8/C-9 bond. The presence of either a Δ7 functionality or an OH-7 group may decrease the resultant activity.16

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135.9, 123.9) was used as reference for chemical shifts. An Agilent QTOF Micro mass spectrometer was used to obtain the HRMS. HPLC purification was carried out on an Agilent 1100 system with a YMC Pack ODS-A column (250 × 10 mm, 5 μm). Open column chromatography (CC) was conducted on commercial silica gel (300−400 mesh, Huanghai, Yantai). TLC was carried out on glass sheets with precoated silica gel (HSGF-254, Huanghai, Yantai). Spots on TLC were detected by spraying with 10% anisaldehyde in H2SO4, followed by heating. Animal Material. The marine sponge Theonella swinhoei (2.9 kg, dry weight) was re-collected from the sea area around Xisha Islands in the South China Sea in May 2015. The species of sponge was previously identified by Prof. Jin-He Li (Institute of Oceanology, Chinese Academy of Sciences, People’s Republic of China).16 A voucher specimen (TY-23) was deposited in the Second Military Medical University, Shanghai, People’s Republic of China. Extraction and Isolation. The frozen sponge was minced and extracted in turn using acetone (3 L × 3) and methanol (3 L × 3) under ultrasonic conditions. A crude extract was obtained by evaporating the organic solvent under vacuum. The concentrated extract was suspended between water and ethyl acetate. The ethyl acetate extract was concentrated and then partitioned between petroleum ether and 90% methanol to afford a petroleum ether-soluble residue (38.1 g). This residue was subjected to CC on silica gel, eluting with petroleum ether in gradient acetone (from 50:1 to 0:100), to afford 15 fractions. Fraction 9 (559.0 mg) was chromatographed on a column containing Sephadex LH-20, eluting with CH2Cl2−MeOH (2:1), to afford three subfractions (Fr.9-1 to Fr.9-3). Fr.9-3 (333.3 mg) was subjected to CC on silica gel (petroleum ether−acetone, 20:1) and purified by semipreparative HPLC to yield 1 (3.4 mg, MeOH−H2O, 90:10, 1.5 mL/min, tR 54.2 min), 3 (2.2 mg, MeOH−H2O, 88:12, 1.5 mL/min, tR 81.1 min), and 5 (55.0 mg, MeOH−H2O, 88:12, 1.5 mL/min, tR 91.2 min). Fraction 10 (494.9 mg) was subjected to CC on Sephadex LH-20 (CH2Cl2−MeOH, 2:1) and silica gel (petroleum ether−acetone, 20:1), followed by semipreparative HPLC, to yield 2 (1.9 mg, MeOH−H2O, 95:5, 1.5 mL/min, tR 22.5 min) and 4 (0.6 mg, MeOH−H2O, 95:5, 1.5 mL/min, tR 39.8 min). Swinhoeisterol C (1): off-white, noncrystalline solid (CH2Cl2); Rf 0.48 (petroleum ether−acetone, 3:1); [α]25 D +29.3 (c 0.271, CHCl3); UV (CH3CN) λmax (log ε) 196 (4.92), 231 (4.09) nm; ECD (CH3CN, c 0.00135 M) λmax (Δε) 195 (+2.76), 286 (−0.80) nm; IR (film) νmax 3436, 2956, 2928, 2863, 1711, 1667, 1460, 1379, 1169, 899 cm−1; 1H and 13C NMR data, Table 1; HRESIMS m/z 465.3338 [M + Na]+ (calcd for C29H46O3Na, 465.3345). Swinhoeisterol D (2): colorless, noncrystalline solid (CH2Cl2); Rf 0.43 (petroleum ether−EtOAc, 3:1); [α]25 D +30.7 (c 0.0521, CHCl3);

EXPERIMENTAL SECTION

General Experimental Procedures. An Autopol VI polarimeter was used to record optical rotations, while a JASCO-715 spectropolarimeter was used to record ECD spectra. Varian Cary 300 Bio UV−visible and Nexus 470 FT-IR spectrophotometers were employed to measure UV and IR spectra, respectively. Bruker DRX 600, DRX 500, and Varian Inova-400 spectrometers were applied for acquiring NMR spectra at 300 K. The residual CDCl3 signal (δH 7.26 ppm; δC 77.0 ppm) or C5D5N signal (δH 8.74, 7.58, 7.22; δC 150.3, 1647



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Table 2. 1H and 13C NMR Data for Compounds 3 and 4 (in CDCl3) 3 position

δC,a type

1α

37.4, CH2

1β 2α 2β 3 4 5 6α 6β 7 8 9 10 11α

33.0, CH2 73.3, CH 151.0, C 44.8, CH 27.5, CH2

1.42, m 1.75, ovd 2.02, ovd 1.49, m 3.99, m 2.00, ovd 1.99, ovd 2.54, ovd

4 δC,a type 41.1, CH2

32.6, CH2 73.4, CH 150.7, C 43.2, CH 22.5, CH2

129.3, C 158.6, C 57.2, CH

2.38, m

46.9, CH 88.7, C 64.5, CH

36.7, C 22.8, CH2

1.72, ovd

36.5, C 26.5, CH2

11β 12α 12β 13 14 15α

δHb (J in Hz)

1.36, m 40.7, CH2 50.8, C 209.2, C 45.1, CH2

15β

1.57, m 1.77, ovd

2.50, ovd

16α 16β 17 18 19 20 21 22

51.6, CH 23.7, CH3 12.7, CH3 34.5, CH 21.0, CH3 29.8, CH2

23

32.8, CH2

2.66, ddd (13.9, 6.8, 2.9) 1.85, dd (6.8, 3.6) 1.98, ovd 1.65, d (10.1) 0.97, s 0.57, s 1.78, m 0.95, d (6.8) 1.47, dd (11.4, 3.1) 1.05, m 1.19, m

24 25 26 27 28 29

38.7, CH 32.2, CH 20.2, CH3 18.1, CH3 15.4, CH3 103.9, CH2

1.22, m 1.53, m 0.85, d (6.8) 0.80, d (6.9) 0.79, d (6.4) 5.17, s 4.87, s

22.8, CH2

34.1, CH2 53.3, C 215.9, C 39.1, CH2

24.5, CH2 85.7, C 19.0, CH3 15.4, CH3 38.9, CH 11.9, CH3 28.0, CH2 31.4, CH2 38.3, CH 32.2, CH 20.1, CH3 18.2, CH3 15.5, CH3 104.2, CH2

δHc (J in Hz) 1.41, dd (8.9, 6.8) 1.76, ovd 1.94, m 1.42, ovd 3.95, m 2.03, ovd 1.64, ovd 2.02, ovd 2.52, m

Figure 3. Experimental ECD spectrum of 3 in CH3CN compared with the Boltzmann-weighted CAM-B3LYP/TZVP PCM/CH3CN//CAMB3LYP/TZVP PCM/CH3CN spectrum of the (3S,5R,9R,10R,13R,17R,20R,24R) form of 3.

1.97, dd (13.1, 6.6) 1.88, dd (12.0, 5.9) 1.35, dd (12.6, 5.7) 2.49, ovd 1.53, ovd

3.16, td (12.6, 7.0) 2.39, td (13.0, 3.7) 2.04, ovd 1.77, ovd 0.93, s 0.66, s 2.22, m 0.84, d (6.6) 1.02, m 0.83, ovd 1.21, ovd 1.18, m 1.21, ovd 1.51, ovd 0.86, d (6.9) 0.81, d (6.8) 0.78, d (6.7) 5.21, s 4.86, s

Figure 4. Experimental ECD spectrum of 4 in CH3CN compared with the Boltzmann-weighted CAM-B3LYP/TZVP PCM/CH3CN//CAMB3LYP/TZVP PCM/CH3CN spectrum of the (3S,5R,7R,8S,9R,10S,13R,17S,20R,24R) form of 4. UV (CH3CN) λmax (log ε) 196 (4.97), 225 (4.11) nm; ECD (CH3CN, c 0.001 M) λmax (Δε) 194.5 (+0.68), 293.5 (−0.70) nm; IR (film) νmax 3417, 2956, 2925, 2855, 1696, 1460, 1380, 1260, 905, 806 cm−1; 1H and 13 C NMR data, Table 2; HRESIMS m/z 443.3515 [M + H]+ (calcd for C29H47O3, 443.3525). Computational Methods. The Macromodel 10.8.011 software was used to perform mixed torsional/low-mode conformational analysis35 with the MMFF using an implicit solvent model for CHCl3 and a 21 kJ/mol energy window. The geometries of the resultant conformers were reoptimizations at the B3LYP/6-31G+(d,p) level in vacuo and CAM-B3LYP/TZVP with the PCM solvent model for CH3CN and CHCl3. OR and ECD calculations were carried out with the Gaussian 09 software package.36 Chiroptical values were computed using various functionals such as CAM-B3LYP, PBE0, B3LYP, BH&HLYP, and the TZVP basis set. ECD spectra were produced as the sum of Gaussians37 with 3000 cm−1 half-height width, which corresponds to ca. 16 at 250 nm, using dipole-velocity-computed rotational strength values. B3LYP and CAM-B3LYP energies were utilized to estimate the Boltzmann distributions. For visualization of the results, the MOLEKEL software package was applied.38 Biological Assay. The primary evaluation of inhibitory activity toward (h)p300 of compounds 1−5 was tested by measurement of their capacity to transfer acetyl groups in a radioactivity assay.16,25 (H)p300 used in the test was expressed in E. coli. Test compounds or vehicle (1%

a

100 MHz. b400 MHz. c500 MHz. dov = overlapped signal.

UV (CH3CN) λmax (log ε) 197 (4.68), 231 (3.61) nm; ECD (CH3CN, c 0.0026 M) λmax (Δε) 194.5 (+1.09), 214.5 (−0.16) nm; IR (film) νmax 3492, 3360, 3198, 2955, 2924, 2854, 1712, 1659, 1463, 898 cm−1; 1H and 13C NMR data, Table 1; HRESIMS m/z 481.3297 [M + Na]+ (calcd for C29H46O4Na, 481.3294). Swinhoeisterol E (3): off-white, noncrystalline solid (CH2Cl2); Rf 0.54 (petroleum ether−acetone, 3:1); [α]25 D +45.9 (c 0.221, CHCl3); UV (CH3CN) λmax (log ε) 193 (4.43), 228 (3.82), 252 (3.83) nm; ECD (CH3CN, c 0.0014 M) λmax (Δε) 197.5 (+1.20), 252 (+2.13) nm; IR (film) νmax 3437, 2956, 2926, 2858, 1709, 1664, 1379, 1178, 899 cm−1; 1H and 13C NMR data, Table 2; HRESIMS m/z 427.3575 [M + H]+ (calcd for C29H47O4, 427.3576). Swinhoeisterol F (4): off-white, noncrystalline solid (CH2Cl2); Rf 0.45 (petroleum ether−EtOAc, 3:1); [α]25 D −25.6 (c 0.0861, CHCl3); 1648



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DMSO) were preincubated for 15 min at 37 °C with 1.0 μg/mL enzyme in a buffer containing 50.0 mM Tris-HCl (pH 8.5), 1.0 mM dithiothreitol, 5 mM MgCl2, 50.0 mM NaCl, and 1.0 mM phenylmethylsulfonyl fluoride . The reaction was initiated by adding 3.3 μg/ mL core histone and 0.10 μCi [3H]acetyl-CoA. Separate bound and free ligand by filtermats and counts were made to determine the amount of [3H]acetyl histone formed. The results were expressed as a percent inhibition of the control enzyme activity. Garcinol was used as a positive control.21

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(7) De Marino, S.; Ummarino, R.; D’Auria, M. V.; Chini, M. G.; Bifulco, G.; D’Amore, C.; Renga, B.; Mencarelli, A.; Petek, S.; Fiorucci, S.; Zampella, A. Steroids 2012, 77, 484−495. (8) Fukuhara, K.; Takada, K.; Okada, S.; Matsunaga, S. Org. Lett. 2015, 17, 2646−2648. (9) Festa, C.; De Marino, S.; D’Auria, M. V.; Monti, M. C.; Bucci, M.; Vellecco, V.; Debitus, C.; Zampella, A. Tetrahedron 2012, 68, 2851− 2857. (10) Renga, B.; Mencarelli, A.; D’Amore, C.; Cipriani, S.; D’Auria, M. V.; Sepe, V.; Chini, M. G.; Monti, M. C.; Bifulco, G.; Zampella, A.; Fiorucci, S. PLoS One 2012, 7, e30443. (11) De Marino, S.; Ummarino, R.; D’Auria, M. V.; Chini, M. G.; Bifulco, G.; Renga, B.; D’Amore, C.; Fiorucci, S.; Debitus, C.; Zampella, A. J. Med. Chem. 2011, 54, 3065−3075. (12) Guo, J.-K.; Chiang, C.-Y.; Lu, M.-C.; Chang, W.-B.; Su, J.-H. Mar. Drugs 2012, 10, 1536−1544. (13) Sun, Y.-Z.; Kurtán, T.; Mándi, A.; Tang, H.; Chou, Y.; Soong, K.; Su, L.; Sun, P.; Zhuang, C.-L.; Zhang, W. J. Nat. Prod. 2017, 80, 2930− 2940. (14) Li, J.; Li, C.; Riccio, R.; Lauro, G.; Bifulco, G.; Li, T.-J.; Tang, H.; Zhuang, C.-L.; Ma, H.; Sun, P.; Zhang, W. Mar. Drugs 2017, 15, 129− 141. (15) Sun, P.; Yu, Q.; Li, J.; Riccio, R.; Lauro, G.; Bifulco, G.; Kurtán, T.; Mándi, A.; Tang, H.; Li, T.-J. J. Nat. Prod. 2016, 79, 2552−2558. (16) Gong, J.; Sun, P.; Jiang, N.; Riccio, R.; Lauro, G.; Bifulco, G.; Li, T.-J.; Gerwick, W. H.; Zhang, W. Org. Lett. 2014, 16, 2224−2227. (17) Xu, D.-X.; Sun, P.; Kurtán, T.; Mandi, A.; Tang, H.; Liu, B.; Gerwick, W. H.; Wang, Z.-W.; Zhang, W. J. Nat. Prod. 2014, 77, 1179− 1184. (18) Goodman, R. H.; Smolik, S. Genes Dev. 2000, 14, 1553−1577. (19) Wang, F.; Marshall, C. B.; Ikura, M. Cell. Mol. Life Sci. 2013, 70, 3989−4008. (20) Gao, X.; Lin, J.; Ning, Q.; Gao, L.; Yao, Y.; Zhou, J.; Li, Y.; Wang, L.; Yu, L. PLoS One 2013, 8, e55481. (21) Maddox, S. A.; Watts, C. S.; Doyère, V.; Schafe, G. E. PLoS One 2013, 8, e54463. (22) Santer, F. R.; Hoschele, P. P.; Oh, S. J.; Erb, H. H.; Bouchal, J.; Cavarretta, I. T.; Parson, W.; Meyers, D. J.; Cole, P. A.; Culig, Z. Mol. Cancer Ther. 2011, 10, 1644−1655. (23) Balasubramanyam, K.; Varier, R. A.; Altaf, M.; Swaminathan, V.; Siddappa, N. B.; Ranga, U.; Kundu, T. K. J. Biol. Chem. 2004, 279, 51163−51171. (24) Ravindra, K. C.; Selvi, B. R.; Arif, M.; Reddy, B. A. A.; Thanuja, G. R.; Agrawal, S.; Pradhan, S. K.; Nagashayana, N.; Dasgupta, D.; Kundu, T. K. J. Biol. Chem. 2009, 284, 24453−24464. (25) Stimson, L.; Rowlands, M. G.; Newbatt, Y. M.; Smith, N. F.; Raynaud, F. I.; Rogers, P.; Bavetsias, V.; Gorsuch, S.; Jarman, M.; Bannister, A.; Kouzarides, T.; McDonald, E.; Workman, P.; Aherne, G. W. Mol. Cancer Ther. 2005, 4, 1521−1532. (26) Madia, V. N.; Benedetti, R.; Barreca, M. L.; Ngo, L.; Pescatori, L.; Messore, A.; Pupo, G.; Saccoliti, F.; Valente, S.; Mai, A.; Scipione, L.; Zheng, Y. G.; Tintori, C.; Botta, M.; Cecchetti, V.; Altucci, L.; Di Santo, R.; Costi, R. ChemMedChem 2017, 12, 1359−1368. (27) Reece, K. M.; Richardson, E. D.; Cook, K. M.; Campbell, T. J.; Pisle, S. T.; Holly, A. J.; Venzon, D. J.; Liewehr, D. J.; Chau, C. H.; Price, D. K.; Figg, W. D. Mol. Cancer 2014, 13, 91−102. (28) Demarco, P. V.; Farkas, E.; Doddrell, D.; Mylari, B. L.; Wenkert, E. J. Am. Chem. Soc. 1968, 90, 5480−5486. (29) Zhang, W.; Guo, Y.-W.; Mollo, E.; Cimino, G. Helv. Chim. Acta 2004, 87, 2919−2925. (30) Li, C.; Lee, D.; Graf, T. N.; Phifer, S. S.; Nakanishi, Y.; Burgess, J. P.; Riswan, S.; Setyowati, F. M.; Saribi, A. M.; Soejarto, D. D.; Farnsworth, N. R.; Falkinham, J. O., III; Kroll, D. J.; Kinghorn, A. D.; Wani, M. C.; Oberlies, N. H. Org. Lett. 2005, 7, 5709−5712. (31) Mándi, A.; Mudianta, I. W.; Kurtán, T.; Garson, M. J. J. Nat. Prod. 2015, 78, 2051−2056. (32) Stefano, S.; Patrizia, S.; Marcin, G.; Gennaro, P. Curr. Med. Chem. 2018, 25, 287−320. (33) Polavarapu, P. L. Chirality 2008, 20, 664−672.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.8b00281.

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Supplementary tables and figures of the MS and NMR spectroscopic data for compounds 1−4, the low-energy conformers, and calculated OR values of the low-energy conformers for compounds 3 and 4. (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Jiao Li: 0000-0003-4386-2340 Tibor Kurtán: 0000-0002-8831-8499 Attila Mándi: 0000-0002-7867-7084 Chun-Lin Zhuang: 0000-0002-0569-5708 Wen Zhang: 0000-0002-5747-4413 Author Contributions ‡

J. Li and H. Tang contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The research work was financially supported by the NSFC (U1405227, 41576157, 81741159, 81502978), the key project of STCSM (14431902900), and the Program of the Shanghai Subject Chief Scientist (15XD1504600). T.K. and A.M. thank the National Research, Development and Innovation Office (NKFI K120181 and PD121020) for financial support and the Governmental Information-Technology Development Agency (KIFÜ ) for CPU time.

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REFERENCES

(1) Sinisi, A.; Calcinai, B.; Cerrano, C.; Dien, H. A.; Zampella, A.; D’Amore, C.; Renga, B.; Fiorucci, S.; Taglialatela-Scafati, O. Bioorg. Med. Chem. 2013, 21, 5332−5338. (2) Issac, M.; Aknin, M.; Gauvin-Bialecki, A.; De Voogd, N.; Ledoux, A.; Frederich, M.; Kashman, Y.; Carmeli, S. J. Nat. Prod. 2017, 80, 1110−1116. (3) Fukuhara, K.; Takada, K.; Okada, S.; Matsunaga, S. J. Nat. Prod. 2016, 79, 1694−1697. (4) Rodríguez, J.; Jiménez, C.; Blanco, M.; Tarazona, G.; Fernández, R.; Cuevas, C. Org. Lett. 2017, 18, 5832−5835. (5) Takada, K.; Imae, Y.; Ise, Y.; Ohtsuka, S.; Ito, A.; Okada, S.; Yoshida, M.; Matsunaga, S. J. Nat. Prod. 2016, 79, 2384−2390. (6) Mencarelli, A.; Amore, C.; Renga, B.; Cipriani, S.; Carino, A.; Sepe, V.; Perissutti, E.; Auria, M.; Zampella, A.; Distrutti, E.; Fiorucci, S. Mar. Drugs 2014, 12, 36−53. 1649



Article

(34) Yanai, T.; Tew, D. P.; Handy, N. C. Chem. Phys. Lett. 2004, 393, 51−57. (35) MacroModel;Schrödinger, L. http://www.schrodinger.com/ MacroModel, 2015. (36) Frisch, M. J. T.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö .; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision E.01; Gaussian, Inc.: Wallingford, CT, 2013. (37) Stephens, P. J.; Harada, N. Chirality 2010, 22, 229−233. (38) Varetto, U. MOLEKEL 5.4; Swiss National Supercomputing Centre: Manno, Switzerland, 2009.

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