Rare Cembranoids from Chinese Soft Coral Sarcophyton ehrenbergi

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Rare Cembranoids from Chinese Soft Coral Sarcophyton ehrenbergi: Structural and Stereochemical Studies Geng Li, Heng Li, Quan Zhang, Min Yang, Yu-Cheng Gu, Lin-Fu Liang, Wei Tang, and Yue-Wei Guo J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00030 • Publication Date (Web): 02 Apr 2019 Downloaded from http://pubs.acs.org on April 2, 2019

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The Journal of Organic Chemistry

Page 1

Rare Cembranoids from Chinese Soft Coral Sarcophyton ehrenbergi: Structural and Stereochemical Studies Geng Li,⊥,†,§ Heng Li,⊥,⁋,§ Quan Zhang,† Min Yang,†,§ Yu-Cheng Gu,# Lin-Fu Liang,*,†,‡ Wei Tang,*,⁋,§ and Yue-Wei Guo*,†,§,║ †

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences,

555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China ⁋

Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences,

Shanghai 201203, China ‡

College of Materials Science and Engineering, Central South University of Forestry and Technology, 498

South Shaoshan Road, Changsha 410004, China §

University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China

║

Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine

Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, China #

Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, United Kingdom

⊥

G.L. and H.L. contributed equally to this work.

*Authors for correspondence: [email protected] (Lin-Fu Liang); [email protected] (Wei Tang); [email protected] (Yue-Wei Guo)

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ABSTRACT A detailed chemical research of soft coral Sarcophyton ehrenbergi from South China Sea yielded five new cembranoids 1–5 featuring an α,β-unsaturated-γ-lactone moiety rarely at C-6 to C-19, along with one known related diterpene 6. The structures and absolute configurations of 1–5 were established in the light of extensive spectroscopic data analysis, chemical reaction, X-ray diffraction analysis, TDDFT-ECD calculations and biosynthesis path. This study led to the stereostructural revision of 6, which was misassigned by erroneously applying the empirical ECD helicity rule, indicating a challenging and risky work to determine the structure of this type of marine cembranoids. In the TNF-α inhibitory biotest, compound 2 exhibited potent inhibitory activity (IC50 = 8.5 μM), which was analogous to the positive control dexamethasone (IC50 = 8.7 μM). INTRODUCTION Cembranoids are a group of abundant diterpenoids frequently encountered in marine and terrestrial organisms featuring a 14-membered carbocyclic ring.1 Intriguingly, a wide range of structurally diverse derivatives of cembranoids have been discovered to date, including skeletal variants,2,3 norcembranoids,4,5 and biscembranoids.6,7 Those secondary metabolites deserve intensive investigation for their significant biological activities ranging from antibacterial8 and cytotoxicity9 to NF-κB inhibitory9 properties. Their fascinating structures and potent bioactivities make them attractive for total synthesis.10


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Page 3 As part of our continuous research project aiming for bioactive chemicals from Chinese marine invertebrates,11-13 we made a collection of soft corals off the coast of Weizhou Island which were identified as Sarcophyton ehrenbergi. A literature survey on this species revealed a wealth of structurally diverse secondary metabolites,14 including ceramides,15 terpenes,16,17 prostaglandins,18 and steroids.19 Among these secondary metabolites, cembrane diterpenoids emerged as characteristic constituents of this species. Our recent investigation of the title animals has now resulted in the discovery of five new cembranoids 1–5 and a known related diterpenoid 6. Herein, the isolation, structural elucidation, and biological evaluations of these compounds are reported. RESULTS AND DISCUSSION In our investigation for novel cembranoids from the octocorals, we tried to discover new chemical frameworks using a structure-guided isolation method. UV screening can be used to recognize the structural feature of cembranoids promptly and directly, based on our longestablished cembranoids library.20 Several cembranoids embodying a lactone moiety with different structural features such as an α-methylene-γ-lactone,21 an α,β-unsaturated-γlactone,9,22,23 and an α,β-unsaturated-ε-lactone,8,24 and even biscembranoids biogenerated from Diels-Alder addition involving an α,β-unsaturated-γ-lactone6,23 had been discovered from soft corals collected in South China Sea by using this method. Attracted by their complex and unique structures, medicinal chemists showed great attentions on them.10,25,26 Meanwhile, investigating the isolates and the data in published works,16,27 we noticed that almost the group of cembranoids with an α,β-unsaturated-γ-lactone at C-6 to C-19 are rare from soft corals. A maximum UV absorption band around 247 nm with minor variation in peak shapes, which is an attribute of the α,β-unsaturated-γ-lactone moiety, has been displayed. Thus, unless there is an exception to the aforementioned instances in soft corals, it



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Page 4 allows us to hypothesize that the structural characteristics may exist and then a new secondary metabolite appears to be prospective. Consequently, we made a UV-guided fractionation aiming for the abovementioned rare type of marine cembranoids from the samples of S. ehrenbergi, yielding pure metabolites 1–6 (Figure 1). The known compound 6 was readily identified as ehrenbergol D, a cembranoid that previously isolated from the soft coral S. ehrenbergi collected at the San-Hsian-Tai, Taiwan, based on the comparison of its NMR spectral and specific optical data with those reported in the literature.16 Compounds 1−5 showed similar NMR spectroscopic data with coisolated 6 indicating that they also belonged to the type of marine cembranoids featuring an α,β-unsaturated-γ-lactone moiety rarely at C-6 to C-19. In fact, 1–5 differed from each other in either oxidative patterns, and/or migration of double bonds in their molecules. Moreover, the absolute stereochemistry of 1 was unambiguously determined by a single-crystal X-ray diffraction analysis using Cu Kα radiation, while the absolute configurations of 2 and 4 were identified by TDDFT-ECD calculations, respectively, leading to the structural revision of 6 at the C-6 configuration.

O

19

O 8

18

5

6

4 3

7

16

2 1

9

13

10 11

14

O

O

6

O

O 4

18

15

18

OAc

17

OAc 10

12

12

OH

20

1

3

2 6a

18

O O

COOMe

O

O

6

O

O

OH

13

4

O

6 6S (Revised) 6 6R (Lit. reported)

5

Figure 1. Chemical structures of 1−6 and 6a.


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Page 5 Table 1 13C-NMR data for compounds 1–5 in CDCl3a No.

1

2

3

4

5

C-1

148.0, C

150.7, C

151.7, C

143.2, C

160.1, C

C-2

118.4, CH

118.6, CH

117.9, CH

119.0, CH

120.1, CH

C-3

127.4, CH

129.8, CH

128.9, CH

126.2, CH

142.2, CH

C-4

128.1, C

125.6, C

126.7, C

131.2, C

120.1, C

C-5

42.9, CH2

30.5, CH2

30.6, CH2

41.3, CH2

40.1, CH2

C-6

81.0, CH

81.1, CH

80.5, CH

80.8, CH

80.2, CH

C-7

148.6, CH

147.6, CH

147.1, CH

149.9, CH

148.4, CH

C-8

133.5, C

133.2, C

131.0, C

133.1, C

133.7, C

C-9

25.2, CH2

26.0, CH2

C-10

24.8, CH2

26.4, CH2

C-11

124.7, CH

126.4, CH

C-12

135.5, C

133.8, C

29.2, CH2 125.3, CH 133.0, CH

24.7, CH2

24.9, CH2

25.6, CH2

24.9, CH2

141.1, CH

126.0, CH

85.3, C

136.6, C

136.2, C

201.0, C

C-13

37.5, CH2

38.3, CH2

37.0, CH2

C-14

28.3, CH2

27.9, CH2

25.3, CH2

41.8, CH2

29.9, CH2

C-15

33.3, CH

33.3, CH

32.0, CH

33.3, CH

34.0, CH

C-16

22.4, CH3

21.7, CH3

21.4, CH3

21.5, CH3

21.8, CH3

C-17

22.8, CH3

23.5, CH3

23.5, CH3

22.6, CH3

22.9, CH3

C-18

18.7, CH3

70.1, CH2

70.3, CH2

19.8, CH3

C-19 C-20 C-1' C-2' a

174.3, C 18.0, CH3

173.6, C 16.3, CH3 171.0, C 21.2, CH3

172.8, C 20.6, CH3 170.8, C

173.4, C 11.8, CH3

37.9, CH2

167.7, C 173.8, C 18.5, CH3 51.7, CH3

21.2, CH3

Recorded at 125 MHz in CDCl3, chemical shifts (ppm) referred to CHCl3 (δC 77.2). Assignments were deduced by analysis of 1D and 2D

NMR spectra.



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Page 6 Table 2 1H-NMR data (δ in ppm, J in Hz) for compounds 1–5 in CDCl3a 1

2

3

4

5

2

5.97, d (11.2)

5.87, d (11.5)

5.61, d (11.7)

6.01, d (10.9)

7.09, d (11.9)

3

5.77, d (11.1)

6.28, d (11.5)

6.35, d (11.7)

5.92, d (10.9)

6.59, d (11.9)

5a

2.64, dd (13.3, 3.4)

2.87, d (14.4)

2.88, dd (14.4, 6.4)

2.80, dd (13.8, 6.5)

3.18, dd (12.8,5.2)

5b

2.48, dd (13.2,7.4)

2.79, dd (14.6, 5.4)

2.75, d (14.4)

2.64, d (13.7)

2.26, m

6

5.15, dd (5.8, 1.8)

5.18, dd (5.1, 1.9)

5.29, dd (6.6, 1.8)

5.28, dd (6.2, 1.2)

5.15, m

7

6.84, d (1.7)

6.80, s

6.82, s

7.04, d (1.4)

6.82, d (1.7)

9a

2.39, m

2.53, ddd (13.3, 6.3, 1.3)

3.11, dd (13.7, 3.0)

2.65, dd (13.8, 0.9)

2.40, m

9b

2.26, m

2.08, m

2.81, dd (13.8, 9.4)

2.28, m

2.29, m

10a

2.37, m

2.24, m

5.50, ddd (15.8, 9.4, 4.4)

2.57, dddd (15.8, 9.5, 6.4, 3.0)

2.40, m

10b

2.30, m

2.45, m

2.29, m

11

4.96, dd (8.5, 3.9)

4.64, dd (10.2, 2.4)

5.22, d (15.8)

6.53, ddd (9.3, 4.9, 1.2)

5.04, m

13a

2.14, m

2.19, m

2.02, td (13.5, 1.8)

2.31, m

13b

2.14, m

2.03, m

1.80, ddd (13.6, 8.4, 2.0)

2.12, m

14a

2.41, m

2.64, td (13.0, 3.1)

2.52,m

3.99, d (12.9)

2.51, m

14b

2.19, m

1.98, m

2.11, m

3.03, d (12.9)

2.30, m

15

2.32, m

2.30, m

2.49, m

2.22, sept (6.9)

2.47, sept (6.9)

16

1.05, d (6.8)

1.13, d (6.8)

1.17, d (6.8)

0.98, d (6.8)

1.15, d (6.8)

17

1.05, d (6.8)

1.03, d (6.7)

1.02, d (6.8)

1.00, d (6.8)

1.10, d (6.8)

18a

1.78, d (1.8)

4.53, d (12.5)

4.57, d (12.4)

1.83, d (1.5)

4.44, d (12.5)

4.52, d (12.7)

1.50, s

1.39, s

18b 20

1.65, s

1.75, t (1.4)

1'

1.60, s 3.79, s

2'

2.06, s a

2.08, s

Recorded at 500 MHz in CDCl3, chemical shifts (ppm) referred to CHCl3 (δH 7.26). Assignments were deduced by analysis of 1D and 2D

NMR spectra.

Sarcoehrenolide A (1) was isolated as an optically active colorless oil. Its molecular formula, C20H28O2, was established by the HRESIMS ion peak at m/z 301.2161 [M+H]+ (calcd 301.2162), indicating 16 mass units less than that of co-isolated ehrenbergol D (6).16 Similar to 6, the NMR data (Tables 1 and 2) of 1 revealed the presence of an α,β-unsaturatedγ-lactone moiety, three trisubstituted double bonds, two of those double bonds represented a


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Page 7 conjugated diene moiety, as shown in Figure 1. In fact, it was found that 1 differed from 6 by the absence of a hydroxyl group at C-18 (δC 18.7) in 1, which was further corroborated by the HMBC correlations from Me-18 (δH 1.78) to C-3 (δC 127.4), C-4 (δC 128.1) and C-5 (δC 42.9) (Figure 2). Due to the structural change, the chemical shift of the carbon at C-4 was obviously shifted downfield and that of C-5 was prominently shifted upfield, compared to 6. The NOE correlations of H-2 (δH 5.97)/H-16 (δH1.05) and H-18, H-3 (δH5.77)/H-5a (δH 2.64) and H-14a (δH 2.41), H-7 (δH 6.84)/H-9a (δH 2.39) and H-11 (δH 4.96)/H-13b (δH2.14) were indicative of 1E,3E,7Z,11E configurations. Finally its absolute stereochemistry confirmed by single-crystal X-ray crystallographic analysis using Cu Kα radiation with Flack parameter of 0.09(8) (Figure 3, Table S1), which allowed the unambiguous determination as 6S. In addition, its absolute configuration in C-6 also could be deduced from TDDFT-ECD calculation. The comparisons of experimental ECD spectrum with both ones of calculated (6S)- and (6R)-1 enantiomers revealed that the Boltzmann-averaged ECD spectrum of (6S)-1 displayed an identical curve compared to the experimental one, while that of (6R)-1 found to be the near-mirror image of the experimental one (Figure 4). Both results of X-ray crystallography and TDDFT-ECD calculation led to the same 6S absolute configuration for 1.

Figure 2. 1H-1H COSY, selected key HMBC, and NOESY correlations of 1.



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Page 8

Figure 3. Perspective ORTEP drawing of X-ray structure of 1 (displacement ellipsoids are drawn at the 50% probability level).

Figure 4. Experimental ECD spectrum of 1 (black), the calculated ECD spectra of 6S-1 (red) and 6R-1 (blue), respectively. Sarcoehrenolide B (2), an optically active colorless oil, displayed a molecular formula of C22H30O4 as established by the HRESIMS ion peak at m/z 381.2042 [M+H]+ (calcd 381.2036). Careful analysis revealed the NMR spectroscopic features of 2 (Tables 1 and 2) mostly resembled to those of co-isolated 6.16 In fact, the only difference was at C-13 position, where the hydroxyl group in 6 was replaced by an acetoxy (δH 2.06; δC 21.2, 171.0) in 2,


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Page 9 consist with their 42 mass units difference. Due to the acetylation, chemical shift of C-13 was shifted downfield from δC 68.5 in 6 to δC 70.1 in 2. A detailed 2D NMR (Figures S14–S16) analysis further confirmed the planar structure of 2. As the patterns of NOESY correlations of 2 (Figure S17) were similar with those of 6, accordingly the structure of 2 was established as the 18-acetyl derivative of 6. In order to make sure their structural relationship, acetylation of 6 had been done. Successfully the acetylated product 6a was obtained by treating 6 with acetic anhydride in dry pyridine for 1h at room temperature, whose NMR data (Figures S55 and S56) and the specific optical value were fully agreement with those of 2. As a result, sarcoehrenolide B (2) is the acetylate of ehrenbergol D (6) indeed.

Figure 5. Experimental ECD spectrum of 2 (black), the calculated ECD spectra of 6S-2 (red) and 6R-2 (blue), respectively. The absolute configuration of 2 was identified by TDDFT-ECD calculation, which are frequently used in the stereochemical studies of conformationally flexible macrolides, and the reliability of this approach has been employed.8,11,28,29 The Boltzmann-averaged ECD spectrum of (6S)-2 displayed an identical curve compared to the experimental one (Figure 5), which was suggestive of 6S absolute configuration for 2.



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Page 10

Figure 6. Experimental ECD spectra of compounds 1–3 and 6. It is interesting to find that this new metabolite 2 possessed 6S absolute configuration while its closely related compound 6 was reported to have the opposite 6R,16 which was determined by applying a empirical ECD helicity rule.30 These contrast results promoted us to check out their ECD spectra. As shown in Figure 6, the ECD spectrum of 2 displayed a positive CE at 260 nm (Δε = +78.7) and a negative CE around λmax 210 nm (Δε = −25.0), which was almost identical to the co-existed 6. Their same ECD features raised concerns for the correct absolute configuration for C-6 of the α,β-unsaturated-γ-lactone moiety at C-6 to C-19 in 6. As reported, the empirical ECD helicity rule used in the case of 6 was summarized on the basis of ECD profiles of 5-alkyl- and 5-alkoxy-substituted butenolides, whose structures possessed the α,β-unsaturated-γ-lactone moiety as the sole chromophore.30 It is a pity that we could not speculate the effects of other chromophore(s) in every case when use this rule. However, the consistent ECD spectral and structural features between 2 and 6 indicated that the contribution of another important chromophoric group, the conjugated diene from C-1 to C-4 in 6,16 to the ECD spectrum could not be ignored. Recently, a similar case was reported by Pescitelli et al in the structural restudy of laucysteinamide A, leading to the revision of its absolute configuration.31 In addition, the research work of Batista and co-


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Page 11 workers revealed that acetogenins with a hydroxyl group substituted at C-4 were a possible exception to this rule.32 Hereto, based on the intimate structural relationship between 2 and 6, the absolute configuration of 6 subsequently was revised as 6S, indicating the empirical ECD helicity rule was not suitable for applying in this case. The revision was further supported by the results of TDDFT-ECD calculations for both (6S)- and (6R)-6 enantiomers, which clearly showed the whole pattern of calculated ECD spectrum of (6S)-6 was in line with the experimental data (Figure 7).

Figure 7. Experimental ECD spectrum of 6 (black), the calculated ECD spectra of 6S-6 (red) and 6R-6 (blue), respectively. Sarcoehrenolide C (3) was isolated as an optically active colorless oil with the chemical formula of C22H30O5 as suggested by the HRESIMS ion at m/z 397.1988 [M+Na]+ (calcd 397.1985), which was the same as that of 2, indicating eight degrees of unsaturation. Similar to 2, an α,β-unsaturated-γ-lactone moiety, three C=C bonds, and an acetoxyl group in 3 could be identified based on its NMR data. An obvious difference was realized for signals designated to fragment C-9–C-13 (Table 1).The diagnostic downfield 1H-NMR signals and coupling patterns (δH 5.50, ddd, J = 15.8, 9.4, 4.4 Hz and 5.22, d, J = 15.8 Hz) clearly indicated the presence of a trans-disubstituted double bond in 3 . The proton sequence of H2-



Page 12 of 27

Page 12 9/H-10/H-11 displayed in 1H–1H COSY spectrum disclosed the location of the double bond at Δ10. The HMBC cross-peaks of Me-20 with C-11, C-12, and C-13 corroborated the NMR assignment and consequently led the oxygenated tertiary carbon (δC 85.3) at C-12. The absolute configuration of C-6 in 3 was assigned as 6S due to its ECD spectrum was almost identical to that of co-occurred 2 (Figure 6). As for the relative configuration at C-12, the 3D-DFT models (6S,12R)-3 and (6S,12S)-3 (Figure S58), which were the most energetically favorable conformer optimized with Gaussian 09 at the B3LYP/6-311G (d, p) level, was constructed and analyzed. According to the calculated distances among the key protons in 3D-DFT model, the NOE correlations among some key protons leading the relative relationship between H-6 and Me-20 seems not reliable. Whereas the other efforts, such as crystallization, TDDFT-ECD calculation and

13

C-NMR calculation etc. were also

unsuccessful. In light of these results, the absolute configuration at C-12 remains undefined. Sarcoehrenolide D (4) was isolated as an optically active colorless oil. From the molecular ion peak at m/z 315.1953 [M+H]+ (calcd 315.1955) in the HRESIMS spectrum, a molecular formula of C20H26O3 was established, 14 mass units more than that of 1. The 1Hand

13

C-NMR data of 4 showed high similarity to those of 1, except for the presence of an

keto group at C-13 in 4, leading to the formation of α,β-unsaturated enone (ketone) functionality. Due to the change, the carbon chemical shift of the carbon at C-20 (δC 11.8) was significantly shifted upfield (Δδ = −16.2 ppm) whereas C-11 (δC 141.1) was prominently shifted downfield (Δδ = +16.4 ppm) compared to 1. Further evidences confirmed by the 2D NMR including NOESY (Figures S34–S37), 4 was determined to be a ketone derivative of 1, which was agreed with their 14 mass units difference. The absolute configuration of 4 was determined as 6S by TDDFT-ECD calculation. As shown in Figure 8, the Boltzmannaveraged ECD spectrum of (6S)-4 displayed an identical curve compared to the experimental one.


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Page 13

Figure 8. Experimental ECD spectrum of 4 (black), the calculated ECD spectra of 6S-4 (red) and 6R-4 (blue), respectively. The colorless oil, sarcoehrenolide E (5), had the chemical formula of C21H28O4 as established by the HRESIMS ion at m/z 345.2065 [M+H]+ (calcd 345.2060), 44 mass units more than that of 1. Comparing the NMR data of 5 with those of 1 (Tables 1 and 2), indicated existing a structural similarity. An oxidation on vinyl methyl Me-18 of 1 to give a methyl ester in 5 was indicated by the significantly shifted downfield peaks in 1H-NMR spectrum (H-2: from δH 5.97 in 1 to 7.09 in 5, H-3: from δH 5.77 in 1 to 6.59 in 5). Detailed investigation of 2D NMR data (Figures S42–S44) fully corroborated this speculation. Finally, NOESY data suggested that the four double bonds within the 14-membered macrocycle of 5 (Figure S45) and 1 possessed the same geometries. Due to the great similarity among the structure of 5 and the co-occurring 1–4, as well as the biogenetic consideration, it is reasonable that the absolute stereochemistry of C-6 of 5 should be in agreement with S configuration. It may be worth to point out that the cembranoids featuring an α,β-unsaturated-γ-lactone moiety at C-6 to C-19 are rare. To date, only four metabolites belonging to this type have been reported from marine soft corals. They were ehrenbergol D (6) from S. ehrenbergi,16



Page 14 of 27

Page 14 sarcophytolin D (7) from Lobophytum sarcophytoides,27 8 and 9 from Sarcophyton sp.34 (Figure 9) Among them, the absolute stereochemistry of C-6 in compound 7 was deduced as 6R using the empirical ECD helicity rule that applied in the case of 6. While the relative configuration of C-6 in 9 was assigned by NOESY correlations, that in 8 was unknown. Due to their similar structural features between 6 and 7, the empirical ECD helicity rule was not suitable to apply for 7 yet as discussed in the aforementioned case of 6. In fact, its absolute configuration was supposed tentatively to be revised as 6S according to its reported ECD spectroscopic data27 which were consistent with those of sarcoehrenolides A–E (1–5). Meanwhile, the absolute configurations of 8 and 9 could be assigned based on the comparison of their ECD spectra with those of 1–5.

Figure 9. Originally proposed chemical structures of 7−9. As for their biological properties, sarcoehrenolides A–E (1–5) as well as the co-isolated ehrenbergol D (6) were evaluated using a number of biological models according to the wellrecognized protocols, which included bioassays of cytotoxic activity against A549, HT-29, SNU-398 and Capan-1 cell lines, as well as inhibition of TNF-α (Table 3). Due to sample quantity limitations, bioactivity evaluation of 3 was not feasible. The results showed none of them were active in the cytotoxic assays, while compounds 1, 2, 4 and 6 displayed moderate TNF-α inhibition with IC50 values of 28.5, 8.5, 27.3 and 24.2 μM, respectively. Of them, 2 showed potent TNF-α inhibitory activity being similar to that of positive control dexamethasone (IC50 = 8.7μM). Although the elaborated mechanism is still under investigation, the current preliminary pharmacological results indicate that these rare


Page 15 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Page 15 cembranoids may be developed as a new and prospective chemotype of TNF-α inhibitory agents, especially 2 may serve as an anti-inflammatory lead compound or a drug candidate . Table 3 Anti-inflammatory effects of compounds 1, 2, 4–6 Compounds

IC50 (μM) CC50 (μM)

SI (selective index)

1

28.5

>50

>1.8

2

8.5

>50

>5.9

4

27.3

>50

>1.8

5

>50

>50

—

6

24.2

>50

>2.1

Dexamethasone

8.7

>50

>5.7

Since the tested compounds shared homogeneous structural scaffold, some preliminary structure–activity relationships could be deduced from the pharmacological data. The common structural characteristics for the active compounds 1, 2, 4 and 6 were a diene functionality at C-1 to C-4, an α,β-unsaturated-γ-lactone moiety at C-6 to C-19, and a double bond Δ11. Structural comparison for the pair of 1 and 4 and that of 1 and 6 clearly revealed that a keto group at C-13 and a hydroxyl group at C-18 could only slightly increase TNF-α inhibitory activity, respectively. However, the moderate potency of 1 and the inactivity of 5 suggested the presence of a carbomethoxy group at C-18 was responsible for a remarkable decrease of the activity. Interestingly, the acetoxy at C-18 was regarded as the key pharmacophore leading to the significant activity for 2 which was comparable with the positive control dexamethasone.



Page 16 of 27

Page 16 CONCLUSION The chemical investigation of South China Sea soft coral S. ehrenbergi led to the isolation of five new cembranoids 1–5 along with a related known one 6 through a UVguided fractionation. Structurally, compounds 1–5 represent rare cembranoids featuring an α,β-unsaturated-γ-lactone at C-6 to C-19. The absolute stereochemistry of compound 1 was confirmed by single-crystal X-ray crystallographic analysis with Cu Kα radiation, while the absolute configurations of compounds 2 and 4 were assigned by TDDFT-ECD calculations, respectively. This is the first time to unambiguously determine the absolute stereochemistry of these rare kind of marine natural products by using a single-crystal X-ray crystallographic analysis and TDDFT-ECD calculations, indicating that they could be used as models in the stereochemical study for other related compounds. In addition, all of them possess the same S absolute configuration for C-6, which is opposite to those misassigned for ehrenbergol D (6)16 and its relative27 by erroneously applying the empirical ECD helicity rule.30 Further, based on the chemical conversion, the absolute stereochemistry of 6 was revised as 6S by ECD spectroscopy analysis, which was further supported by its TDDFT-ECD calculation. In light of these observations, it is noteworthy that to use the empirical ECD helicity rule to judge the absolute stereochemistry of the five-membered unsaturated lactone in the macrocyclic system containing more than one chromophore within the molecule is risky. In the bioassay, compounds 1, 2, 4 and 6 displayed moderate TNF-α inhibition with IC50 values from 8.5 to 28.5 μM. Of them, 2 showed potent TNF-α inhibitory activity being comparable with that of positive control dexamethasone (IC50 = 8.7 μM). The exploration of sarcoehrenolides A–E (1–5) enriched the diverse structural chemotypes of cembranoids from marine source and probably led the more in-depth medicinal chemistry research because of their interesting structure characteristics. The ecological roles and the biogenetic origins of 1–5 in soft coral deserve a further research.


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Page 17 EXPERIMENTAL DETAILS General Experimental Procedures. Optical rotations were measured on a PerkinElmer 241MC polarimeter. UV spectra were recorded on a Varian Cary 300 Bio spectrophotometer. IR spectra were recorded on a Nicolet 6700 spectrometer (Thermo Scientific, Waltham, MA, USA). CD spectrums were measured on a JASCO J-810 instrument. NMR spectra were measured on a Bruker DRX-400, Bruker DRX-500, or Bruker DRX-600 spectrometer (Bruker Biospin AG, Fällanden, Germany) with the residual CHCl3 (δH 7.26 ppm, δC 77.16  ppm) as an internal standard. HRESIMS spectra of 1–5 were carried out on a Agilent G6520 Q-TOF mass spectrometer. Reversed phase HPLC (Agilent 1260 Infinity liquid chromatography using a VWD G1314B detector at 210  nm and 254 nm and a semipreparative Agilent Eclipse XDB-C18 [5  μm, 9.4  mm (i.d.) × 250  mm] column) was employed. Commercial Si gel (Sinopharm Chemical Reagent Co., Ltd, 200–300 and 300–400 mesh) and Sephadex LH-20 (GE Healthcare) was used for column chromatography, and precoated Si gel plates (Merck Chemicals (Shanghai) Co., Ltd, G60 F254) were used for analytical TLC. X-ray diffraction studies were carried out on a Bruker APEX2 CCD diffractometer. Biological Material. Specimens of the soft coral S. ehrenbergi were collected from the Weizhou island, Guangxi Province, China, in 2007, at a depth of −10 m, and were frozen immediately after collection. The soft coral was identified by Prof. X. B. Li (Hainan University). A voucher specimen (07-WZ-23) was deposited at Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. Extraction and Isolation. The frozen animals (301  g, dry weight) were cut into pieces and extracted exhaustively with Me2CO at room temperature (3 × 1.5  L, 15  min in ultrasonic bath). The organic extract was evaporated to give a brown residue, which was partitioned between Et2O and H2O. The Et2O solution was concentrated under reduced pressure to give a



Page 18 of 27

Page 18 dark brown residue (29.0 g), which was fractionated by gradient Si gel (200–300 mesh) column chromatography (CC) (0 → 100% Et2O in petroleum ether (PE)), yielding ten fractions (A – J). The fractions were detected by TLC under UV light at 254 nm for the α,βunsaturated-γ-lactone, leading to the selection of fractions Fr. G, I and J. Fr. G was subjected to a column of Sephadex LH-20 eluting with PE/CH2Cl2/MeOH (2:1:1) to give three subfractions Fr. Ga, Gb and Gc. Compound 1 (22.0 mg; tR 9.2 min) was obtained from Gc by stepwise HPLC (MeOH/H2O, 90:10→100:0, 3.0  mL/min). Fr. I was subjected to silica gel CC (300–400 mesh, PE/Et2O, 8:2) to give compounds 2 (20.1 mg), 3 (2.2 mg) and 4 (8.0 mg). While, 5 (8.3 mg; tR 9.3 min) was obtained from Fr. Ia by stepwise HPLC (MeOH/H2O 80:20→100:0, 3.0  mL/min). 6 (7.1 mg) was obtained from Fr. J through Sephadex LH-20 CC (CH2Cl2/MeOH, 1:1) followed by repeated silica gel CC (300–400 mesh, PE/Et2O, 8:2→1:1). Sarcoehrenolide A (1): Colorless crystals (MeOH); mp 105–106 °C; [α]D25 +183.3 (c 0.30, CHCl3); UV (MeOH) λmax (log ε) 248 (3.97) nm; ECD (MeCN) λmax (Δε) 245 (+32.3), 210 (−23.6) nm; IR (KBr) νmax 2953, 2921, 2850, 1752, 1191, 1130, 1069 cm−1; 1H- and

13

C-

NMR data, see Tables 1 and 2; HRMS (ESI/QTOF) m/z: [M + H]+ Calcd for C20H29O2 301.2162; Found 301.2161. Sarcoehrenolide B (2): colorless oil; [α]D25 +506.7 (c 0.10, CHCl3); UV (MeOH) λmax (log ε) 247 (3.92) nm; ECD (MeCN) λmax (Δε) 260 (+78.7), 210 (−25.0) nm; IR (KBr) νmax 2958, 2926, 2866, 1754, 1440, 1379, 1359, 1227, 1044 cm−1; 1H- and 13C-NMR data, see Tables 1 and 2; HRMS (ESI/QTOF) m/z: [M + Na]+ Calcd for C22H30NaO4 381.2036; Found 381.2042. Sarcoehrenolide C (3): colorless oil; [α]D25 +342.0 (c 0.05, CHCl3); UV (MeOH) λmax (log ε) 247 (4.22) nm; ECD (MeCN) λmax (Δε) 267 (+10.4), 212 (−6.0) nm; IR (KBr) νmax 3379, 2959, 2921, 2866, 1736, 1374, 1223, 1191, 1130, 1073, 1034, 1018 cm−1; 1H- and 13C-NMR


Page 19 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Page 19 data, see Tables 1 and 2; HRMS (ESI/QTOF) m/z: [M + Na]+ Calcd for C22H30NaO5 397.1985; Found 397.1988. Sarcoehrenolide D (4): colorless oil; [α]D25 +85.5 (c 0.1, CHCl3); ECD (MeCN) λmax (Δε) 334 (−0.7), 261 (+1.8), 232 (+4.6), 204 (−2.0) nm; IR (KBr) νmax 2959, 2922, 2849, 1741, 1657, 1196, 1132, 1077 cm−1; 1H- and

13

C-NMR data, see Tables 1 and 2; HRMS

(ESI/QTOF) m/z: [M + H]+ Calcd for C20H27O3 315.1955; Found 315.1953. Sarcoehrenolide E (5): colorless oil; [α]D25 +56.2 (c 0.20, CHCl3); UV (MeOH) λmax (log ε) 285 (4.05) nm; IR (KBr) νmax 2953, 2921, 2847, 1710, 1438, 1377, 1246, 1194, 1079 cm−1; 1

H- and

13

C-NMR data, see Tables 1 and 2; HRMS (ESI/QTOF) m/z: [M + H]+ Calcd for

C21H29O4 345.2060; Found 345.2065. X-ray crystallographic analysis for 1. Colorless blocks, C20H28O2, Mr = 300.42, orthorhombic, crystal size 0.32×0.18×0.12 mm, space group P212121, a = 6.3002(4) Å, b = 12.8333(6) Å, c = 22.1179(10) Å, V = 1788.28 (16) Å3, Z = 4, Dcalcd = 1.116 g/cm3 , F(000) = 656, 20108 collected reflections, 3056 unique reflections (Rint = 0.0442), final R1 = 0.0301 (wR2 = 0.0801) reflections with I≥2σ (I), R1 = 0.0322, wR2 = 0.0815 for all unique data. The X-ray measurements were made on a Bruker APEX-II CCD X-ray diffractometer with graphite-monochromated Cu Kα (λ = 1.54178) radiation at 173.0 K. The structure was solved by direct methods (SHELXS-97) and refined with full-matrix leastsquares on F2 (SHELXL97). Crystallographic data for 1 have been deposited at the Cambridge Crystallographic Data Centre (Deposition nos. CCDC 1876727). Copies of these data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK. [Fax: (+44) 1223-336-033. E-mail: [email protected].] Computational Section. Conformational search was accomplished using the torsional sampling (MCMM) method and OPLS_2005 force field with the conformational search was



Page 20 of 27

Page 20 using an energy window of 21 kJ/mol. Conformers which were above 1% Boltzmann populations were re-optimized at the B3LYP/6-311G (d, p) level with IEFPCM solvent model for acetonitrile.35 Frequency analysis was performed as well to confirm that the reoptimized geometries were at the energy minima. ECD spectra were obtained by TDDFT calculations displayed with the identical functional basis set and solvent model as the energy optimization. Eventually, the Boltzmann-averaged ECD spectra of the compounds were obtained with SpecDis 1.62.36 Anti-inflammatory activity assay. Murine macrophage cell line, RAW264.7 cells, was obtained from American Type Culture Collection (ATCC, Manassas, VA, USA). In the bioassay for anti-inflammation, cells were cultured in DMEM containing 10% FBS, 2 mmol/L L-glutamine, 100 μg/mL streptomycin and, 100 U/mL penicillin in a humidified incubator of 5% CO2 at 37 ℃. For the cytotoxicity part, RAW264.7 cells were incubated with compounds or the media (0.125% DMSO in DMEM containing 10% FBS) for 24h, respectively. CCK-8 reagents (20 μL per well) were added and the OD values were collected after 1h incubation at 450 nm (650 nm calibration) by a microplate reader (Molecular Devices, Sunnyvale, CA, USA). For the anti-inflammatory activity assay, RAW264.7 cells were incubated with compounds or the media (0.125% DMSO in DMEM containing 10% FBS), and then cells were primed with LPS (1 μg/mL) for 24 h. The supernatants were centrifuged and then measured using the mouse TNF-α ELISA kit. The CC50 and IC50 were estimated using the log (inhibitor) vs. normalized response non-linear fit (Graph Pad Prism 6.0). Dexamethasone was used as a positive control. Cytotoxic activity assay. The cytotoxicity of the compounds was evaluated against the A549, HT-29, SNU-398 and Capan-1 line by the Cell Counting Kit-8 (CCK-8). Briefly, the cells were seeded into 96-well plates and grown for 24h. The cells were then treated with increasing concentrations of compounds and regenerated for further 72h. At the end of the


Page 21 of 27 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Page 21 exposure time, 10 μL CCK8 (Dojindo, Kumamoto, Japan) was added to each well. The plates then were kept in an incubator for 4h and measured at 450 nm using multi-well spectrophotometer (SpectraMax, Molecular Devices, USA). The inhibition rate was calculated as (1 − A450 treated/A450 control) × 100%.The cytotoxicity of the compounds was expressed as an IC50, determined by the logit method.37 Taxol was used as a positive control. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/ acs.joc.xxx. The crystallographic data of 1; details of TDDFT-ECD calculations for compounds 1, 2, 4 and 6; HRESIMS, UV, IR, NMR and ECD spectra of compounds 1–3; HRESIMS, IR, NMR and ECD spectra of compound 4; HRESIMS, IR and NMR spectra of compound 5; 1H- and 13

C-NMR spectra of compound 6 and its acetylated derivative 6a (PDF)

Crystal data for 1 in CIF format (CIF) AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] (L.-F. Liang) *E-mail: [email protected] (W. Tang) *E-mail: [email protected] (Y.-W. Guo) ORCID Wei Tang: 0000-0002-2662-217X Lin-Fu Liang: 0000-0002-7453-5572 Yue-Wei Guo: 0000-0003-0413-2070 Author Contributions ⊥

These two authors contributed equally.



Page 22 of 27

Page 22 The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest. ACKNOWLEDGEMENTS This research work was financially supported by the National Key Research and Development Program of China (No. 2018YFC0310903), the Drug Innovation Major Project (No. 2018ZX09711-001-001-009), the National Natural Science Foundation of China (Nos. 81520108028, 21672230, 41876194, 41506187, 81603022), the NSFC-Shandong Joint Fund for Marine Science Research Centers (No. U1606403), the SKLDR/SIMM Projects (SIMM 1705ZZ-01), and financial support of Syngenta-SIMM-PhD Studentship Project. We are also grateful to Prof. Tibor Kurtán of University of Debrecen for his helpful discussions about TDDFT-ECD calculations. REFERENCES (1)

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Rare Cembranoids from Chinese Soft Coral Sarcophyton ehrenbergi

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