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Article

Novel Caryophyllane-Related Sesquiterpenoids with Anti-Inflammatory Activity from Rumphella antipathes (Linnaeus, 1758)

by
Yu-Chia Chang
1,†,
Chih-Chao Chiang
2,†,
Yuan-Shiun Chang
3,
Jih-Jung Chen
4,
Wei-Hsien Wang
5,
Lee-Shing Fang
5,6,7,
Hsu-Ming Chung
8,*,
Tsong-Long Hwang
1,9,10,11,12,* and
Ping-Jyun Sung
5,13,14,15,16,*
1
Research Center for Chinese Herbal Medicine, Graduate Institute of Healthy Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333324, Taiwan
2
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
3
Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University, Taichung 404333, Taiwan
4
Faculty of Pharmacy, School of Pharmaceutical Sciences, National Yang-Ming University, Taipei 112304, Taiwan
5
Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-sen University, Kaohsiung 804201, Taiwan
6
Center for Environmental Toxin and Emerging-Contaminant Research, Cheng Shiu University, Kaohsiung 833301, Taiwan
7
Super Micro Mass Research and Technology Center, Cheng Shiu University, Kaohsiung 833301, Taiwan
8
Department of Applied Chemistry, College of Science, National Pingtung University, Pingtung 900393, Taiwan
9
Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
10
Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan
11
Department of Chemical Engineering, College of Environment and Resources, Ming Chi University of Technology, New Taipei City 243303, Taiwan
12
Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333324, Taiwan
13
National Museum of Marine Biology and Aquarium, Pingtung 944401, Taiwan
14
Graduate Institute of Marine Biology, College of Marine Sciences, National Dong Hwa University, Pingtung 944401, Taiwan
15
Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 404394, Taiwan
16
Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
 
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*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Mar. Drugs 2020, 18(11), 554; https://doi.org/10.3390/md18110554
Submission received: 21 September 2020 / Revised: 30 October 2020 / Accepted: 2 November 2020 / Published: 6 November 2020
(This article belongs to the Special Issue Reef Cnidaria and Porifera as Sources of Bioactive Secondary Metabolites—Honoring the 70th Birthday of Professor Yang-Chang Wu)
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Abstract

:
Two previously undescribed caryophyllane-related sesquiterpenoids, antipacids A (1) and B (2), with a novel bicyclo[5.2.0] core skeleton, and known compound clovane-2β,9α-diol (3), along with rumphellolide L (4), an esterified product of 1 and 3, were isolated from the organic extract of octocoral Rumphella antipathes. Their structures, including the absolute configurations were elucidated by spectroscopic and chemical experiments. In vivo anti-inflammatory activity analysis indicated that antipacid B (2) inhibited the generation of superoxide anions and the release of elastase by human neutrophils, with IC50 values of 11.22 and 23.53 μM, respectively, while rumphellolide L (4) suppressed the release of elastase with an IC50 value of 7.63 μM.

1. Introduction

Rumphella (family Gorgoniidae) is a genus of soft coral consisting of four species, R. aggregata, R. antipathes, R. suffruticosa, and R. torta, the center of marine diversity of this genus being found in the Indo-Pacific Ocean. Corals were described by Shi-Zhen Li in his ancient herbal Compendium of Chinese Materia Medica, published in 1596, as “sweet, neutral and non-toxic; used to remove eye vision obstruction; clear abiding static blood; blow the powder to nose to stop nose bleeding; brighten the eye and calm the spirit; stop epileptic seizure; apply to the eye to improve floater.” Previous studies showed that the Rumphella genus exhibited extensive bioactivities, including antiproliferative [1], cytotoxic [2,3,4], antifungal [5], antibacterial [6,7,8,9], and anti-inflammatory [10,11,12,13,14,15,16,17,18] activities. Studies of the chemical constituents of octocorals of the Rumphella genus have led to the isolation of a series of compounds, including caryophyllanes [2,6,7,8,9,10,11,12,16,17,18,19,20,21,22], clovanes [13,14,15,23], steroids [3,4,5,24,25], glycerols [5], and fatty acids and lipids [25,26,27,28,29]. Our continuing studies of the constituents of the same extract from R. antipathes (Figure 1) resulted in the isolation of two novel caryophyllane-related sesquiterpenoids, antipacids A (1) and B (2), featuring a bicyclo[5.2.0] carbon core; a known sesquiterpenoid, clovane-2β,9α-diol (3); and rumphellolide L (4), an esterified product of 1 and 3 (Figure 1). This paper describes the isolation, structure determination, biosynthetic pathway analysis, and anti-inflammatory properties of sesquiterpenoids 1–4.

2. Results and Discussion

Antipacid A (1) was obtained as a colorless colloid, showing an electrospray ionization mass spectrum (ESIMS) quasimolecular ion peak at m/z 253, and was found to have the molecular formula C15H24O3 by analysis of 13C and 1H NMR data (Table 1); this conclusion was confirmed by a positive- mode high-resolution-ESIMS ([+]-HRESIMS) peak at m/z 253.1792 [M + H]+ (calcd. for C15H24O3 + H, 253.1789), with four indexes of hydrogen deficiency. The IR spectrum showed absorption bands at 3600–2400 (carboxyl group) and 1708 cm−1 (ketonic carbonyl). From the 13C NMR data of 1 (Table 1), ketonic (δC 212.8, C-4) and carboxyl (δC 179.1, C-5) groups were deemed present. Thus, 1 was identified as a bicyclic compound. 1H–1H correlation spectroscopy (COSY) enabled identification of two spin systems, H2-10/H-9/H-1/H2-2/H2-3 and H2-6/H2-7 (Figure 2). These findings, together with the 2J- and 3J-1H–13C long-range correlations between protons and non-protonated carbons, such as H2-3, H2-12/C-4; H2-6, H2-7/C-5; H2-6, H2-7, H-9, H2-10, H2-12, H3-13/C-8; and H-1, H2-10, H3-14, H3-15/C-11 in the heteronuclear multiple-bond coherence (HMBC) experiment (Figure 2), permitted elucidation of the main carbon skeleton of 1.
The relative configuration of 1 was assigned from the results of a nuclear Overhauser effect spectroscopy (NOESY) experiment (Figure 2) and vicinal coupling constants. The trans geometries of H-9 (δH 1.87) and H-1 (δH 1.77) were indicated by a large coupling constant (J = 10.4 Hz) between these two ring juncture protons, and H-9 and H-1 were α- and β-oriented, respectively. H-1 exhibited a correlation with H3-13, setting Me-13 at C-8 on the β face. Based on the above findings, the stereogenic carbons of 1 were elucidated as (1R*,8S*,9S*). Antipacids A (1) and B (2) were isolated along with natural products rumphellaone A, a novel 4,5-seco-caryophyllane [2], and (8R,9R)-isocaryolane-8,9-diol [21,30] (the numbering system used in reference [30] was different to that in this study) from the same target organism, R. antipathes [2,21]. The structures, including the absolute configurations, of rumphellaone A [31,32,33] and (8R,9R)-isocaryolane-8,9-diol [30], were confirmed by synthetic methods. Based on these findings and previous studies [2,6,7,8,9,10,11,12,16,17,18,19,20,21,22], all marine-origin naturally occurring caryophyllane-type sesquiterpenoids have the H-9 trans to H-1, which are assigned as α- and β-oriented, respectively. Therefore, it is reasonable on biogenetic grounds to suggest that 1 and 2 have the same absolute configuration as rumphellaone A and (8R,9R)-isocaryolane-8,9-diol, tentatively, and the configurations of the stereogenic carbons of 1 can be elucidated as (1R,8S,9S) (Supplementary Materials, Figures S1–S7).
Antipacid B (2) was isolated as a colorless colloid that showed a sodiated adduct ion peak in (+)-HRESIMS at m/z 261.1468 [M + Na]+, which accounted for the molecular formula, C14H22O3 (calcd. for C14H22O3 + Na, 261.1467), with 4 degrees of unsaturation. The spectroscopic data of 2 resembled those of 1 (Table 1). The one-dimensional (1D) and two-dimensional (2D) NMR spectra revealed that the signals corresponding to the propanoic acid moiety in 1 were replaced by those of an acetic acid in 2 (Figure 3). Therefore, 2 was assigned as having a structure with the same stereochemistry as 1 because of the stereogenic carbons that 2 had in common with 1 by correlations observed in the NOESY spectrum (Figure 3); therefore, the configurations of the stereogenic carbons of 2 were elucidated as (1R,8S,9S) (Supplementary Materials, Figures S8–S14).
Compound 3 was identified by comparison of its spectroscopic data with those of clovane-2β,9α-diol, which had been previously isolated from terrestrial plants Dipterocarpus pilosus [34], Salvia canariensis [35], Viguiera excelsa [36], Viguiera linearis [37], and Sindora sumatrana [38]. This was the first occasion in which this metabolite was obtained from a marine source. Clovane 3 was treated with (R)-(–)- and (S)-(+)-MTPA chloride to yield (S)- and (R)-MTPA esters 3a and 3b, respectively. A comparison of the 1H NMR chemical shifts of 3a and 3b (Δδ values shown in Figure 4) led to the assignment of the S-configuration at C-2 (Supplementary Materials, Figures S15–S16). Therefore, the absolute configurations of the stereogenic centers of 3 were determined as (1S,2S,5S,8R,9R).
Rumphellolide L (4) was isolated as a colorless colloid that showed a sodiated adduct ion peak [M + Na]+ at m/z 495.3447 in (+)-HRESIMS. The result revealed that this compound had a molecular formula of C30H48O4 (calcd. for C30H48O4 + Na, 495.3450), with 7 degrees of unsaturation. Strong bands at 3485, 1731, and 1704 cm−1 in the IR spectrum indicated the presence of hydroxy, ester, and ketonic groups. The 13C NMR and distortionless enhancement by polarization transfer (DEPT) spectra revealed that 4 had 30 carbons (Table 2), including six methyls, twelve methylenes, five methines (including two oxymethines), five sp3 quaternary carbons, an ester carbonyl, and a ketonic carbonyl. Therefore, 4 was identified as having five rings.
From the 1H–1H COSY spectrum, the data differentiated the spin systems H2-10/H-9/H-1/H2-2/H2-3, H2-6/H2-7, H-2’/H2-3´, H-5´/H2-6´/H2-7´, and H-9´/H2-10´/H2-11´ (Figure 5), and these findings together with the results of key HMBC correlations shown in Figure 5 confirmed the carbon skeleton of 4. An HMBC correlation between H-2´ (δH 4.83), an oxymethine proton, and the C-5 ester carbonyl carbon (δC 173.6) was found, which proved the existence of an ester linkage in 4. It was found that the NMR data were similar to those of 1 and 3, and this compound was proven to be the dehydrated product of 1 and 3. Due to the absolute configurations of 1 and 3 having been determined, the absolute configurations of the stereogenic carbons of 4 were assigned as (1R,8S,9S,1´S,2´S,5´S,8´R,9´R) (Supplementary Materials, Figures S17–S23).
The proposed biogenetic pathway of sesquiterpenoids 1–4 is outlined in Scheme 1. The ring- opening reaction might be rationally derived from (8R,9R)-isocaryolane-8,9-diol [30] (the numbering system used in reference [30] was different to that in this study), which had also been isolated from R. antipathes [21], and might subsequently, under oxidation, produce the carbon skeletons of 1 and 2.
The in vitro anti-inflammatory effects of 1–4 were assessed (Table 3). Antipacid B (2) displayed inhibitory effects on the generation of superoxide anions and the release of elastase by human neutrophils (IC50 = 11.22 and 23.53 μM, respectively). Antipacid A (1) did not show activity, implying that the presence of a large substituent at C-8 weakens the activity in comparison with the structure and anti-inflammatory activities of 2. Although 1 and 3 were not active, rumphellolide L (4), the dehydrated product of 1 and 3 with esterification, showed activity in inhibiting the release of elastase (IC50 = 7.63 μM).

3. Materials and Methods

3.1. General Experimental Procedures

Optical rotations were recorded on a JASCO-P1010 polarimeter (Japan Spectroscopic Corporation, Tokyo, Japan). IR spectra were obtained on a Varian Diglab FTS 1000 FT-IR spectrometer (Varian Inc., Palo Alto, CA, USA). NMR spectra were recorded on a Varian Mercury Plus 400 spectrometer (400 MHz for 1H and 100 MHz for 13C) (Varian Inc.) using the residual CHCl3 (δH 7.26 ppm) and CDCl3 (δC 77.1 ppm) signals as internal references for 1H and 13C NMR, respectively.
Chemical shifts are shown in δ (ppm) and coupling constants (J) are given in Hz. ESIMS and HRESIMS data were recorded using a Bruker APEX II FTMS system (Bremen, Germany). Silica gel (230–400 mesh, Merck, Darmstadt, Germany) was used for column chromatography. Thin-layer chromatography (TLC) was performed on plates precoated with Kieselgel 60 F254 (0.25-mm-thick, Merck), then sprayed with 10% H2SO4 solution followed by heating to visualize the spots. Normal-phase HPLC (NP-HPLC) (Hitachi L-7100 series using a L-7455 photodiode array detector, Hitachi Ltd., Tokyo, Japan; and a semi-preparative Hibar 250 mm × 10 mm, LiChrospher Si 60, 5 μm column, Merck) was employed.

3.2. Animal Material

The octocoral R. antipathes (Linnaeus, 1758) was collected by hand by self-contained underwater breathing apparatus (SCUBA) divers off the coast of South Taiwan in May 2004. The samples were stored in a −20 °C freezer until used for extraction. Identification of the species of this organism was performed by comparison as described in previous studies [39,40]. A voucher specimen (no.: NMMBA-TWGC-010) was deposited in the National Museum of Marine Biology and Aquarium, Taiwan.

3.3. Extraction and Isolation

R. antipathes (wet/dry weight = 402/144 g) was sliced and then extracted with a solvent mixture of MeOH and dichloromethane (DCM) (1:1). The extract was partitioned between ethyl acetate (EtOAc) and H2O. The EtOAc layer (1.23 g) was then applied on silica gel column and eluted with gradients of hexanes/EtOAc (from 25:1 to 100% EtOAc) to furnish 29 subfractions. Fraction 18 was purified by NP-HPLC using a solvent mixture of n-hexane/EtOAc (5:1; at a flow rate = 3.0 mL/min) to yield 4 (3.5 mg, 5:1). Fraction 22 was separated by NP-HPLC using a mixture of DCM and EtOAc (10:1; at a flow rate = 5.0 mL/min) to afford 2 (3.5 mg). Fraction 24 was separated by NP-HPLC using a mixture of n-hexane and EtOAc (1:1; at a flow rate = 5.0 mL/min) to afford 1 (5.8 mg) and 3 (60.1 mg), respectively.
Antipacid A (1): Colorless colloid; [α]25D −9.2 (c 0.29, CHCl3); IR (neat) νmax 3600−2400 (broad), 1708 cm−1; 1H and 13C NMR data, see Table 1; ESIMS: m/z 253 [M + H]+; HRESIMS: m/z 253.1792 [M + H]+ (calcd. for C15H24O3 + H, 253.1789).
Antipacid B (2): Colorless colloid; [α]25D −9.4 (c 0.18, CHCl3); IR (neat) νmax 3600−2600 (broad), 1710 cm−1; 1H and 13C NMR data, see Table 1; ESIMS: m/z 261 [M + Na]+; HRESIMS: m/z 261.1468 [M + Na]+ (calcd. for C14H22O3 + Na, 261.1467).
Clovane-2β,9α-diol (3): Amorphous powder; [α]23D +3.5 (c 1.82, CHCl3) (ref. [38] [α] D +3.19 (c 2.27, CHCl3)); IR (neat) νmax 3378 cm−1; 1H (400 MHz, CDCl3) and 13C (100 MHz, CDCl3) NMR data were found to be in complete agreement with a previous report [37]; ESIMS: m/z 261 [M + Na]+.
Rumphellolide L (4): Colorless colloid; [α]25D −7.5 (c 0.18, CHCl3); IR (neat) νmax 3485, 1731, 1704 cm−1; 1H and 13C NMR data, see Table 2; ESIMS: m/z 495 [M + Na]+; HRESIMS: m/z 495.3447 [M + Na]+ (calcd. for C30H48O4 + Na, 495.3450).

3.4. (S)- and (R)-MTPA Esters of 3

To a solution of 3 (10.0 mg) in pyridine (0.4 mL) (−)-α-methoxy-α-(trifluoromethyl)-phenylacetyl (MTPA) chloride was added (25.0 μL) at 25 °C for 4−5 h. The mixture was dried and purified by a silica gel column with n-hexane/EtOAc (10:1) to give (S)-MTPA ester 3a (8.5 mg). The (R)-MTPA ester 3b (0.2 mg) was prepared from (+)-MTPA chloride by the same method (10 mg compound 3 was used). Selected Δδ values are shown in Figure 4.

3.5. Superoxide Anion Generation and Elastase Release by Human Neutrophils

The proinflammatory suppression assay was employed to assess the activities of isolated compounds 1–4 against the generation of superoxide anions and the release of elastase by human neutrophils according to the protocols described in the literature [41].

4. Conclusions

The current work illustrated the anti-neutrophilic inflammatory properties of caryophyllane-related sesquiterpenoids, and two metabolites with novel structures, antipacids A and B (1 and 2), clovane-2β,9α-diol (3), and rumphellolide L (4), an esterified product of 1 and 3, were isolated from R. antipathes. Compound 2 displayed inhibitory effects on the generation of superoxide anions and the release of elastase, and 4 showed activity in suppressing the release of elastase. These results indicated a structural-dependent specificity of C-8 in 1, 2, and 4 in neutrophilic targets, which will motivate future research examining this specificity, as well as clarify the molecular mechanisms of the active leads.

Supplementary Materials

The following are available online at https://www.mdpi.com/1660-3397/18/11/554/s1, Figure S1: HRESIMS spectrum of 1; Figures S2–S7: 1H NMR (400 MHz), 13C NMR (100 MHz), HMQC, 1H-1H COSY, HMBC and NOESY Spectrum of 1 in CDCl3; Figure S8: HRESIMS spectrum of 2; Figures S9–S14: 1H NMR (400 MHz), 13C NMR (100 MHz), HMQC, 1H-1H COSY, HMBC and NOESY Spectrum of 2 in CDCl3; Figure S15: 1H NMR (S)-MTPA ester of 3 in CDCl3; Figure S16: 1H NMR (R)-MTPA ester of 3 in CDCl3; Figure S17: HRESIMS spectrum of 4; Figures S18–S23: 1H NMR (400 MHz), 13C NMR (100 MHz), HMQC, 1H-1H COSY, HMBC and NOESY Spectrum of 4 in CDCl3.

Author Contributions

Conceptualization, H.-M.C., T.-L.H., and P.-J.S.; investigation, Y.-C.C., C.-C.C., Y.-S.C., J.-J.C., W.-H.W., L.-S.F., and H.-M.C.; writing—original draft preparation, Y.-C.C., H.-M.C., and P.-J.S.; writing—review and editing, Y.-C.C., H.-M.C., T.-L.H., and P.-J.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by grants from the NMMBA; and the Ministry of Science and Technology, Taiwan (Grant Nos: MOST 107-2320-B-291-001-MY3 and 109-2320-B-291-001-MY3) awarded to P.-J. Sung.

Acknowledgments

This research was supported by grants from the National Museum of Marine Biology and Aquarium; and the Ministry of Science and Technology (Grant Nos MOST 106-2320-B-291-001-MY3, 107-2320-B-291-001-MY3, and 109-2320-B-291-001-MY3), Taiwan, awarded to P.-J.S.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Nourry, M.; Urvois, A.P.; Tomasoni, C.; Biard, J.F.; Verbist, J.F.; Roussakis, C. Antiproliferative effects of a product isolated from the gorgonian Rumphella aggregata. Anticancer. Res. 1999, 19, 1881–1885. [Google Scholar]
  2. Chung, H.-M.; Chen, Y.-H.; Lin, M.-R.; Su, J.-H.; Wang, W.-H.; Sung, P.-J. Rumphellaone A, a novel caryophyllane-related derivative from the gorgonian coral Rumphella antipathes. Tetrahedron Lett. 2010, 51, 6025–6027. [Google Scholar] [CrossRef]
  3. Liu, C.-X.; Li, P.-L.; Tang, X.-L.; Li, G.-Q. Studies on chemical constituents of the South China Sea gorgonian Rumphella aggregata. Chin. J. Mar. Drugs 2012, 31, 5–10. [Google Scholar]
  4. Yin, F.-Z.; Yang, M.; Li, S.-W.; Wu, M.-J.; Huan, X.-J.; Miu, Z.-H.; Wang, H.; Guo, Y.-W. Two new hydroperoxy steroids from the South China Sea gorgonian Rumphella sp. Steroids 2020, 155, 108558. [Google Scholar] [CrossRef] [PubMed]
  5. Alarif, W.M. Glycerol Derivatives and Steroid Constituents from the Soft Coral Rumphella aggregata (Gorgoniidae) of Saudi Red Sea Water. J. King Abdulaziz Univ. Sci. 2012, 23, 57–67. [Google Scholar] [CrossRef]
  6. Sung, P.-J.; Chuang, L.-F.; Kuo, J.; Chen, J.-J.; Fan, T.-Y.; Li, J.-J.; Fang, L.-S.; Wang, W.-H. Rumphellolides A–F, six new caryophyllane-related derivatives from the Formosan gorgonian coral Rumphella antipathes. Chem. Pharm. Bull. 2007, 55, 1296–1301. [Google Scholar] [CrossRef] [Green Version]
  7. Sung, P.-J.; Chuang, L.-F.; Kuo, J.; Fan, T.-Y.; Hu, W.-P. Rumphellatin A, the first chloride-containing caryophyllane-type norsesquiterpenoid from Rumphella antipathes. Tetrahedron Lett. 2007, 48, 3987–3989. [Google Scholar] [CrossRef]
  8. Sung, P.-J.; Chuang, L.-F.; Hu, W.-P. Rumphellatins B and C, two new caryophyllane-type hemiketal norsesquiterpenoids from the Formosan gorgonian coral Rumphella antipathes. Bull. Chem. Soc. Jpn. 2007, 80, 2395–2399. [Google Scholar] [CrossRef]
  9. Chuang, L.-F.; Fan, T.-Y.; Li, J.-J.; Kuo, J.; Fang, L.-S.; Wang, W.-H.; Sung, P.-J. Isokobusone, a caryophyllane-type norsesquiterpenoid from the gorgonian coral Rumphella antipathes (Gorgoniidae). Platax 2007, 4, 61–67. [Google Scholar]
  10. Sung, P.-J.; Su, Y.-D.; Hwang, T.-L.; Chuang, L.-F.; Chen, J.-J.; Li, J.-J.; Fang, L.-S.; Wang, W.-H. Rumphellatin D, a novel chlorinated caryophyllane from gorgonian coral Rumphella antipathes. Chem. Lett. 2008, 37, 1244–1245. [Google Scholar] [CrossRef]
  11. Hwang, T.-L.; Su, Y.-D.; Hu, W.-P.; Chuang, L.-F.; Sung, P.-J. Rumphellolide H, a new natural caryophyllane from the gorgonian Rumphella antipathes. Heterocycles 2009, 78, 1563–1567. [Google Scholar]
  12. Sung, P.-J.; Su, Y.-D.; Hwang, T.-L.; Chuang, L.-F.; Chung, H.-M.; Chen, J.-J.; Li, J.-J.; Fang, L.-S.; Wang, W.-H. Rumphellolide I, a novel caryophyllane-related tetrahydropyran norsesquiterpenoid from gorgonian coral Rumphella antipathes. Chem. Lett. 2009, 38, 282–283. [Google Scholar] [CrossRef]
  13. Chung, H.-M.; Hwang, T.-L.; Chen, Y.-H.; Su, J.-H.; Lu, M.-C.; Chen, J.-J.; Li, J.-J.; Fang, L.-S.; Wang, W.-H.; Sung, P.-J. Rumphellclovane B, a novel clovane analogue from the gorgonian coral Rumphella antipathes. Bull. Chem. Soc. Jpn. 2011, 84, 119–121. [Google Scholar] [CrossRef]
  14. Chung, H.-M.; Su, J.-H.; Hwang, T.-L.; Li, J.-J.; Chen, J.-J.; Chen, Y.-H.; Chang, Y.-C.; Su, Y.-D.; Chen, Y.-H.; Fang, L.-S.; et al. Rumphellclovanes C–E, new clovane-type sesquiterpenoids from the gorgonian coral Rumphella antipathes. Tetrahedron 2013, 69, 2740–2744. [Google Scholar] [CrossRef]
  15. Chung, H.-M.; Wang, W.-H.; Hwang, T.-L.; Wu, Y.-C.; Sung, P.-J. Natural clovanes from the gorgonian coral Rumphella antipathes. Nat. Prod. Commun. 2013, 8, 1037–1040. [Google Scholar]
  16. Chung, H.-M.; Wang, W.-H.; Hwang, T.-L.; Li, J.-J.; Fang, L.-S.; Wu, Y.-C.; Sung, P.-J. Rumphellaones B and C, new 4,5-seco-caryophyllane sesquiterpenoids from Rumphella antipathes. Molecules 2014, 19, 12320. [Google Scholar] [CrossRef] [Green Version]
  17. Chung, H.-M.; Wang, W.-H.; Hwang, T.-L.; Fang, L.-S.; Wen, Z.-H.; Chen, J.-J.; Wu, Y.-C.; Sung, P.-J. Rumphellaoic acid A, a novel sesquiterpenoid from the Formosan gorgonian coral Rumphella antipathes. Mar. Drugs 2014, 12, 5856. [Google Scholar] [CrossRef] [Green Version]
  18. Chung, H.-M.; Wang, W.-H.; Hwang, T.-L.; Chen, J.-J.; Fang, L.-S.; Wen, Z.-H.; Wang, Y.-B.; Wu, Y.-C.; Sung, P.-J. Rumphellols A and B, New Caryophyllene Sesquiterpenoids from a Formosan Gorgonian Coral, Rumphella antipathies. Int. J. Mol. Sci. 2014, 15, 15679. [Google Scholar] [CrossRef] [Green Version]
  19. Chuang, L.-F.; Fan, T.-Y.; Li, J.-J.; Sung, P.-J. Kobusone: Occurrence of a norsesquiterpenoid in the gorgonian coral Rumphella antipathes (Gorgoniidae). Biochem. Syst. Ecol. 2007, 35, 470–471. [Google Scholar] [CrossRef]
  20. Sung, P.-J.; Chuang, L.-F.; Fan, T.-Y.; Chou, H.-N.; Kuo, J.; Fang, L.-S.; Wang, W.-H. Rumphellolide G, a new caryophyllane-type tetrahydropyran norsesquiterpenoid from the gorgonian coral Rumphella antipathes (Gorgoniidae). Chem. Lett. 2007, 36, 1322–1323. [Google Scholar] [CrossRef] [Green Version]
  21. Chung, H.-M.; Wang, W.-H.; Hwang, T.-L.; Wu, Y.-C.; Sung, P.-J. Natural caryophyllane sesquiterpenoids from Rumphella antipathes. Nat. Prod. Commun. 2015, 10, 835–838. [Google Scholar]
  22. Lin, C.-C.; Chung, H.-M.; Su, Y.-D.; Peng, B.-R.; Wang, W.-H.; Hwang, T.-L.; Wu, Y.-C.; Sung, P.-J. Rumphellolide J, an ester of 4β,9β-epoxycaryophyllan-5-ol and rumphellaoic acid A, from the gorgonian Rumphella antipathes. Nat. Prod. Commun. 2017, 12, 1835–1837. [Google Scholar]
  23. Chung, H.-M.; Chen, Y.-H.; Hwang, T.-L.; Chuang, L.-F.; Wang, W.-H.; Sung, P.-J. Rumphellclovane A, a novel clovane-related sesquiterpenoid from the gorgonian coral Rumphella antipathes. Tetrahedron Lett. 2010, 51, 2734–2736. [Google Scholar] [CrossRef]
  24. Ciereszko, L.S.; Johnson, M.A.; Schmidt, R.W.; Koons, C.B. Chemistry of coelenterates—VI. Occurrence of gorgosterol, A C30 sterol, in coelenterates and their zooxanthellae. Comp. Biochem. Physiol. 1968, 24, 899–904. [Google Scholar] [CrossRef]
  25. Kader, N.A.A.; Habib, E.S.; Hasanean, H.A.; Ahmed, S.A.E.; Abdelhameed, R.F.; Ibrahim, A.K. B:Chemical Investigation of the Red Sea Gorgonian Coral Rumphella torta. Rec. Pharm. Biomed. Sci. 2020, 4, 16–24. [Google Scholar]
  26. Joseph, J.D. Lipid composition of marine and estuarine invertebrates: Porifera and cnidaria. Prog. Lipid Res. 1979, 18, 1–30. [Google Scholar] [CrossRef]
  27. Urvois, P.A.; Barnathan, G.; Biard, J.F.; Debitus, C.; Verbist, J.F. Fatty acid composition of the New Caledonian gorgonian Rumphella aggregata: Identification of 9-methyl-6,9-heptadecadienoic acid. In Proceedings of Marine Lipids, Brest, France, 19–20 November 1988; Baudimant, G., Guézennec, J., Roy, P., Samain, J.F., Eds.; IFREMER: Plouzańe, France, 2000; pp. 44–49. [Google Scholar]
  28. Bergé, J.-P.; Barnathan, G. Fatty Acids from Lipids of Marine Organisms: Molecular Biodiversity, Roles as Biomarkers, Biologically Active Compounds, and Economical Aspects. Aestivation 2005, 96, 49–125. [Google Scholar]
  29. Imbs, A.B.; Demidkova, D.A.; Dautova, T.N.; Latyshev, N.A. Fatty Acid Biomarkers of Symbionts and Unusual Inhibition of Tetracosapolyenoic Acid Biosynthesis in Corals (Octocorallia). Lipids 2008, 44, 325–335. [Google Scholar] [CrossRef] [PubMed]
  30. Racero, J.C.; Macías-Sánchez, A.J.; Hernández-Galán, R.; Hitchcock, P.B.; Hanson, J.R.; Collado, I.G. Novel Rearrangement of an Isocaryolane Sesquiterpenoid under Mitsunobu Conditions. J. Org. Chem. 2000, 65, 7786–7791. [Google Scholar] [CrossRef]
  31. Hirokawa, T.; Kuwahara, S. Synthesis of rumphellaone A via epoxy nitrile cyclization. Tetrahedron 2012, 68, 4581–4587. [Google Scholar] [CrossRef]
  32. Ranieri, B.; Obradors, C.; Mato, M.; Echavarren, A.M. Synthesis of Rumphellaone A and Hushinone by a Gold-Catalyzed [2 + 2] Cycloaddition. Org. Lett. 2016, 18, 1614–1617. [Google Scholar] [CrossRef] [Green Version]
  33. Beck, J.C.; Lacker, C.R.; Chapman, L.M.; Reisman, S.E. A modular approach to prepare enantioenriched cyclobutanes: Synthesis of (+)-rumphellaone A. Chem. Sci. 2019, 10, 2315–2319. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Gupta, A.S.; Dev, S. Studies in sesquiterpenes–XLVI. Sesquiterpenes from the oleoresin of Dipterocarpus pilosus: Humulene epoxide-III, caryophyllenol-I and caryophyllenol-II. Tetrahedron 1971, 27, 635–644. [Google Scholar] [CrossRef]
  35. González, A.G.; Fraga, B.M.; Luis, J.G.; Ravelo, A.G. Componentes de la “Salvia canariensis L.”. An. Quim. 1975, 71, 701–705. [Google Scholar]
  36. Delgado, G.; Cárdenas, H.; Peláez, G.; De Vivar, A.R.; Pereda-Miranda, R. Terpenoids From Viguiera excelsa and Viguiera oaxacana. J. Nat. Prod. 1984, 47, 1042–1045. [Google Scholar] [CrossRef]
  37. Delgado, G.; Alvarez, L.; De Vivar, A.R. 15-Hydroxy-acetylerioflorin and other constituents from Viguiera linearis. Phytochem. 1985, 24, 2736–2738. [Google Scholar] [CrossRef]
  38. Heymann, H.; Tezuka, Y.; Kikuchi, T.; Supriyatna, S. Constituents of Sindora sumatrana MIQ. I. Isolation and NMR Spectral Analysis of Sesquiterpenes from the Dried Pods. Chem. Pharm. Bull. 1994, 42, 138–146. [Google Scholar] [CrossRef] [Green Version]
  39. Bayer, F.M. Key to the genera of octocorallia exclusive of Pennatulacea (Coelenterata: Anthozoa), with diagnoses of new taxa. Proc. Biol. Soc. Wash. 1981, 94, 902–947. [Google Scholar]
  40. Dai, C.-F.; Chin, C.-H. Octocoral Fauna of Kenting National Park; Kenting National Park Headquaters: Kenting, Pingtung, Taiwan, 2019; pp. 484–485. [Google Scholar]
  41. Chen, P.-J.; Ko, I.-L.; Lee, C.-L.; Hu, H.-C.; Chang, F.-R.; Wu, Y.-C.; Leu, Y.-L.; Wu, C.-C.; Lin, C.-Y.; Pan, C.-Y.; et al. Targeting allosteric site of AKT by 5,7-dimethoxy-1,4-phenanthrenequinone suppresses neutrophilic inflammation. EBioMedicine 2019, 40, 528–540. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Marinedrugs 18 00554 g001 550
Figure 1. Structures of antipacids A (1) and B (2), clovane-2β,9α-diol (3), and rumphellolide L (4), and an image of Rumphella antipathes.
Figure 1. Structures of antipacids A (1) and B (2), clovane-2β,9α-diol (3), and rumphellolide L (4), and an image of Rumphella antipathes.
Marinedrugs 18 00554 g001
Marinedrugs 18 00554 g002 550
Figure 2. (A) Key COSY (Marinedrugs 18 00554 i001), HMBC (Marinedrugs 18 00554 i002), and (B) NOESY (Marinedrugs 18 00554 i003) correlations of 1.
Figure 2. (A) Key COSY (Marinedrugs 18 00554 i001), HMBC (Marinedrugs 18 00554 i002), and (B) NOESY (Marinedrugs 18 00554 i003) correlations of 1.
Marinedrugs 18 00554 g002
Marinedrugs 18 00554 g003 550
Figure 3. Key COSY (Marinedrugs 18 00554 i004), HMBC (Marinedrugs 18 00554 i005), and NOESY (Marinedrugs 18 00554 i006) correlations of 2.
Figure 3. Key COSY (Marinedrugs 18 00554 i004), HMBC (Marinedrugs 18 00554 i005), and NOESY (Marinedrugs 18 00554 i006) correlations of 2.
Marinedrugs 18 00554 g003
Marinedrugs 18 00554 g004 550
Figure 4. 1H NMR chemical shift differences Δδ (δS–δR) in ppm for the MPTA esters of 3.
Figure 4. 1H NMR chemical shift differences Δδ (δS–δR) in ppm for the MPTA esters of 3.
Marinedrugs 18 00554 g004
Marinedrugs 18 00554 g005 550
Figure 5. Key COSY (Marinedrugs 18 00554 i007) and HMBC (Marinedrugs 18 00554 i008) correlations of 4.
Figure 5. Key COSY (Marinedrugs 18 00554 i007) and HMBC (Marinedrugs 18 00554 i008) correlations of 4.
Marinedrugs 18 00554 g005
Marinedrugs 18 00554 sch001 550
Scheme 1. Plausible biogenetic pathway of 1–4.
Scheme 1. Plausible biogenetic pathway of 1–4.
Marinedrugs 18 00554 sch001
Table
Table 1. 1H (400 MHz, CDCl3) and 13C (100 MHz, CDCl3) NMR data of 1 and 2.
Table 1. 1H (400 MHz, CDCl3) and 13C (100 MHz, CDCl3) NMR data of 1 and 2.
12
C/HδH (J in Hz)δC, TypeδH (J in Hz)δC, Type
11.77 ddd (10.4, 10.4, 3.6)45.3, CH1.81 ddd (10.8, 10.8, 3.6)44.9, CH
2a/b1.70 m; 1.64 m23.7, CH21.71 m; 1.62 m23.7, CH2
3a/b2.48 m; 2.41 m43.8, CH22.49 m43.7, CH2
4-212.8, C-212.5, C
5-179.1, C--
62.27 m29.3, CH2-176.0, C
7a/b1.72 m; 1.53 m36.5, CH22.29 d (13.6); 2.28 d (13.6)44.7, CH2
8-35.0, C-34.9, C
91.87 ddd (10.4, 10.4, 8.0)46.3, CH1.98 ddd (10.8, 10.8, 8.4)46.2, CH
10a/b1.57 dd (10.4, 8.0); 1.49 dd (10.4, 10.4)35.5, CH21.56 dd (10.8, 8.4); 1.48 dd (10.8, 10.8)34.9, CH2
11-34.4, C-33.9, C
12a/b2.35 d (11.2); 2.30 d (11.2)54.8, CH22.60 d (11.2); 2.49 d (11.2)54.1, CH2
130.92 s20.5, CH31.08 s21.2, CH3
141.01 s30.1, CH31.02 s30.1, CH3
151.01 s22.1, CH31.01 s22.1, CH3
Table
Table 2. 1H (400 MHz, CDCl3) and 13C (100 MHz, CDCl3) NMR data for 4.
Table 2. 1H (400 MHz, CDCl3) and 13C (100 MHz, CDCl3) NMR data for 4.
C/HδH (J in Hz)δC, TypeC/HδH (J in Hz)δC, Type
11.77 m45.2, CH1´-44.5, C
21.64 m23.6, CH22´4.83 dd (8.8, 6.0)82.1, CH
3a/b2.48 ddd (12.4, 7.6, 4.0); 2.39 m43.7, CH23´a/b1.78 dd (12.0, 6.0); 1.51 m44.3, CH2
4-212.2, C4´-38.0, C
5-173.6, C5´1.48 m50.3, CH
62.21 t (7.6)29.8, CH26´1.46 m20.8, CH2
71.73 m36.7, CH27´1.40 m33.0, CH2
8-35.1, C8´-34.6, C
91.87 ddd (10.8, 10.8, 8.4)46.4, CH9´3.31 br s74.9, CH
101.54 m35.5, CH210´a/b2.00 m; 1.65 m26.3, CH2
11-34.4, C11´1.58 m27.3, CH2
122.31 s54.9, CH212´a/b1.53 m; 1.01 m35.4, CH2
130.90 s20.5, CH313´1.05 s31.4, CH3
141.02 s30.1, CH314´0.91 s25.3, CH3
151.00 s22.1, CH315´0.94 s28.2, CH3
Table
Table 3. Inhibitory effects of sesquiterpenoids 1–4 on superoxide anion generation and elastase release by human neutrophils in response to N-Formyl-l-methionyl-l-leucyl-l-phenylalanine/ Cytochalasin B (fMLF/CB).
Table 3. Inhibitory effects of sesquiterpenoids 1–4 on superoxide anion generation and elastase release by human neutrophils in response to N-Formyl-l-methionyl-l-leucyl-l-phenylalanine/ Cytochalasin B (fMLF/CB).
Superoxide AnionElastase
CompoundIC50 (μM) aInh % bIC50 (μM) aInh % b
1-11.89 ± 5.13-13.69 ± 2.33 *
211.22-23.53-
3-22.92 ± 4.27 *-35.33 ± 6.40 *
4-19.57 ± 3.69 **7.63-
a Concentration necessary for 50% inhibition (IC50). b Percentage of inhibition (Inh %) at 10 μg/mL. Results are presented as means ± S.E.M (standard error of the mean) (n = 3). * p < 0.05, ** p < 0.01 compared with the control (solvent, dimethyl sulfoxide-DMSO).
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Chang, Y.-C.; Chiang, C.-C.; Chang, Y.-S.; Chen, J.-J.; Wang, W.-H.; Fang, L.-S.; Chung, H.-M.; Hwang, T.-L.; Sung, P.-J. Novel Caryophyllane-Related Sesquiterpenoids with Anti-Inflammatory Activity from Rumphella antipathes (Linnaeus, 1758). Mar. Drugs 2020, 18, 554. https://doi.org/10.3390/md18110554

AMA Style

Chang Y-C, Chiang C-C, Chang Y-S, Chen J-J, Wang W-H, Fang L-S, Chung H-M, Hwang T-L, Sung P-J. Novel Caryophyllane-Related Sesquiterpenoids with Anti-Inflammatory Activity from Rumphella antipathes (Linnaeus, 1758). Marine Drugs. 2020; 18(11):554. https://doi.org/10.3390/md18110554

Chicago/Turabian Style

Chang, Yu-Chia, Chih-Chao Chiang, Yuan-Shiun Chang, Jih-Jung Chen, Wei-Hsien Wang, Lee-Shing Fang, Hsu-Ming Chung, Tsong-Long Hwang, and Ping-Jyun Sung. 2020. "Novel Caryophyllane-Related Sesquiterpenoids with Anti-Inflammatory Activity from Rumphella antipathes (Linnaeus, 1758)" Marine Drugs 18, no. 11: 554. https://doi.org/10.3390/md18110554

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