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Mar. Drugs 2018, 16(9), 339; https://doi.org/10.3390/md16090339

Review
Natural Product Chemistry of Gorgonian Corals of Genus Junceella–Part III
by 1,†, 2,†, 3,4, 5,6, 3, 7,8, 9,10,11,12,*, 13,14,15,16,* and 3,13,16,17,18,*
1
Department of Applied Chemistry, National Pingtung University, Pingtung 900, Taiwan
2
Division of Cardiology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung 802, Taiwan
3
Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan
4
Division of Dentistry, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 813, Taiwan
5
Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 802, Taiwan
6
Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
7
Center for Environmental Toxin and Emerging-Contaminant Research, Cheng Shiu University, Kaohsiung 833, Taiwan
8
Super Micro Mass Research and Technology Center, Cheng Shiu University, Kaohsiung 833, Taiwan
9
Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
10
Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan
11
Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, Graduate Institute of Healthy Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
12
Department of Anaesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
13
Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan
14
Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung 807, Taiwan
15
Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
16
Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 404, Taiwan
17
National Museum of Marine Biology and Aquarium, Pingtung 944, Taiwan
18
Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung 944, Taiwan
*
Correspondence: [email protected] (T.-L.H.); [email protected] (Y.-C.W.); [email protected] (P.-J.S.); Tel.: +886-3-211-8800 (ext. 5523) (T.-L.H.); +886-7-312-1101 (ext. 5347) (Y.-C.W.); +886-8-882-5037 (P.-J.S.); Fax: +886-3-211-8506 (T.-L.H.); +886-7-311-4773 (Y.-C.W.); +886-8-882-5087 (P.-J.S.)
These authors contributed equally to this work.
Received: 28 August 2018 / Accepted: 15 September 2018 / Published: 17 September 2018

Abstract

:
The structures, names, bioactivities, and references of 82 natural products, including 48 new metabolites, purified from the gorgonian corals belonging to the genus Junceella are described in this review. All compounds mentioned in this review were obtained from Junceella fragilis, Junceella gemmacea, Junceella juncea, and Junceella sp., collected from tropical Indo-Pacific Ocean. Some of these compounds exhibited potential biomedical activities.
Keywords:
Junceella; gorgonian; briarane; biomedical activity

1. Introduction

Following previous review articles focused on marine-origin natural products, this review covers the literature from October 2011 to August 2018, and describes 82 natural products (including 48 new metabolites) from gorgonian corals belonging to the genus Junceella (family Ellisellidae) [1,2,3,4]. Extending from previous reviews in 2004 and 2011 [5,6], this review provides structures, names, bioactivities, and references for all compounds including briarane- and norcembrane-type diterpenoids, sterol, and nucleosides. Many of these compounds exhibited interesting bioactivities in vitro, which might indicate a potential for use in biomedical applications. This survey of natural products from Junceella is presented taxonomically according to species.

2. Junceella

2.1. Junceella Fragilis

Eight 8-hydroxybriaranes, including four new compounds, frajunolides P–S (14), and four known metabolites, umbraculolide A (5) [7,8], juncenolide C (6) [9], junceellonoid A (7) [10], and juncin R (8) [11], were isolated from J. fragilis, collected from the waters of Taiwan [12] (Figure 1). The structures of briaranes 14 were established by spectroscopic methods, and determination of the absolute configuration of 1 was completed by X-ray diffraction analysis [12]. At a concentration of 10 μg/mL, briaranes 1 and 2 were found to exert inhibitory activities on elastase release (inhibition rate = 35.6% and 34.1%, respectively) and superoxide anion production (inhibition rate = 32.5 and 28.7%, respectively) by human neutrophils [12].
In 2014, J. fragilis, collected from the South China Sea, was found to contain 12 new briaranes, fragilisinins A–L (920) [13], along with seven known analogues, junceellolides A (21) and B (22) [14], junceol A (23) [15], junceellonoid D (24) [16,17], fragilide C (25) [18], and frajunolides A (26) [19] and E (27) [20] (Figure 2) [13]. The structures of briaranes 920 were determined by spectroscopic methods. Briaranes 1720 were the first iodine-containing briaranes to be isolated. The absolute configuration of briarane 9 was confirmed by single-crystal X-ray diffraction data [13]. Briaranes 13, 14, 18, 21, and 24 showed potent antifouling activities against the settlement of barnacle Balanus amphitrite larvae, with EC50 values of 14.0, 12.6, 11.9, 5.6, and 10.0 μM, respectively [13].
In addition, a new norditerpenoid, fragilolide A (28), 16 new briaranes, fragilolides B–Q (2944), along with two known briaranes, frajunolides H (45) [20] and N (46) [21], and three known norcembranoids, scabrolide D (47) [22], sinuleptolide (48) [23], and 5-epi-sinuleptolide (49) [24,25,26], were obtained from J. fragilis, collected from the inner coral reef around in Hainan Island of China [27] (Figure 3). The structures of metabolites 2844 were determined by spectroscopic methods, including calculated electronic circular dichroism (ECD) data. The structures, including the absolute configurations of briaranes 37 and 46, were further established by single-crystal X-ray diffraction analysis using Flack parameter in this study [27]. Compound 28 featured an unprecedented 4,13- and 7,11-fused tetracyclic norcembranoid [27].
Briarane 45 exhibited cytotoxicity toward Hep G2 (human hepatocellular carcinoma), Huh7 (human hepatocellular carcinoma), SMMC-7721 (human papillomavirus-related endocervical adenocarcinoma), A2780 (human ovarian carcinoma), BGC-823 (human gastric adenocarcinoma), HGC-27 (human gastric carcinoma), MGC-803 (human gastric carcinoma), NCI-H1650 (human bronchoalveolar carcinoma), and PA-1 (human ovarian mixed germ cell tumor) cells with IC50 values 0.89, 16.52, 0.61, 1.18, 2.10, 0.61, 1.97, 6.47, and 0.42 μM, respectively. Briaranes 31, 34, 36, 39, 43, and 46 exerted selective inhibitory effects toward hepatitis B and antigen (HBeAg) in a dose of 10 μM, whereas no activity was observed against the expression of hepatitis B surface antigen (HBsAg) [27].
Moreover, the norcembranoids 28 and 4749 were assayed for their potential inhibitory effects against nitric oxide (NO) production induced by lipopolysaccharides (LPS) (large molecules consisting of lipids and polysaccharide composed of O-antigen joined by chemical bonds), in RAW264.7 cells, and these four compounds exhibited the inhibitory activities with 27.8%, 43.5%, 56.0%, and 57.9% inhibition, respectively, at a dose of 100 μM [27]. In order to explore the mechanism of these NO inhibitors, the expression of the antioxidant response element (ARE) mediated lufiferase and NF-κB was evaluated. Norcembranoids 48 and 49 showed the effects against NF-κB by the inhibitory rates of 25.1% and 28.6% in a dose of 50 μM, respectively. Significant induction of luciferase was observed as the dose of 50 μM for 48 and 49 with 3.8 and 5.6 folds more than that of blank control [27]. The antioxidant capacity of 28 and 4749 were evaluated by the modified 2,2′- azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) radical cation decolorization assay [27].
In 2017, Cheng et al. reported the occurrence of four pairs of chlorinated briarane derivatives, including five new metabolites, 3-deacetylpraelolide (50), 13-α-acetoxy-3-deacetylpraelolide (51), 13-α-acetoxy-2-deacetylpraelolide (52), 13-α-acetoxy-3-deacetyljunceellin (53), 13-α-acetoxy-2- deacetyljunceellin (54), along with three known metabolites, fragilide J (55) [28], 3-deacetyl- junceellin (56), and 2-deacetyljunceellin (57) [29], from J. fragilis, collected off the inner coral reef in Hainan Island, China (Figure 4), although briaranes 56 and 57 were obtained as a pair of inseparable mixture [30].
The structures of briaranes 5054 were elucidated by spectroscopic methods in association with chemical conversion. The absolute configurations of briaranes 50 and 55 were further determined by acetylation of these two compounds to yield the same crystal product and analyses of X-ray crystal data of this compound by Flack parameter further confirmed the absolute configurations of briaranes 50 and 55 [30], although briaranes 56 and 57 existed in an inseparable mixture in CHCl3 at room temperature. Lowering the temperature to 4 °C resulted in the generation of a crystal, while the X-ray diffraction analysis using Flack parameter determined the crystal product to be in accordance with briarane 56. Each pair of the isomers (50/55, 51/52, 53/54, and 56/57) featured by dynamical interconversion through as acetyl migration in 1,2-diol, which was postulated to be generated under the formation of cyclic orthoacetate intermediated. In the mixture of briaranes 56 and 57, increasing temperature gradients resulted in the variation of 56/57 ratio, while the ratio of 56/57 varied from 1:1 to 2:3 at 50 °C [30]. The mixtures of 50/55, 51/52, 53/54, and 56/57 were tested for their inhibitory effects against NO production induced by LPS in RAW264.7 cells and these four components displayed inhibitory activities against NO production with the inhibition rates of 39.4%, 46.4%, 42.7%, and 36.3%, respectively, at a concentration of 50 μM [30].
Two new briaranes, fragilides K (58) and L (59), along with five known chlorinated briaranes, gemmacolides V (60) and X (61) [31], praelolide (62) [7,14,16,32,33,34,35,36,37], and juncins P (63) [35] and ZI (64) [11], were obtained from a Formosan J. fragilis [38] (Figure 5).
Based on spectroscopic methods, the structures of briaranes 58 and 59 were elucidated and the cyclohexane rings in 58 and 59 were found to exist in chair and twist boat conformation, respectively. At a concentration of 10 μM, briaranes 59, 61, and 64 showed anti-inflammatory activity against the expression of pro-inflammatory protein inducible nitric oxide synthase (iNOS) to 49.13%, 36.22%, and 43.33%, respectively, and briaranes 60 and 61 elicited reduction of the pro-inflammatory protein cyclooxygenase-2 (COX-2) to 47.49% and 43.64%, respectively [38].

2.2. Junceella Gemmacea

Four new briaranes, junceellolides M–P (6568), along with seven known briaranes, junceellolides A–D (21,22,69,70) [14] (the structures of briaranes 21 and 22, please see Figure 2), junceellin A (= junceellin) (71) [7,14,16,34,35,36,37,39,40], praelolide (62) [7,14,16,32,33,34,35,36,37], and juncin ZI (64) [11] (the structures of briaranes 62 and 64, please see Figure 5) were isolated from J. gemmacea, collected from the South China Sea [41] (Figure 6). The structures, including the absolute configurations, of new briaranes 6568 were deduced on the basis of spectroscopic analyses, particularly with ECD experiments.

2.3. Junceella Juncea

Five 8-hydroxybriaranes, including a new briarane, (1S*,2S*,8S*,9S*,10S*,11R*,12R*,14S*,17R*)- 11,20-epoxy-14-(3-methylbutanoyl)-2,9,12-triacetoxy-8-hydroxybriar-5(16)-en-18,7-olide (72) along with four known metabolites, gemmacolides A (73) and B (74) [42,43], and juncins H (75) [44] and K (76) [45], were isolated from J. juncea collected from Tuticorin coast of the Indian Ocean (Figure 7) [46]. The structure of briarane 72 was established by spectroscopic data and 72 was found to exhibit activities against the fungi Aspergillus niger, Candida albicans, and Penicillium notatum. Briaranes 73 and 74 displayed activities against the bacteria Bascillus pumilis and Escherichia coli. While the briaranes 75 and 76 showed activities against B. subtilis, B. pumilis, Proteus vulgaris, and E. coli [46].
Furthermore, Chang et al. isolated three new briaranes, juncenlides M–O (7779), from J. juncea, collected in the waters of Taiwan [47] (Figure 8). Structures of new briaranes 7779 were established by spectroscopic methods. Briaranes 78 and 79 showed inhibitory activities against the release of elastase and 79 also exhibited inhibitory activity against the generation of superoxide anon [47].

2.4. Junceella sp.

Three known briaranes, junceellolide A (21) [14], praelolide (62) [7,14,16,32,33,34,35,36,37], and junceellin A (71) [7,14,16,34,35,36,37,39,40], (the structures of briaranes 21, 62, and 71, please see Figure 2, Figure 5, and Figure 6, respectively), and a known sterol, 5α,8α-epidioxy-24(ξ)-methylcholesta-6,22-dien-3β-ol (80) [48] (Figure 9), were obtained from the ethanol extract of a gorgonian coral identified as Junceella sp., collected off the Vietnam Thu Island in May 2010 [49]. However, by assuming that enantiomeric series for sterols, the configuration at C-24 in 80 should be assigned as S*-form on the basis of the 13C NMR chemical shift of C-24 and C-28 [50]. Furthermore, two nucleosides, deoxyadenosine (81) and deoxythymidine (82) [51,52], were obtained from aqueous solution of this specimen. Structures of all isolates were established using spectroscopic data (Figure 9) [49].
In the cytotoxic activity test, briaranes 71 and sterol 80 exhibited weak cytotoxicity toward the THP-1 (human acute monocytic leukemia) tumor cells with IC50 values 55.4 and 130 μM, respectively. Sterol 80 also possessed weak clonogenic activity with INCC50 53.3 μM toward THP-1. Moreover, sterol 80 produced an inhibition zone 12 mm in diameter against Bacillus subtilis. Briarane 62 inhibited weakly Candida albicans. Briaranes 21 and 71 and sterol 80 inhibited weakly Vibrio parahaemolyticus [49].

3. Conclusions

The natural products obtained from gorgonian corals belonging to the genus Junceella complied in this review indicated that the terpenoid derivatives, particularly briarane-type diterpenoids, are the major components of the natural products isolated. Of the 82 metabolites, 75 compounds (91.5%) are briarane-type diterpenoids. Of the briaranes, 50 compounds are halogenated (50/75 = 66.7%). Briarane-type natural products are a large family of natural products that are only isolated from marine organisms and the compounds of this type were suggested originally synthesized from the 3,8-cyclization of cembranoids by the host corals and not by their zooxanthellae [37,53,54]. Briarane-type diterpenoids continue to attract attention owing to their complex structures and potential biomedical activities.
Studies on the novel substances for biomedical use from the marine invertebrates originally distributed in the Indo-Pacific Ocean will play an important role in natural product research [55]. Marine natural products currently under clinical trials are limited. Based on the potential medical use and complex structures, it is very difficult to obtain enough material for further studies by chemical methods. How to make the best use of aquaculture technology to enhance in captivity mass production of raw materials needed for extraction of biomedical use marine natural compounds is very important in the future [56].

Author Contributions

H.-M.C. and Y.-C.W. contributed in terms of writing the manuscript. T.-L., Y.-C.W., and P.-J.S. conceived and designed the format of the manuscript. All the authors contributed in terms of critical reading and discussion of the manuscript.

Funding

This research was supported by grants from the National Museum of Marine Biology and Aquarium; the National Dong Hwa University; and the Ministry of Science and Technology (Grant Nos. MOST 104-2320- B-291-001-MY3, 106-2320-B-291-001-MY3, and 107-2320-B-291-001-MY3), Taiwan, awarded to, Ping-Jyun Sung.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Structures of frajunolides P–S (14), umbraculolide A (5), juncenolide C (6), junceellonoid A (7), and juncin R (8).
Figure 1. Structures of frajunolides P–S (14), umbraculolide A (5), juncenolide C (6), junceellonoid A (7), and juncin R (8).
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Figure 2. Structures of fragilisinins A–L (920), junceellolides A (21) and B (22), junceol A (23), junceellonoid D (24), fragilide C (25), and frajunolides A (26) and E (27).
Figure 2. Structures of fragilisinins A–L (920), junceellolides A (21) and B (22), junceol A (23), junceellonoid D (24), fragilide C (25), and frajunolides A (26) and E (27).
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Figure 3. Structures of fragilolides A–Q (2844), frajunolides H (45) and N (46), scabrolide D (47), sinuleptolide (48), and 5-epi-sinuleptolide (49).
Figure 3. Structures of fragilolides A–Q (2844), frajunolides H (45) and N (46), scabrolide D (47), sinuleptolide (48), and 5-epi-sinuleptolide (49).
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Figure 4. Structures of 3-deacetylpraelolide (50), 13-α-acetoxy-3-deacetylpraelolide (51), 13-α- acetoxy-2-deacetylpraelolide (52), 13-α-acetoxy-3-deacetyljunceellin (53), 13-α-acetoxy-2-deacetyl- junceellin (54), fragilide J (55), 3-deacetyljunceellin (56), and 2-deacetyljunceellin (57).
Figure 4. Structures of 3-deacetylpraelolide (50), 13-α-acetoxy-3-deacetylpraelolide (51), 13-α- acetoxy-2-deacetylpraelolide (52), 13-α-acetoxy-3-deacetyljunceellin (53), 13-α-acetoxy-2-deacetyl- junceellin (54), fragilide J (55), 3-deacetyljunceellin (56), and 2-deacetyljunceellin (57).
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Figure 5. Structures of fragilides K (58) and L (59), gemmacolides V (60) and X (61), praelolide (62), juncins P (63) and ZI (64).
Figure 5. Structures of fragilides K (58) and L (59), gemmacolides V (60) and X (61), praelolide (62), juncins P (63) and ZI (64).
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Figure 6. Structures of junceellolides M–P (6568), junceellolides C (69) and D (70), and junceellin A (71).
Figure 6. Structures of junceellolides M–P (6568), junceellolides C (69) and D (70), and junceellin A (71).
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Figure 7. Structures of (1S*,2S*,8S*,9S*,10S*,11R*,12R*,14S*,17R*)-11,20-epoxy-14-(3-methyl- butanoyl)-2,9,12-triacetoxy-8-hydroxybriar-5(16)-en-18,7-olide (72), gemmacolides A (73) and B (74), and juncins H (75) and K (76).
Figure 7. Structures of (1S*,2S*,8S*,9S*,10S*,11R*,12R*,14S*,17R*)-11,20-epoxy-14-(3-methyl- butanoyl)-2,9,12-triacetoxy-8-hydroxybriar-5(16)-en-18,7-olide (72), gemmacolides A (73) and B (74), and juncins H (75) and K (76).
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Figure 8. Structures of juncenolides M–O (7779).
Figure 8. Structures of juncenolides M–O (7779).
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Figure 9. Structures of 5α,8α-epidioxy-24(ξ)-methylcholesta-6,22-dien-3β-ol (80), deoxyadenosine (81), and deoxythymidine (82).
Figure 9. Structures of 5α,8α-epidioxy-24(ξ)-methylcholesta-6,22-dien-3β-ol (80), deoxyadenosine (81), and deoxythymidine (82).
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