Mar. Drugs 2013, 11(10), 4083-4126; doi:10.3390/md11104083

Review
Anti-Inflammatory Activities of Natural Products Isolated from Soft Corals of Taiwan between 2008 and 2012
Wen-Chi Wei 1, Ping-Jyun Sung 2,3, Chang-Yih Duh 4, Bo-Wei Chen 4, Jyh-Horng Sheu 4,5,6,* and Ning-Sun Yang 1,7,8,*
1
Agricultural Biotechnology Research Center, Academia Sinica, Taipei 128, Taiwan; E-Mail: jackwei@gate.sinica.edu.tw
2
National Museum of Marine Biology & Aquarium, Pingtung 944, Taiwan; E-Mail: pjsung@nmmba.gov.tw
3
Graduate Institute of Marine Biotechnology, National Dong Hwa University, Pingtung 944, Taiwan
4
Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan; E-Mails: yihduh@mail.nsysu.edu.tw (C.-Y.D.); a6152761@yahoo.com.tw (B.-W.C.)
5
Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan
6
Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan
7
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan
8
Department of Life Science, National Central University, Taoyuan 320, Taiwan
*
Authors to whom correspondence should be addressed; E-Mails: sheu@mail.nsysu.edu.tw (J.-H.S.); nsyang@gate.sinica.edu.tw (N.-S.Y.); Tel./Fax: +886-7525-2000 (ext. 5030) (J.-H.S.), +886-2-2787-2067 (N.-S.Y.).
Received: 30 July 2013; in revised form: 12 September 2013 / Accepted: 13 September 2013 /
Published: 23 October 2013

Abstract

: This review reports details on the natural products isolated from Taiwan soft corals during the period 2008–2012 focusing on their in vitro and/or in vivo anti-inflammatory activities. Chemical structures, names, and literature references are also reported. This review provides useful and specific information on potent anti-inflammatory marine metabolites for future development of immune-modulatory therapeutics.
Keywords:
soft coral; anti-inflammatory activity; iNOS; COX-2; superoxide anion; elastase

1. Introduction

Marine natural products, especially those from stationary or slow moving marine organisms, are used naturally as a chemical defense to protect the organisms from dangerous predators, stressful local environments, and/or the encroachment of competitors. Due to the biological and chemical diversity of marine habitats, and the identification and greater understanding of marine secondary metabolites with unique chemical structures and biological activities, natural products from marine organisms are increasingly being considered as a major source of new therapeutics [1,2,3]. More than 20,000 novel compounds have been isolated and identified from marine organisms since the 1960s [4]. At least two current drugs and a series of anti-tumor drug candidates in preclinical or clinical trials have been developed from marine natural products [2,3,4]. The soft corals or Alcyonacea, an order of Anthozoa widely distributed in warm seawaters, have been a particular focus of attention. An abundance of unique secondary metabolites including sesquiterpenoids, diterpenoids, steroids and other chemical compounds have been isolated and identified from various species of soft corals [5,6,7]. It has been estimated that the percentage of new metabolites discovered from soft corals represents up to 22% of the total new marine natural products reported from 2010 to 2011 [5,6]. Importantly, many of the natural products discovered from soft corals have been demonstrated to exhibit a spectrum of biological activities such as anti-tumor, antiviral, antifouling and anti-inflammatory [5,6,7,8].

Inflammation processes often constitute an initial activation of the mammalian immune system, and the body’s normal defense or protective mechanisms in response to microbial infection or irritation or injury of tissues/organs. Increasing evidence suggests a critical link between inflammation and the chronic promotion/progression of various human diseases, including atherosclerosis, diabetes, arthritis, inflammatory bowel disease, cancer and Alzheimer. Proinflammatory enzymes, particularly the inducible nitric oxide synthase (iNOS) for nitric oxide production and cyclooxygenase (COX-2) for prostaglandin production, have been demonstrated to play central roles in the development of inflammatory diseases. In addition, it is also known that during the initial phase of acute inflammation, neutrophils are one of the first leukocyte populations to migrate towards the damaged tissue sites [9]. Neutrophils play a key role in the pathogenesis of various chronic inflammation diseases such as rheumatoid arthritis [10,11]. Activated neutrophils can secrete the superoxide anion, reactive oxygen species (ROS) and enzymes that are associated with the killing of invading pathogens [12]. Furthermore, elastase secreted by stimulated neutrophils has been recognized to play a key contribution in the demolition of tissues affected by chronic inflammatory disease [13]. Therefore, evaluation of the inhibition of iNOS and COX-2 expression, the production of superoxide anion, and the release of elastase in inflammatory cells/tissues by various natural products have been extensively employed in a spectrum of in vitro preliminary screening systems for lead compound or drug discovery. Recently, a number of marine biology and chemistry researchers in Taiwan (including our laboratory) have systematically screened several marine natural products isolated from soft corals for such in vitro anti-inflammatory activities, mainly by measuring the inhibition of iNOS, COX-2, superoxide anion or elastase in murine immune cells. Animal models were further used to evaluate the potential therapeutic activities of candidate compounds in specific disease models. This report reviews some recent representative studies and examples of marine natural products with anti-inflammatory and other related bioactivities that have been isolated from soft corals of Taiwan. Soft corals are abundant in the off-shore environment of the island of Taiwan, and have hence become a focus of local studies of marine nature products. We hope that this review will provide a useful data for the further study of marine natural products.

2. Results and Discussion

In the reports reviewed here, anti-inflammatory activities of natural products from the soft corals of Taiwan were generally determined in vitro by their inhibition of LPS-induced expression of iNOS and COX-2 in murine macrophage cells (RAW264.7) or by their inhibition of the production of superoxide anion and the release on the elastase from human neutrophils in response to FMLP/CB.

2.1. Sesquiterpenoids

2.1.1. Triquinane-Type Sesquiterpenoids

Table 1 summarizes nine triquinane-type sesquiterpenoids (19) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 1.

Table 1. Chemical constituents of triquinane-type sesquiterpenoids from soft corals of Taiwan.

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Table 1. Chemical constituents of triquinane-type sesquiterpenoids from soft corals of Taiwan.
No.NameSourcesActivities *Reference
1Δ9(12)-Capnellene-8β,10α-diolCapnella imbricataI,C[14]
28α-Acetoxy-Δ9(12)-capnellene-10α-olCapnella imbricataI,C[14]
3Δ9(12)-Capnellene-10α-ol-8-oneCapnella imbricataI[14]
4Δ9(12)-Capnellene-8β,15-diolCapnella imbricata [14]
5Δ9(12)-Capnellene-8β,10α,13-triolCapnella imbricata [14]
68β,10α-Diacetoxy-Δ9(12)-capnelleneCapnella imbricata [14]
78β-Acetoxy-Δ9(12)-capnelleneCapnella imbricata [14]
8Δ9(12)-Capnellene-8β-olCapnella imbricata [14]
9Δ9(12)-Capnellene-12-ol-8-oneCapnella imbricataI,C[14]

* Inhibition of iNOS (I) and COX-2 (C).

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Figure 1. The structures of triquinane-type sesquiterpenoids (19).

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Figure 1. The structures of triquinane-type sesquiterpenoids (19).
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2.1.2. Nardosinane-Type Sesquiterpenoids

Table 2 summarizes seven nardosinane-type sesquiterpenoids (1016) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 2.

Table 2. Chemical constituents of nardosinane-type sesquiterpenoids from soft corals of Taiwan.

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Table 2. Chemical constituents of nardosinane-type sesquiterpenoids from soft corals of Taiwan.
No.NameSourcesActivities *Reference
10Paralemnolin JParalemnalia thyrsoides [15]
11Paralemnolin KParalemnalia thyrsoides [15]
12Paralemnolin LParalemnalia thyrsoides [15]
13Flavalin ALemnalia flavaI,C[16]
14Flavalin BLemnalia flava [16]
15Flavalin CLemnalia flava [16]
16Flavalin DLemnalia flava [16]

* Inhibition of iNOS (I) and COX-2 (C).

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Figure 2. The structures of nardosinane-type sesquiterpenoids (1016).

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Figure 2. The structures of nardosinane-type sesquiterpenoids (1016).
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2.1.3. Aromadendrane-Type Sesquiterpenoids

Table 3 summarizes six aromadendrane-type sesquiterpenoids (1722) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 3.

Table 3. Chemical constituents of aromadendrane-type sesquiterpenoids from soft corals of Taiwan.

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Table 3. Chemical constituents of aromadendrane-type sesquiterpenoids from soft corals of Taiwan.
No.NameSourcesActivities *Reference
17Lochmolin ASinularia lochmodesC[17]
18Lochmolin BSinularia lochmodesC[17]
19Lochmolin CSinularia lochmodes [17]
20Lochmolin D Sinularia lochmodes [17]
21Lochmolin ESinularia lochmodesC[17]
22Lochmolin F Sinularia lochmodesC[17]

* Inhibition of COX-2 (C).

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Figure 3. The structures of aromadendrane-type sesquiterpenoids (1722).

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Figure 3. The structures of aromadendrane-type sesquiterpenoids (1722).
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2.1.4. Selinane- and Oppositane-Type Sesquiterpenoids

Table 4 summarizes four selinane- and oppositane-type sesquiterpenoids (2326) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 4.

Table 4. Chemical constituents of selinane- and oppositane-type sesquiterpenoids from soft corals of Taiwan.

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Table 4. Chemical constituents of selinane- and oppositane-type sesquiterpenoids from soft corals of Taiwan.
No.NameSourcesActivities *Reference
231β-Hydroxy-6α-acetoxyeudesm-4(15)-eneSinularia leptoclados [18]
241β,6α-Dihydroxyeudesm-4(15)-ene Sinularia leptocladosI[18]
25Leptocladolin ASinularia leptoclados [18]
26Leptocladolin BSinularia leptoclados [18]

* Inhibition of iNOS (I).

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Figure 4. The structures of selinane- and oppositane-type sesquiterpenoids (2326).

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Figure 4. The structures of selinane- and oppositane-type sesquiterpenoids (2326).
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2.1.5. Ylangene-Type Sesquiterpenoids

Table 5 summarizes three ylangene-type sesquiterpenoids (2729) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 5.

Table 5. Chemical constituents of ylangene-type sesquiterpenoids from soft corals of Taiwan.

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Table 5. Chemical constituents of ylangene-type sesquiterpenoids from soft corals of Taiwan.
No.NameSourcesActivities *Reference
27(1S,2S,4R,6S,7R,8S)-4α-Formyloxy-β-ylangeneLemnalia flavaI,C[16]
28LemnalolLemnalia flava [16]
29Isolemnalol Lemnalia flava [16]

* Inhibition of NOS (I) and COX-2 (C).

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Figure 5. The structures of ylangene-type sesquiterpenoids (2729).

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Figure 5. The structures of ylangene-type sesquiterpenoids (2729).
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2.1.6. Germacrane-Type Sesquiterpenoids

Table 6 summarizes three germacrane-type sesquiterpenoids (3032) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 6.

Table 6. Chemical constituents of germacrane-type sesquiterpenoids from soft corals of Taiwan.

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Table 6. Chemical constituents of germacrane-type sesquiterpenoids from soft corals of Taiwan.
No.NameSourcesActivities *Reference
30Lochmolin GSinularia lochmodes [17]
31Menelloide DMenella sp.E[19]
32Menelloide EMenella sp. [20]

* Inhibition of elastase (E).

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Figure 6. The structures of germacrane-type sesquiterpenoids (3032).

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Figure 6. The structures of germacrane-type sesquiterpenoids (3032).
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2.1.7. Other-Type Sesquiterpenoids

Table 7 summarizes six other-type sesquiterpenoids (3338) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 7.

Table 7. Chemical constituents of other-type sesquiterpenoids from soft corals of Taiwan.

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Table 7. Chemical constituents of other-type sesquiterpenoids from soft corals of Taiwan.
No.NameSourcesActivities *Reference
33ErectathiolNephthea erectaI[21]
34Scabralin ASinularia scabraI[22]
35Leptocladol ASinularia leptoclados [23]
36Paralemnolin DParalemnalia thyrsoides [15]
371- epi-Chabrolidione ASinularia leptoclados [23]
38(–)-HydroxylindestrenolideMenella sp.S[24]

* Inhibition of iNOS (I) and superoxide anion (S).

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Figure 7. The structures of other-type sesquiterpenoids (3338).

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Figure 7. The structures of other-type sesquiterpenoids (3338).
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At a concentration of 10 µM, compounds 13, 13, 24, 28, 33 and 34 reduced LPS-induced expression of iNOS in murine macrophage cells [14,15,16,18,21,22]. Compounds 1, 2, 13, 17, 18, 21 and 28 suppressed LPS-induced expression of COX-2 in these cells [14,15,16,17]. At 10 µg/mL, compound 38 was shown to slightly inhibit the generation of superoxide anion in FMLP/CB-stimulated human neutrophils, and compound 31 weakly inhibited the release of elastase by activated human neutrophils [19,24]. In addition, an inflammation animal model induced by intraplantar injection of carrageenan into rat hind paws was also used to evaluate in vivo anti-inflammatory activity of lemnalol (28). Intramuscular injection of 28 (15 mg/kg) significantly inhibited the carrageenan-induced rat paw edema and thermal hyperalgesia behavior. Moreover, lemnalol significantly suppressed the carrageenan-induced expression of iNOS and COX-2 in paw tissue of test rats. Post-intrathecal injection of lemnalol provided an antinociceptive effect in carrageenan-injected rats (1 and 5 μg) [25]. Δ9(12)-capnellene-8β,10α-diol (GB9, 1) and its acetylated derivative, 8α-acetoxy-Δ9(12)-capnellene-10α-ol (GB10, 2) were reported to inhibit the expression of iNOS and COX-2 in BV2 cells post-stimulation by IFN-γ.

Intraperitoneal administration of GB9 reduced CCI-induced thermal hyperalgesia, suppressed microglial cells activation and COX-2 upregulation in the dorsal horn of the lumbar spinal cord, ipsilateral to the injury. Also, intrathecal administration of GB9 and GB10 suppressed activities of CCl-induced nociceptive sensitization and thermal hyperalgesia [26]. The above findings suggest that some of these compounds may warrant systematic investigation for future development as immune-modifiers.

2.2. Diterpenoids

2.2.1. Cembrane-Based Diterpenoids

Table 8 summarizes 92 cembrane-based diterpenoids (39130) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 8.

Table 8. Chemical constituents of cembrane-based diterpenoids from soft corals of Taiwan.

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Table 8. Chemical constituents of cembrane-based diterpenoids from soft corals of Taiwan.
NameSourcesActivities *Reference
39Gibberosene BSinularia gibberosaI,C[27]
40(+)-11,12-Epoxysarcophytol ASinularia gibberosa[27]
41Grandilobatin BSinularia grandilobata[28]
42Grandilobatin DSinularia grandilobataI[28]
43Durumolide ALobophytum durumI,C[29]
4413S-HydroxylobolideLobophytum durumI,C[29]
4513R-HydroxylobolideLobophytum durumI[29]
46Deacetyl-13-hydroxylobolideLobophytum durumI,C[27]
47(7E,11E)-13,18-Dihydroxy-3,4-epoxy-7,11,15(17)-cembratrien-16,14-olideLobophytum durumI,C[27]
48Durumolide BLobophytum durumI[28]
49(3E,7E,11E)-18-Acetoxy-3,7,11,15(17)-cembratetraen-16,14-olideLobophytum durumI,C[28]
50Durumolide CLobophytum durumI,C[29]
51Durumolide DLobophytum durumI[29]
52Durumolide ELobophytum durumI[29]
53Granosolide CSinularia granosa[30]
54Querciformolide ESinularia querciformisI[30]
55Granosolide DSinularia granosaI[30]
56Flexibilisolide ASinularia granosaI[30]
57FlexilarinSinularia granosaI[30]
58SinulariolideSinularia granosaI[30]
59Sinulaflexiolide ESinularia granosa[30]
60Crassumolide ALobophytum crassumI,C[31]
61Crassumolide BLobophytum crassumI[31]
62Crassumolide CLobophytum crassumI,C[31]
63Crassumolide FLobophytum crassumI[31]
64LobohedleolideLobophytum crassumI,C[31]
6517-DimethylaminolobohedleolideLobophytum crassumI[31]
66Sinulariol ALobophytum crassumI,C[31]
67DentivulatolideLobophytum crassumI,C[31]
68Durumhemiketalolide ALobophytum durumI,C[32]
69Durumhemiketalolide BLobophytum durumI[32]
70Durumhemiketalolide CLobophytum durumI,C[32]
71Durumolide FLobophytum durumI,C[33]
72Durumolide GLobophytum durumI[33]
73Durumolide HLobophytum durumI[33]
74Durumolide ILobophytum durumI[33]
75Durumolide JLobophytum durumI[33]
76Sinularolide DLobophytum durumI[33]
77Durumolide KLobophytum durumI,C[33]
78Durumolide LLobophytum durumI[33]
79Sarcocrassocolide ASarcophyton crassocauleI[34]
80Sarcocrassocolide CSarcophyton crassocauleI[34]
81Sarcocrassocolide BSarcophyton crassocauleI[34]
82Sarcocrassocolide DSarcophyton crassocauleI[34]
83Sarcocrassocolide ESarcophyton crassocauleI[34]
84SarcocrassolideSarcophyton crassocauleI,C[34]
85SinularolideSarcophyton crassocauleI[34]
8613-AcetoxysarcocrassolideSarcophyton crassocauleI[34]
87Thioflexibilolide ASinularia flexibilisI,C[35]
88Triangulene ASinularia triangular[36]
89Triangulene BSinularia triangular[36]
90SinularinSinularia triangularI[36]
91DihydrosinularinSinularia triangularI,C[36]
92(−)14-DeoxycrassinSinularia triangularI,C[36]
93Sarcocrassocolide FSarcophyton crassocauleI[37]
94Sarcocrassocolide GSarcophyton crassocauleI[37]
95Sarcocrassocolide HSarcophyton crassocauleI[37]
96Sarcocrassocolide ISarcophyton crassocauleI,C[37]
97Sarcocrassocolide JSarcophyton crassocauleI[37]
98Sarcocrassocolide KSarcophyton crassocauleI[37]
99Sarcocrassocolide LSarcophyton crassocauleI[37]
100Sarcophytolin ALobophytum sarcophytoidesI[38]
101Sarcophytolin BLobophytum sarcophytoidesI[38]
102Sarcophytolin CLobophytum sarcophytoides[38]
103Sarcophytolin DLobophytum sarcophytoidesI[38]
10411-DehydrosinulariolideSinularia discrepansI,C[39]
10511-epi-Sinulariolide acetateSinularia discrepansI,C[39]
106Crassumolide GLobophytum crassumI[40]
107Crassumolide HLobophytum crassumI[40]
108Crassumolide ILobophytum crassumI[40]
109Crassarine ASinularia crassa[41]
110Crassarine BSinularia crassa[41]
111Crassarine CSinularia crassa[41]
112Crassarine DSinularia crassa[41]
113Crassarine ESinularia crassa[41]
114Crassarine FSinularia crassaC[41]
115Crassarine GSinularia crassa[41]
116Crassarine HSinularia crassaI[41]
117Sarcocrassocolide MSarcophyton crassocauleI[42]
118Sarcocrassocolide NSarcophyton crassocauleI[42]
119Sarcocrassocolide OSarcophyton crassocauleI[42]
120Culobophylin ALobophytum crassum[43]
121Culobophylin BLobophytum crassum[43]
122Culobophylin CLobophytum crassum[43]
123Lobophylin BLobophytum crassum[43]
124Lobophylin ALobophytum crassum[43]
125Lobocrassin ALobophytum crassum[44]
126Lobocrassin BLobophytum crassumS,E[44]
127Lobocrassin CLobophytum crassum[44]
128Lobocrassin DLobophytum crassum[44]
129Lobocrassin ELobophytum crassum[44]
130Lobocrassin FLobophytum crassumE[20]

* Inhibition of iNOS (I), COX-2 (C), superoxide anion (S) and elastase (E).

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Figure 8. The structures of cembrane-based diterpenoids (39130).

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Figure 8. The structures of cembrane-based diterpenoids (39130).
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At the concentration of 10 µM, compounds 39, 4252, 5458, 6087, 90101, 103108 and 116119 reduced LPS-induced expression of iNOS in murine macrophage (RAW264.7) cells [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42]. Compounds 39, 43, 44, 46, 47, 49, 50, 62, 64, 6668, 70, 71, 77, 84, 87, 91, 92, 96, 104, 105 and 114 suppressed LPS-induced expression of COX-2 in these cells [27,29,31,32,33,34,35,36,37,39,41]. At 10 µg/mL, compound 126 inhibited the generation of superoxide anion and the release of elastase in human neutrophils [44]. Compound 130 inhibited the release of elastase by activated human neutrophils [24]. For in vivo anti-inflammatory activities, subcutaneous (s.c.) administration of sinularin (90) (80 mg/kg) significantly inhibited carrageenan-induced nociceptive behaviors as well as carrageenan-induced activation of microglial and astrocyte, and the iNOS expression in the dorsal horn of the lumbar spinal cord [45]. Due to its promising anti-inflammatory profile, sinularin may warrant future exploration as a lead compound for immune-/inflammation-modulation.

2.2.2. Eunicellin-Based Diterpenoids

Table 9 summarizes 58 eunicellin-based diterpenoids (131188) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 9.

Table 9. Chemical constituents of eunicellin-based diterpenoids from soft corals of Taiwan.

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Table 9. Chemical constituents of eunicellin-based diterpenoids from soft corals of Taiwan.
No.NameSourcesActivities *Reference
131Simplexin AKlyxum simplexI[46]
132Simplexin BKlyxum simplex[46]
133Simplexin CKlyxum simplex[46]
134Simplexin DKlyxum simplexI [46]
135Simplexin EKlyxum simplexI,C[46]
136Simplexin FKlyxum simplex[46]
137Simplexin IKlyxum simplex[46]
138Klysimplexin IKlyxum simplex[47]
139Klysimplexin JKlyxum simplexI[47]
140Klysimplexin KKlyxum simplexI[47]
141Klysimplexin LKlyxum simplexI[47]
142Klysimplexin MKlyxum simplexI[47]
143Klysimplexin NKlyxum simplexI[47]
144Klysimplexin OKlyxum simplex[47]
145Klysimplexin PKlyxum simplex[47]
146Klysimplexin QKlyxum simplex[47]
147Klysimplexin RKlyxum simplexI[47]
148Klysimplexin SKlyxum simplexI,C[47]
149Klysimplexin TKlyxum simplex[47]
150Hirsutalin ACladiella hirsuta[48]
151Hirsutalin BCladiella hirsutaI,C[48]
152Hirsutalin CCladiella hirsutaI[48]
153Hirsutalin DCladiella hirsutaI[48]
154Hirsutalin ECladiella hirsuta[48]
155Hirsutalin FCladiella hirsuta[48]
156Hirsutalin GCladiella hirsuta[48]
157Hirsutalin HCladiella hirsutaI[48]
158Klysimplexin sulfoxide AKlyxum simplexI[49]
159Klysimplexin sulfoxide BKlyxum simplexI[49]
160Klysimplexin sulfoxide CKlyxum simplexI,C[49]
161Lymollin AKlyxum molle[50]
162Lymollin BKlyxum molleI[50]
163Lymollin CKlyxum molleI,C[50]
164Lymollin DKlyxum molleI,C[50]
165Lymollin EKlyxum molleI[50]
166Lymollin FKlyxum molleI,C[50]
167Lymollin GKlyxum molleI,C[50]
168Lymollin HKlyxum molleI,C[50]
169Krempfielin ACladiella krempfi[51]
170Krempfielin DCladiella krempfiI[51]
171Krempfielin BCladiella krempfiI[51]
172krempfielin CCladiella krempfiI[51]
173Litophynol BCladiella krempfiI[51]
174(1R*,2R*,3R*,6S*,7S*,9R*,10R*,14R*)3-Butanoyloxycladiell-11(17)-en-6,7-diolCladiella krempfiI[51]
175Klysimplexin UKlyxum simplex[52]
176Klysimplexin VKlyxum simplex[52]
177Klysimplexin WKlyxum simplex[52]
178Klysimplexin XKlyxum simplex[52]
179Cladieunicellin ACladiella sp.S,E[53]
180Cladieunicellin CCladiella sp.[53]
181Cladieunicellin DCladiella sp.[53]
182Cladieunicellin ECladiella sp.[53]
183Cladieunicellin GCladiella sp.S,E[54]
1846-epi-Cladieunicellin FCladiella sp.[54]
185Cladieunicellin FCladiella sp.S,E[54]
186(–)-Solenopodin CCladiella sp.[55]
187Cladielloide ACladiella sp.[56]
188Cladielloide BCladiella sp.S,E[56]

* Inhibition of iNOS (I), COX-2 (C), superoxide anion (S) and elastase (E).

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Figure 9. The structures of cembrane-based diterpenoids (131188).

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Figure 9. The structures of cembrane-based diterpenoids (131188).
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2.2.3. Briarane-based Diterpenoids

Table 10 summarizes 35 briarane-based diterpenoids (189223) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 10.

Table 10. Chemical constituents of briarane-type diterpenoids from soft corals of Taiwan.

Click here to display table

Table 10. Chemical constituents of briarane-type diterpenoids from soft corals of Taiwan.
No.NameSourcesActivities *Reference
189Excavatolide BBriareum excavatum[57]
190Excavatolide KBriareum excavatum[57]
191Excavatolide FBriareum excavatum[57]
192Briaexcavatolide RBriareum excavatum[57]
193Excavatolide ZBriareum excavatum[57]
194Briaexcavatolide BBriareum excavatum[57]
195Briaexcavatolide KBriareum excavatum[57]
196Briaexcavatolide HBriareum excavatum[57]
197Junceol DJunceella juncea[58]
198Junceol EJunceella junceaS[58]
199Junceol FJunceella junceaS[58]
200Junceol GJunceella junceaS[58]
201Junceol HJunceella junceaS[58]
202Excavatoid LBriareum excavatumS,E[59]
203Excavatoid M Briareum excavatumS,E[59]
204Excavatoid NBriareum excavatumS,E[59]
205Briarenolide FBriareum sp.S[60]
206Briarenolide GBriareum sp.[60]
207Fragilide JEllisella robustaE[61]
208Robustolide LEllisella robustaS[61]
209Briaexcavatin PBriareum excavatumS[62]
210Frajunolide LJunceella fragilisS,E[63]
211Frajunolide MJunceella fragilis[63]
212Frajunolide NJunceella fragilisE[63]
213Frajunolide OJunceella fragilisS,E[63]
214Juncenolide MJunceella juncea[64]
215Juncenolide NJunceella junceaE[64]
216Juncenolide OJunceella junceaS,E[64]
217Frajunolide EJunceella fragilisS,E[65]
218Frajunolide FJunceella fragilis[65]
219Frajunolide GJunceella fragilis[65]
220Frajunolide HJunceella fragilis[65]
221Frajunolide IJunceella fragilis[65]
222Frajunolide JJunceella fragilisS,E[65]
223Frajunolide KJunceella fragilis [65]

* Inhibition of superoxide anion (S) and elastase (E).

Marinedrugs 11 04083 g010 200
Figure 10. The structures of briarane-type diterpenoids (189223).

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Figure 10. The structures of briarane-type diterpenoids (189223).
Marinedrugs 11 04083 g010 1024

2.2.4. Verticillane-Based Diterpenoids

Table 11 summarizes 10 verticillane-based diterpenoids (224233) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 11.

Table 11. Chemical constituents of verticillane-type diterpenoids from soft corals of Taiwan.

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Table 11. Chemical constituents of verticillane-type diterpenoids from soft corals of Taiwan.
No.NameSourcesActivities *Reference
224Cespitularin RCespitularia hypotentaculata [66]
225Cespitularin SCespitularia hypotentaculataI,C[66]
226Cespitularin JCespitularia hypotentaculata [66]
227Cesputularin KCespitularia hypotentaculataI[66]
228Cespitularin MCespitularia hypotentaculata [66]
229Cespitularin ICespitularia hypotentaculataI[66]
230Cespitularin FCespitularia hypotentaculataI[66]
231Cespitularin QCespitularia hypotentaculata [66]
232Cespitulin ECespitularia taenuateS,E[67]
233Cespitulin GCespitularia taenuateS,E[67]

* Inhibition of iNOS (I), COX-2 (C), superoxide anion (S) and elastase (E).

Marinedrugs 11 04083 g011 200
Figure 11. The structures of verticillane-based diterpenoids (224233).

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Figure 11. The structures of verticillane-based diterpenoids (224233).
Marinedrugs 11 04083 g011 1024

2.2.5. Norditerpenoids

Table 12 summarizes 18 norditerpenoids (234251) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 12.

Table 12. Chemical constituents of norditerpenoids from soft corals of Taiwan.

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Table 12. Chemical constituents of norditerpenoids from soft corals of Taiwan.
No.NameSourcesActivities *Reference
234Gyrosanolide ASinularia gyrosa[68]
235Gyrosanolide BSinularia gyrosaI[68]
236Gyrosanolide CSinularia gyrosaI[68]
237Gyrosanolide DSinularia gyrosa[68]
238Gyrosanolide ESinularia gyrosa[68]
239Gyrosanolide FSinularia gyrosaI[68]
240Gyrosanin ASinularia gyrosaI[68]
241(1 S*,5R*,8S*,10R*,11S*)-11-Hydroxyl-1-isopropenyl-8-methyl-3,6-dioxo-5,8-epoxycyclotetradec-12-ene-10,12-carbonlactoneSinularia gyrosaI[68]
242(1 S*,5S*,8S*,10R*,11S*)-11-Hydroxyl-1-isopropenyl-8-methyl-3,6-dioxo-5,8-epoxycyclotetradec-12-ene-10,12-carbonlactoneSinularia gyrosaI[68]
243NorcembreneSinularia gyrosa[68]
244epi-NorcembreneSinularia gyrosa[68]
245Leptocladolide BSinularia gyrosaI[68]
246Scabrolide DSinularia gyrosaI[68]
247NorcembreneSinularia gyrosa[68]
248IneleganolideSinularia gyrosa[68]
249Sinulochemodin CSinularia gyrosa[68]
250Scabrolide ASinularia gyrosa[68]
251YanarolideSinularia gyrosa[68]

* Inhibition of iNOS (I).

Marinedrugs 11 04083 g012 200
Figure 12. The structures of norditerpenoids (234251).

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Figure 12. The structures of norditerpenoids (234251).
Marinedrugs 11 04083 g012 1024

2.2.6. Xenicane-Type Diterpenoids

Table 13 summarizes six xenicane-type diterpenoids (252257) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 13.

Table 13. Chemical constituents of xenicane-type diterpenoids from soft corals of Taiwan.

Click here to display table

Table 13. Chemical constituents of xenicane-type diterpenoids from soft corals of Taiwan.
No.NameSourcesActivities *Reference
252Asterolaurin AAsterospicularia laurae [69]
253Asterolaurin BAsterospicularia laurae [69]
254Asterolaurin CAsterospicularia laurae [69]
255Asterolaurin DAsterospicularia lauraeS,E[69]
256Asterolaurin EAsterospicularia laurae [69]
257Asterolaurin FAsterospicularia laurae [69]

* Inhibition of superoxide anion (S) and elastase (E).

Marinedrugs 11 04083 g013 200
Figure 13. The structures of xenicane-type diterpenoids (252257).

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Figure 13. The structures of xenicane-type diterpenoids (252257).
Marinedrugs 11 04083 g013 1024

2.2.7. Other-Type Diterpenoids

Table 14 summarizes five other-type diterpenoids (258262) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 14.

Table 14. Chemical constituents of other type diterpenoids from soft corals of Taiwan.

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Table 14. Chemical constituents of other type diterpenoids from soft corals of Taiwan.
No.NameSourcesActivities *Reference
258Gyrosanol ASinularia gyrosaC[70]
259Gyrosanol BSinularia gyrosaC[70]
260Echinohalimane AEchinomuricea sp.E[71]
261Echinoclerodane AEchinomuricea sp.S,E[72]
262Echinolabdane AEchinomuricea sp. [73]

* Inhibition of COX-2 (C), superoxide anion (S) and elastase (E).

Marinedrugs 11 04083 g014 200
Figure 14. The structures of other type diterpenoids (258262).

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Figure 14. The structures of other type diterpenoids (258262).
Marinedrugs 11 04083 g014 1024

At a concentration of 10 μM, compounds 131, 133, 134, 139, 140143, 147, 148, 151153, 157160, 162168, 170 ceramide and cerebrosides 174, 225, 229, 230, 235, 236, 239242, 244, 245, 258 and 259 reduced LPS-induced expression of iNOS in murine macrophage cells [46,47,48,49,50,51,66,68,70]. Compounds 134, 148, 151, 160, 163, 164, 166168, 225, 258 and 259 suppressed the LPS-induced expression of COX-2 in these cells [46,47,48,49,50,66,70]. At 10 µg/mL, compounds 180, 184, 186, 188, 198205, 208210, 213, 216, 217, 222, 232, 233, 255 and 261 inhibited the generation of superoxide anion by activated human neutrophils [54,55,56,58,59,60,61,62,63,64,65,67,69,70,72]. Compounds 180, 184, 186, 188, 202204, 207, 210, 212, 213, 215217, 222, 232, 233, 255, 260 and 261 inhibited the release of elastase from these activated human neutrophils [53,54,55,56,59,61,63,65,67,69,71,72]. These results provided useful baseline information on the immune-regulatory and anti-oxidant activities of various marine diterpenoids. Compound 184, as 185 epimer at C-6, was showed to be more potent in the inhibition of the generation of superoxide anion and in inducing the release of elastase by active human neutrophils, suggesting that the stereochemistry at C-6 may play a key role in the above biological effects [54].

The briarane-type diterpenoid excavatolide B (189) has been demonstrated to significantly inhibit TPA-induced cutaneous inflammation activities in mice, including those related to vascular permeability, edema, and TPA-induced expression of iNOS, COX-2 and matrixmetalloproteinase-9. Excavatolide B also suppressed LPS-induced expression of TNF-α and IL-6 in mouse bone marrow derived dendritic cells (BMDCs) [57]. Also, excavatolide F (191), K (190) and Z (193) and briaexcavatolide B (194), H (196), K (195) and R (192) exhibited a broad spectrum of activity in inhibition of LPS-induced expression of IL-6 in BMDCs [57]. A study on the structure-activity relationship between the structures of the briarane-type diterpenoids and their inhibition of IL-6 expression in BMDCs revealed that the eight 17-epoxide of briarane-type diterpenoids may play an important role in the inhibition of IL-6 expression in specific immune cells [57]. Replacement of the C-12 hydroxyl group with long esters in briarane-type diterpenoids decreased the inhibition of IL-6 expression [57].

2.3. Steroids

Table 15 summarizes 60 steroids (263322) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 15.

Table 15. Chemical constituents of steroids from soft corals of Taiwan.

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Table 15. Chemical constituents of steroids from soft corals of Taiwan.
No.NameSourcesActivities *Reference
263Stoloniferone RClavularia viridis[74]
264Stoloniferone SClavularia viridisI[74]
265Stoloniferone TClavularia viridisI,C[74]
266(25S)-24-Methylenecholestane-3β,5α,6β-triol-26-acetateClavularia viridisI,C[74]
267Griffinisterone ANephthea griffiniI[75]
268Griffinisterone BNephthea griffiniI[75]
269Griffinisterone CNephthea griffiniI[75]
270Griffinisterone DNephthea griffiniI[75]
271ChabrosterolNephthea chabroliI,C[21]
272Nebrosteroid ANephthea chabroliI[76]
273Nebrosteroid BNephthea chabroliI[76]
274Nebrosteroid CNephthea chabroliI[76]
275Nebrosteroid DNephthea chabroliI,C[76]
276Nebrosteroid FNepthea chabroliI,C[76]
277Nebrosteroid ENepthea chabroli[76]
278Nebrosteroid GNepthea chabroliI,C[76]
279Nebrosteroid HNepthea chabroliI[76]
280Griffinisterone FDendronephthya griffiniI,C[77]
281Griffinisterone GDendronephthya griffiniI,C[77]
282Griffinisterone HDendronephthya griffiniI[77]
283GriffinipregnoneDendronephthya griffiniI,C[77]
2841α,3β-Dihydroxy-24S-methylcholesta-5-eneSinularia sp.I,C[78]
2851α,3β-Dihydroxy-24-methylenecholesta-5-eneSinularia sp.I,C[78]
2865,24(28)-Ergostadien-3β,23S-diolNephthea erectaI,C[79]
2875,24(28)-Ergostadien-3β,23R-diolNephthea erectaI[79]
288(22S)-5,24(28)-Ergostadien-3β,17α,22-triolNephthea erectaI,C[79]
289ErgostanoidNephthea erectaI[79]
290Nebrosteroid INephthea chabroliI,C[80]
291Nebrosteroid JNephthea chabroliI,C[80]
292Nebrosteroid KNephthea chabroli[80]
293Nebrosteroid LNephthea chabroliI,C[80]
294Nebrosteroid MNephthea chabroliIC[80]
295SarcophytosterolLobophytum sarcophytoides[38]
2965α,8α-Epidioxy-24-methylcholesta-6-en-3β-olLobophytum sarcophytoides[38]
2975α,8α-Epidioxy-22,23-methylene-24-methylcholest-6-en-3β-olLobophytum sarcophytoidesI[38]
298Paraminabeolide AParaminabea acronocephalaI[81]
299Paraminabeolide BParaminabea acronocephalaI[81]
300Paraminabeolide CParaminabea acronocephalaI[81]
301Paraminabeolide DParaminabea acronocephalaI[81]
302Paraminabeolide EParaminabea acronocephala[81]
303Minabeolide-1Paraminabea acronocephalaI,C[81]
304Minabeolide-2Paraminabea acronocephalaI,C[81]
305Minabeolide-4Paraminabea acronocephalaI,C[81]
306Minabeolide-5Paraminabea acronocephalaI,C[81]
307Minabeolide-8Paraminabea acronocephala[81]
308Hirsutosterol ACladiella hirsuta[82]
309Hirsutosterol BCladiella hirsuta[82]
310Hirsutosterol CCladiella hirsuta[82]
311Hirsutosterol DCladiella hirsuta[82]
312Hirsutosterol ECladiella hirsuta[82]
313Hirsutosterol FCladiella hirsuta[82]
314Hirsutosterol GCladiella hirsuta[82]
315Crassarosterol ASinularia crassa[83]
316Crassarosteroside ASinularia crassaI[83]
317Crassarosteroside BSinularia crassaI[83]
318Crassarosteroside CSinularia crassaI[83]
3198αH-3β,11-Dihydroxy-5α,6α-expoxy-24-methylene-9,11-secocholestan-9-oneSinularia granosaI,C[84]
3203β,11-Dihydroxy-5β,6β-expoxy-24-methylene-9,11-secocholestan-9-oneSinularia granosaI[84]
3216-epi-Yonarasterol BEchinomuricea sp.S,E[73]
322Carijoside ACarijoa sp.S,E[85]

* Inhibition of iNOS (I), COX-2 (C), superoxide anion (S) and elastase (E).

Marinedrugs 11 04083 g015 200
Figure 15. The structures of steroids (263322).

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Figure 15. The structures of steroids (263322).
Marinedrugs 11 04083 g015 1024

At a concentration of 10 µM, compounds 264275, 277291, 293, 294, 297, 303307 and 316320 reduced LPS-induced expression level of iNOS in murine macrophage cells (RAW264.7) [21,74,75,76,77,78,79,80,81,83,84]. Compounds 265, 266, 271, 275, 277, 278, 280, 281, 283286, 288, 290, 291, 293 and 319 suppressed LPS-induced expression level of COX-2 in murine macrophage cells (RAW264.7) [21,74,75,76,77,78,79,80,84]. At 10 µg/mL, compounds 321 and 322 inhibited the generation of superoxide anion and the release of elastase by activated human neutrophils [73,85].

2.4. Ceramide and Cerebrosides

Table 16 summarizes ceramide (323) and five cerebrosides (324328) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 16.

Table 16. Chemical constituents of ceramide and cerebrosides from soft corals of Taiwan.

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Table 16. Chemical constituents of ceramide and cerebrosides from soft corals of Taiwan.
No.NameSourcesActivities *Reference
323CeramideSarcophyton ehrenbergiI,C[86]
324Sarcoehrenoside ASarcophyton ehrenbergiI[86]
325Sarcoehrenoside BSarcophyton ehrenbergi [86]
326Cerebroside-3Sarcophyton ehrenbergiI[86]
327Cerebroside-5Sarcophyton ehrenbergiI[86]
328Cerebroside-6Sarcophyton ehrenbergiI[86]

* Inhibition of iNOS (I) and COX-2 (C).

Marinedrugs 11 04083 g016 200
Figure 16. The structures of ceramide and cerebrosides (323328).

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Figure 16. The structures of ceramide and cerebrosides (323328).
Marinedrugs 11 04083 g016 1024

2.5. Other Metabolites

Table 17 summarizes 11 secondary metabolites of other types (329339) evaluated for in vitro anti-inflammatory activity in literature published from 2008 to 2012. The corresponding chemical structures are reported in Figure 17.

Table 17. Chemical constituents of other metabolites from soft corals of Taiwan.

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Table 17. Chemical constituents of other metabolites from soft corals of Taiwan.
No.NameSourcesActivities *Reference
329CapilloquinoneSinularia capillosaI[87]
330CapillobenzopyranolSinularia capillosaI[87]
331CapillobenzofuranolSinularia capillosa [87]
332CapillofuranocarboxylateSinularia capillosa [87]
333(E)-5-(2,6-Dimethylocta-5,7-dienyl)furan-3-carboxylic acidSinularia capillosa [87]
3342-[(2E,6E)-3,7-Dimethyl-8-(4-methylfuran-2-yl)octa-2,6-dienyl]-5-methylcyclohexa-2,5-diene-1,4-dioneSinularia capillosaI,C[87]
3352-[(2E,6E)-3,7-Dimethyl-8-(4-methylfuran-2-yl)octa-2,6-dienyl]-5-methylbenzene-1,4-diolSinularia capillosaI[87]
336(–)-LoliolideSinularia capillosa [87]
3373,4,11-Trimethyl-7-methylenebicyclo[6.3.0]undec-2-en-11R-olSinularia capillosa [87]
338AustrasulfoneCladiella australis [88]
339Dihydroaustrasulfone alcoholCladiella australisI,C[88]

* Inhibition of iNOS (I) and COX-2 (C).

Marinedrugs 11 04083 g017 200
Figure 17. Structures of other metabolites (329339).

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Figure 17. Structures of other metabolites (329339).
Marinedrugs 11 04083 g017 1024

At a concentration of 10 µM, compounds 323, 324, 326330, 334, 335 and 339 reduced LPS-induced expression level of iNOS in murine macrophage cells (RAW264.7) [86,87,88]. Compounds 323, 334 and 339 suppressed LPS-induced expression levels of COX-2 in murine macrophage cells (RAW264.7) [86,88]. Austrasulfone (338) was found to exhibit a potent neuroprotective effect in human dopaminergic neuron cells (SH-SY5Y) [89,90]. In animal disease models, the synthetic precursor of austrasulfone dihydroaustrasulfone alcohol (339) was not only demonstrated to attenuate neuropathic pain, but also to suppress the progression of multiple sclerosis and atherosclerosis [88].

3. Conclusions

Marine invertebrates, particularly octocorals, are rich potential sources of drug leads. Most of our own and other studies on anti-inflammatory activities of natural products from soft corals have been focused on “screening-like” assays using COX-2 and iNOS as target markers. These assay studies have been useful in generating small libraries of anti-oxidant and anti-inflammatory activities from a broad spectrum of soft corals. These results, however, apparently have limitations. For example, the findings are usually generic in nature, and there is often difficulty in immediate or specific application of such results to drug/pharmaceutical discovery, as compared to the existing synthetic chemicals or phytochemicals or those being developed for clinical use. We [45,57,88] and others [25,26] have recently initiated a number of cross-disciplinary studies, employing bio-organic chemistry, cellular immunology and animal disease models for systematic and in-depth studies. As a result, we believe that useful information on the possible application of specific natural products from soft corals for future clinical studies have been obtained. We consider such approaches [57] may need to be encouraged and organized at the international level, and hopefully be integrated into systematic studies, aiming to create translational research of marine natural products for pharmaceuticals/nutraceuticals. Special emphasis may need to be placed on new or specific cell biological/disease model systems.

In terms of evaluating marine natural products for future pharmaceutical application, despite the abundance of unique marine natural products identified, the extremely low quantity of a given compound of interest that can be isolated from marine organisms may be a big hurdle for evaluation of in vivo bioactivities and development for pharmaceutical applications.

Fortunately, due to the recent advancement in aquaculture technologies, aquacultural cultivation of various types of specific soft corals is becoming possible. Our team has successfully cultured a number of species of soft corals, including Klyxum simplex and Briareum excavatum [47,91]. As a result, more abundant and routine preparations of experimental materials will become available for global distribution and collaborative research purposes. Nonetheless, the vast volume of marine organisms and the small base of knowledge so far assembled on soft coral-derived marine chemicals calls for increased international cooperation in this field.

Acknowledgments

We thank Ms. Miranda Loney of the Agricultural Biotechnology Research Center, Academia Sinica, Taiwan; and Subramanian Senthilkumar of Shanmugha Arts, Science, Technology & Research Academy, India for editing the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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