1. Introduction

Marine Drugs

1660-3397

Molecular Diversity Preservation International

10.3390/md9101860

marinedrugs-09-01860

Review

Cnidarians as a Source of New Marine Bioactive Compounds—An Overview of the Last Decade and Future Steps for Bioprospecting

Rocha

Joana

12* Peixe

Luisa

3 Gomes

Newton C.M.

2 Calado

Ricardo

1Instituto de Ciencias Biomedicas Abel Salazar, Universidade do Porto, Largo Professor Abel Salazar no. 2, 4099-003 Porto, Portugal 2Departmento de Biologia & CESAM, Universidade de Aveiro, Campus Universitario de Santiago, 3810-193 Aveiro, Portugal; E-Mail: gomesncm@ua.pt 3REQUIMTE, Laboratorio de Microbiologia, Faculdade de Farmacia, Universidade do Porto, Rua Anibal Cunha no. 164, 4050-047 Porto, Portugal; E-Mail: lpeixe@ff.up.pt

*Authors to whom correspondence should be addressed; E-Mails: joanacmrocha@ua.pt (J.R.); rjcalado@ua.pt (R.C.); Tel.: +351-965-245-543 (J.R.); +351-234-370-779 (R.C.); Fax: +351-234-372-587 (R.C.).

2011

10 10 2011

9 10 1860 1886 03 9 2011 20 9 2011 21 9 2011

2011

This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).

Marine invertebrates are rich sources of bioactive compounds and their biotechnological potential attracts scientific and economic interest worldwide. Although sponges are the foremost providers of marine bioactive compounds, cnidarians are also being studied with promising results. This diverse group of marine invertebrates includes over 11,000 species, 7500 of them belonging to the class Anthozoa. We present an overview of some of the most promising marine bioactive compounds from a therapeutic point of view isolated from cnidarians in the first decade of the 21st century. Anthozoan orders Alcyonacea and Gorgonacea exhibit by far the highest number of species yielding promising compounds. Antitumor activity has been the major area of interest in the screening of cnidarian compounds, the most promising ones being terpenoids (monoterpenoids, diterpenoids, sesquiterpenoids). We also discuss the future of bioprospecting for new marine bioactive compounds produced by cnidarians.

coral sea fan sea anemone biotechnology

1. Introduction

In terms of biodiversity, marine environments are among the richest and most complex ecosystems. Harsh chemical and physical conditions in the environment have been important drivers for the production of a variety of molecules with unique structural features. These marine molecules exhibit various types of biological activities [1], with compounds of high economic interest having potential applications in the pharmaceutical and medical sectors. Although nearly 20,000 compounds have been discovered since the field of marine bioactive compound biochemistry began in the mid-1960s, only a very limited number have seen industrial application. It has been clear since marine bioprospecting began that the world’s oceans and their diverse biota represent a significant resource, perhaps the greatest resource on Earth, for the discovery of new bioactive compounds. Early National Cancer Institute (NCI) programs in the USA demonstrated that marine invertebrates were a superb source of potential lead molecules. The decisive boost to this new age of bioprospecting was provided by the NCI when it was found that bioassays with marine organism extracts were far more likely to yield anticancer drugs than terrestrial sources [2]. In this way, it is not surprising that over the past 40 years major advances in the discovery of marine drugs have been recorded in clinical trials for cancer [3]. Apart from anticancer activity, these compounds have proven to be an abundant source of pharmacologically active agents for the production of therapeutic entities [4] against AIDS, inflammatory conditions and microbial diseases.

Marine bioactive compounds display varied potential applications, namely as molecular tools, in cosmetics, as fine chemicals, as nutraceuticals and in agrochemical industries [5]. Although only a few marine-derived products are currently on the market (e.g., Prialt^® and Yondelis^®), several new compounds are now in the clinical pipeline and several more are in clinical development. The few approvals so far for the commercialization of drugs from the sea have not been due to a lack of discovery of novel marine bioactive compounds, but because of the complexity of issues raised upon the development of these products [4]. Faulkner [6–20], Blunt et al. [21–29], and Mayer [30–38] have provided extensive reviews on the total number of marine natural products (MNPs) discovered over the last 25 years, the most promising ones being produced by marine invertebrates. Sponges (phylum Porifera) have long been recognized as the most interesting group of marine invertebrates for the discovery of new drugs [5,39,40]. However, with growing bioprospecting efforts and the screening of previously unexplored marine habitats, the biotechnological potential of other groups of marine invertebrates has also started to attract the attention of researchers. The ability of cnidarians (such as jellyfish, sea anemones and corals) to produce powerful toxins and venoms [41] has been well documented. However, further research has demonstrated that MNPs produced by cnidarians are more than toxins and venoms. The phylum Cnidaria is a large, diverse and ecologically important group of marine invertebrates that includes over 11,000 extant species [42]. Over 3000 MNPs have been described from this phylum alone, mostly in the last decade.

In this work, we present an overview of the most promising marine bioactive compounds isolated from cnidarians in the first decade of the 21st century, which may have applications in the therapy of human diseases. The present study also discusses future perspectives for the bioprospecting of new MNPs produced by this speciose group of marine invertebrates.

2. Methodology

The most relevant peer reviewed literature published during the first decade of the 21st century covering MNPs was surveyed for the present work [18–37]. During this period alone, over 2000 molecules from cnidarians were described. In order to focus our study and address only those compounds displaying a high potential for industrial applications, we have decided to use as guidelines the values of IC₅₀ (half maximal inhibitory concentration). IC₅₀ is a quantitative measure which indicates how much of a particular substance (inhibitor) is needed to inhibit a given biological process or component of a process by half. It is important to highlight that the NCI has renamed the IC₅₀ to GI₅₀ [43] in order to emphasize the correction for cell count at time zero in cancer cells; in this way, some results on this quantitative measure are now also presented under these directives. Additionally, the ED₅₀ (the median dose that produces the desired effect of a drug in half the test population) was also used to identify promising marine bioactive compounds produced by cnidarians. Only the compounds displaying an IC₅₀ ≤ 10.0 μg/mL or μM (except where stated otherwise) and ED₅₀ ≤ 4.0 μg/mL were considered for the present study, as these values are commonly used in the surveyed literature to ascertain relevant bioactivity (e.g., [44,45]). In the few cases were neither IC₅₀ nor ED₅₀ values were described for a MNP in a manuscript, that compound was selected to be part of the present survey only if either the authors of that manuscript, or those citing that manuscript, clearly stated that the results recorded were highly promising for industrial applications. All species producing the compounds selected for the present work were grouped into classes and orders of phylum Cnidaria (Table 1) (according to the classification proposed in the World Register of Marine Species (WoRMS)) [46].

This approach allowed us to identify which taxonomic groups of cnidarians screened so far display the highest potential to yield new drugs or pharmacological products derived from marine bioactive compounds. Nonetheless, it is important to highlight that cnidarian species identification is a challenging task and it is possible that some of the species (or even genera) referred to in the scientific literature may not be correct [47]. In this way, it is of paramount importance that in future works the authors addressing marine bioactive compounds produced by cnidarians provide a detailed description on how target species have been identified.

3. Class Anthozoa

Class Anthozoa currently includes 10 orders and over 7500 valid species (about 2/3 of all known cnidarian species) (Table 1). Within the Anthozoa, the order Alcyonacea (soft corals) and Gorgonacea (sea fans) are the ones which have contributed with the highest number of promising bioactive marine compounds, although other orders, such as Actiniaria (sea anemones) and Scleractinia (hard corals), have also yielded relevant compounds [48–51].

3.1. Order Alcyonacea (Soft Corals)

Soft corals are generally brightly colored and rich in nutritionally important substances. However, the incidence of predation in the majority of these organisms is low due to the toxic compounds they produce to deter predators [52]. Several biosynthetic studies have been carried out on the metabolites of soft corals [53] and some of those compounds have already shown to have great potential for the development of new pharmaceuticals and antifoulants. Table 2 summarizes the most promising compounds from order Alcyonacea (class Anthozoa) described in the present review.

Soft corals are rich sources of secondary metabolites such as diterpenes, sesquiterpenes, furanoditerpenes, terpenoids, capnellenes and steroids (e.g., Lobophytum, Sinularia (Figure 1A), Sarcophyton [86] (Figure 1C), Capnella [87], Dendronephthya [78]), that have shown to display HIV-inhibitory [57], cytotoxic [88,89], anti-inflammatory [90,91], anticancer [92,93] and antimicrobial activity [94], as well as cardiac and vascular responses [95]. Soft corals of the family Nephtheidae are known for their content of sesquiterpenes and particularly capnellenes [28]. Some sesquiterpenes isolated from Capnella imbricate [87,96–98] showed anti-inflammatory activity and a dihydroxycapnellene (capnell-9(12)-ene-8β,10α-diol) from Dendronephthya rubeola demonstrated a good antiproliferative activity against murine fibroblasts cell line (L-929, GI₅₀ 6.8 μM/L) and a good cytotoxicity against cancer cell lines implicated in human leukemia (K-562, IC₅₀ 0.7 μM) and human cervix carcinoma (HeLa, IC₅₀ 7.6 μM) [78]. Capnell-9(12)-ene-8β,10α-diol strongly inhibits the interaction of the oncogenic transcription factor Myc with its partner protein Max [79,80], making it a therapeutically interesting compound in oncology [78]. Nephthea chabroli also produces a nor-sisquiterpene compound, chabranol, which displays moderate cytotoxicity against P-388 (mouse lymphocytic leukemia cells) with an ED₅₀ 1.81 μg/mL [81]. Nephthea erecta produces two proteins in mediated inflammatory responses, the oxygenated ergostanoids 1 and 3. These compounds at a concentration of 10 μM significantly reduced the levels of the iNOS (inducible nitric oxide synthase) (45.8 ± 9.9 and 33.6 ± 20.6%, respectively) and COX-2 (cyclooxygenase-2) protein (68.1 ± 2.3 and 10.3 ± 6.2%, respectively), when compared with the control cells stimulated with lipopolysaccharides (LPS) [82].

Species in the genus Xenia (family Xeniidae) (Figure 1B) are a rich source of diterpenoids. Xeniolides I, isolated from Xenia novaebrittanniae demonstrated antibacterial activity at a concentration of 1.25 mg/mL in Escherichia coli ATCC and Bacillus subtilis [85]. Blumiolide C, a diterpenoid from the Xenia blumi (presently accepted as Xenia plicata), exhibited potent cytotoxicity against mouse lymphocytic leukemia (P-388, ED₅₀ 0.2 μg/mL) and human colon adenocarcinoma (HT-29, ED₅₀ 0.5 μg/mL) cells [44].

Polyoxygenated cembranoids, crassocolides H–M from Sarcophyton crassocaule, demonstrated cytotoxicity against cancer cell lines of human medulloblastoma (Daoy cells) where crassocolides I and M were found to be more active (IC₅₀ 0.8 and 1.1 μg/mL, respectively). Crassocolide H was also found to inhibit the growth of human oral epidermoid carcinoma (KB) cells (IC₅₀ 5.3 μg/mL) and crassocolide L active against human cervical epitheloid carcinoma (HeLa) cells (IC₅₀ 8.0 μg/mL) [62].

Another example of a potential new therapeutic anticancer agent is a cembranolide diterpene from Lobophytum cristagalli, which has shown a potent inhibitory activity (IC₅₀ 0.15 μM) [59] over farnesyl protein transferase (FPT, an important protein in signal transduction and regulation of cell differentiation and proliferation [99]). This type of FPT inhibition enhanced interest in this group of metabolites [86]. Other species of this genus also showed cembranolide diterpenes (lobophytene) with significant cytotoxic activity against human lung adenocarcinoma (A549) and human colon adenocarcinoma (HT-29) cell lines [56]. Lobophytum durum and Lobophytum crassum produce durumolides A–C [60], durumhemiketalolide A–C [61] and crassumolides A and C [58], with anti-inflammatory effects. They have been shown to inhibit up-regulation of the pro-inflammatory iNOS and COX-2 proteins in LPS-stimulated murine macrophage cells at IC₅₀ < 10 μM [58,60]. The diterpenoids, lobohedleolide, (7Z)-lobohedleolide, and 17-dimethylaminolobohedleolide, were isolated from the aqueous extract of Lobophytum species and exhibited moderate HIV-inhibitory activity (IC₅₀ approximately 7–10 μg/mL) in a cell-based in vitro anti-HIV assay [57]. Klyxum simplex produces diterpene compounds, such as simplexin E, which at a concentration of 10 μM was found to considerably reduce the levels of iNOS and COX-2 proteins to 4.8 ± 1.8% and 37.7 ± 4.7%, respectively. These results have shown that this compound significantly inhibits the accumulation of the pro-inflammatory iNOS and COX-2 proteins in LPS-stimulated RAW264.7 macrophage cells [54]. This species also produces two diterpene compounds, klysimplexins B and H, exhibiting moderate cytotoxicity towards human carcinoma cell lines. Klysimplexin B exhibits cytotoxicity toward human hepatocellular carcinoma (Hep G2 and Hep 3B), human breast carcinoma (MDA-MB-231 and MCF-7), human lung carcinoma (A549) and human gingival carcinoma (Ca9-22) cell lines with IC₅₀’s of 3.0, 3.6, 6.9, 3.0, 2.0, and 1.8 μg/mL, respectively. Metabolite klysimplexin H demonstrated cytotoxicity (IC₅₀’s 5.6, 6.9, 4.4, 5.6, 2.8 and 6.1 μg/mL) toward human hepatocellular carcinoma (Hep G2 and Hep 3B), human breast carcinoma (MDA-MB-231 and MCF-7), human lung carcinoma (A549) and human gingival carcinoma (Ca9-22) cell lines, respectively [55].

In Sinularia sp. (Figure 1A), a tetraprenylated spermine derivative has been isolated—sinulamide— which revealed an H,K-ATPase inhibitory activity. H,K-ATPase is a gastric proton pump of stomach and is the enzyme primarily responsible for the acidification of the stomach contents. Its inhibition is a very common clinical intervention used in diseases including dyspepsia, peptic ulcer, and gastroesophageal reflux (GORD/GERD). Sinulide is a potential antiulcer drug, as it inhibits production of gastric acid by H,K-ATPase (IC₅₀ 5.5 μM) [63]. Although it has been synthesized [100], no clinical trials seem to have been reported. The steroid gibberoketosterol [67], isolated from Sinularia gibberosa, and the diterpenoid querciformolide C [68] from Sinularia querciformis, showed significant inhibition of the up-regulation of the pro-inflammatory iNOS and COX-2 proteins in LPS-stimulated murine macrophages at concentration <10 μM [67,68]. Paralemnalia thyrsoides showed significant inhibition of pro-inflammatory iNOS protein expression (70% at IC₅₀ 10 μM) [101]. Sinularia species produce significant molecules: lipids from Sinularia grandilobata and another unspecified species of Sinularia possesses antibacterial and antifungal activity [64]. The diterpene 11-episinulariolide from Sinularia flexibilis is an interesting antifoulant exhibiting strong algacidal properties [66]. This species also produces cembrenoids, named flexilarins, which evidence cytotoxic activity in cancer cell lines. Flexilarin D exhibited potent cytotoxicity in human hepatocarcinoma (Hep2) cells with IC₅₀ 0.07 μg/mL, and moderate cytotoxic activity against human cervical epitheloid carcinoma (HeLa, IC₅₀ 0.41 μg/mL), human medulloblastoma (Daoy, 1.24 μg/mL) and human breast carcinoma (MCF-7, 1.24 μg/mL) cell lines [65].

Antifouling agents from natural sources are of increasing interest since the International Maritime Organization (IMO) banned the use of certain antifouling agents, such as tri-n-butyltin (TBT), due to the ecological impacts of these biocides in the marine environment. Several studies have demonstrated that soft corals can yield large quantities of promising antifouling metabolites [102,103]. In fact, 17.95% of potential antifouling natural compounds are from cnidarians (e.g., soft coral) [104]. One of the most promising natural antifouling agent identified so far is an isogosterone isolated from an unspecified Dendronephthya [77].

The genus Clavularia contains secondary metabolites with unique structures and remarkable biological activities. Some of the species in this genus produce prostanoids (icosanoids) [45,72,73,105,106], steroids [75] and diterpenoids [70,107]. The bioactive marine diterpene, stolonidiol, isolated from an unidentified Clavularia, showed potent choline acetyltransferase (ChAT) inducible activity in primary cultured basal forebrain cells and clonal septal SN49 cells, suggesting that it may act as a potent neurotrophic factor-like agent on the cholinergic nervous system [69]. Cholinergic neurons in the basal forebrain innervate the cortex and hippocampus, and their function may be closely related to cognitive function and memory. The degeneration of neuronal cells in this brain region is considered to be responsible for several types of dementia including Alzheimer’s disease. One of the neurotransmitters, acetylcholine, is synthesized from acetyl coenzyme A and choline by the action of ChAT. Therefore, induction of ChAT activity in cholinergic neurons may improve the cognitive function in diseases exhibiting cholinergic deficits [108–110].

Prostanoids (claviridic acid) isolated from Clavularia viridis exhibited potent inhibitory effects on phytohemagglutinin-induced proliferation of peripheral blood mononuclear cells (PBMC, 5 μg/mL), as well as significant cytotoxic activity against human gastric cancer cells (AGS, IC₅₀ 1.73–7.78 μg/mL) [71]. Claviridenone extracts also showed potent cytotoxicity against mouse lymphocytic leukemia (P-388) and human colon adenocarcinoma (HT-29), and exceptionally potent cytotoxicty against human lung adenocarcinoma (A549) cells, with ED₅₀ between 0.52 pg/mL and 1.22 μg/mL [45]. Halogenated prostanoids also showed cytotoxic activity against human T lymphocyte leukemia cells (MOLT-4, IC₅₀ 0.52 μg/mL), human colorectal adenocarcinoma (DLD-1, IC₅₀ 0.6 μg/mL) and human diploid lung fibroblast (IMR-90, IC₅₀ 4.5 μg/mL) cells [72]. The cyclopentenone prostanoid, bromovulone III-a promising marine natural compound for treatment of prostate, colon and hepatocellular carcinoma-showed anti-tumor activity against human prostate (PC-3) and human colon (HT29) cancer cells at an IC₅₀ of 0.5 μM [73], and induced apoptotic signaling in a sequential manner in Hep3B cells [74]. In the case of prostate cancer cells, this compound displayed an anti-tumor activity 30 to 100 times more effective than cyclopentenone prostaglandins (known to suppress tumor cell growth and to induce apoptosis in prostate cancer cells), by causing a rapid redistribution and clustering of Fas (member of the tumor necrosis factor (TNF) receptor superfamily). Apoptotic stimulation of Fas by specific ligand or antibodies causes the formation of a membrane-associated complex comprising Fas clustering) in PC-3 cells [111]. C. viridis also produces steroids that show cytotoxic activity against human colorectal adenocarcinoma (DLD-1, 0.02 < IC₅₀ < 50 μg/mL) and also against human T lymphocyte leukemia cells (MOLT-4, 0.01 < IC₅₀ < 10 μg/mL), in the case of yonarasterols [75]. Stoloniferone additionally displayed potent cytotoxicity against mouse lymphocytic leukemia (P-388), human colon adenocarcinoma (HT-29) and human lung adenocarcinoma (A549) cells [45]. This species produces several compounds with anti-tumor activity in different types of human tumors, although more in vitro studies are needed to determine which compound are potential anticancer agents. Clavularia koellikeri produces diterpenoids as secondary metabolites, which display cytotoxic activity against human colorectal adenocarcinoma (DLD-1, IC₅₀ 4.2 μg/mL) and strong growth inhibition against human T lymphocyte leukemia cells (MOLT-4, IC₅₀ 0.9 μg/mL) [70].

In the genus Cespitularia, several interesting diterpenes of cembrane and neodolabellane skeletons have been identified. In Cespitularia hypotentaculata (family Xeniidae) a significant production of diterpenoids was detected. Cespitularin C exhibited potent cytotoxicity against mouse lymphocytic leukemia (P-388, ED₅₀ 0.01 μg/mL) and human lung adenocarcinoma (A549, ED₅₀ 0.12 μg/mL) cells, while cespitularin E exhibited potent cytotoxicity against human lung adenocarcinoma (A549, ED₅₀ 0.034 μg/mL) cell cultures [84]. A less active diterpene, Asterolaurin A, from Asterospicularia laurae (a species from the same family) exhibited cytotoxicity against human hepatocellular carcinoma (HepG2) cells with an IC₅₀ 8.9 μM [83].

Telesto riisei produces punaglandins, highly functional cyclopentadienone and cyclopentenone prostaglandins. Cyclopentenone prostaglandins have unique antineoplastic activity and are potent growth inhibitors in a variety of cultured cells. These punaglandins have been shown to inhibit P53 accumulation (a tumor suppressor protein) and ubiquitin isopeptidase activity (IC₅₀ between 0.04 and 0.37 μM) (enzyme involved in protein degradation system) in vitro and in vivo [76]. Since these proteasome inhibitors exhibit higher antiproliferative effects than other prostaglandins [112], they may represent a new class of potent cancer therapeutics.

3.2. Order Gorgonacea (Sea Fans)

Gorgonians are a well-known source of compounds exhibiting significant biological activity [113]. Table 3 summarizes the most promising compounds from order Gorgonacea (class Anthozoa) described in the present review. Studies on Isis hippuris have resulted in the isolation of a series of novel metabolites such as sesquiterpenes [114], steroids [115], A-nor-hippuristanol [116] and isishippuric acid B [116]. These compounds exhibit potent cytotoxicity against cancer cell lines of human hepatocellular carcinoma (HepG2 and Hep3B, IC₅₀ 0.08–4.64 μg/mL and 0.10–1.46 μg/mL, respectively) [116,117], human breast carcinoma (MCF-7, IC₅₀ 0.20–4.54 μg/mL and MDA-MB-231, IC₅₀ 0.13–2.64 μg/mL) [117], mouse lymphocytic leukemia (P-388), human lung adenocarcinoma (A549), and human colon adenocarcinoma (HT-29) with ED₅₀ values less than 0.1 μg/mL [115,116] and IC₅₀ of 0.1 μg/mL [114].

Species from the genus Pseudopterogorgia are a rich source of unusual biologically active diterpenoids, sesquiterpenes, and polyhydroxylated steroids, which exhibit diverse structures [127,140,141]. A sample of the organic extract of Pseudopterogorgia bipinnata was included in an initial screening carried out as part of an effort in the discovery of new antimalarial agents. This extract was found to be active in inhibiting the growth of Plasmodium falciparum (a protozoan parasite responsible for the most severe forms of malaria). Caucanolide A and D demonstrated significant in vitro antiplasmodial activity against chloroquine-resistant P. falciparum W2 (IC₅₀ 17 μg/mL and IC₅₀ 15 μg/mL, respectively) [128]. Three secosterols isolated from an unidentified gorgonian from genus Pseudopterogorgia inhibited human protein kinase C (PKC) α, βI, βII, γ, δ, ɛ, η, and ζ, with IC₅₀ values in the range 12–50 μM [125]. PKC is a key player in cellular signal transduction and has been implicated in cancer, cardiovascular and renal disorders, immunosuppression, and autoimmune diseases such as rheumatoid arthritis [99]. Semisynthetic derivatives also showed a similar activity [125]. Promising antimicrobial substances were also reported from Pseudopterogorgia rigida (e.g., curcuphenol) [136] and from Pseudopterogorgia elisabethae (e.g., pseudopterosin X and Y) [129]. Ileabethoxazole, homopseudopteroxazole, caribenols A and B and elisapterosin B from P. elisabethae and bipinnapterolide B from P. bipinnata inhibit Mycobacterium tuberculosis H₃₇Rv at a concentration of 12.5 μg/mL [131,133] (for elisapterosin B and homopseudopteroxazole) and at a concentration range of 128–64 μg/mL [130,132,142] (for others compounds). In fact, the inhibition of M. tuberculosis H₃₇Rv is within the ranges recorded for rifampin [130]. P. elisabethae and P. bipinnata also produce antituberculosis compounds. Bielschowskysin, a naturally occurring diterpene isolated from Pseudopterogorgia kallos [135] and aberrarone isolated from P. elisabethae [134] exhibited antiplasmodial activity (IC₅₀ 10 μg/mL) when tested against P. falciparum. The first compound was also found to display strong and specific in vitro cytotoxicity against the EKVX non-small cell lung cancer (GI₅₀ < 0.01 μM) and CAKI-1 renal cancer (GI₅₀ 0.51 μM) [135]. Bis(pseudopterane) amine from Pseudopterogorgia acerosa was found to exhibit selective activity against HCT116 (IC₅₀ 4 μM) cell lines [126].

Fuscosides, originally isolated from Eunicea fusca [138], selectively and irreversibly inhibited leukotriene synthesis. Leukotrienes are molecules of the immune system that contribute to inflammation in asthma and allergic rhinitis and its production is usually related to histamine release [143]. Pharmacological studies indicated that fuscoside B inhibits the conversion of arachidonic acid (AA) to leukotriene B₄ and C₄ (LTB₄ and LTC₄) [138,144] by inhibiting the 5-Lipoxygenase (5-LO), in the case of LTB₄ with an IC₅₀ of 18 μM [144]. These selective inhibitors of lipoxygenase isoforms can be useful as pharmacological agents, as nutraceuticals or as molecular tools [99]. Sesquiterpenoids metabolites isolated from Eunicea sp. display antiplasmodial activity against the malaria parasite P. falciparum W2 (chloroquine-resistant) strain, with IC₅₀ values ranging from 10 to 18 μg/mL [137].

The gorgonian Junceella fragilis produces secondary metabolites, frajunolides B and C, with anti-inflammatory effects towards superoxide anion generation and elastase release by human neutrophils, with an IC₅₀ > 10 μg/mL [121]. When properly stimulated, activated neutrophils secrete a series of cytotoxins, such as the superoxide anion (O₂^·−), a precursor of other reactive oxygen species (ROS), granule proteases, and bioactive lipids [145,146]. The production of the superoxide anion is linked to the killing of invading microorganisms, but it can also directly or indirectly damage surrounding tissues. On the other hand, neutrophil elastase is a major secreted product of stimulated neutrophils and a major contributor to the destruction of tissue in chronic inflammatory disease [147]. The anti-inflammatory butenolide lipide [148] from the gorgonian Euplexaura flava [139] can be currently synthesized, opening the possibility of advancing into a new level of anti-inflammatory pharmaceuticals.

Some of the most interesting compounds identified so far in the on-going search for new anti-fouling agents have been recorded in the order Gorgonacea. Good examples of such compounds are juncin ZII from Junceella juncea [122], homarine from Leptogorgia virgulata and Leptogorgia setacea [123], pukalide and epoxypukalide recorded so far only from L. virgulata [124].

Species of genus Briareum (family Briareidae) (Figure 1D) (which commonly exhibit an incrusting appearance rather than the fan-like shape of many gorgonians) are widely abundant in Indo-Pacific and Caribean coral reefs. These organisms have been recognized as a valuable source of bioactive compounds with novel structural features. Briarane-related natural products are a good example of such promising compounds due to their structural complexity and biological activity [149,150]. Briaexcavatin E, from Briareum excavata (Nutting 1911), also occasionally referred to as Briarium excavatum, inhibited human neutrophil elastase (HNE) release with an IC₅₀ between 5 and 10 μM [118]. Briaexcavatolides L and P, diterpenoids from the same species exhibited significant cytotoxicity against mouse lymphocytic leukemia (P-388) tumor cells with ED₅₀ of 0.5 [119] and 0.9 μg/mL [151], respectively. Diterpenoids produced from Briareum polyanthes (presently accepted as Briareum asbestinum), namely Briarellin D, K and L, exhibited antimalarial activity against P. falciparum with an IC₅₀ between 9 and 15 μg/mL [120].

3.3. Other Orders

Sea anemones (order Actiniaria) are a rich source of biologically-active proteins and polypeptides. Several cytolytic toxins, neuropeptides and protease inhibitors have been identified from them [48]. In addition to several equinatoxins, potent cytolytic proteins and an inhibitor of papain-like cysteine proteinases (equistatin), were isolated from the sea anemone Actinia equina [152]. Equistatin has been shown to be a very potent inhibitor of papain and a specific inhibitor of the aspartic proteinase cathepsin D [153]. While papain-like cysteine proteases have been implicated in various diseases of the central nervous system, such as brain tumors, Alzheimer’s disease, stroke, cerebral lesions, neurological autoimmune diseases and certain forms of epilepsy [154], aspartic proteinase cathepsin D is involved in the pathogenesis of breast cancer [155] and possibly Alzheimer’s disease [156].

Cycloaplysinopsin C, a bis(indole) alkaloid isolated from Tubastrea sp. (order Scleractinia), was found to inhibit growth of two strains of P. falciparum, one chloroquine-sensitive (F32/Tanzania) and other chloroquine-resistant (FcB1/Colombia) with IC₅₀ 1.48 and 1.2 μg/mL, respectively [51]. Cladocorans A and B, isolated from Cladocora caespitosa (order Scleractinia) [49], are marine sesterterpenoids which possess a γ-hydroxybutenolide moiety, which is thought to be responsible for the biological activity of these compounds. The potent anti-inflammatory activity of these natural metabolites was attributed to the inhibition of secretory phospholipase A₂ (sPLA₂, IC₅₀ 0.8–1.9 μM). Given the general role of inflammation in diseases that include bronchial asthma and rheumatoid arthritis, identifying and developing potent inhibitors of sPLA2 continues to be of great importance for the pharmaceutical industry, with this type of metabolite being of paramount importance for future research [50].

4. Class Hydrozoa

Class Hydrozoa includes seven orders and nearly 3500 valid species (Table 1), some of which are solitary, some of which are colonial. Among the most emblematic species are probably hydroids and the Portuguese man-o-war (Physalia physalis). Despite the large number of species in class Hydrozoa, only a few of them have yielded interesting MNPs in the last decade.

Immune escape plays an important role in cancer progression and, although not completely understood, it has been proposed that indoleamine 2,3-dioxygenase (IDO) plays a central role in evasion of T-cell-mediated immune rejection [157]. IDO catalyzes the oxidative cleavage of the 2,3 bond of tryptophan, which is the first and rate-limiting step in the kynurenine pathway of tryptophan catabolism in mammalian cells [158]. The polyketides annulins A, B, and C, purified from the marine hydroid Garveia annulata (order Anthoathecata), potently inhibited IDO in vitro (K_i 0.12–0.69 μM) [159]. These annulins are more powerful than most tryptophan analogues known to be IDO inhibitors. These compounds are active at concentrations higher than ~10 μM and therefore more effective than 1-methyltryptophan (K_i 6.6 μM), one of the most potent IDO inhibitors currently available [160]. Solandelactones C, D, and G are cyclopropyl oxylipins isolated from the hydroid Solanderia secunda (order Anthoathecata) and exhibit moderate inhibitory activity against farnesyl protein transferase (FPT, 69, 89, and 61% inhibition, respectively) at a concentration of 100 μg/mL [161]. Note that FPT is associated with cell differentiation and proliferation and its inhibition may be a target for novel anticancer agents (as already referred above for the soft coral L. cristagalli).

5. Class Scyphozoa

Approximately 200 species are currently classified in three orders in class Scyphozoa (Table 1). However, in the last decade, only a single MNP purified from the mesoglea of the jellyfish Aurelia aurita (order Semaeostomeae) was considered to be promising enough to be included in the present work. This compound is a novel endogenous antibacterial peptide, aurelin, which exhibited activity against Gram-positive and Gram-negative bacteria. As an example, aurelin displayed an IC₅₀ of 7.7 μg/mL for Esherichia coli (Gram negative bacteria) [162].

6. Other Classes

The classes Staurozoa, Cubozoa and Polypodiozoa are the least speciose in the phylum Cnidaria (Table 1). This fact may explain the current lack of data on secondary metabolites produced by these organisms. It is possible that with growing bioprospecting new MNPs may be revealed once these cnidarian species are screened. Cubozoa (box jellies), for example, produce some of the most harmful cnidarian toxins for humans [163].

7. Exploring the Unexplored and Being Creative: Future Perspectives for the Bioprospecting of Cnidarians

For several years, the bioprospecting of cnidarians was commonly limited to habitats that could be readily sampled by researchers, such as shallow coral reefs and the intertidal region. However, with improvements in SCUBA gear, researchers are now able to dive deeper and longer, allowing them to collect a wider range of cnidarian species for the screening of MNPs. The growing efforts to explore Earth’s last frontier, the deep sea, made it possible to start bioprospecting several unique marine ecosystems that had remained either previously unrecorded or inaccessible to researchers [164]. New cnidarian species (some of them belonging to new genera and probably even to new families) (e.g., [165,166]) are currently being sampled from the deep sea. These findings suggest that many new species are yet to be discovered along deep continental margins [167] and open good perspectives for the discovery of new MNPs with ongoing surveys of deep sea fauna. Cnidarians are known to colonize unique deep sea biotopes, namely chemosynthetic sites (such as hydrothermal vents, cold seeps and whale falls [168]), as well as seamounts [169]. Some of these organisms are endemic to these habitats and display remarkable adaptations to extreme environments (e.g., chemosynthetic sea anemones) [170]. These species are certainly interesting candidates for the discovery of new MNPs [171]. However, some of these remarkable biotopes, namely deep sea coral reefs, are already facing serious threats to their conservation [169] and thus, the bioprospecting of these and other endangered habitats must be carefully addressed [164,172].

Another interesting source of cnidarian species for bioprospecting is the marine aquarium industry. Over 200 species of hard and soft corals, along with several other anemone, zoanthid and corallimorph species, are harvested every year from coral reefs to supply the marine aquarium trade [173]. However, researchers using these organisms in the bioprospecting of new MNPs must be aware that it is not commonly possible to get reliable information on either the place of origin or the scientific name of most traded specimens. With the advent of high-throughput screening (HTS) [174], it will be possible to rapidly survey these organisms for interesting MNPs, although HTS of natural sources may present several challenges (see [175,176]). If necessary, additional biomass of target organisms producing interesting MNPs can be achieved using inexpensive techniques [177,178] and eliminate problems commonly faced by researchers screening marine organisms for MNPs–the loss of the source and reproducibility [176].

The discovery of a new compound commonly requires only small amounts of biomass. However the production of these compounds at a scale large enough to fulfill commercial applications is still nearly impossible [179]. In theory, large-scale production of bioactive compounds can be achieved by chemical synthesis or through extraction from marine animals, either harvested from the sea or maricultured. The existence of ecophysiological diversity (e.g., differences between individuals often due to differences in environmental interactions) can interfere with the production of MNPs and must be carefully addressed in future efforts for large-scale production of these compounds. The harvest of target animals from the wild for the production of chemical compounds is commonly an unsustainable solution, while mariculture has proven to be more technically challenging and expensive than previously assumed [180]. In other considerations, chemical synthesis is not yet developed to synthesize complex molecules at the kilogram scale and, in cases where this may already be technically possible, most of the compounds cannot be synthesized at a price affordable for commercial applications [179]. Potential solutions for such bottlenecks may be the use of diverted total synthesis [181] and/or metabolic engineering [182].

There is growing evidence that microbes associated with marine invertebrates may be the true producers of some of the bioactive compounds isolated from these animals [179]. Whether this is the case of bioactive compounds currently assumed to be produced by cnidarians remains unanswered [183,184]. If so, we face another constraint for the commercial use of these compounds, as the culture of symbiotic microorganisms is generally not possible using classic/standardized methodologies.

8. Conclusions

The intense pressure to find and develop more profitable molecules for all sorts of industries continues to fuel the bioprospecting of marine invertebrates. Although the phylum Cnidaria is not the most significantly bioprospected at present, this review shows that some cnidarian species are promising sources of marine bioactive compounds of medical, economic and scientific interest. Green fluorescent protein (GFP), GPF-like proteins, red fluorescent and orange fluorescent protein (OPF) are good examples of biotechnological metabolites currently employed as molecular biomarkers. They were first purified from a fluorescent hydrozoan medusa [185] and since then have been recorded in other cnidarian species [186–191].

In the present survey, only about 0.31% of extant cnidarian species are represented, with class Anthozoa displaying by far the highest number of promising MNPs (Figure 2). This result is probably due to the fact that this class is the most speciose in the phylum (Table 1). Additionally, many anthozoans occupy marine habitats which can be readily accessed for the collection of biomass (e.g., coral reefs and intertidal regions), which facilitates bioprospecting. Of all the compounds presented in this review, 84% were detected in cnidarians collected from tropical waters (mostly from Southeast Asia and the Caribbean Sea) and the remaining 16% were recorded from species mostly occupying temperate waters (e.g., European countries and Japan).

Antitumor drugs are the main area of interest in the screening of MNPs from cnidarians (41%, Figure 3). This is not surprising, as the major financial effort for the screening of new marine compounds is made in cancer research [192]. Terpenoids (terpenoid, diterpenoid, sesquiterpenoid, sesterterpenoid, cembranoid) [193] (Figure 4) are the main chemistry group within the MNPs analyzed in this survey.

Even though most pharmaceutical industries abandoned their natural product-based discovery programs over a decade ago, the lack of new compounds in their pipelines in some strategic areas (e.g., antibiotics) suggests that renewed interest in this field is imminent. The establishment of small biotech companies can play a decisive role in the initial discovery of promising marine bioactive compounds, as these enterprises will work closely together with academics and governmental agencies performing the initial steps in the discovery of new MNPs. Collaboration between private companies and public institutions can be of paramount importance for financial support in the discovery process. On the other side, crude extracts and pure compounds produced by academic laboratories may be screened by diverse bioassays as a part of broader collaboration programs, nationally and internationally, with private biotech companies. One challenge for universities is to devise mechanisms that protect intellectual property and simultaneously encourage partnerships with the private sector, by recognizing that the chances of a major commercial pay-off are small if drug discovery is pursued by a single institution [3].

The commercial use of some promising marine bioactive compounds isolated from cnidarians may be several years away. New compounds other than toxins and venoms produced by members of this highly diverse group of marine invertebrates may be discovered in the quest for new marine products.

Acknowledgements

Joana Rocha is supported by a Fundação para a Ciência e Tecnologia PhD Grant (SFRH/BD/33476/ 2008) by PhD Program in Marine and Environmental Sciences. This research was partially financed by project LUSOEXTRACT (project no. 13107, QREN-SI I&DT, co-promotion and co-financed by POR Lisboa, AdI). The authors would like to acknowledge one anonymous reviewer and Daphne Fautin for their valuable comments on the manuscript.

References 1

Jain

Sonawane

Mandrekar

Marine organisms: Potential source for drug discovery

Curr. Sci200894292 2

Fenical

Jensen

Palladino

Lam

Lloyd

Potts

Discovery and development of the anticancer agent salinosporamide A (NPI-0052)

Bioorg. Med. Chem20091721752180

10.1016/j.bmc.2008.10.075

19022674

Hill

Fenical

Pharmaceuticals from marine natural products: Surge or ebb?

Curr. Opin. Biotechnol201021777779

10.1016/j.copbio.2010.10.007

21055916

Glaser

Mayer

AMS

A renaissance in marine pharmacology: From preclinical curiosity to clinical reality

Biochem. Pharmacol200978440448

10.1016/j.bcp.2009.04.015

19393227

Fusetani

Biotechnological potential of marine natural products

Pure Appl. Chem2010821726

10.1351/PAC-CON-09-01-11

Faulkner

Marine natural products

Nat. Prod. Rep199916155198

10.1039/a804469d

Faulkner

Marine natural products

Nat. Prod. Rep199815113158

10.1039/a815113y

9586223

Faulkner

Marine natural products

Nat. Prod. Rep199714259302

10.1039/np9971400259

Faulkner

Marine natural products

Nat. Prod. Rep19961375125

10.1039/np9961300075

8622813

Faulkner

Marine natural products

Nat. Prod. Rep199512223269

10.1039/np9951200223

Faulkner

Marine natural products

Nat. Prod. Rep199411355395

10.1039/np9941100355

15200019

Faulkner

Marine natural products

Nat. Prod. Rep199310497539

10.1039/np9931000497

8295744

Faulkner

Marine natural products

Nat. Prod. Rep1991897147

10.1039/np9910800097

1679913

Faulkner

Marine natural products

Nat. Prod. Rep19907269309

10.1039/np9900700269

2250800

Faulkner

Marine natural products

Nat. Prod. Rep19885613663

10.1039/np9880500613

3072499

Faulkner

Marine natural products

Nat. Prod. Rep19874539576

10.1039/np9870400539

3328831

Faulkner

Marine natural products

Nat. Prod. Rep19863133

10.1039/np9860300001

2872636

Faulkner

Marine pharmacology

Antonie Van Leeuwenhoek200077135145

10.1023/A:1002405815493

10768472

Faulkner

Marine natural products

Nat. Prod. Rep200118149

10.1039/b006897g

11245399

Faulkner

Marine natural products

Nat. Prod. Rep200219148

11902436

Blunt

Copp

Munro

MHG

Northcote

Prinsep

Marine natural products

Nat. Prod. Rep200320148

10.1039/b207130b

12636082

Blunt

Copp

Munro

MHG

Northcote

Prinsep

Marine natural products

Nat. Prod. Rep200421149

10.1039/b305250h

15039834

Blunt

Copp

Munro

MHG

Northcote

Prinsep

Marine natural products

Nat. Prod. Rep2005221561

10.1039/b415080p

15692616

Blunt

Copp

Munro

MHG

Northcote

Prinsep

Marine natural products

Nat. Prod. Rep2006232678

10.1039/b502792f

16453031

Blunt

Copp

Munro

MHG

Northcote

Prinsep

Marine natural products

Nat. Prod. Rep2007243186

10.1039/b603047p

17268607

Blunt

Copp

Munro

MHG

Northcote

Prinsep

Marine natural products

Nat. Prod. Rep2008253594

10.1039/b701534h

18250897

Blunt

Copp

Munro

MHG

Northcote

Prinsep

Marine natural products

Nat. Prod. Rep200926170244

10.1039/b805113p

19177222

Blunt

Copp

Munro

MHG

Northcote

Prinsep

Marine natural products

Nat. Prod. Rep201027165237

10.1039/b906091j

20111802

Blunt

Copp

Munro

MHG

Northcote

Prinsep

Marine natural products

Nat. Prod. Rep201128196268

10.1039/c005001f

21152619

Mayer

Hamann

Marine Pharmacology in 2000: Marine compounds with antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiplatelet, antituberculosis, and antiviral activities; affecting the cardiovascular, immune, and nervous systems and other miscellaneous mechanisms of action

Mar. Biotechnol200463752

10.1007/s10126-003-0007-7

14583811

Mayer

AMS

Hamann

Marine pharmacology in 2001–2002: Marine compounds with anthelmintic, antibacterial, anticoagulant, antidiabetic, antifungal, anti-inflammatory, antimalarial, antiplatelet, antiprotozoal, antituberculosis, and antiviral activities; affecting the cardiovascular, immune and nervous systems and other miscellaneous mechanisms of action

Comp. Biochem. Physiol. C Toxicol. Pharmacol2005140265286

10.1016/j.cca.2005.04.004

15919242

Mayer

AMS

Gustafson

Marine pharmacology in 2001–2002: Antitumour and cytotoxic compounds

Eur. J. Cancer20044026762704

10.1016/j.ejca.2004.09.005

15571951

Mayer

AMS

Rodríguez

Berlinck

RGS

Hamann

Marine pharmacology in 2003–2004: Marine compounds with anthelmintic antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiplatelet, antiprotozoal, antituberculosis, and antiviral activities; affecting the cardiovascular, immune and nervous systems, and other miscellaneous mechanisms of action

Comp. Biochem. Physiol. C Toxicol. Pharmacol2007145553581

10.1016/j.cbpc.2007.01.015

17392033

Mayer

AMS

Gustafson

Marine pharmacology in 2003–2004: Anti-tumour and cytotoxic compounds

Eur. J. Cancer20064222412270

10.1016/j.ejca.2006.05.019

16901686

Mayer

AMS

Rodriguez

Berlinck

RGS

Hamann

Marine pharmacology in 2005–2006: Marine compounds with anthelmintic, antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiprotozoal, antituberculosis, and antiviral activities; affecting the cardiovascular, immune and nervous systems, and other miscellaneous mechanisms of action

Biochim. Biophys. Acta Gen. Subj20091790283308

10.1016/j.bbagen.2009.03.011

Mayer

AMS

Gustafson

Marine pharmacology in 2005–2006: Antitumour and cytotoxic compounds

Eur. J. Cancer20084423572387

10.1016/j.ejca.2008.07.001

18701274

Mayer

AMS

Rodríguez

Berlinck

RGS

Fusetani

Marine pharmacology in 2007–2008: Marine compounds with antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiprotozoal, antituberculosis, and antiviral activities; affecting the immune and nervous system, and other miscellaneous mechanisms of action

Comp. Biochem. Physiol. C Toxicol. Pharmacol2011153191222

10.1016/j.cbpc.2010.08.008

20826228

Mayer

AMS

Hamann

Marine pharmacology in 1999: Compounds with antibacterial, anticoagulant, antifungal, anthelmintic, anti-inflammatory, antiplatelet, antiprotozoal and antiviral activities affecting the cardiovascular, endocrine, immune and nervous systems, and other miscellaneous mechanisms of action

Comp. Biochem. Physiol. C Toxicol. Pharmacol2002132315339

10.1016/S1532-0456(02)00094-7

12161166

Sipkema

Franssen

MCR

Osinga

Tramper

Wijffels

Marine sponges as pharmacy

Mar. Biotechnol20057142162

10.1007/s10126-004-0405-5

15776313

Newman

Cragg

Marine natural products and related compounds in clinical and advanced preclinical trials

J. Nat. Prod20046712161238

10.1021/np040031y

15332835

Turk

Kem

The phylum Cnidaria and investigations of its toxins and venoms until 1990

Toxicon20095410311037

10.1016/j.toxicon.2009.06.031

19576920

Daly

Brugler

Cartwright

Collins

Dawson

Fautin

France

McFadden

Opresko

Rodriguez

The phylum Cnidaria: A review of phylogenetic patterns and diversity 300 years after Linnaeus

Zootaxa20071668127182 43

Boyd

Paull

Rubinstein

Data display and analysis strategies for the NCI disease-oriented in vitro antitumor drug screen

Cytotoxic Anticancer Drugs: Models and Concepts for Drug Discovery and DevelopmentSpringer

Dordrecht, The Netherlands

199220 44

El-Gamal

AAH

Chiang

C-Y

Huang

S-H

Wang

S-K

Duh

C-Y

Xenia diterpenoids from the Formosan soft coral Xenia blumi

J. Nat. Prod20056813361340

10.1021/np058047r

16180809

Duh

El-Gamal

AAH

Chu

Wang

Dai

New cytotoxic constituents from the Formosan soft corals Clavularia viridis and Clavularia violacea

J. Nat. Prod20026515351539

10.1021/np0201873

12444673

Appeltans

Bouchet

Boxshall

Fauchald

Gordon

Hoeksema

Poore

GCB

van Soest

RWM

Stöhr

Walter

Costello

Cnidaria. World Register of Marine Species2010Available online: http://www.marinespecies.org/aphia.php?p=taxdetails&id=1267

accessed on 4 January 2011

Fautin

University of Kansas

Lawrence, KS, USA

Personal communication by e-mail2011 48

Strukelj

Lenarcic

Gruden

Pungercar

Rogelj

Turk

Bosch

Jongsma

Equistatin, a protease inhibitor from the sea anemone Actinia equina, is composed of three structural and functional domains

Biochem. Biophys. Res. Commun2000269732736

10.1006/bbrc.2000.2356

10720485

Fontana

Ciavatta

Cimino

Cladocoran A and B: Two novel γ-hydroxybutenolide sesterterpenes from the Mediterranean coral Cladocora cespitosa

J. Org. Chem19986328452849

10.1021/jo971586j

Miyaoka

Yamanishi

Mitome

PLA₂ inhibitory activity of marine sesterterpenoids cladocorans, their diastereomers and analogues

Chem. Pharm. Bull200654268270

10.1248/cpb.54.268

16462082

Meyer

Delberghe

Liron

Guillaume

Valentin

Guyot

An antiplasmodial new (bis)indole alkaloid from the hard coral Tubastraea sp

Nat. Prod. Res200923178182

10.1080/14786410801925134

19173125

Hooper

Davies-Coleman

New metabolites from the South African soft coral Capnella thyrsoidea

Tetrahedron19955199739984

10.1016/0040-4020(95)00570-X

Bhakuni

Rawat

Bioactive Marine Natural ProductsSpringer

Dordrecht, The Netherlands

2005396 54

Wen

Hsu

Chen

Dai

Kuo

Sheu

Simplexins A–I, eunicellin-based diterpenoids from the soft coral Klyxum simplex

J. Nat. Prod2009729941000

10.1021/np900064a

19391605

Chen

Chiang

Wang

Fan

Sheu

Eunicellin-based diterpenoids from the cultured soft coral Klyxum simplex

Tetrahedron20096570167022

10.1016/j.tet.2009.06.047

Nguyen

Chau

Phan

Hoang

Nguyen

Tran

Nguyen

Hyun

Kang

Chemical components from the Vietnamese soft coral Lobophytum sp

Arch. Pharm. Res201033503508

10.1007/s12272-010-0402-3

20422357

Rashid

Gustafson

Boyd

HIV-inhibitory cembrane derivatives from a Philippines collection of the soft coral Lobophytum species

J. Nat. Prod200063531533

10.1021/np990372p

10785433

Chao

C-H

Wen

Z-H

Y-C

Yeh

H-C

Sheu

J-H

Cytotoxic and anti-inflammatory cembranoids from the soft coral Lobophytum crassum

J. Nat. Prod20087118191824

10.1021/np8004584

18973388

Coval

Patton

Petrin

James

Rothofsky

Lin

Patel

Reed

McPhail

Bishop

A cembranolide diterpene farnesyl protein transferase inhibitor from the marine soft coral Lobophytum cristagalli

Bioorg. Med. Chem. Lett19966909912

10.1016/0960-894X(96)00142-4

Cheng

S-Y

Wen

Z-H

Chiou

S-F

Hsu

C-H

Wang

S-K

Dai

C-F

Chiang

Duh

C-Y

Durumolides A–E, anti-inflammatory and antibacterial cembranolides from the soft coral Lobophytum durum

Tetrahedron20086496989704

10.1016/j.tet.2008.07.104

Cheng

Wen

Wang

Chiou

Hsu

Dai

Chiang

Duh

Unprecedented hemiketal cembranolides with anti-inflammatory activity from the soft coral Lobophytum durum

J. Nat. Prod200972152155

10.1021/np800686k

19177635

Huang

Chao

Kuo

Sheu

Crassocolides G–M, cembranoids from the Formosan soft coral Sarcophyton crassocaule

Chem. Biodivers2009612321242

10.1002/cbdv.200800142

19697342

Fusetani

Research toward drugs from the sea

New J. Chem199014721728 64

Dmitrenok

Radhika

Anjaneyulu

Subrahmanyam

Subba Rao

Dmitrenok

Boguslavsky

New lipids from the soft corals of the Andaman Islands

Russ. Chem. Bull20035218681872

10.1023/A:1026089612129

Lin

Chen

Liaw

Chen

Kuo

Shen

Cembrane diterpenoids from the Taiwanese soft coral Sinularia flexibilis

Tetrahedron20096591579164

10.1016/j.tet.2009.09.031

Michalek

Bowden

A natural algacide from soft coral Sinularia flexibilis (Coelenterata, Octocorallia, Alcyonacea)

J. Chem. Ecol199723259273

10.1023/B:JOEC.0000006358.47272.56

Ahmed

Hsieh

Y-T

Wen

Z-H

Y-C

Sheu

J-H

Polyoxygenated sterols from the Formosan soft coral Sinularia gibberosa

J. Nat. Prod20066912751279

10.1021/np0601509

16989519

Huang

Lin

Wen

Kuo

Chiang

Sheu

Anti-inflammatory cembranoids from the soft corals Sinularia querciformis and Sinularia granosa

J. Nat. Prod20087117541759

10.1021/np8003563

18831569

Yabe

Yamada

Shimomura

Miyaoka

Yamada

Induction of choline acetyltransferase activity in cholinergic neurons by stolonidiol: structure-activity relationship

J. Nat. Prod200063433435

10.1021/np990263a

10785408

Iwashima

Matsumoto

Takahashi

Iguchi

New marine cembrane-type diterpenoids from the Okinawan soft coral Clavularia koellikeri

J. Nat. Prod20006316471652

10.1021/np000309w

11141107

Lin

Khalil

Chiou

Kuo

Cheng

Liaw

Shen

Bioactive marine prostanoids from octocoral Clavularia viridis

Chem. Biodivers20085784792

10.1002/cbdv.200890075

18493965

Watanabe

Sekine

Takahashi

Iguchi

New halogenated marine prostanoids with cytotoxic activity from the Okinawan soft coral Clavularia viridis

J. Nat. Prod20016414211425

10.1021/np010244c

11720524

Shen

Cheng

Lin

Guh

Teng

New prostanoids with cytotoxic activity from Taiwanese octocoral Clavularia viridis

J. Nat. Prod200467542546

10.1021/np030435a

15104481

Chiang

P-C

Chien

C-L

Pan

S-L

Chen

W-P

Teng

C-M

Shen

Y-C

Guh

J-H

Induction of endoplasmic reticulum stress and apoptosis by a marine prostanoid in human hepatocellular carcinoma

J. Hepatol200543679686

10.1016/j.jhep.2005.02.049

16023761

Iwashima

Nara

Nakamichi

Iguchi

Three new chlorinated marine steroids, yonarasterols G, H and I, isolated from the Okinawan soft coral Clavularia viridis

Steroids2001662532

10.1016/S0039-128X(00)00144-6

11090655

Verbitski

Mullally

Fitzpatrick

Ireland

Punaglandins, chlorinated prostaglandins, function as potent Michael receptors to inhibit ubiquitin isopeptidase activity

J. Med. Chem20044720622070

10.1021/jm030448l

15056003

Tomono

Hirota

Fusetani

Isogosterones A–D, antifouling 13,17-Secosteroids from an octocoral Dendronephthya sp

J. Org. Chem19996422722275

10.1021/jo981828v

Grote

Hanel

Dahse

Seifert

Capnellenes from the soft coral Dendronephthya rubeola

Chem. Biodivers2008516831693

10.1002/cbdv.200890157

18816521

Peukert

Staller

Schneider

Carmichael

Hanel

Eilers

An alternative pathway for gene regulation by Myc

EMBO J19971656725686

10.1093/emboj/16.18.5672

9312026

Hermeking

The MYC oncogene as a cancer drug target

Curr. Cancer Drug Targets20033163175

10.2174/1568009033481949

12769686

Cheng

Huang

Wang

Wen

Hsu

Dai

Duh

New terpenoids from the soft corals Sinularia capillosa and Nephthea chabroli

Org. Lett20091148304833

10.1021/ol901864d

19863144

Cheng

Wen

Wang

Chiang

El-Gamal

AAH

Dai

Duh

Revision of the absolute configuration at C(23) of Lanostanoids and isolation of secondary metabolites from Formosan soft coral Nephthea erecta

Chem. Biodivers200968695

10.1002/cbdv.200800015

19180458

Lin

Abd El-Razek

Hwang

Chiang

Kuo

Dai

Shen

Asterolaurins A–F, xenicane diterpenoids from the Taiwanese soft coral Asterospicularia laurae

J. Nat. Prod20097219111916

10.1021/np900231e

19863101

Duh

C-Y

El-Gamal

AAH

Wang

S-K

Dai

C-F

Novel terpenoids from the Formosan soft coral Cespitularia hypotentaculata

J. Nat. Prod20026514291433

10.1021/np020077w

12398538

Bishara

Rudi

Goldberg

Benayahu

Kashman

Novaxenicins A–D and xeniolides I–K, seven new diterpenes from the soft coral Xenia novaebrittanniae

Tetrahedron2006621209212097

10.1016/j.tet.2006.09.050

Konig

Wright

New cembranoid diterpenes from the soft coral Sarcophyton ehrenbergi

J. Nat. Prod199861494496

10.1021/np9704112

Chang

Wen

Wang

Duh

Capnellenes from the Formosan soft coral Capnella imbricata

J. Nat. Prod200871619621

10.1021/np0706116

18302334

Duh

Hou

Cytotoxic cembranoids from the soft corals Sinularia gibberosa and Sarcophyton trocheliophorum

J. Nat. Prod199659595598

10.1021/np960174n

Ahmed

Sung

Chao

Kuo

Sheu

Manaarenolides A–I, diterpenoids from the soft coral Sinularia manaarensis

J. Nat. Prod20066911341139

10.1021/np050483q

16933863

Norton

Kazlauskas

C-13 NMR-study of flexibilide, an anti-inflammatory agent from a soft coral

Experientia198036276278

10.1007/BF01952273

Williams

Faulkner

Two practical syntheses of an anti-inflammatory sesquiterpene furoic acid from Sinularia spp

Tetrahedron19965242454256

10.1016/0040-4020(96)00133-0

Weinheimer

Matson

Hossain

van der Helm

Marine anticancer agents: sinularin and dihydrosinularin, new cembranolides from the soft coral Sinularia flexibilis

Tetrahedron Lett19771829232926

10.1016/S0040-4039(01)83115-4

Zhang

Deng

van Ofwegen

Proksch

Lin

Cytotoxic cembranoid Diterpenes from a soft coral Sinularia gibberosa

J. Nat. Prod200568649652

10.1021/np040197z

15921403

Aceret

Coll

Uchio

Sammarco

Antimicrobial activity of the diterpenes flexibilide and sinulariolide derived from Sinularia flexibilis Quoy and Gaimard 1833 (Coelenterata: Alcyonacea, Octocorallia)

Comp. Biochem. Physiol. C Pharmacol. Toxicol. Endocrinol1998120121126

10.1016/S0742-8413(98)00032-2

9827024

Aceret

Brown

Miller

Coll

Sammarco

Cardiac and vascular responses of isolated rat tissues treated with diterpenes from Sinularia flexibilis (Coelenterata: Octocorallia)

Toxicon19963411651171

10.1016/0041-0101(96)00044-X

8931257

Sheikh

Singy

Kaisin

Eggert

Djerassi

Tursch

Daloze

Braekman

Terpenoids—LXXI: Chemical studies of marine invertebrates-XIV. Four representatives of a novel sesquiterpene class—the capnellane skeleton

Tetrahedron19763211711178

10.1016/0040-4020(76)85041-7

Kaisin

Sheikh

Durham

Djerassi

Tursch

Daloze

Braekman

Losman

Karlsson

Capnellane—a new tricyclic sesquiterpene skeleton from the soft coral Capnella imbricata

Tetrahedron Lett19741522392242

10.1016/S0040-4039(01)92222-1

Kaisin

Braekman

Daloze

Tursch

Novel acetoxycapnellenes from the alcyonacean Capnella imbricata

Tetrahedron19854110671072

10.1016/S0040-4020(01)96474-9

Nakao

Fusetani

Enzyme inhibitors from marine invertebrates

J. Nat. Prod200770689710

10.1021/np060600x

17362037

100

Sata

Sugano

Matsunaga

Fusetani

Sinulamide: An H,K-ATPase inhibitor from a soft coral Sinularia sp

Tetrahedron Lett199940719722

10.1016/S0040-4039(98)02438-1

101

Huang

H-C

Wen

Z-H

Chao

C-H

Ahmed

Chiang

Kuo

Y-H

Hsu

C-H

Sheu

J-H

Novel sesquiterpenoids from the Formosan soft coral Paralemnalia thyrsoides

Tetrahedron Lett20064787518755

10.1016/j.tetlet.2006.10.002

102

Coll

The chemistry and chemical ecology of octocorals (Coelenterata, Anthozoa, Octocorallia)

Chem. Rev199292613631

10.1021/cr00012a006

103

Maida

Sammarco

Coll

A diffusion chamber for assessing efficacy of natural anti-fouling defenses in marine organisms

J. Exp. Mar. Biol. Ecol20063375964

10.1016/j.jembe.2006.06.008

104

Chambers

Stokes

Walsh

Wood

RJK

Modern approaches to marine antifouling coatings

Surf. Coat. Technol200620136423652

10.1016/j.surfcoat.2006.08.129

105

Watanabe

Iwashima

Iguchi

New marine prostanoid carboxylate salts from the Okinawan soft coral Clavularia viridis

J. Nat. Prod199659980982

10.1021/np9603481

106

Iwashima

Terada

Okamoto

Iguchi

Tricycloclavulone and clavubicyclone, novel prostanoid-related marine oxylipins, isolated from the Okinawan soft coral Clavularia viridis

J. Org. Chem20026729772981

10.1021/jo011043g

11975555

107

Kusumi

Hamada

Hara

Ishitsuka

Ginda

Kakisawa

Structure and absolute-configuration of Isoclavukerin-A, a component from an Okinawan soft coral

Tetrahedron Lett19923320192022

10.1016/0040-4039(92)88129-S

108

Davies

Maloney

AJF

Selective loss of central cholinergic neurons in Alzheimer’s disease

Lancet197630814031403 109

Whitehouse

Price

Struble

Clark

Coyle

Delon

Alzheimer’s disease and senile dementia: Loss of neurons in the basal forebrain

Science198221512371239

10.1126/science.7058341

7058341

110

Bartus

Dean

Beer

Lippa

The cholinergic hypothesis of geriatric memory dysfunction

Science1982217408414

10.1126/science.7046051

7046051

111

Chiang

Kung

Huang

Fan

Pan

Shen

Guh

Induction of Fas clustering and apoptosis by coral prostanoid in human hormone-resistant prostate cancer cells

Eur. J. Pharmacol20065422230

10.1016/j.ejphar.2006.05.030

16806159

112

Tsukamoto

Yokosawa

Inhibition of the ubiquitin-proteasome system by natural products for cancer therapy

Planta Med20107610641074

10.1055/s-0029-1240901

20186654

113

Chai

Sun

Tang

Yang

Huang

Zhou

Yang

Liu

A novel cyclopentene derivative and a polyhydroxylated steroid from a South China sea gorgonian Menella sp

Chem. Pharm. Bull20105813911394

10.1248/cpb.58.1391

20930410

114

Sheu

J-H

Hung

K-C

Wang

G-H

Duh

C-Y

New Cytotoxic Sesquiterpenes from the Gorgonian Isis hippuris

J. Nat. Prod20006316031607

10.1021/np000271n

11141096

115

González

Barral

Rodríguez

Jiménez

New cytotoxic steroids from the gorgonian Isis hippuris. Structure-activity studies

Tetrahedron20015734873497

10.1016/S0040-4020(01)00223-X

116

Sheu

Chao

Wang

Hung

Duh

Chiang

The first A-nor-hippuristanol and two novel 4,5-secosuberosanoids from the Gorgonian Isis hippuris

Tetrahedron Lett20044564136416

10.1016/j.tetlet.2004.07.001

117

Chao

C-H

Huang

L-F

Yang

Y-L

J-H

Wang

G-H

Chiang

Y-C

Dai

C-F

Sheu

J-H

Polyoxygenated steroids from the gorgonian Isis hippuris

J. Nat. Prod200568880885

10.1021/np050033y

15974612

118

Sung

P-J

Chen

Y-P

Hwang

T-L

W-P

Fang

L-S

Y-C

J-J

Sheu

J-H

Briaexcavatins C–F, four new briarane-related diterpenoids from the Formosan octocoral Briareum excavatum (Briareidae)

Tetrahedron20066256865691

10.1016/j.tet.2006.03.086

119

Sung

P-J

J-H

Duh

C-Y

Chiang

Sheu

J-H

Briaexcavatolides K–N, new briarane diterpenes from the Gorgonian Briareum excavatum

J. Nat. Prod200164318323

10.1021/np000287d

11277747

120

Ospina

Rodríguez

Ortega-Barria

Capson

Briarellins J–P and Polyanthellin A: New Eunicellin-based diterpenes from the gorgonian coral Briareum polyanthes and their antimalarial activity

J. Nat. Prod200366357363

10.1021/np0204500

12662092

121

Shen

Chen

Hwang

Guh

Khalil

Four new briarane diterpenoids from the gorgonian coral Junceella fragilis

Helv. Chim. Acta20079013911398

10.1002/hlca.200790141

122

Zhang

Qian

Antifeedant and antifouling briaranes from the South China Sea gorgonian Junceella juncea

Chem. Nat. Compd2009454954

10.1007/s10600-009-9255-8

123

Targett

Bishop

McConnell

Yoder

Antifouling agents against the benthic marine diatom Navicula salinicola: Homarine from the gorgonians Leptogorgia virgulata and L. setacea and analogs

J. Chem. Ecol19839817829

10.1007/BF00987807

124

Gerhart

Rittschof

Mayo

Chemical ecology and the search for marine antifoulants—Studies of a predatory-prey symbiosis

J. Chem. Ecol19881419051917

10.1007/BF01013485

125

Kulanthaivel

Baker

Kalter

Darges

Cofield

Wolff

Adams

New antiproliferative and antiinflammatory 9,11-secosterols from the gorgonian Pseudopterogorgia sp

Tetrahedron1995515158

10.1016/0040-4020(94)00962-T

126

Kate

Pearson

Ramanathan

Richard

Kerr

Isolation, biomimetic synthesis, and cytotoxic activity of bis(pseudopterane) amines

J. Nat. Prod20097213311334

10.1021/np8008144

19572740

127

Ospina

Rodríguez

Zhao

Raptis

Bipinnapterolide B, a bioactive oxapolycyclic diterpene from the Colombian gorgonian coral Pseudopterogorgia bipinnata

Tetrahedron Lett20074875207523

10.1016/j.tetlet.2007.08.069

128

Ospina

Rodríguez

Sánchez

Ortega-Barria

Capson

Mayer

AMS

Caucanolides A–F, unusual antiplasmodial constituents from a Colombian collection of the gorgonian coral Pseudopterogorgia bipinnata

J. Nat. Prod20056815191526

10.1021/np050239z

16252918

129

Ata

Win

Holt

Holloway

Segstro

Jayatilake

New antibacterial diterpenes from Pseudopterogorgia elisabethae

Helv. Chim. Acta20048710901098

10.1002/hlca.200490099

130

Rodríguez

Wang

Franzblau

Ileabethoxazole: A novel benzoxazole alkaloid with antimycobacterial activity

Tetrahedron Lett20064732293232

10.1016/j.tetlet.2006.03.048

131

Rodríguez

Homopseudopteroxazole, a new antimycobacterial diterpene alkaloid from Pseudopterogorgia elisabethae

J. Nat. Prod200366855857

10.1021/np030052c

12828474

132

Wei

Rodríguez

Barnes

Caribenols A and B, sea whip derived norditerpenes with novel tricarbocyclic skeletons

J. Org. Chem20077273867389

10.1021/jo070649n

17715964

133

Rodriguez

Ramirez

Rodriguez

Barnes

Novel terpenoids from the West Indian sea whip Pseudopterogorgia elisabethae (Bayer). Elisapterosins A and B: Rearranged diterpenes possessing an unprecedented cagelike framework

J. Org. Chem20006513901398

10.1021/jo9914869

10814100

134

Rodriguez

Zhao

Aberrarone: A gorgonian-derived diterpene from Pseudopterogorgia elisabethae

J. Org. Chem20097475817584

10.1021/jo901578r

19736920

135

Marrero

Rodríguez

Baran

Raptis

Sánchez

Ortega-Barria

Capson

Bielschowskysin, a gorgonian-derived biologically active diterpene with an unprecedented carbon skeleton

Org. Lett2004616611664

10.1021/ol049495d

15128261

136

McEnroe

Fenical

Structures and synthesis of some new antibacterial sesquiterpenoids from the gorgonian coral Pseudopterogorgia rigida

Tetrahedron19783416611664

10.1016/0040-4020(78)80198-7

137

Garzón

Rodríguez

Sánchez

Ortega-Barria

Sesquiterpenoid metabolites with antiplasmodial activity from a Caribbean gorgonian coral Eunicea sp

J. Nat. Prod20056813541359

10.1021/np0501684

16180813

138

Shin

Fenical

Fuscosides A–D: Antinflammatory diterpenoid glycosides of new structural classes from the Caribbean gorgonian Eunicea fusca

J. Org. Chem19915631533158

10.1021/jo00009a042

139

Kikuchi

Tsukitani

Nakanishi

Shimizu

Saitoh

Iguchi

Yamada

New butenolides from the gorgonian Euplexaura flava (Nutting)

Chem. Lett198211233236 140

Rodríguez

The natural products chemistry of West Indian gorgonian octocorals

Tetrahedron19955145714618

10.1016/0040-4020(95)00216-U

141

Fenical

Marine soft corals of the genus Pseudopterogorgia: A resource for novel anti-inflammatory diterpenoids

J. Nat. Prod19875010011008

10.1021/np50054a001

2895165

142

Marrero

Ospina

Rodríguez

Baran

Zhao

Franzblau

Ortega-Barria

New diterpenes of the pseudopterane class from two closely related Pseudopterogorgia species: Isolation, structural elucidation, and biological evaluation

Tetrahedron20066269987008

10.1016/j.tet.2006.04.070

143

Martelletti

Adriani

Bonini

Celestino

Lenti

Armaleo

Dipastena

Misasi

Giacovazzo

Basophil histamine-release and Leukotriene (LTB4-LTC4) production in cluster headache

Headache1989294648

10.1111/j.1526-4610.1989.hed2901046.x

2466813

144

Jacobson

Jacobs

Fuscoside—An antiinflammatory marine natural product which selectively inhibits 5-lipoxygenase. Biochemical-studies in the human neutrophil

J. Pharmacol. Exp. Ther1992262874882

1323665

145

Nathan

Neutrophils and immunity: challenges and opportunities

Nat. Rev. Immunol20066173182

10.1038/nri1785

16498448

146

Lacy

Eitzen

Control of granule exocytosis in neutrophils

Front. Biosci20081355595570

18508605

147

Pham

CTN

Neutrophil serine proteases: specific regulators of inflammation

Nat. Rev. Immunol20066541550

10.1038/nri1841

16799473

148

Boukouvalas

Loach

General, regiodefined access to alpha-substituted butenolides through metal-halogen exchange of 3-bromo-2-silyloxyfurans. Efficient synthesis of an anti-inflammatory gorgonian lipid

J. Org. Chem20087381098112

10.1021/jo8015924

18798671

149

Sung

Sheu

Survey of briarane-type diterpenoids of marine origin

Heterocycles200257535579

10.3987/REV-01-546

150

Sung

Chang

Fang

Sheu

Chen

Lin

Survey of briarane-related diterpenoids—part II

Heterocycles200565195204

10.3987/REV-04-589

151

Sung

Chiang

Sheu

New polyoxygenated briarane diterpenoids, Briaexcavatolides O–R, from the Gorgonian Briareum excavatum

J. Nat. Prod20016414151420

10.1021/np010253l

11720523

152

Lenarcic

Ritonja

Strukelj

Turk

Equistatin, a new inhibitor of cysteine proteinases from Actinia equina, is structurally related to thyroglobulin type-1 domain

J. Biol. Chem19972721389913903

9153250

153

Lenarcic

Turk

Thyroglobulin Type-1 domains in equistatin inhibit both Papain-like cysteine proteinases and Cathepsin D

J. Biol. Chem1999274563566

10.1074/jbc.274.2.563

9872988

154

Brömme

Petanceska

Papain-Like Cysteine Proteases and Their Implications in Neurodegenerative Diseases

Role of Proteases in the Pathophysiology of Neurodegenerative DiseasesLajtha

Banik

Springer

New York, NY, USA

20024761 155

Wolf

Clark-Lewis

Buri

Langen

Lis

Mazzucchelli

Cathepsin D specifically cleaves the chemokines macrophage inflammatory protein-la, macrophage inflammatory protein-1 beta, and SLC that are expressed in human breast cancer

Am. J. Pathol200316211831190

10.1016/S0002-9440(10)63914-4

12651610

156NCBI

CTSD cathepsin D [Homo sapiens]

Entrez Gene—Genes and mapped phenotypes2010Available online: http://www.ncbi.nlm.nih.gov/gene/1509

accessed on 7 December 2010

157

Muller

DuHadaway

Donover

Sutanto-Ward

Prendergast

Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy

Nat. Med200511312319

10.1038/nm1196

15711557

158

Grohmann

Fallarino

Puccetti

Tolerance, DCs and tryptophan: much ado about IDO

Trends Immunol200324242248

10.1016/S1471-4906(03)00072-3

12738417

159

Pereira

Vottero

Roberge

Mauk

Andersen

Indoleamine 2,3-dioxygenase inhibitors from the northeastern Pacific marine hydroid Garveia annulata

J. Nat. Prod20066914961499

10.1021/np060111x

17067170

160

Muller

Malachowski

Prendergast

Indoleamine 2,3-dioxygenase in cancer: Targeting pathological immune tolerance with small-molecule inhibitors

Expert Opin. Ther. Targets20059831849

10.1517/14728222.9.4.831

16083346

161

Seo

Cho

Rho

Shin

Kwon

Bok

Song

Solandelactones A–I, lactonized cyclopropyl oxylipins isolated from the hydroid Solanderia secunda

Tetrahedron1996521058310596

10.1016/0040-4020(96)00606-0

162

Ovchinnikova

Balandin

Aleshina

Tagaev

Leonova

Krasnodembsky

Men’shenin

Kokryakov

Aurelin, a novel antimicrobial peptide from jellyfish Aurelia aurita with structural features of defensins and channel-blocking toxins

Biochem. Biophys. Res. Commun2006348514523

10.1016/j.bbrc.2006.07.078

16890198

163

Brinkman

Burnell

Biochemical and molecular characterisation of cubozoan protein toxins

Toxicon20095411621173

10.1016/j.toxicon.2009.02.006

19232527

164

Synnes

Bioprospecting of organisms from the deep sea: Scientific and environmental aspects

Clean Technol. Environ. Policy200795359

10.1007/s10098-006-0062-7

165

Moura

Cunha

Schuchert

Tubiclavoides striatum gen. nov et sp nov (Cnidaria: Hydrozoa) a new bathyal hydroid from the Gulf of Cadiz, north-east Atlantic Ocean

J. Mar. Biol. Assoc. UK200787421428

10.1017/S002531540705415X

166

Rodriguez

Lopez-Gonzalez

Daly

New family of sea anemones (Actiniaria, Acontiaria) from deep polar seas

Polar Biol200932703717

10.1007/s00300-008-0575-0

167Census of Marine LifeAvailable online: http://www.coml.org/discoveries/species/bathyal_hydroid

accessed on 3 January 2011

168

Fautin

Structural diversity, systematics, and evolution of cnidae

Toxicon20095410541064

10.1016/j.toxicon.2009.02.024

19268491

169

Clark

Tittensor

Rogers

Brewin

Schlacher

Rowden

Stocks

Consalvey

Seamounts, Deep-sea Corals and Fisheries: Vulnerability of Deep-Sea Corals to Fishing on Seamounts Beyond Areas of National JurisdictionUNEP-WCMC

Cambridge, UK

2006 170

Rodriguez

Daly

Phylogenetic relationships among deep-sea and chemosynthetic sea anemones: Actinoscyphiidae and actinostolidae (Actiniaria: Mesomyaria)

PLoS One20105e10958

10.1371/journal.pone.0010958

20532040

171

Skropeta

Deep-sea natural products

Nat. Prod. Rep20082511311166

10.1039/b808743a

19030606

172

Kingston

DGI

Modern natural products drug discovery and its relevance to biodiversity conservation

J. Nat. Prod201074496511

21138324

173

Wabnitz

Taylor

Green

Razak

From Ocean to AquariumUNEP-WCMC

Cambridge, UK

2003 174

White

High-throughput screening in drug metabolism and pharmacokinetic support of drug discovery

Ann. Rev. Pharmacol. Toxicol200040133157

10.1146/annurev.pharmtox.40.1.133

175

Koehn

Carter

The evolving role of natural products in drug discovery

Nat. Rev. Drug Discov20054206220

10.1038/nrd1657

15729362

176

JWH

Vederas

Drug discovery and natural products: End of an Era or an endless frontier?

Science2009325161165

10.1126/science.1168243

19589993

177

Shafir

Van Rijn

Rinkevich

Coral nubbins as source material for coral biological research: A prospectus

Aquaculture2006259444448

10.1016/j.aquaculture.2006.05.026

178

Sella

Benayahu

Rearing cuttings of the soft coral Sarcophyton glaucum (Octocorallia, Alcyonacea): Towards mass production in a closed seawater system

Aquaculture Res20104117481758

10.1111/j.1365-2109.2009.02475.x

179

Qian

Fusetani

Natural products as antifouling compounds: recent progress and future perspectives

Biofouling201026223234

10.1080/08927010903470815

19960389

180

Mendola

Aquaculture of three phyla of marine invertebrates to yield bioactive metabolites: process developments and economics

Biomol. Eng200320441458

10.1016/S1389-0344(03)00075-3

12919831

181

Paterson

Anderson

The renaissance of natural products as drug candidates

Science2005310451453

10.1126/science.1116364

16239465

182

Khosla

Keasling

Timeline—Metabolic engineering for drug discovery and development

Nat. Rev. Drug Discov2003210191025

10.1038/nrd1256

14654799

183

Piel

Metabolites from symbiotic bacteria

Nat. Prod. Rep200926338362

10.1039/b703499g

19240945

184

Piel

Metabolites from symbiotic bacteria

Nat. Prod. Rep200421519538

10.1039/b310175b

15282634

185

Shimomura

Johnson

Saiga

Extraction, purification and properties of aequorin, a bioluminescent protein from luminous hydromedusan, Aequorea

J. Cell. Comp. Physiol196259223239

10.1002/jcp.1030590302

13911999

186

Schnitzler

Keenan

McCord

Matysik

Christianson

Haddock

Spectral diversity of fluorescent proteins from the Anthozoan Corynactis californica

Mar. Biotechnol200810328342

10.1007/s10126-007-9072-7

18330643

187

DTM

Wong

Wan

DCC

Characterization of novel orange fluorescent protein cloned from cnidarian tube anemone Cerianthus sp

Mar. Biotechnol20079469478

10.1007/s10126-007-9005-5

17530459

188

Chan

MCY

Karasawa

Mizuno

Bosanac

Prive

Miyawaki

Ikura

Structural characterization of a blue chromoprotein and its yellow mutant from the sea anemone Cnidopus japonicus

J. Biol. Chem20062813781337819

10.1074/jbc.M606921200

17028187

189

Henderson

Remington

Campbell

Directed evolution of a monomeric, bright and photostable version of Clavularia cyan fluorescent protein: Structural characterization and applications in fluorescence imaging

Biochem. J2006400531540

10.1042/BJ20060874

16859491

190

Goulding

Shrestha

Dria

Hunt

Deo

Red fluorescent protein variants with incorporated non-natural amino acid analogues

Protein Eng. Des. Sel200821101106

10.1093/protein/gzm075

18203801

191

Xiong

Zhen

Zhong

Peng

Chen

Jiang

Liu

Yang

Wei

Dong

A naturally enhanced green fluorescent protein from magnificent sea anemone (Heteractis magnifica) and its functional analysis

Biochem. Biophys. Res. Commun2003301879885

10.1016/S0006-291X(03)00019-6

12589794

192

Pomponi

The oceans and Human health: The discovery and development of marine-derived drugs

Oceanography2001147887 193

Blunt

Munro

MHG

Dictionary of Marine Natural Products with CD-ROMChapman & Hall/CRC, Taylor & Francis Group

Boca Raton, FL, USA

2008119

Figures and Tables Figure 1

Some cnidarians addressed in this review (all images by Ricardo Calado). (A) Sinularia sp.; (B) Xenia sp.; (C) Sarcophyton sp.; (D) Briareum sp.

Figure 2

Marine bioactive compounds with high biotechnological potential studied from the phylum Cnidaria in the last decade.

Figure 3

Distribution in drug classes of marine bioactive compounds with high biotechnological potential studied from cnidarian species in the last decade.

Figure 4

Distribution of chemistry classes of marine bioactive compounds with high biotechnological potential studied from cnidarian species in the last decade.

Table 1

Classes and orders in the phylum Cnidaria followed in this paper.

Phylum	Class	Order
Cnidaria (≈11,287 species)	Anthozoa (≈7500 species)	ActiniariaAntipathariaCerianthariaCorallimorphariaScleractinia	ZoanthideaAlcyonaceaGorgonaceaHelioporaceaPennatulacea
	Cubozoa (≈36 species)	Carybdeida	Chirodropida
	Hydrozoa (≈3500 species)	AnthoathecataLeptothecataSiphonophoraeActinulida	LimnomedusaeNarcomedusaeTrachymedusae
	Polypodiozoa (1 species)
	Scyphozoa (≈200 species)	CoronataeRhizostomeae	Semaeostomeae
	Staurozoa (≈50 species)	Stauromedusae

Table 2

Most promising compounds studied in the last decade from cnidarian species in order Alcyonacea (soft corals), class Anthozoa.

Family and Species	Drug Class	Compound	Chemistry	Country	Ref.
Alcyoniidae
Klyxum simplex	Anti-inflammatory	Simplexin E	Diterpenoid	TAIW	[54]
Klyxum simplex	Antitumor	Klysimplexin B and H	Diterpenoid	TAIW	[55]
Lobophytum sp.	Antitumor	Lobophytene	Diterpenoid	VN	[56]
Lobophytum sp.	Anti-HIV	Lobohedleolide	Diterpenoid	PHL	[57]
Lobophytum sp.	Anti-HIV	(7Z)-lobohedleolide,	Diterpenoid	PHL	[57]
Lobophytum sp.	Anti-HIV	17-dimethylamino lobohedleolide	Diterpenoid	PHL	[57]
Lobophytum crassum	Anti-inflammatory	Crassumolides A and C	Terpenoid	TAIW	[58]
Lobophytum cristagalli	Antitumor	Cembranolide diterpene	Diterpenoid	RSC	[59]
Lobophytum durum	Anti-inflammatory	Durumolides A–C	Terpenoid	TAIW	[60]
Lobophytum durum	Anti-inflammatory	Durumhemiketalolide A–C	Cembranoid	TAIW	[61]
Sarcophyton crassocaule	Antitumor	Crassocolides H–M	Cembranoid	TAIW	[62]
Sinularia sp.	Antiulcer	Sinulide	Spermine		[63]
Sinularia sp.	Antimicrobial	Lipids	Polyketide	RUS	[64]
Sinularia flexibilis	Antitumor	Flexilarin D	Cembranoid	TAIW	[65]
Sinularia flexibilis	Antifoulant	11-episinulariolide	Diterpenoid	AUS	[66]
Sinularia gibberosa	Anti-inflammatory	Gibberoketosterol	Steroid	TAIW	[67]
Sinularia querciformis	Anti-inflammatory	Querciformolide C	Terpenoid	TAIW	[68]
Clavulariidae
Clavularia sp.	Nervous system	Stolonidiol	Diterpenoid	JPN	[69]
Clavularia koellikeri	Antitumor	Cembrane-type diterpenoid	Diterpenoid	JPN	[70]
Clavularia viridis	Antitumor	Claviridic acid	Prostanoid	TAIW	[71]
Clavularia viridis	Antitumor	Clavulones	Prostanoid	TAIW	[71]
Clavularia viridis	Antitumor	Claviridenone	Prostanoid	TAIW	[45]
Clavularia viridis	Antitumor	Halogenated prostanoids	Prostanoid	JPN	[72]
Clavularia viridis	Antitumor	Bromovulone III	Prostanoid	TAIW	[73,74]
Clavularia viridis	Antitumor	Yonarasterols	Steroid	JPN	[75]
Clavularia viridis	Antitumor	Stoloniferone E	Steroid	TAIW	[45]
Telesto riisei	Antitumor	Punaglandins	Prostaglandin	USA	[76]
Nephtheidae
Dendronephthya sp.	Antifoulant	Isogosterones A–D	Steroid	JPN	[77]
Dendronephthya rubeola	Antitumour	Capnell-9(12)-ene-8β,10α-diol	Sesquiterpenoid	DE	[78,79,80]
Nephthea chabroli	Antitumor	Chabranol	Terpenoid	TAIW	[81]
Nephthea erecta	Anti-inflammatory	Ergostanoids 1 and 3	Ergostanoid	TAIW	[82]
Xeniidae
Asterospicularia laurae	Antitumor	Asterolaurin A	Diterpenoid	TAIW	[83]
Cespitularia hypotentaculata	Antitumor	Cespitularin C	Diterpenoid	TAIW	[84]
Xenia novaebritanniae	Antibacterial	Xeniolide I	Diterpenoid	ISR	[85]
Xenia plicata	Antitumor	Blumiolide C	Diterpenoid	TAIW	[44]

AUS: Australia; DE: Germany; ISR: Israel; JPN: Japan; PHL: Philippines; RSC: Republic of Seychelles; RUS: Russia; TAIW: Taiwan; VN: Vietnam.

Table 3

Most promising compounds studied in the last decade from cnidarian species in order Gorgonacea (sea fans), class Anthozoa.

Family and Species	Drug Class	Compound	Chemistry	Country	Ref.
Briareidae
Briareum excavate	Anti-inflammatory	Briaexcavatin E	Diterpenoid	TAIW	[118]
Briareum excavate	Antitumor	Briaexcavatolides L and P	Diterpenoid	TAIW	[119]
Briareum asbestinum	Antimalarial	Briarellin D, K and L	Diterpenoid	PAN, USA	[120]
Ellisellidae
Junceella fragilis	Anti-inflammatory	Frajunolides B and C	Terpenoid	TAIW	[121]
Junceella juncea	Antifoulant	Juncin ZII	Diterpenoid	TAIW	[122]
Gorgoniidae
Leptogorgia setácea	Antifoulant	Homarine	Pyridine	GEO	[123]
Leptogorgia virgulata	Antifoulant	Homarine	Pyridine	GEO	[123]
Leptogorgia virgulata	Antifoulant	Pukalide	Diterpenoid	USA	[124]
Leptogorgia virgulata	Antifoulant	Epoxypukalide	Diterpenoid	USA	[124]
Pseudopterogorgia sp.	Antitumor	Secosterols	Sterol	USA	[125]
Pseudopterogorgia sp.	Anti-inflammatory	Secosterols	Sterol	USA	[125]
Pseudopterogorgia acerosa	Antitumor	Bis(pseudopterane) amine	Dialkylamine	BHS	[126]
Pseudopterogorgia bipinnata	Antituberculosis	Bipinnapterolide B	Terpenoid	USA	[127]
Pseudopterogorgia bipinnata	Antimalarial	Caucanolide A and D	Diterpenoid	COL, PAN, USA	[128]
Pseudopterogorgia elisabethae	Antimicrobial	Pseudopterosin X	Diterpenoid	USA	[129]
Pseudopterogorgia elisabethae	Antituberculosis	Ileabethoxazole	Diterpenoid	USA	[130]
Pseudopterogorgia elisabethae	Antituberculosis	Homopseudopteroxazole	Diterpenoid	USA	[131]
Pseudopterogorgia elisabethae	Antituberculosis	Caribenols A and B	Terpenoid	USA	[132]
Pseudopterogorgia elisabethae	Antituberculosis	Elisapterosin B	Diterpenoid	USA	[133]
Pseudopterogorgia elisabethae	Antimalarial	Aberrarone	Diterpenoid	COL	[134]
Pseudopterogorgia kallos	Antimalarial	Bielschowskysin	Diterpenoid	PAN, USA	[135]
Pseudopterogorgia kallos	Antitumor	Bielschowskysin	Diterpenoid	PAN, USA	[135]
Pseudopterogorgia rígida	Antimicrobial	Curcuphenol	Terpenoid	USA	[136]
Isididae
Isis hippuris	Antitumor	Suberosenol B	Terpenoid	TAIW	[114]
Isis hippuris	Antitumor	Polyoxygenated steroids	Steroid	IND	[115,117]
Isis hippuris	Antitumor	A –nor-hippuristanol	Steroid	TAIW	[116]
Isis hippuris	Antitumor	Isishippuric acid B	Steroid	TAIW	[116]
Plexauridae
Eunicea sp.	Antimalarial	Sesquiterpenoids	Sesquiterpenoid	COL, PAN, USA	[137]
Eunicea fusca	Anti-inflammatory	Fuscisides	Diterpenoid	USA	[138]
Euplexaura flava	Anti-inflammatory	Butenolide	Lipid	JPN	[139]

ND: Not Determined; BHS: Bahamas; COL: Colombia; GEO: Georgia; IND: Indonesia; PAN: Panama; TAIW: Taiwan; USA: United States of America.