Bioactive Compounds From Zoanthids (Cnidaria_Anthozoa)_A Brief Review With Emphasis on Alkaloids

8/13/2019 Bioactive Compounds From Zoanthids (Cnidaria_Anthozoa)_A Brief Review With Emphasis on Alkaloids

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International Research Journal of Biochemistry and Bioinformatics (ISSN-2250-9941) Vol. 3(1) pp. 1-6, January, 2013Available online http://www.interesjournals.org/IRJBBCopyright 2013 International Research Journals

Review

Bioactive compounds from zoanthids (Cnidaria:Anthozoa): A brief review with emphasis on alkaloidsC. A. M. da Rocha

Instituto Federal de Educao, Cincia e Tecnologia do Par - IFPA. Av. Almirante Barroso, 1155, Marco, CEP 66093-020, Belm, PA, Brazil

E-mail:[email protected] January 16,2013

The marine diversity has been the source of unique chemical compounds with the potential for industrialdevelopment as cosmetics, nutritional supplements, molecular probes, fine chemicals andagrochemicals, besides the production of pharmaceuticals. Their secondary metabolites derive from two

main biosynthetic pathways (the route of pyruvic and acetic acids and shikimic acid pathway) and belongto large groups such as alkaloids, phenolic compounds and terpenoids. Zoanthidea consists mostly ofsessile colonial anthozoans with individuals united by the basal portion. They have no skeleton, but thebody wall is usually encrusted with sediment. Zoanthids produce two main types of alkaloids: a uniqueclass of heteroaromatic amines known collectively as zoanthoxanthins responsible for their brightpigmentation, and the zoanthamine type with an original skeleton identified mainly from the genusZoanthus. Recently, was reported the isolation and structural characterization of a new class of alkaloidsnamed parazoanthines. These alkaloids were isolated as the major constituents of the Mediterranean Seaanemone Parazoanthus axinellae.

Keywords: Alkaloids; secondary metabolites; zoanthids.

INTRODUCTION

Alkaloids are nitrogen-containing compounds that occurnaturally not only in plants but also in microorganisms,marine organisms, and animals. Although it is not clearwhy alkaloids show significant biological activity, they areoften useful as drugs or biological probes forphysiological studies. As new and more complicateddiseases are encountered worldwide, the importance ofbioactive alkaloids has increased due to their potentialapplication in chemotherapy. As the application ofalkaloids has expanded, the definition of alkaloids hasbecome less restricted (Kuramoto et al., 2004).

Plants produce most of the bioactive alkaloids,including the anticancer action. One of the mostimportant is the Catharanthus roseus (L.) G. Don, alsoknown as Vinca, which is used by the population inMadagascar in treating diabetes. During testing ofhypoglycemic activity, extracts of this species producedgranulocytopenia as a result of suppression of bonemarrow of animals, suggesting evaluation in models ofleukemias and lymphomas. Confirmation of activity inthese models led to the isolation of the alkaloidsvinblastine and vincristine, which currently are of greatutility in the treatment of Hodgkin's lymphoma, Kaposi's

sarcoma, ovarian and testicular cancers and childhoodacute lymphoblastic leukemia (Brando et al., 2010).

Marine environments are among the richest inbiodiversity and most complex ecosystems. Marineinvertebrates are rich sources of bioactive compoundsand their biotechnological potential attracts scientific andeconomic interest worldwide. Although nearly 20,000compounds have been discovered since the field ofmarine bioactive compound biochemistry began in themid-1960s, only a very limited number have seenindustrial application. It has been clear since marine

bioprospecting began that the worlds oceans and theirdiverse biota represent a significant resource, perhapsthe greatest resource on Earth, for the discovery of newbioactive compounds (Rocha et al., 2011).

In the dearth of information about theethnopharmacology of species of marine invertebrates, itis worth considering comments on its ecology andevolutionary history to make inferences about thepresence of chemical defense mechanisms. Soft-bodiedlacking in obvious physical defense structures and oftencolorful that would be easy prey are strong candidates toholders of chemical defense (Faulkner, 2000).


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2 Int. Res. J. Biochem. Bioinform.

Figure1.Major pathways of secondary metabolism and their interconnectionsCnidarians, sponges, molluscs, sea squirts and algae

make up the group of chemically most prolific marinerepresentatives (Wilke, 2009). Among the cnidarians, theclass of anthozoans hitherto been the most studied,observing a reasonable number of biologically activesubstances, particularly in soft corals and gorgonians(Teixeira, 2009)

Cnidaria is a diverse group of marine invertebratesincludes over 11,000 species, 7500 of them belonging tothe class Anthozoa (Rocha et al., 2011). The orderZoanthidea consists mostly of sessile colonialanthozoans with individuals united by the basal portion.

They have no skeleton, but the body wall is usuallyencrusted with sediment and, usually, harborzooxanthellae symbionts (Longo, 2002).

Antitumor activity has been the major area of interestin the screening of cnidarian compounds, the mostpromising ones being terpenoids (monoterpenoids,diterpenoids, sesquiterpenoids) (Rocha et al., 2011).Apart from anticancer activity, these compounds haveproven to be an abundant source of pharmacologicallyactive agents for the production of therapeutic entities(Glaser and Mayer, 2009) against AIDS, inflammatoryconditions and microbial diseases.

Besides the production of pharmaceuticals, thismarine diversity has been the source of unique chemical

compounds with the potential for industrial developmentas cosmetics, nutritional supplements, molecular probes,fine chemicals and agrochemicals (Kijjoa andSawangwong, 2004).

This review attempted to bring together several recentpublications that focus on some of the most promisingmarine bioactive alkaloids isolated from zoanthids.Printed materials were used, as well as studies obtainedfrom scientific databases on the internet, such as: (1)Scielo (www.scielo.br), (2) BIREME/BVS - BibliotecaVirtual em Sade [Virtual Health Library]

(www.bireme.br), and (3) PubMed(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi).

Main groups of secondary metabolites

The products of secondary metabolism are substancesbelonging to a single type of organism, or a small groupof genetically related organisms (Mann, 1987). Accordingto Teixeira (2009), these products mediate ecologicainteractions between organisms and environment andbetween various organisms of the same species or

between different species. Such substances, whichallowed the success of the current representatives, havebeen studied by chemists of natural products and havealso been a source of food, fragrances, pigmentsinsecticides and medicines. Natural products osecondary metabolites derive from two main biosyntheticpathways (the route of pyruvic and acetic acids andshikimic acid pathway) and belong to large groups suchas alkaloids, phenolic compounds and terpenoids (Figure1).

The term alkaloid was first proposed by Meissner in1818 referring to their alkaline properties. In general, thenitrogen atom present in these molecules is from aminoacids and the heterocyclic ring formed provides the basis

for classification (Bruneton, 1999). The alkaloids arederived from aromatic amino acids (tryptophan, tyrosine)which are derivatives of shikimic acid, as well as aliphaticamino acids (ornithine, lysine).

Phenolic compounds are a large and diversegroup of molecules, which includes many differenfamilies of aromatic secondary metabolites in plantsThese phenolics are the most abundant secondarymetabolites in plants and can be classified into non-soluble compounds such as condensed tannins, ligninscell-wall bound hydroxycinammic acids, and soluble


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compounds such as phenolic acids, phenylpropanoids,flavonoids and quinones. All these groups are involved inmany processes in plants and animals. One family, theflavonoids, is of particular interest because of its multipleroles in plants and its impact on human health (Harborneand Williams, 2000).

Terpenoids (also called isoprenoids) constituteone of the largest families of natural products accountingfor more than 40,000 individual compounds of bothprimary and secondary metabolisms. Several terpenoidshave been shown to be available for pharmaceuticalapplications, for example, artemisinin and taxol asmalaria and cancer medicines, respectively (Goto et al.,2010).

Isoprene or Isopentyl diphosphate (IPP) and its isomerdimethylallyl diphosphate (DMAPP) are the universal five-carbon precursors of all terpenoids. After the discovery ofthe mevalonate (MVA) pathway in yeast and animals, itwas assumed that IPP was synthesized from acetyl-CoAvia MVA and then isomerized to DMAPP in all eukaryotesand some Gram-positive prokaryotes (Withers andKeasling, 2007).

Monoterpenoids (C10H16), made up of two isopreneunits, are the smallest and simplest type of terpenoids;sesquiterpenoids (C15H24) are made up three units;diterpenoids (C20H32), triterpenoids(C30H48) andtetraterpenoids (C40H64) are made up four, six and eightunits, respectively.

Ahmed et al. (2005) isolated three new oxygenatedsesquiterpenoids, (gibberodione, peroxygibberol, andsinugibberodiol), along with sarcophytol L from aFormosan soft coral, Sinularia gibberosa. The structuresof the new metabolites were determined on the basis of

extensive spectroscopic analyses and by comparison ofNMR data with those of related metabolites.Peroxygibberol and sarcophytol L were found to exhibitmoderate cytotoxicity toward a human liver carcinomacell line.

Other secondary metabolites from cnidarians

Palytoxin

Palytoxin (PLTX), found in Palythoa zoanthids andOstreopsis dinoflagellates, has also been detected in

crabs and fish, through which it can enter into the foodchain. Indeed, PLTX is considered the causative agent ofseveral cases of human seafood poisoning resulting insystemic symptoms. Available epidemiological data onPLTX human toxicity suggest that the intestinal tract maybe one of its in vivo targets and its potential site of accessinto the bloodstream (Pelin et al., 2012). It is a complexmolecule polyether initially isolated from the soft coralPalythoa toxica (Moore and Scheuer 1971).

Research on palytoxin action generally falls into twomajor areas. One broad class of studies focuses on how

palytoxin affects ion flux, which is the immediate effect othis compound on the cell. Another broad class ofstudies, discussed later, focuses on subsequent cellulaeffects stimulated by palytoxin that may be related totumor promotion. Palytoxin stimulates sodium influx andpotassium efflux, and thus depolarization of the

membrane, in a wide range of systems (Habermann1989). In excitable systems, palytoxin-stimulateddepolarization can modulate calcium channel activityresulting in a rise in intracellular calcium, which can thenstimulate events that are regulated by calcium-dependenpathways.

Palytoxin is a novel skin tumor promoter, which hasbeen used to help probe the role of different types ofsignaling mechanisms in carcinogenesis. The multistagemouse skin model indicates that tumor promotion is anearly, prolonged, and reversible phase of carcinogenesisUnderstanding the molecular mechanisms underlyingtumor promotion is therefore important for developingstrategies to prevent and treat cancer (Wattenberg2007).

Prostaglandins

A class of lipids with much pharmacological potential iscomposed by prostaglandins. These compounds arederivatives of prostanoic acid. The first structures oprostaglandins were elucidated in 1962 and so namedbecause it was believed they were synthesized inprostate. All natural prostaglandins have a hydroxyl groupat C-15, the trans double bond between C-13 and C-14and an oxygenated function at C-9 (Vieira et al., 2002).

Han et al. (2006) isolated two prostaglandins, PGA2and PGB2, from the Okinawan zoanthid Palythoa kochiiduring a search for paclitaxel-like neurite-degeneratingcompounds from natural sources using a cell-basedassay method. In the presence of PGA2 at 30 M, theneuronal processes induced in rat pheochromocytomacell line (PC12) by the nerve growth factor (NGF)degenerated over 24 h, whereas PGB2had no effect onthe neuronal processes of PC12 cells. This activity oPGA2 was similar to that of the microtubule-stabilizingagents, paclitaxel (Taxol) and epothilone A, unlike themicrotubule-depolymerizing agent, colchicine, whichbrought about quick neurite degeneration within 3 h

PGA2 stimulated tubulin polymerization although lesspotently than paclitaxel.

Lipidic -amino Acids

Lipidic -amino acids (LAAs) have been described asnon-natural amino acids with long saturated orunsaturated aliphatic chains. In the continuing prospect todiscover anticancer agents from marine sources, Wilke eal. (2010) have obtained a mixture of two cytotoxic LAAs


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from the zoanthid Protopalythoa variabilis. The anti-proliferative potential of 14 synthetic LAAs and of the twonatural LLAs was evaluated on four tumor cell lines(HCT-8, SF-295, MDA-MB-435, and HL-60). Five of thesynthetic LAAs showed high percentage of tumor cellinhibition, while the two natural LLAs completely inhibited

tumor cell growth. Additionally, apoptotic effects of theseLLAs were studied on HL-60 cell line. Treated cellsshowed apoptosis morphology, loss of mitochondrialpotential, and DNA fragmentation.

Bioactive alkaloids from zoanthids

Alkaloids are only rarely found in marine coelenteratesand they also appear to be restricted to animals withinthe order Zoanthidea. These organisms produce twotypes of alkaloids: a unique class of heteroaromaticamines known collectively as zoanthoxanthinsresponsible for their bright pigmentation, and thezoanthamine type with an original skeleton identifiedmainly from the genus Zoanthus (Daranas et al., 2000).

Zoanthoxanthins

Zoanthoxanthin alkaloids are yellow fluorescentsubstances emanate solely from colonial anthozoans inboth major families (Epizoanthidae and Zoanthidae) ofthe order Zoanthidea. Their molecules can vary amongthree skeletal types: 3H- zoanthoxanthin, 3H-pseudozoanthoxanthin and 4H-pseudozoanthoxanthin(Jimnez and Crews, 1993).

Turk et al. (1995) obtained an ethanolic extract from azoanthid crust coral Parazoanthus axinellae, which waslethal to mice and crabs and exhibited anticholinesteraseactivity. The isolation of several acetylcholinesterase(AChE) inhibitors was made with the aid of RP-HPLC.The most abundant of the inhibitors present in the P.axinellaeextract was identified as pseudozoanthoxanthinor an almost identical compound which belongs to thechemically well-characterized series oftetrazacyclopentazulene natural pigments from thegenera Parazoanthus, Epizoanthus, Zoanthus andPalythoa. The inhibitor has a molecular weight of 242 andacts as a competitive inhibitor with aKi of 4 M. The

inhibitor exhibited a strong blue fluorescence. In vivoaction of crude extract and the isolated inhibitor showed atypical picture of systemic AChE inhibition. Atropinizationof experimental animals prior to injection of the inhibitoralmost entirely neutralized its activity.

In the Turk et al. (1995) study, the most abundant ofthe inhibitors characterized as a methylatedpseudozoanthoxanthin variant, and some other pigmentsnot well characterized, expressed a potentanticholinesterase activity in vitro but was inactive withtrypsin or alkaline phosphate. Sepciet al. (1998) have

taken advantage of the chemical synthesis of therepresentative of zoanthoxanthins, parazoanthoxanthinA, to provide evidence for anticholinesterase activity ofthe linear form of these natural pigmentsParazoanthoxanthin A (ParaA) is a strongly fluorescenpigment occurring in zoanthids, which has been found to

inhibit electric eel (Electrophorus electricusacetylcholinesterase in the micromolar range.Nicotinic acetylcholine receptors are implicated in

different nervous system-related disorders, and theirmodulation could improve existing therapy of thesediseases. Since Parazoanthoxanthin A (ParaA) is apotent acetylcholinesterase inhibitor, it may also bind tonicotinic acetylcholine receptors (nAChRs). For thisreason its effect on Torpedo nAChR (12transplanted to Xenopus laevisoocytes was evaluated byRozman et al. (2010), using the voltage-clamp techniquePara A dose-dependently reduced the acetylcholineinduced currents. This effect was fully reversible only atlower concentrations. ParaA also reduced the Hilcoefficient and the time to peak current, indicating achannel blocking mode of action. On the other hand, thecombined effect of ParaA and d-tubocurarine (d-TC) onacetylcholine-induced currents exhibited only partiaadditivity, assuming a competitive mode of action oParaA on nAChR. These results indicate a dual mode oaction of ParaA on the Torpedo AChR.

Zoanthamines

Zoanthamine alkaloids, the first of which were isolatedover 20 years ago, are of particular interest to the

synthetic community because they feature a novestructural framework and exhibit a broad range obiological activities. Zoanthamine (1) was isolated byFaulkner et al. in 1984 from an unidentified coloniazoanthid Zoanthus sp. collected at the Visakhapatnamcoast of India and this compound was identified as thefirst member of a new class of alkaloids (Behenna et al.2008).

In 1995, Uemura and co-workers identified five newzoanthamine natural products isolated from a Zoanthusspecies collected off the Ayamaru coast of the AmamIslands south of Japan: norzoanthaminenorzoanthaminone, oxyzoanthamine, cyclozoanthamine

and epinorzoanthamine. The authors reported that thesezoanthamine natural products display significancytotoxicity against P388 murine leukemia cells (Table 1)The most potent cytotoxicity was displayed bynorzoanthaminone and oxyzoanthamine (Fukuzawa eal., 1995).

Norzoanthamine has also been reported as apromising candidate for an osteoporotic drug as an IL-6inhibitor. IL-6 is known to stimulate osteoclast formationand the suppression of IL-6 secretion can be effective inthe prevention of osteoporosis. Norzoanthamine and


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Table1.Cytotoxicity of the zoanthamine alkaloids

norzoanthamine hydrochloride inhibit IL-6 induction atvalues of 13 and 4.7 g/mL, respectively (Kuramoto etal., 1997). Furthermore, norzoanthamine andnorzoanthamine hydrochloride, both of which counteractdecreases in bone weight and strength in ovariectomizedmice, could be good candidates for osteoporotic drugs(Kuramoto et al., 2004).

Villar et al. (2003) evaluated ten zoanthamine-typealkaloids from two marine zoanthids belonging to theZoanthus genus (Zoanthus nymphaeus and Zoanthussp.) along with one semisynthetic derivative for theirantiplatelet activities on human platelet aggregationinduced by several stimulating agents. 11-Hydroxyzoanthamine and a synthetic derivative ofnorzoanthamine showed strong inhibition againstthrombin-, collagen- and arachidonic acid-inducedaggregation, zoanthenol displayed a selective inhibitoryactivity induced by collagen, while zoanthaminonebehaved as a potent aggregant agent. These evaluationsallowed to deduce several structureactivity relationshipsand suggested some mechanisms of action for this type

of compounds.Recently, Cachet et al. (2009) reported the isolation

and structural characterization of a new class of alkaloidsnamed parazoanthines A-E. These alkaloids wereisolated as the major constituents of the Mediterraneansea anemone Parazoanthus axinellae. Their structuralelucidation was achieved through NMR spectroscopicand mass spectrometric analyses. This family of alkaloidsrepresents the first example of natural 3,5-disubstitutedhydantoins which do not exhibit a methyl at N-3. Allcompounds were tested for their antitumor (MDA-MB-231, HT-29, and A-549) and antimalarial (FcB1) activitiesand none of them exhibited significant bioactivity.

During a screening of marine organisms for theirnatural toxicity, P. axinellaewas found to exhibit the mostbioactive extract among the cnidarians (Mart et al.,2005). Cachet et al. (2009) then decided to evaluate allthe isolated compounds in this Microtox

assay.

Parazoanthine C showed the highest natural toxicity(EC50= 1.64 M) and may consequently be responsiblefor the results obtained with the extract.

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Bioactive Compounds From Zoanthids (Cnidaria_Anthozoa)_A Brief Review With Emphasis on Alkaloids