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NPR
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View Article OnlineView Journal
Biogeography and
aDepartamento de Biologia & CESAM, Unive
de Santiago, 3810-193 Aveiro, Portugal. E-mbUniversity of Georgia, Skidaway Institute o
31411 Savannah, GA, USAcDepartment of Chemistry, University of CandZoo Logical – Associaç~ao de Inovaç~ao
Conservaç~ao da Fauna, Lisboa, PortugaleLUNAM universite, Universite de Nantes, M
Sciences et des Techniques, B.P. 92208, 443fCentro de Biodiversidade, Genomica Integr
Ciencias, Universidade de Lisboa, Campo GgCentro de Oceanograa, Faculdade de Ci
Grande, 1749-016 Lisboa, Portugal
Cite this: DOI: 10.1039/c3np70057g
Received 18th June 2013
DOI: 10.1039/c3np70057g
www.rsc.org/npr
This journal is ª The Royal Society of
biodiscovery hotspots of macroalgalmarine natural products
Miguel C. Leal,*ab Murray H. G. Munro,c John W. Blunt,c Jo~ao Puga,d Bruno Jesus,ef
Ricardo Calado,a Rui Rosag and Carolina Madeirag
Coverage period: 1965 to 2012
This review covers the literature published for marine natural products isolated from macroalgae and
addresses the taxonomic details of source organisms, the chemical types of isolated compounds and the
location of sampling sites. The emphasis of this review is on the identification of the most
bioprospected taxa and regions, as well as on how these trends have shifted over time.
1 Introduction2 The role of macroalgae in marine natural products
research2.1 Macroalgal taxonomy and discovery of marine natural
products2.2 Chemistry of macroalgal natural products3 Biogeography of macroalgal marine natural products3.1 Latitudinal trends3.2 Marine ecoregions3.3 Hotspots of natural product discovery3.4 Natural product discovery in Exclusive Economic Zones4 Conclusions5 References
1 Introduction
Biogeography aims to describe and understand the spatialpatterns of biodiversity based on the abundance and distribu-tion of biological communities.1 One of the most importantgoals in this eld of research is the denition of distinct regionsthrough the analysis of affinities and/or differences amongbiotas.2 Biogeography thus provides researchers a unique
rsidade de Aveiro, Campus Universitario
ail: [email protected]
f Oceanography, 10 Ocean Science Circle,
terbury, Christchurch, New Zealand
para o Conhecimento, Divulgaç~ao e
er Molecules Sante EA 2160, Faculte des
22 Nantes cedex 3, France
ativa e Funcional (BioFIG), Faculdade de
rande, 1749-016 Lisboa, Portugal
encias, Universidade de Lisboa, Campo
Chemistry 2013
insight into the mechanisms that constitute and maintaindiversity. Additionally, biogeography also attempts to under-stand the biological and physicochemical factors controllingthe structure of communities. This eld has been has beentraditionally associated with biology and macroecology,1,3 butapplications to marine chemical ecology have been rare. Fromthe perspective of marine natural product (MNP) chemists,information on biodiversity hotspots, species distribution andlatitudinal and longitudinal gradients may be useful to under-stand and predict the distribution of MNPs in the world'soceans. Further, the application of biogeography to MNPresearch may contribute to a better understanding of spatialand temporal patterns in the chemical composition of partic-ular biological groups from different regions, as well as toidentify unscreened taxa and geographical locations.4
It is unanimously acknowledged that the marine environ-ment presents an invaluable source of new natural products(NPs) that may hold noteworthy leads for future drug discoveryand development.5 It is therefore important to use currentbiogeographical information to direct future bioprospectingefforts and maximize the chances of discovering new chemicalentities. Because of the limited understanding of certain oceanareas (e.g. open ocean and deep-sea habitats) this is particularlyrelevant. Along with this limitation there are also discrepanciesin the consistency and quality of taxonomic and collection data,the key elements of the large datasets used in biogeography. It isworth noting that the information provided by MNP researchmay also be included in such datasets.6
The lack of a comprehensive dataset displaying chemical,taxonomic and geographic information is currently beingaddressed by the marine literature database MarinLit.7 The rstgroup of marine organisms with a dataset compiled and ana-lysed in this database is the macroalgae. Macroalgae have beenan historically important source of MNPs with relevant appli-cations, such as in the cosmetic, nutraceutical and
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pharmaceutical industries.8,9 To compile available informationon macroalgal NP discovery theMarinLit database was surveyedfor the period 1965 to 2012.7 Taxonomical, chemical andcollection site information were retrieved from each publicationwhere available. The World Register of Marine Species databasewas used to validate and/or update taxonomic classications.10
The goal of this review is to characterise the trends of MNPdiscovery frommacroalgae as a means to highlight biodiscoveryhotspots, as well as temporal and spatial patterns associatedwith macroalgal bioprospecting. The role of biogeography inguiding future efforts in algal natural product discovery is alsodiscussed.
Fig. 1 The cumulative number of new marine natural products (MNPs) from themacroalgal phyla between 1965 and 2012. Inset: ratio of new MNPs per genusand new MNPs per species for each phylum between 1965 and 2012.
2 The role of macroalgae in marine naturalproducts research
Algae are a heterogeneous group of organisms that arecommonly divided based on size: microalgae and macroalgae;with the microalgae commonly grouped within microorganismsin previous Marine Natural Products reviews.11,12 Macroalgae,also known as seaweeds, display a complex and dynamictaxonomy.13 The three main algal phyla are Rhodophyta (redalgae), Ochrophyta (brown algae) and Chlorophyta (greenalgae), from which a total of 3129 MNPs have been discoveredbetween 1965 and 2012 (Rhodophyta, 1658 NPs or 53% of thetotal; Ochrophyta, 1213 NPs; 39%; Chlorophyta, 258 NPs; 8%).
Macroalgae have been historically an important group oforganisms for marine drug development. While the pharma-cological properties of MNPs frommacroalgae were already wellknown from traditional and folk medicine prior to the 1950s,14
the rst comprehensive publications were only published in the1970s and covered MNPs discovered since the 1960s.15,16 It wasin the 1970s that MNP research began with great promise, fol-lowed by a period of rapid discovery of novel molecules.17
Marine algae were an important source of new MNPs during the1970s and 1980s and at that time represented about 28% of allnewly discovered MNPs.7 The increase in the discovery of algalMNPs that started in the 1970s was mostly associated with theRhodophyta (Fig. 1), which continued to provide new moleculesin the 1980s along with Ochrophyta. Between 1980 and 1994 a
Miguel Leal received his M. Sc. inMarine Ecology from the Univer-sity of Lisbon (Portugal) in 2009.He is currently completing hisPhD at the University of Aveiro(Portugal) in collaboration withthe Skidaway Institute of Ocean-ography (University of Georgia,USA). Miguel's work focuses oncoral reef ecology, particularlytrophic interactions. His researchinterests also include naturalproduct discovery and biogeog-
raphy, as well as marine biotechnology, with particular emphasison aquaculture of marine invertebrates and drug discovery.
Nat. Prod. Rep.
total of 1288 new NPs were discovered, representing an increaseof 153% relatively to the previous period (1965–1979). Thisincrease was associated with bioprospecting of red and brownalgae, which display a relatively high number of NPs per speciesand genus (Fig. 1, inset). It is worth noting that although asmaller number of NPs have been discovered from the Ochro-phyta as compared to the Rhodophyta, similar averages of NPsper species and genus are observed. These results also suggesthigh chemical diversity in macroalgae as the species targetedbefore 1990 represented less than 2% of all known marine algalspecies.10 Regardless of the large algal biodiversity thatremained unexplored, it is worth noting that there was only a4% increase in the discovery of macroalgal NPs from 1995 to2012 in relation to the period between 1980 and 1994.
2.1 Macroalgal taxonomy and discovery of marine naturalproducts
The macroalgal phyla producing MNPs are associated with 11classes, 38 orders, 68 families, 157 genera and 427 species. Thediscovery rate for algal MNPs has been relatively stable in thepast years, but different biodiscovery rates have been observedamong taxonomic groups (Fig. 1). Although 11 algal classes arecovered, we have focused on those classes that represent 99% ofthe macroalgal MNPs: Bryopsidophyceae, Floridophyceae,Phaeophyceae and Ulvophyceae. The most representative classis Floridophyceae, followed by Phaeophyceae (Table 1). Thealgal orders with the largest numbers of MNPs are Ceramiales,Dictyotales and Fucales, representing 33%, 16% and 17% of thetotal macroalgal MNPs, respectively. Within each of theseorders, the families Rhodomelaceae, Dictyotaceae and Sargas-saceae are highlighted (Table 1), as studies on these familiesaccount for the greater part of the MNP discoveries. These algalfamilies also contain a greater number of species. In contrast,some families with a lower number of species show a relativelyhigher number of MNPs, thus displaying a higher chemicaldiversity per species. For example, the families Areschougia-ceae, Rhizophyllidaceae, Sphaerococcaceae and Plocamiaceaeshow an average of 3, 5, 11 and 2 NPs per species. Especiallynoteworthy is the family Notheiaceae with 25 new NPs
This journal is ª The Royal Society of Chemistry 2013
Table 1 Total number of new natural products (NPs) from marine macroalgae for each time period and number of valid algal species currently accepted for eachtaxon. Only the most representative taxa (>95% of NPs) of each taxonomic level (class, order and family) are displayed.
Taxon
Total number of new NPsTotal number of valid species10 a
1965–1979 1980–1994 1995–2012
Phylum Chlorophyta 18 117 123 1798Class Bryopsidophyceae 10 89 66 498Order Bryopsidales 10 89 66 498Family Caulerpaceae 5 48 33 87Family Udoteaceae 5 23 8 79
Class Ulvophyceae 7 26 36 697Order Dasycladales 7 11 7 41Order Ulotrichales 0 10 2 83Order Ulvales 0 3 13 223
Phylum Ochrophyta 111 634 468 5025Class Phaeophyceae 111 619 466 1970Order Dictyotales 59 303 149 248Family Dictyotaceae 59 303 149 248
Order Fucales 48 239 257 576Family Sargassaceae 43 211 253 500Family Notheiaceae 0 24 1 1
Order Laminariales 0 52 27 135Family Lessoniaceae 0 38 14 28
Order Scytosiphonales 0 4 7 83Order Sporochnales 1 6 8 32
Phylum Rhodophyta 379 537 742 6401Class Florideophyceae 379 537 738 5930Order Bonnemaisoniales 113 22 10 34Family Bonnemaisoniaceae 113 22 10 25
Order Ceramiales 164 352 509 2460Family Rhodomelaceae 164 339 483 940Family Delesseriaceae 0 11 25 426
Order Corallinales 1 5 12 620Order Gigartinales 45 100 77 810Family Areschougiaceae 0 6 37 15Family Rhizophyllidaceae 32 40 10 16Family Sphaerococcaceae 3 19 20 14
Order Gracilariales 1 15 36 240Family Gracilariaceae 1 15 36 230
Order Halymeniales 0 13 7 280Order Nemaliales 0 4 24 245Family Galaxauraceae 0 0 24 33
Order Plocamiales 54 17 40 46Family Plocamiaceae 54 23 34 46
a Note that the number of valid species for each taxa include all algal species, regardless of being macro- or microalgae.
Fig. 2 The cumulative number of marine macroalgal species with naturalproducts discovered between 1965 and 2012.
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discovered from a single species: Notheia anomala is the solerepresentative of this family. Overall, the information presentedcontributes to a better understanding of which taxa have alargely unexplored chemical diversity.
A total of 427 macroalgal species belonging to 157 differentgenera yielded new MNPs. However, bioprospecting effortsthrough the years have not been evenly distributed across algalbiodiversity (Fig. 2). Although the bioprospecting efforts havebeen steadily increasing, there are still thousands of species tobe screened. Further, bioprospecting efforts among algalspecies have been extremely biased, as ve algal species alonewere the source of more than 50 new compounds each, whereas344 species have yielded less than ten new chemical entitieseach (Fig. 3). The ve species of algae yielding the highestnumber of NPs were: Laurencia obtusa (130 NPs), Dictyota
This journal is ª The Royal Society of Chemistry 2013 Nat. Prod. Rep.
Fig. 3 Number of new marine natural products (MNPs) discovered in each marine algal species. The values are ranked from the species with higher to lower MNPs.
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dichotoma (96 NPs), Laurencia nipponica (73 NPs), Plocamiumcartilagineum (65 NPs) and Portieria hornemannii (58 NPs).
2.2 Chemistry of macroalgal natural products
The classication of chemical types used in the Dictionary ofMarine Natural Products18 was used in the present work as aguideline. That is: aliphatic, carbohydrates, oxygen heterocy-cles, simple aromatic, polyketides, terpenoids, steroids, aminoacids and peptides, alkaloids, and polypyrroles. Please note thatalthough the carbohydrates as dened by the Dictionary ofMarine Natural Products include polysaccharides, MarinLit doesnot cover these chemical entities.
More than half of the MNPs covered in the present review areterpenoids (59%; Fig. 4); the other chemical groups account fora notably lower number of MNPs: simple aromatic (11%),polyketides (10%), aliphatic (9%), alkaloids (3.5%) and carbo-hydrates (3%). The remaining MNPs (<5%) were distributedamong the other chemical groups.
Terpenoids have been the chemical group that includes themost NPs isolated so far from marine environments.7,19,20
Conversely, alkaloids are relatively rare in marine algae.21 Only8% of the 427 algal species covered were the source of newalkaloids. This number is lower than the terrestrial counterpart,
Fig. 4 Chemical groups of macroalgal marine natural products (MNP). Thecumulative number of natural products (NP) from different chemical groupsdiscovered from 1965 to 2012. Inset: ratio of MNPs per genus and species for themain chemical groups. Only the chemical groups accounting for 95% of allmacroalgal MNPs are displayed.
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as alkaloids are found in approximately 20% of all terrestrialplant species.22 In contrast to alkaloids, terpenoids were recor-ded in 53% of the algal species covered in this review.
The temporal trends of MNP discovery by chemical entityevidence the dominance of terpenoids in macroalgal chemistry(Fig. 4). The average number of new terpenoids per year was 21between 1965–1979 and increased to 49 and 43 for the periods1980–1994 and 1995–2012, respectively. Terpenoids also displayhigher ratios of new NPs per genus and species (see inset inFig. 4). The trends observed for terpenoids suggest that they arefound across a wider range of taxa than other molecular types.On the other hand, this may also be a reection of biased bio-prospecting efforts towards this chemical group. Terpenoidsdisplay an immense variety of structural types, which is in partassociated with the fact that the isoprenoid biosynthetic unitcan be readily rearranged and oxidized.18,23 Consequently,terpenoids have a wide array of bioactivities and biologicalfunctions with potential applications for drug discovery. Theseproperties are highly desired by chemists and thus heavily tar-geted during bioprospecting.24 Thus, the results observed bychemical entity may not reect the true chemical diversitypresent in marine macroalgae, but rather the result of directedefforts towards the discovery of these specic molecular types.
The distribution of chemical groups across the differentalgal taxa displays contrasting trends (Fig. 5). The overalldominance of terpenoids is observed among all phyla, but is
Fig. 5 The distribution of marine natural products from different chemicalgroups by macroalgal phyla. Only the chemical groups representing 95% of allmacroalgal MNP are displayed.
This journal is ª The Royal Society of Chemistry 2013
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more evident in the Ochrophyta and less pronounced in theChlorophyta. The proportion of aliphatic and steroidal MNPs isrelatively higher in Chlorophyta, whereas the proportion ofpolyketides is relatively higher in Rhodophyta. The trendsobserved for the taxonomical level of order and family follow thesame trends that are generally observed across taxa, i.e., largedominance of terpenoids followed by polyketides, aliphatic, etc.However, some exceptions can be highlighted, namely (order/family): Bonnemaisoniales/Bonnemaisoniaceae, where poly-ketides are the main group (31%); Gracilariales/Gracilariaceaewhere aliphatic represented 46% of new NPs; Laminariales/Lessoniaceae where simple aromatic compounds correspond to44/50%; and Nemaliales/Galaxauraceae, that display 46/54%steroids.
Chemical information can also be displayed by chemicalentity. Fig. 6 shows the percentage of MNPs discovered from thethree algal phyla for each chemical entity. The results suggestthat the discovery of new molecules from each taxon varies withchemical group and may contrast to the overall trend whereRhodophyta, Ochrophyta and Chlorophyta represent 53%, 39%and 8% of the discoveries of macroalgal MNPs. Notable differ-ences from this proportion among algae phyla may suggesteither a predominance of that particular chemical entity withinthe respective taxa, or biased screening or isolation effortstowards particular chemical groups in each taxon. As anexample, 75% and 89% of all alkaloids and polyketides,respectively, are associated with Rhodophyta (Fig. 6), which is alarger fraction as compared to the results observed when ana-lysing all chemical types, i.e., Rhodophyta representing 53% ofall algal MNPs. A similar trend is observed for carbohydratesand steroids discovered in Chlorophyta.
3 Biogeography of macroalgal marinenatural products
Biogeographic classications are essential for grouping repre-sentative systems throughout the world. Such approaches areintended to support biodiversity analysis and understandingunderlying macroecological and phylogeographical trends.Biogeography can also be used to direct future efforts ingovernance, resource management and conservation. Although
Fig. 6 The distribution of marine natural products from macroalgae phyla bychemical entity. Only chemical entities representing 95% of all macroalgal MNPsare displayed.
This journal is ª The Royal Society of Chemistry 2013
mapped biodiversity patterns have been an important tool inecology25–27 and conservation studies,28,29 such geographicalorganization systems have rarely been applied to MNPresearch.4
Researchers continue to discover new chemical entities fromthe ocean every day, but to effectively survey chemical diversityit is essential to employ optimised sampling strategies. Threedifferent sampling strategies are commonly used:30
� exploring untapped geographical sources;� exploring new groups of marine organisms;� combining both strategies.Geographical selection of collection sites is a highly relevant
aspect in bioprospecting efforts, as it is the rst step fordiscovering new MNPs.31 Collection sites must be carefullychosen to:
� combine high biological diversity and density;� maximise the number of different species sampled;� avoid adverse impacts to the sampling site.Impact assessment of the sampling site is also a major
concern that is essential whenmonitoring chemical diversity, asthe loss of biodiversity through over-exploitation and habitatdegradation are currently primary issues in marineconservation.32
It is possible to describe geographical patterns of macroalgalMNP research through the use of different geographicalapproaches:
� latitudinal gradients;� marine ecoregions;1
� biodiversity hotspots;33
� exclusive economic zones (EEZ).The information on collection sites for algal MNPs was used
to group the NPs among the above-mentioned geographiccategories. Primarily we used geographical coordinates data.However, only 78% of all macroalgal NPs displayed sufficientinformation to collect coordinate information. Although forsome of the remaining cases we were able to use the descrip-tions of collection sites to attribute a geographical region, 14%of the macroalgal NPs remained uncategorized. However, it isimportant to note that the number of algal MNPs withoutdetailed information on the collection site have been signi-cantly decreasing over the past two decades (data not shown).
3.1 Latitudinal trends
Ecological theories suggest an inverse correlation betweenlatitude and diversity of chemical defence strategies.34
Following the principle that chemical defence is mainly drivenby predation pressure, it has been hypothesised that chemicaldiversity is higher in the tropics than in the poles. Because thelatter regions have not been the focus of most bioprospectingefforts it is not easy to refute or conrm such latitudinalhypotheses. In fact, a higher number of algal MNPs has beenrecorded in temperate rather than in tropical algae (Table 2).However, these results are likely a result of biased bio-prospecting efforts by scientists screening the algae present inthe coastal regions of their countries located in temperateregions, such as Italy and Spain. Simultaneously, it is
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Table 2 Numbers of new algal marine natural products by phylum and latitudinal regionsa for the periods 1965–79, 1980–94 and 1995–2012.
Region
Chlorophyta Ochrophyta Rhodophyta
65–79 80–94 95–12 Total 65–79 80–94 95–12 Total 65–79 80–94 95–12 Total
NorthPolar 0 0 0 0 0 0 0 0 0 0 0 0Temperate 1 30 50 81 31 281 273 585 192 246 320 758Tropical 9 73 43 125 12 87 55 154 70 89 214 373
SouthTropical 3 0 6 9 0 30 17 47 0 47 78 125Temperate 3 1 13 17 4 76 66 146 44 71 78 193Polar 0 0 0 0 0 2 2 4 16 0 28 44
Total 16 104 112 232 47 476 413 936 322 453 718 1493
a Latitude was organized as Polar (above the Arctic Circle and below the Antarctic Circle), Temperate (between the Tropic of Cancer and the ArcticCircle and between the Tropic of Capricorn and the Antarctic Circle) and Tropical, and each was divided as North or South (between the Tropic ofCancer and Tropic of Capricorn).
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acknowledged that chemical defences of marine algae are morepotent in tropical than in temperate regions.35 Thus, increasingbioprospecting efforts should be expected in tropical areas andconsequently increasing numbers of new MNPs should bedescribed from these latitudinal regions. This trend wasobserved for Chlorophyta between 1980 and 1994 (Table 2). Forphylum Rodophyta a notable increase inMNP numbers has alsobeen observed since 1995 in tropical areas, as well as in northtemperate and south polar regions (Table 2).
3.2 Marine ecoregions
Ecoregions are areas exhibiting relatively homogenous speciescompositions, a feature that makes them clearly distinct fromadjacent systems.1 In theory, species composition is deter-mined by the predominance of a small number of ecosystemsand/or a distinct suite of oceanographic or topographicfeatures.1 Thus, different ecoregions will show differentdominant biogeographic forcing agents. The geographic clas-sication of ecoregions may also be of importance for analy-sing geographical trends of algal MNP discovery, as certainchemical compounds are known to be species-specic36–38
whereas others result from interspecic interactions.39–41 Fig. 7shows the distribution of algal MNPs for different time inter-vals according to the classication of marine ecoregions.1 Since1965 the Mediterranean has been an important region for thediscovery of algal MNPs, particularly the Western Mediterra-nean and Ionean Sea ecoregions. Marine ecoregions in theeastern Pacic, such as the Southern Californian Bight, the Seaof Cortez and Hawaii, were relatively important until 1980.These three ecoregions represented 31% of all macroalgalMNPs discovered between 1965 and 1979. In contrast, theyrepresented only 2% of the MNPs discovered from macroalgaebetween 1980 and 1994 and aer 1995 (Fig. 7). Some marineecoregions in the Temperate Northern Pacic and the CentralIndo-Pacic evidenced a contrasting trend. Particularly, theEast China Sea, the Gulf of Tonkin, South Kuroshio and theYellow Sea ecoregions that together represented 2% of algalMNPs between 1965–1979 and 1980–1994, and aer 1995
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encompassed 26% of the MNPs. This nding evidences theincreasing macroalgal bioprospecting efforts generallyobserved in regions surrounding Asiatic countries.4 Otherregions that are worth highlighting are the Azores, Canariesand Madeira ecoregion, in the Lusitanean province of theTemperate Northern Atlantic, and the Sea of Japan ecoregion,in the Cold Temperate Northwest Pacic province of theTemperate Northern Pacic. Each of these two ecoregions (theAzores, Canaries and Madeira, and the Sea of Japan) represent4% of all algal MNPs discovered since 1965.
Different trends are observed when analysing macroalgalMNP discovery per phylum for the top 10 marine ecoregions(Ionian Sea: 137; Yellow Sea: 136; Sea of Japan: 135; Azores,Canaries and Madeira: 126; Central Kuroshio Current: 124;Aegean Sea: 114; Western Mediterranean 113; South Kuroshio:107; Hawaii: 95; East China Sea: 77). Although Chlorophyta onlyrepresented 8% of all macroalgal MNP, this phylum represented25% of the MNP discoveries in the Western Mediterranean.Ochrophyta represented 39% of the overall MNP discoveries;however, they represented 56%, 58% and 53% of the algal MNPdiscovered in the Central Kuroshio Current, Ionean Sea andEast China Sea ecoregions, respectively. Finally, although Rho-dophyta were already the phylum with the highest representa-tion (53%), in the Azores, Canaries and Madeira ecoregion thisphylum represented 75% of the algal MNP discoveries. Theseresults may indicate a:
� higher biodiversity of these phyla in these ecoregions;� biased bioprospecting effort for each phyla in each ecor-
egion; and/or� higher chemical diversity of these particular algal groups in
these ecoregions.Although the collected dataset is not suitable to make
conclusive statements for each of the hypotheses stated above,some interpretation is possible. It has been advocated thatRhodophyta are mostly found in subtropical and tropical water,whereas Ochrophyta are more common in cooler waters.35
However, collected data suggests that this hypothesis is notvalid. The ecoregion where a higher number of MNPs fromRhodophyta was observed was neither subtropical nor tropical
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Fig. 7 New marine natural products from macroalgae for each marine ecoregions. The following time periods are represented: a) 1965–1979, b) 1980–1994, c)1995–2012.
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(Azores, Canaries and Madeira), and the ecoregions whereOchrophyta displayed a higher dominance are characterized bywarm temperate waters in the northwest Atlantic province,apart from the Ionian Sea that belongs to theMediterranean Seaprovince. Further studies should test these hypotheses based onthe biogeographic distribution of each algal phylum and thechemical diversity of the same algal species in differentecoregions.
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The analysis of the dominant chemical groups in eachecoregion shows, in general, the same trend of terpenoids(representing �59% of the algal MNPs), followed by simplearomatic, polyketides, aliphatic, etc. Some notable exceptionsare the Western Mediterranean ecoregion that shows anabnormally high contribution of terpenoids (77%; 87 MNPs)and the Yellow Sea ecoregion, where 60MNPs (corresponding to44%) were simple aromatic compounds.
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The number of new MNPs per algal genus or species alsorevealed different trends among the top 10 ecoregions. TheAegean Sea ecoregion showed an average of 16 MNPs per genusand 10 MNPs per species. These relatively high values may beassociated with the high bioprospecting efforts in this region.However, the Sea of Japan ecoregion, which showed a highernumber of algal MNPs, displayed lower results (10 MNPs pergenus and 5 MNPs per species). Also, relatively lower resultswere observed in the Ionean Sea and Western Mediterranean (8MNPs per genus and 4MNPs per species, and 9MNPs per genusand 6 MNPs per species, respectively). These results suggest:
� different numbers of algal genus/species in each ecoregion;� different chemical diversity of each algal genus/species in
each ecoregion; and/or� biased bioprospecting efforts towards particular algal
genus/species in each region.Although the relationships between macroalgae taxonomy
and natural products have been investigated in severalchemotaxonomy studies,36,37 the role of biodiversity drivingMNP diversity still requires further research.
3.3 Hotspots of natural product discovery
Marine regions of the world can also be classied according totheir biodiversity richness. A popular classication amongecologists is that of Biodiversity Hotspots (BHs), which are areasfeaturing exceptionally high concentrations of endemic speciesand experiencing exceptional loss of habitat.33 BH boundariesare determined by “biological commonalities“, i.e., each BHfeatures separate biota or communities of species that ttogether as a biogeographic unit. This approach is largely tar-geted to identify conservation priority areas. The use of BHs toanalyse the biogeography of MNP discovery is also important, aschemical diversity is usually associated with biodiversity.42
Furthermore, it is also important to identify and preserve areaswith high species and chemical diversity, as future marinedrugs waiting to be discovered may be present in these areas.
The geographical origin of the macroalgal MNPs analysed inthis review was also grouped according to BH. The majority(61%) of all algal MNPs were discovered in BH as opposed to the25% that were discovered in organisms collected outside a BH
Fig. 8 New marine natural products from macroalgae for each biodiversityhotspot, discovered between 1965 and 2012.
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(the remaining 14% correspond to MNPs that were not possibleto categorize due to insufficient geographic information in theoriginal publication). The number of algal MNPs discovered ineach BH is displayed in Fig. 8. Although the MediterraneanBasin (563 MNPs) and Japan (457 MNPs) BHs accounted for54% of the algal MNPs discovered in all BHs, this trend wasdifferent if we consider the period between 1965 and 1979,when the California Floristic Province BH accounted for 39% ofthe MNPs discovered in all BHs (116 MNPs; data not shown).This same BH represented <4% of the algal MNPs discovered inBHs aer 1980.
3.4 Natural product discovery in Exclusive Economic Zones
The biodiscovery of macroalgal MNPs is likely to be associatedwith regions displaying high algal biodiversity or environmentalproperties that favour the evolutionary development of newsecondary metabolites. Nevertheless, we also have to considerthe possibility that the geographic analysis of bioprospectingreects researchers' preferences when selecting their targetspecies or sampling sites. Although such motivation is noteasily detected in this dataset, the analysis of geographic datausing an organization by political borders may highlight thecountries where higher bioprospecting efforts have beenobserved. Worldwide marine regions are politically dividedthrough EEZs, which are areas over which a state has jurisdic-tion concerning the exploration and use of marine resourcespresent therein. However, it is important to note that thediscovery of a particular MNP in a specic EEZ does notnecessarily mean that this particular country made the bio-prospecting efforts. Although this issue has only had raisedawareness in recent years due to biopiracy and benet-sharingissues,43,44 it is relatively easy to nd scientic publicationswhere the researchers describing a new MNP do not belong tothe country where the sampling was performed.
The EEZ analysis of algal MNPs shows higher biodiscoveryareas in temperate areas surrounding developed countries,such as Japan, Australia and China (Fig. 9). These three coun-tries, together with Italy, USA and the EEZ of the Canary Islands(under legal jurisdiction of Spain) represented 44% of the algalMNPs discovered since 1965.
Different bioprospecting efforts have been observed in eachEEZ since 1965 (Table 3). Decreasing efforts have been observedin the USA and Mexico, whereas an increasing trend has beenobserved, for example, in the Canary Islands, China, Greece andSouth Korea.
The biogeographic analysis using a political approach (EEZ)does not reect any ecological trend and reveals a biased anal-ysis of biodiscovery areas, particularly for large EEZs, such asAntarctica, Australia, Brazil, Russia, USA, among others.Through the comparison of the maps illustrating the world'sEEZs (Fig. 9) and ecoregions (Fig. 7) it is possible to observecontrasting trends. This nding highlights that the use of EEZscould be misleading as it may over-represent the importance ofthe whole EEZ as a biodiscovery hotspot. While the EEZapproach facilitates the identication of the entities withjurisdiction over a particular area, it will overestimate the MNP
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Fig. 9 New marine natural products discovered from macroalgae between 1965 and 2012 for each Exclusive Economic Zone.
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biodiscovery potential of a particular area. This issue is partic-ularly important to dene proper jurisdiction areas that can beactually managed and preserved. EEZs oen encompass shelf
Table 3 Number of algal marine natural products (MNPs) discovered in the exclusivare shown.
Exclusive Economic Zone
Numb
1965–1979
Antarctic 16Australia 41Belize 4Brazil 0Canary Islands 6Canada 2Chile 0China 0Fiji 0France 11Greece 2Hawaii 60India 0Italy 10Japan 70Mexico 67Morocco 0New Zealand 13Northern Mariana Islands and Guam 0Pakistan 0Philippines 0South Africa 0South Korea 0Taiwan 0Turkey 0United Kingdom 10United States of America 58
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and deep-sea environments and are therefore difficult tomanage and protect. One way to provide a more accurategeographic denition of macroalgal MNP biodiscovery hotspots
e economic zones (EEZs) of the world. Only the EEZs representing 90% of the MNP
er of algal marine natural products
1980–1994 1995–2012 Total
2 30 48136 67 24421 2 274 21 25
63 57 12623 0 2510 17 272 250 2520 55 55
51 37 992 120 1248 27 95
44 15 59129 38 177206 143 419
7 2 765 23 28
50 44 10714 10 2413 22 3510 17 271 23 240 65 651 23 249 17 26
13 1 2477 11 146
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within each EEZ is to consider the bathymetry of each area, asmacroalgae are only present in the photic zone.
In order to provide a depth distribution of macroalgal MNP,the dataset used in this review included the collection depth ofthe biological material. However, we recorded a serious infor-mation gap in the depth data. Namely, depth data was missingin 71% of the MNP algal publications. The analysis of theremaining 29% revealed that 583 MNPs (64%) were obtainedfrom algae collected in the rst 3 meters of the water column,which largely overlaps with intertidal areas. The advent of scubadiving technology is also observed in data depth information, as25% of the MNP were collected between 10 and 20 m.
4 Conclusions
This overview highlights the important role that macroalgaedisplayed for MNP discovery. Although there is a large algaldiversity yet to be explored, the biodiscovery trends observed inthe past decade suggest that researchers are now focusing theirbioprospecting efforts on other targets, such as microorganismsand marine invertebrates.4,45,46 These latter groups display anextremely large biodiversity, which is likely to encompass agreater chemical diversity. This overview highlights particularmacroalgal groups that display low biodiversity but largechemical diversity, such as certain families within order Giga-rtinales. While the present review may help researchersfocusing their bioprospecting efforts on such taxa, the role ofbiodiversity in MNP diversity still requires further investigation.
Biodiversity is the fundamental resource for discovering newchemical entities. It is therefore expected that most bio-prospecting efforts have been focused in BHs. The biogeo-graphic data summarised here also indicates several temperateregions with high biodiscovery rates of macroalgal MNPs, suchas particular areas in the Temperate North-Eastern Atlantic andNorth-Western Pacic. This information may help in guidingfuture steps of macroalgal MNP discovery, as these regions maybe used as case studies to understand the factors drivingchemical diversity. Besides using biogeographic data to guidebioprospecting efforts and to investigate ecological and evolu-tionary theories on biological and chemical diversity, thegeographical information presented in this study may also beused to guide future efforts in governance, resource manage-ment and conservation. It is important to preserve areas thathold great biodiscovery potential because well-regulated bio-prospecting contributes to the joint goals of ecosystemconservation and social and economic development throughpartnerships and benet sharing. However, in order to providesuch information to stakeholders and decision makers oneneeds accurate and reliable taxonomical and geographical data,which is still largely unavailable for a large number of studiesdescribing new NPs. Although this issue has been improving inthe last decade, particularly through the need to deposit avoucher specimen of the organism with a recognized taxono-mist, it is important to note the relevance of having coordinateand depth data of sampling sites. Scientic journals should alsorequest accurate coordinate and depth data of collectedorganisms in order to allow future studies to use such
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information on meta-analysis and investigate global biogeo-graphic chemical ecology trends. Meta-analysis of MNP datamay also be used on smaller geographic scales to betterunderstand the drivers of chemical diversity and thus charac-terize the environmental factors that may generate biodiscoveryhotspots. However, in order to investigate these hypotheses atan ecosystem scale it is important to broaden the biogeographicstudies to other taxonomic levels. This study focused on marinemacroalgae, as it was the rst group with a complete tax-onomical, chemical and geographical dataset available in theMarinLit database.7 Other taxonomic groups, such as microor-ganisms and marine invertebrates, will follow soon and providea more complete dataset that will allow detailed analysis of allMNP diversity.
5 References
1 M. D. Spalding, H. E. Fox, G. R. Allen, N. Davidson,Z. A. Ferda~na, M. Finlayson, B. S. Halpern, M. A. Jorge,A. L. Lombana, S. A. Lourie, K. D. Martin, E. McManus,J. Molnar, C. A. Recchia and J. Robertson, BioScience, 2007,57, 573–583.
2 UNESCU, in Global opean oceans and deep seabed (GOODS) –Biogeographic classications, UNESCU-IOC, Paris, 2009, vol.84, pp. 84.
3 R. O'Dor, P. Miloslavich and K. Yarincik, PLoS One, 2010, 5,e11871.
4 M. C. Leal, J. Puga, J. Serodio, N. C. M. Gomes and R. Calado,PLoS One, 2012, 7, e30580.
5 R. Montaser and H. Luesch, Future Med. Chem., 2011, 3,1475–1489.
6 J. W. Blunt, M. H. G. Munro and M. Upjohn, in Handbook ofmarine natural products, ed. E. Fattorusso andW. H. Gerwick,Springer Science+Business Media B.V., 2012, pp. 389–421.
7 J. W. Blunt and M. H. G. Munro, MarinLit database, 2012,Department of Chemistry, University of Canterbury, http://www.chem.canterbury.ac.nz/marinlit/marinlit.shtml.
8 D. J. Faulkner, Nat. Prod. Rep., 1984, 1, 251–280.9 K. Cardozo, T. Guaratini, M. Barros, V. Falc~ao, A. Tonon,N. Lopes, S. Campos, M. Torres, A. Souza, P. Colepicoloand E. Pinto, Comp. Biochem. Physiol., Part B: Biochem. Mol.Biol., 2007, 146, 60–78.
10 W. Appeltans, P. Bouchet, G. A. Boxshall, C. De Broyer,N. J. de Voogd, D. P. Gordon, B. W. Hoeksema, T. Horton,M. Kennedy, J. Mees, G. C. B. Poore, G. Read, S. Stohr,T. C. Walter and M. J. Costello, World Register of MarineSpecies, 2012, http://www.marinespecies.org, .
11 J. W. Blunt, B. R. Copp, R. A. Keyzers, M. H. G. Munro andM. R. Prinsep, Nat. Prod. Rep., 2012, 29, 144.
12 J. W. Blunt, B. R. Copp, M. H. G. Munro, P. T. Northcote andM. R. Prinsep, Nat. Prod. Rep., 2011, 28, 196–268.
13 F. Rindi, A. Soler-Villa and M. D. Guiry, in Marine BioactiveCompounds, ed. M. Hayes, Springer US, 2012, pp. 1–53.
14 R. A. Lincoln, K. Strupinski and J. M.Walker, Life Chem. Rep.,1991, 8, 97–183.
15 D. Faulkner, Tetrahedron, 1977, 33, 1421–1443.
This journal is ª The Royal Society of Chemistry 2013
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Publ
ishe
d on
27
Aug
ust 2
013.
Dow
nloa
ded
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Hei
ne U
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rsity
of
Due
ssel
dorf
on
01/0
9/20
13 0
7:47
:36.
View Article Online
16 H. H. Webber and G. D. Ruggieri, Food-Drugs from the Sea,Marine Technology Soc., 1974.
17 D. J. Faulkner, Nat. Prod. Rep., 2000, 17, 1–6.18 J. W. Blunt and M. H. G. Munro, Dictionary of marine natural
products, Chapman & Hall/CRC, Boca Raton, FL, 2008, p.2108.
19 M. Munro, J. W. Blunt, E. Dumdei, S. Hickford, R. Lill, S. Li,C. Battershill and A. Duckworth, J. Biotechnol., 1999, 70, 15–25.
20 M. H. G. Munro, R. T. Ludibrand and J. W. Blunt, inBioorganic Marine Chemistry, ed. P. Scheuer, Springer-Verlag, Berlin, 1987, vol. 1, pp. 93–176.
21 K. C. Guven, A. Percot and E. Sezik,Mar. Drugs, 2010, 8, 269–284.
22 J. Ziegler and P. J. Facchini, Annu. Rev. Plant Biol., 2008, 59,735–769.
23 T. Maimone and P. Baran, Nat. Chem. Biol., 2007, 3, 396–407.24 S. Zwenger and C. Basu, Biotechnol. Mol. Biol. Rev., 2008, 3,
1–7.25 R. Rosa, H. M. Dierssen, L. Gonzalez and B. A. Seibel,
Ecology, 2008, 89, 3449–3461.26 R. Rosa, J. Boavida-Portugal, K. Trubenbach, M. Baptista,
R. Araujo and R. Calado, Deep-Sea Res., Part I, 2012, 64, 9–21.27 R. Rosa, H. M. Dierssen, L. Gonzalez and B. A. Seibel, Global
Ecol. Biogeogr., 2008, 17, 600–610.28 E. Pineda and J. M. Lobo, Global Ecol. Biogeogr., 2012, 21,
935–944.29 M. Becerro, R. Thacker, X. Turon, M. Uriz and V. Paul,
Oecologia, 2003, 135, 91–101.
This journal is ª The Royal Society of Chemistry 2013
30 A. Harvey, Drug Discovery Today, 2000, 5, 294–300.31 D. Faulkner, Antonie van Leeuwenhoek, 2000, 77, 135–145.32 M. J. Costello, M. Coll, R. Danovaro, P. Halpin, H. Ojaveer
and P. Miloslavich, PLoS One, 2010, 5, e12110.33 N. Myers, R. A. Mittermeier, C. G. Mittermeier, G. A. B. da
Fonseca and J. Kent, Nature, 2000, 403, 853–858.34 G. Bakus, Biotropica, 1974, 6, 229–236.35 A. J. Beattie, M. E. Hay, B. Magnusson, R. Nys, J. Smeathers
and J. F. V. Vincent, Aust. Ecol., 2011, 36, 341–356.36 B. M. Howard, A. M. Nonomura and W. Fenical, Biochem.
Syst. Ecol., 1980, 8, 329–336.37 V. Amico, Phytochemistry, 1995, 39, 1257–1279.38 D. J. Chapman, Mar. Chem., 1983, 12, 226.39 V. J. Paul, R. Ritson-Williams and K. Sharp, Nat. Prod. Rep.,
2011, 28, 345–388.40 K. L. Van Alstyne and J. Paul, Oecologia, 1990, 84, 158–163.41 M. Hay and W. Fenical, Oceanography, 1996, 9, 10–20.42 M. Hay, J. Exp. Mar. Biol. Ecol., 1996, 200, 103–134.43 D. Greer and B. Harvey, Blue genes: sharing and conserving the
world's aquatic biodiversity, Earthscan, London, UK, 2004, p.231.
44 J. M. Arrieta, S. Arnaud-Haond and C. M. Duarte, Proc. Natl.Acad. Sci. U. S. A., 2010, 107, 18318–18324.
45 J. W. Blunt, B. R. Copp, W.-P. Hu, M. H. G. Munro,P. T. Northcote and M. R. Prinsep, Nat. Prod. Rep., 2009,26, 170–244.
46 M. C. Leal, C. Madeira, C. A. Brand~ao, J. Puga and R. Calado,Molecules, 2012, 17, 9842–9854.
Nat. Prod. Rep.
