molecules

Review Natural Products from Tongan Marine Organisms

Taitusi Taufa 1 , Ramesh Subramani 1,† , Peter T. Northcote 2 and Robert A. Keyzers 3,*

1 School of Agriculture, Geography, Environment, Ocean and Natural Sciences (SAGEONS), Laucala Campus, The University of the South Pacific, Suva, Fiji; [email protected] 2 Ferrier Research Institute and Centre for Biodiscovery, Victoria University of Wellington, Wellington 6140, New Zealand; [email protected] 3 School of Chemical and Physical Sciences, Centre of Biodiscovery, Victoria University of Wellington, Wellington 6140, New Zealand * Correspondence: [email protected]; Tel.: +64-4-463-5117 † Dedicated to the memory of author Ramesh Subramani, who passed away during the preparation of this manuscript.

Abstract: The islands of the South Pacific Ocean have been in the limelight for natural product biodiscovery, due to their unique and pristine tropical waters and environment. The Kingdom of Tonga is an archipelago in the central Indo-Pacific Ocean, consisting of 176 islands, 36 of which are inhabited, flourishing with a rich diversity of flora and fauna. Many unique natural products with interesting bioactivities have been reported from Indo-Pacific marine sponges and other invertebrate phyla; however, there have not been any reviews published to date specifically regarding natural products from Tongan marine organisms. This review covers both known and new/novel Marine



Natural Products (MNPs) and their biological activities reported from organisms collected within
 Tongan territorial waters up to December 2020, and includes 109 MNPs in total, the majority from

Citation: Taufa, T.; Subramani, R.; the phylum Porifera. The significant biological activity of these metabolites was dominated by Northcote, P.T.; Keyzers, R.A. Natural cytotoxicity and, by reviewing these natural products, it is apparent that the bulk of the new and Products from Tongan Marine interesting biologically active compounds were from organisms collected from one particular island, Organisms. Molecules 2021, 26, 4534. emphasizing the geographic variability in the chemistry between these organisms collected at https://doi.org/10.3390/ different locations. molecules26154534 Keywords: Marine Natural Products (MNPs); tropical marine organisms; Kingdom of Tonga; Academic Editors: Enrique Barrajon, biological activity Vicente Micol and María Herranz-López

Received: 17 June 2021 1. Introduction Accepted: 22 July 2021 Published: 27 July 2021 MNPs are secondary metabolites produced by both micro- and macro- marine organ- isms, produced either as a result of the organism adapting to its surrounding environment

Publisher’s Note: MDPI stays neutral or as a defense mechanism against predators to assist in its survival [1]. With more than 70% with regard to jurisdictional claims in of Earth’s surface covered by oceans, which are home to phyla considered to be exclusively published maps and institutional affil- marine [2], it is logical that the marine environment represents an exceptional reservoir of iations. biodiversity and, hence, biologically active natural products, many of which exhibit unique and novel chemical features. The Kingdom of Tonga (herein referred to as Tonga) harbors an abundance of unex- plored marine biomes that could be sources of new MNPs with unique biological activities.

Copyright: © 2021 by the authors. The majority of Tongan marine organisms have not been investigated for natural product Licensee MDPI, Basel, Switzerland. biodiscovery. Until recently, access to Tonga for bioprospecting has been limited, and This article is an open access article as such, most Pacific-located MNP research has been reported from neighboring island distributed under the terms and groups such as Fiji, Vanuatu, and the Solomon Islands. This review covers the structures conditions of the Creative Commons and bioactivities of Tongan marine-derived NPs up to the end of 2020. Environmental Attribution (CC BY) license (https:// influences on the production of the MNPs reviewed, and their biosyntheses, are beyond creativecommons.org/licenses/by/ the scope of this manuscript and are not included. 4.0/).

Molecules 2021, 26, 4534. https://doi.org/10.3390/molecules26154534 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 26

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2. The Kingdom of Tonga 2. TheTonga Kingdom is an ofarchipelago Tonga comprising 36 inhabited and 140 uninhabited islands in the CentralTonga Indo-Pacific is an archipelago Ocean, situated comprising between 36 inhabited Fiji to the and west 140 and uninhabited Samoa to islandsthe northeast. in the CentralTonga is Indo-Pacific divided into Ocean, four main situated groups; between Tongatapu, Fiji to the Vava‘u, west andHa‘apai, Samoa and to ‘Eua the northeast.(Figure 1), Tongawith several is divided other into smaller four main groups groups; completing Tongatapu, the overall Vava‘u, archipelago. Ha‘apai, and The ‘Eua largest (Figure island,1), withTongatapu, several otheron which smaller the groupscapital completingof Nuku‘alofa the is overall located, archipelago. covers 257 Thekm2 largest. Geologically, island, Tongatapu,the Tonganon islands which are the comprised capital of of Nuku‘alofa two types;is most located, have covers a limestone 257 km base2. Geologically, formed from theuplifted Tongan coral islands formations are comprised while others of two consist types; of most limestone have overlaying a limestone a base volcanic formed base. from Alt- upliftedhough Tonga coral formationsis not located while in close others proximity consist of to limestone the epicenter overlaying of marine a volcanic biodiversity, base. Althoughbounded Tongaby the isPhilippines, not located the in closeMalay proximity Peninsula, to theand epicenterNew Guinea of marine [3], Tongan biodiversity, waters boundedstill have by distinct the Philippines, and exceptional the Malay marine Peninsula, life due and to their New intrinsic Guinea [ 3geographical], Tongan waters isolation still haveand the distinct presence and exceptionalof a number marine of major life ocean due cu torrents their intrinsic in the region. geographical Tonga has isolation a total andland thearea presence of 688 km of2 a with number an Exclusive of major oceanEconomic currents Zone in (EEZ) the region. of 700,000 Tonga km has2, ~1000 a total times land more area 2 2 ofthan 688 its km landwith area, an Exclusivewhich affords Economic a huge Zone diversity (EEZ) of 700,000marine kmcommunities, ~1000 times in which more thanMNP itsstudies land area,could which be undertaken. affords a huge Given diversity the lack of of marine industry communities within Tonga, in which most MNP of the studies collec- couldtion sites be undertaken. referred to herein Given thecan lackbe cons of industryidered as within “pristine” Tonga, marine most ecosystems. of the collection sites referred to herein can be considered as “pristine” marine ecosystems.

FigureFigure 1.1. Map of the the Kingdom Kingdom of of Tonga. Tonga. Image Image courtesy courtesy of ofthe the Ministry Ministry of Lands, of Lands, Survey Survey and andNat- Naturalural Resources, Resources, Tonga. Tonga.

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3. Tropical Marine Organisms and Biodiversity in Tongan Territorial Waters Tropical marine ecosystems harboring a rich diversity of micro-and macro-organisms, including invertebrates, tend to produce larger quantities of structurally diverse metabolites when compared to those from temperate environments [4,5]. This latitudinal hypothesis suggests that chemical defense is mainly driven by predation pressure, and as a result, tropical organisms have evolved to have more effective defenses to deter predators and encroachment, hence having higher chemical diversity [6]. Alternatively, this correlation between source latitude and chemical defense may be attributed in part to a lack of bioprospecting investigations in temperate or polar regions. Studies have shown that organisms from the Antarctic region have comparable levels of bioactivity to those from temperate and perhaps even tropical environments [7]. In addition, Becerro et al. suggested that chemical defenses of tropical and temperate sponges might be equally effective [8]. Tonga has a unique biologically diverse marine environment, influenced by its ge- ographical isolation and the number of major ocean currents in the region. Its marine ecosystem comprises of a number of different and unique species inhabiting the pelagic and coastal areas, including thousands of fish species, marine mammals, turtles, mollusks, crustaceans, urchins, sea cucumbers, and marine algae (seaweeds). A report in 2006 in- dividually identified 202 coral, 150 mollusk, 59 echinoderm, 16 algal, and 54 polychaete worm species in Tongan territorial waters [9]. However, the overall numbers regarding Tongan marine biodiversity is still unknown.

4. A Brief History of Marine Natural Products from Tongan Waters The research group of Professor Philip Crews from the University of California at Santa Cruz (UCSC, Santa Cruz, CA, USA) conducted the first chemical investigations of Tongan marine organisms [10–13]. This was followed by several natural products studies reported by the Frederick National Laboratory for Cancer Research at Maryland, USA, however, the Coral Reef Research Foundation (CRRF, Koror, Palau) conducted the collections of the organisms [14–16]. It should be noted that both organizations were under contract to the United States of America National Cancer Institute (NCI Frederick, MD, USA) to collect marine invertebrates and plants worldwide in search for new naturally occurring anticancer drugs from the ocean. Crews’ research group and the CRRF collection expeditions were made in the 1980s and 1997, respectively, and all the compounds reported from these studies were isolated from specimens collected from the northern Vava‘u group of islands. In addition, all the reported metabolites were obtained simply from marine sponges using bioassay-guided isolation procedures. The apparent lack of chemically driven investigation of Tongan marine fauna presented an opportunity for the research groups of Associate Professors Peter Northcote and Rob Keyzers from Victoria University of Wellington (VUW, Wellington, New Zealand), New Zealand, to shift their research and attention from New Zealand marine organisms to the tropical waters of Tonga. Three collection expeditions were made to Tonga, the first to Tongatapu and ‘Eua in late 2008, followed by the Vava‘u group in late 2009, and a third expedition was to ‘Eua in 2016. These studies employed structure-guided isolation procedures instead of the conventional bioassay-guided isolation methods, which led to the isolation of a wide range of interesting biologically active and new secondary metabolites [17–22].

5. Tongan Marine Invertebrates The majority of the organisms collected from Tongan waters for chemical investigation have been marine sponges. Taxonomic identification of sponges has been a difficult task over the years owing to their complex morphological characters and high degree of physical plasticity. Differences in the size and shape of sponges is due to environmental factors, which implies that their shapes are variable among different species and genera, but can also vary between individuals of the same species. Recent techniques have also been used as tools in sponge taxonomic classification such as chemotaxonomic trends and molecular phylogenetics, leading to the reclassification of numerous species [23], several of which MoleculesMolecules 20212021,, 2626,, xx FORFOR PEERPEER REVIEWREVIEW 44 ofof 2626

Molecules 2021, 26, 4534 4 of 26 beenbeen usedused asas toolstools inin spongesponge taxonomictaxonomic classiclassificationfication suchsuch asas chemotaxonomicchemotaxonomic trendstrends andand molecularmolecular phylogenetics,phylogenetics, leadingleading toto thethe reclassificationreclassification ofof numerousnumerous speciesspecies [23],[23], severalseveral ofof whichwhich areare mentionedmentioned inin thisthis review.review. However,However, manymany ofof thethe spongessponges coveredcovered inin thisthis arereviewreview mentioned remainremain inunidentified.unidentified. this review. AsAs However, muchmuch informinform manyationation of regardingregarding the sponges sitesite covereddescriptiondescription in this wherewhere review biotabiota remainwaswas collectedcollected unidentified. isis provided,provided, As much includingincluding information depth,depth, butbut regarding inin manymany site casescases description thisthis datadata whereisis notnot availableavailable biota was inin collectedthethe publishedpublished is provided, manuscripts.manuscripts. including depth, but in many cases this data is not available in the published manuscripts. 5.1.5.1. Sponge-DerivedSponge-Derived MNPsMNPs 5.1. Sponge-Derived MNPs 5.1.1.5.1.1.5.1.1. Order OrderOrder Poecilosclerida PoeciloscleridaPoecilosclerida ThisThisThis undescribed undescribedundescribed species speciesspecies from fromfrom the thethe order orderorder Poecilosclerida PoeciloscleridaPoecilosclerida appeared appearedappeared blood-red blood-redblood-red under- under-under- water,water,water, and andand was waswas collected collectedcollected in inin 1981 19811981 from fromfrom the thethe Vava‘u VavaVava‘u‘u group groupgroup [ 10[10].[10].]. The TheThe order orderorder Poecilosclerida PoeciloscleridaPoecilosclerida is isis thethethe most mostmost speciose speciosespeciose demosponge demospongedemosponge order, order,order, both bothboth in inin terms termsterms of ofof numbers numbersnumbers of ofof species speciesspecies and andand morphol- morphol-morphol- ogyogyogy [ [24].24[24].]. Poecilosclerid PoeciloscleridPoecilosclerid sponges spongessponges are areare more moremore common commocommonn in inin tropical tropicaltropical and andand subtropical subtropicalsubtropical waters, waters,waters, and andand alsoalsoalso occasionally occasionallyoccasionally found foundfound in inin temperate temperatetemperate and andand cold, cold,cold, deep deepdeep waters waterswaters [ 24[24].[24].]. Chemistry/Bioactivity:Chemistry/Bioactivity:Chemistry/Bioactivity: ( (SS)-(+)-1-tridecoxy-2,3-propanediol)-(+)-1-tridecoxy-2,3-propanediol (( 11)) displaysdisplays toxicitytoxicitytoxicity tototo goldfishgoldfishgoldfish and andand was waswas the thethe first firstfirst novel novelnovel MNP MNPMNP reported reportedreported from fromfrom Tongan TonganTongan sources sourcessources [10 [10].[10].].

5.1.2.5.1.2. DiacarnusDiacarnus spinipoculumspinipoculum 5.1.2. Diacarnus spinipoculum ThisThis large,large, soft,soft, drabdrab spongesponge waswas collectedcollected fromfrom thethe coralcoral reefsreefs aroundaround thethe islandisland ofof This large, soft, drab sponge was collected from the coral reefs around the island of Nuapapu in the Vava‘u group. This sponge was previously identified as Prianos sp.[11] NuapapuNuapapu inin the the Vava‘u Vava‘u group. group. This This sponge sponge was was previously previously identified identified as asPrianos Prianossp. sp.[11] [11] andandand later laterlater revised revisedrevised to totoDiacarnus DiacarnusDiacarnus spinipoculum spinipoculumspinipoculum[ 25[25].[25].]. Chemistry/Bioactivity:Chemistry/Bioactivity:Chemistry/Bioactivity: TheThe The novelnovel novel nuapapuinnuapapuin nuapapuin AA A ((22) () 2 waswas) was reportedreported reported fromfrom from thisthis this specimenspecimen speci- men[11],[11], [ togethertogether11], together withwith withthethe knownknown the known norsesterterpenenorsesterterpene norsesterterpene muqubilinmuqubilin muqubilin ((33)) [26].[26]. (3)[ CompoundCompound26]. Compound 22 isis con-con-2 issideredsidered considered toto bebe thethe to be firstfirst the norditerpenenorditerpene first norditerpene isolatedisolated isolated fromfrom aa marine frommarine a marinesponge,sponge, sponge, andand itit showedshowed and it cytotoxic showedcytotoxic cytotoxicactivityactivity againstagainst activity differentdifferent against different cancercancer cellcell cancer lineliness cell suchsuch lines asas suchHeLaHeLa as humanhuman HeLa human cervixcervix carcinomacarcinoma cervix carcinoma (ED(ED5050 == 16.216.2 μμM),M), mousemouse lymphomalymphoma L5178YL5178Y (ED(ED5050 == 2.22.2 μμM),M), andand PC12PC12 ratrat brainbrain tumortumor (ED(ED5050 == (ED50 = 16.2 µM), mouse lymphoma L5178Y (ED50 = 2.2 µM), and PC12 rat brain tumor 18.318.3 μμM)M) cellscells [27].[27]. MuqubilinMuqubilin ((33)) waswas firstfirst reportedreported fromfrom aa spongesponge ofof thethe genusgenus PrianosPrianos (ED50 = 18.3 µM) cells [27]. Muqubilin (3) was first reported from a sponge of the genus Prianos[26],[26], andand[26 itsits], andabsoluteabsolute its absolute configurationconfiguration configuration waswas determdeterm wasinedined determined inin 19851985 [28].[28]. in 1985 AA recentrecent [28]. article Aarticle recent describeddescribed article describedmuqubilinmuqubilin muqubilin ((33)) asas aa novelnovel (3) as agonistagonist a novel agonistagainstagainst againstseveralseveral severalkeykey nuclearnuclear key nuclear receptors,receptors, receptors, proposingproposing proposing 33 asas aa 3potentialpotentialas a potential candidatecandidate candidate forfor thethe for treatmenttreatment the treatment ofof neurneur of neurologicalologicalological disordersdisorders disorders suchsuch such asas Alzheimer’sAlzheimer’s as Alzheimer’s dis-dis- diseaseeaseease [29].[29]. [29 ].

5.1.3.5.1.3. HyrtiosHyrtios erectuserectus 5.1.3. Hyrtios erectus ThisThis blackblack spongesponge isis aa commoncommon inhabitantinhabitant ofof thethe coralcoral reefsreefs aroundaround thethe Vava‘uVava‘u groupgroup This black sponge is a common inhabitant of the coral reefs around the Vava‘u group andand waswas collectedcollected fromfrom variousvarious locationslocations betweenbetween 19801980 andand 19831983 [12].[12]. H.H. erectuserectus belongsbelongs and was collected from various locations between 1980 and 1983 [12]. H. erectus belongs toto thethe familyfamily ThorectidaeThorectidae (order(order DictyoceratiDictyoceratida)da) andand isis widelywidely distributeddistributed inin thethe Indo-Indo- to the family Thorectidae (order Dictyoceratida) and is widely distributed in the Indo- PacificPacific [30].[30]. Pacific [30]. Chemistry/Bioactivity:Chemistry/Bioactivity: AA studystudy ofof thethe anti-inflammatoryanti-inflammatory activeactive extractsextracts fromfrom thisthis Chemistry/Bioactivity: A study of the anti-inflammatory active extracts from this sponge revealed a novel scalarane norsesterterpenoid, hyrtial (4), together with three spongesponge revealedrevealed aa novelnovel scalarane scalarane norsesterterpenoid, norsesterterpenoid, hyrtialhyrtial (4(4),), togethertogether withwith three three knownknownknown sesterterpenessesterterpenessesterterpenes ( (55––77))[) [12].[12].12]. HyrtialHyrtial Hyrtial waswas was subsequentlysubsequently subsequently re-isolatedre-isolated re-isolated withwith with aa furtherfurther a further fivefive five new (8–12) and two previously described scalaranes (13–14)[13]. It was during this latter study that 4 was shown to decrease the weight of mouse ear oedema by 43% when

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Molecules 2021, 26, 4534 new (8–12) and two previously described scalaranes (13–14) [13]. It was during this5 oflatter 26 new (8–12) and two previously described scalaranes (13–14) [13]. It was during this latter study that 4 was shown to decrease the weight of mouse ear oedema by 43% when inflam- study that 4 was shown to decrease the weight of mouse ear oedema by 43% when inflam- mation was induced with phorbol myristate acetate (PMA) at a concentration of ca. 50 μg mation was induced with phorbol myristate acetate (PMA) at a concentration of ca. 50 μg per ear. The authors suggested that compounds 11 and 12 might be artefacts of extraction inflammationper ear. The authors was induced suggested with that phorbol compounds myristate 11 and acetate 12 might (PMA) be at artefacts a concentration of extraction of with µmethanol. Heteronemin (5), originally isolated from11 the sponge12 Heteronema erecta in ca.with 50 methanol.g per ear. Heteronemin The authors suggested (5), originally that isolat compoundsed from theand spongemight Heteronema be artefacts erecta of in extraction1976 [31], with showed methanol. potent Heteronemin cytotoxic activity (5), originally against several isolated human from thecanc spongeer cell Heteronemalines by dis- 1976 [31], showed potent cytotoxic activity against several human cancer cell lines by dis- erectaruptingin 1976 mitochondrial [31], showed function potent cytotoxicin a recent activity published against article several [32]. human Scalaradial cancer (6 cell), the lines first rupting mitochondrial function in a recent published article [32]. Scalaradial (6), the first bysesterterpenoid disrupting mitochondrial with a scalarane function skeleton, in a recent has publishedalso been reported article [32 from]. Scalaradial the sponge (6), Caco- the sesterterpenoid with a scalarane skeleton, has also been reported from the sponge Caco- firstspongia sesterterpenoid mollior [33], withand exhibits a scalarane significant skeleton, anti-inflammatory has also been reported activity, from boththe in vitro sponge and spongia mollior [33], and exhibits significant anti-inflammatory activity, both in vitro and Cacospongiain vivo, through mollior selective[33], and sPLA2 exhibits inhibition significant [34]. anti-inflammatory Scalarin (7) was first activity, reported both infrom vitro the in vivo, through selective sPLA2 inhibition [34]. Scalarin (7) was first reported from the andItalianin vivo sponge, through Cacospongia selective scalaris sPLA2 [35], inhibition and a recent [34]. Scalarin study by (7) Guzmán was first and reported co-workers from Italian sponge Cacospongia scalaris [35], and a recent study by Guzmán and co-workers theshowed Italian the sponge cytotoxicCacospongia effect of scalaris 7 against[35], several and a recentpancreatic study cancer by Guzm cell álinesn and [36]. co-workers showed the cytotoxic effect of 7 against several pancreatic cancer cell lines [36]. showed the cytotoxic effect of 7 against several pancreatic cancer cell lines [36].

12-Deacetyl-12-epi-scalaradial (8) has been reported to inhibit the proliferation of sev- 12-Deacetyl-12-12-Deacetyl-12-epiepi-scalaradial-scalaradial (8 ()8 has) has been been reported reported to to inhibit inhibit the the proliferation proliferation of of sev- sev- eral cancer cell lines [37]. A recent isolation of 8 allowed further investigation on its mode eraleral cancer cancer cell cell lines lines [37 [37]]. A. A recent recent isolation isolation of of8 8allowed allowed further further investigation investigation on on its its mode mode of action, which showed it to induce apoptosis in human cervical cancer HeLa cells via ofof action, action, which which showed showed it it to to induce induce apoptosis apoptosis in in human human cervical cervical cancer cancer HeLa HeLa cells cells via via extrinsic and MAPK/ERK pathways [38]. Heteronemin acetate (9) displayed cytotoxic ac- extrinsicextrinsic and and MAPK/ERK MAPK/ERK pathways pathways [ 38[38].]. Heteronemin Heteronemin acetate acetate ( 9(9)) displayed displayed cytotoxic cytotoxic ac- ac- tivity against SKOV3 (IC50 = 3.4 μM), SKMEL (IC50 = 15.3 μM), BT549 (IC50 = 11.2 μM) and tivitytivity against against SKOV3 SKOV3 (IC (IC50 50= = 3.4 3.4µ M),μM), SKMEL SKMEL (IC (IC50 50= = 15.3 15.3µ M),μM), BT549 BT549(IC (IC50 50= = 11.2 11.2µ μM)M)and and Vero (IC50 = 8.2µ μM) cells [39]. 12-Epi-heteronemin (10) showed cytotoxicity against human VeroVero (IC (IC5050= = 8.2 8.2 μM)M) cells cells [ 39[39].]. 12- 12-EpiEpi-heteronemin-heteronemin ( 10(10)) showed showed cytotoxicity cytotoxicity against against human human epidermoid carcinoma KB cells (IC50 = 5.1µ μM) [40]. 12-Epi-scalaradial (13) has been re- epidermoidepidermoid carcinoma carcinoma KB KB cells cells (IC (IC5050= = 5.1 5.1 μM)M) [ 40[40].]. 12- 12-EpiEpi-scalaradial-scalaradial ( 13(13)) has has been been re- re- ported to possess cytotoxic activity against DLD-1 (IC50 µ= 6.1 μM), HCT-116 (IC50µ = 8.9 portedported to to possess possess cytotoxic cytotoxic activity activity against against DLD-1 DLD-1 (IC50 (IC= 6.150 = M),6.1 HCT-116μM), HCT-116(IC50 = (IC 8.950 =M) 8.9, μM), T-47D (ICµ50 = 4.7 μM), and K562 (ICµ 50 = 4.4 μM) cells [41], while scalarafuran14 (14) T-47DμM), (ICT-47D50 = 4.7(IC50M), = 4.7 and μM), K562 and (IC 50K562= 4.4 (ICM)50 = cells4.4 μ [41M)], whilecells [41], scalarafuran while scalarafuran ( ) exhibited (14) cytotoxicexhibited activity cytotoxic against activity murine against lymphoma murine L1210 lymphoma (IC = L1210 6.8 µM) (IC and50 = human6.8 μM) epidermoid and human exhibited cytotoxic activity against murine lymphoma50 L1210 (IC50 = 6.8 μM) and human carcinomaepidermoid KB carcinoma (IC = 9.3 KBµM) (IC cells50 = 9.3 [42 ].μM) cells [42]. epidermoid carcinoma50 KB (IC50 = 9.3 μM) cells [42].

5.1.4. Pseudoceratina sp. 5.1.4.5.1.4.Pseudoceratina Pseudoceratinasp. sp. This sponge was collected from the Vava‘u group in 1980 and initially identified as ThisThis sponge sponge was was collected collected from from the the Vava‘u Vava‘u group group in in 1980 1980 and and initially initially identified identified as as Psammaplysilla sp. [43]. However, the genus Psammaplysilla has since been taxonomically PsammaplysillaPsammaplysillasp. sp. [43 [43].]. However, However, the the genus genusPsammaplysilla Psammaplysillahas has since since been been taxonomically taxonomically revised to Pseudoceratina [44]. This genus belongs to the order Verongiida, which are nor- revisedrevised to toPseudoceratina Pseudoceratina [[44].44]. This This genus genus belongs belongs to to the the order order Verongiida, Verongiida, which which are arenor- mally found in tropical to temperate climates. normallymally found found in intropical tropical to totemperate temperate climates. climates. Chemistry/Bioactivity: Psammaplin A (15) is a bromotyrosine metabolite that was Chemistry/Bioactivity:Chemistry/Bioactivity: PsammaplinPsammaplin AA ((1515)) isis a a bromotyrosine bromotyrosine metabolite metabolite that that was was reported in 1987, along with the known compound 3-bromo-4-hydroxyphenylacetonitrile reportedreported in in 1987, 1987, along along with with the the known known compound compound 3-bromo-4-hydroxyphenylacetonitrile 3-bromo-4-hydroxyphenylacetonitrile (16) [43]. Compound 15 is considered to be the first isolated natural product containing (16(16)[)43 [43].]. Compound Compound15 15is is considered considered to to be be the the first first isolated isolated natural natural product product containing containing both oxime and disulfide moieties. Psammaplin A (15) inhibits the activities of several key bothboth oxime oxime and and disulfide disulfide moieties. moieties. Psammaplin Psammaplin A A (15 (15) inhibits) inhibits the the activities activities of of several several key key enzymes in prokaryotic and eukaryotic systems, including those involved in epigenetic enzymesenzymes in in prokaryotic prokaryotic and and eukaryotic eukaryotic systems, systems, including including those those involved involved in in epigenetic epigenetic control of gene expression, DNA replication, angiogenesis, microbial detoxification, and controlcontrol of of gene gene expression, expression, DNA DNA replication, replication, angiogenesis, angiogenesis, microbial microbial detoxification, detoxification, and and tumor cell growth [45–54]. For this reason, psammaplin A (15) has become a major re- tumortumor cell cell growth growth [45 [45–54].–54]. For For this this reason, reason, psammaplin psammaplin A (15 A) has(15) become has become a major a researchmajor re- search focus for chemists and pharmacologists and has been proposed as a natural pro- search focus for chemists and pharmacologists and has been proposed as a natural pro- drug [55]. drug [55].

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focus for chemists and pharmacologists and has been proposed as a natural prodrug [55].

5.1.5.5.1.5. HalichondriaHalichondria sp.sp. 5.1.5. Halichondria sp. SpecimensSpecimens ofof thisthis undescribedundescribed speciesspecies werewere collectedcollected inin Vava‘uVava‘u byby thethe CRRFCRRF underunder Specimens of this undescribed species were collected in Vava‘u by the CRRF under contractcontract withwith thethe NCINCI [14].[14]. TheThe sponspongege waswas originallyoriginally identifiedidentified asas PellinaPellina sp.,sp., howeverhowever contract with the NCI [14]. The sponge was originally identified as Pellina sp., however thisthis genusgenus hashas sincesince beenbeen taxonomicallytaxonomically revisedrevised toto HalichondriaHalichondria [44].[44]. this genus has since been taxonomically revised to Halichondria [44]. Chemistry/Bioactivity:Chemistry/Bioactivity: Bioassay-directedBioassay-directed fractionationsfractionations ofof thethe organicorganic extractextract af-af- Chemistry/Bioactivity: Bioassay-directed fractionations of the organic extract afforded fordedforded pellynolpellynol II ((1717)) [14],[14], togethertogether withwith thethe knownknown compoundscompounds pellynolspellynols A–DA–D ((1818––2121)) pellynol I (17)[14], together with the known compounds pellynols A–D (18–21)[56] and [56][56] andand pellynolpellynol FF ((2222)) [57].[57]. PellynolsPellynols A–DA–D ((1818––2121)) werewere firstfirst reportedreported fromfrom thethe marinemarine pellynol F (22)[57]. Pellynols A–D (18–21) were first reported from the marine sponge spongesponge PellinaPellina triangulatatriangulata [56],[56], whilewhile pellynolpellynol FF ((2222)) waswas firstfirst identifiedidentified fromfrom anan un-un- Pellina triangulata [56], while pellynol F (22) was first identified from an undescribed describeddescribed TheonellaTheonella spongesponge [57].[57]. AllAll compoundscompounds werewere shownshown toto displaydisplay cytotoxiccytotoxic activityactivity Theonella sponge [57]. All compounds were shown to display cytotoxic activity against LOX againstagainst LOXLOX (melanoma)(melanoma) andand OVCAR-3OVCAR-3 (ovarian)(ovarian) humanhuman tumortumor cellcell lines.lines. AgainstAgainst LOXLOX (melanoma) and OVCAR-3 (ovarian) human tumor cell lines. Against LOX cells, pellynols cells,cells, pellynolspellynols AA ((1818),), BB ((1919),), CC ((2020),), DD ((2121),), FF ((2222),), andand II ((1717)) exhibitedexhibited antiproliferativeantiproliferative A(18), B (19), C (20), D (21), F (22), and I (17) exhibited antiproliferative effects with IC50 effects with IC50 values of 0.2–0.8 μM, while presenting IC50 values of 2.0–4.5 μM against valueseffects of with 0.2–0.8 IC50 µvaluesM, while of 0.2–0.8 presenting μM, ICwhilevalues presenting of 2.0–4.5 IC50 µvaluesM against of 2.0–4.5 the OVACAR-3 μM against the OVACAR-3 cell line [14]. 50 cellthe lineOVACAR-3 [14]. cell line [14].

5.1.6. Jaspis sp. 5.1.6.5.1.6.Jaspis Jaspissp. sp. In 1997, the CRRF collected a sponge from the genus Jaspis in Vava‘u [15]. Sponges InIn 1997, 1997, the the CRRF CRRF collected collected a a sponge sponge from from the the genus genusJaspis Jaspisin in Vava‘u Vava‘u [ 15[15].]. Sponges Sponges belongingbelongingbelonging to toto this thisthis genus genusgenus (family (family(family Jaspidae) Jaspidae)Jaspidae) have havehave recently recentlyrecently received receivedreceived considerable considerableconsiderable attention attentionattention dueduedue to toto themthem being being aa a richrich rich sourcesource source ofof of biologicallybiologically biologically activeactive active andand and structurallystructurally structurally novelnovel novel naturalnatural natural prod-prod- productsuctsucts [58].[58]. [ 58 ]. Chemistry/Bioactivity:Chemistry/Bioactivity:Chemistry/Bioactivity: ThreeThree isomalabaricaneisomalabaricaneisomalabaricane triterpenes,triterpenes,triterpenes, 29-hydroxystelliferin 29-hydroxystelliferin29-hydroxystelliferin E EE (23((2323),),), 29-hydroxystelliferin 29-hydroxystelliferin29-hydroxystelliferin A AA ( 24((2424),),), and andand stelliferin stelliferinstelliferin G GG ( 25((2525),),), were werewere obtained obtainedobtained from fromfrom the thethe organic organicorganic extractextractextract of ofof the thetheJaspis JaspisJaspisspecimen, specimen,specimen, along alongalong with withwith the thethe known knownknown triterpene triterpenetriterpene 3- epi 3-3-epi-29-hydroxystelliferinepi-29-hydroxystelliferin-29-hydroxystelliferin E (26EE ()[(262615)) ].[15].[15]. Compounds CompoundsCompounds24 and 2424 andand25 were 2525 werewere the the mostthe mostmost growth-inhibitory growth-inhibitorygrowth-inhibitory against againstagainst the MALME-3M thethe MALME-MALME- 3M melanoma cell line with IC50 values of 0.2 and 0.4 μM, respectively, while both 23 and melanoma3M melanoma cell linecell line with with IC50 ICvalues50 values of 0.2of 0.2 and and 0.4 0.4µM, μM, respectively, respectively, while while both both23 23and and 262626were werewere approximately approximatelyapproximately 10-fold 10-fold10-foldless lesslesspotent, potent,potent,with withwitha aa similar similarsimilar trend trendtrend observed observedobservedwith withwith MOLT-4 MOLT-4MOLT-4 leukemialeukemialeukemia cells cellscells [ 15 [15].[15].].

5.1.7.5.1.7.5.1.7.Coelocarteria CoelocarteriaCoelocarteria singaporensis singaporensissingaporensis TheTheThe sponge spongesponge was waswas collectedcollectedcollected byby SCUBA SCUBA at at aa dede depthpthpth ofof of 77 7 mm m inin in Vava‘uVava‘u Vava‘u andand and identifiedidentified identified asas asHaliclonaHaliclonaHaliclona chrysachrysa chrysa [16],[16],[16 however,however,], however, thisthis this speciesspecies species hashas hassisincence since beenbeen been taxonomitaxonomi taxonomicallycallycally revisedrevised revised toto Coelo-Coelo- to Coelocarteriacarteriacarteria singaporensissingaporensis singaporensis [44].[44].[ 44 ]. Chemistry/Bioactivity:Chemistry/Bioactivity: IsolationIsolation ofof halaminolhalaminol EE ((2727)) resultedresulted fromfrom utilizingutilizing aa newnew au-au- tomated,tomated, high-capacity,high-capacity, andand high-throughputhigh-throughput procedureprocedure developeddeveloped byby thethe NCINCI toto rapidlyrapidly isolateisolate andand identifyidentify biologicallybiologically activeactive naturalnatural productsproducts fromfrom aa pre-fractionatedpre-fractionated library.library.

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MoleculesMolecules 2021 2021, ,26 26, ,x x FOR FOR PEER PEER REVIEW REVIEW 77 ofof 2626 Chemistry/Bioactivity: Isolation of halaminol E (27) resulted from utilizing a new automated, high-capacity, and high-throughput procedure developed by the NCI to rapidly isolate and identify biologically active natural products from a pre-fractionated library. HalaminolHalaminol E E ( (2727)) exhibited exhibited low low micromolar micromolar activity activity with with a a GI GI5050 value value of of 6.76 6.76 μ μMM against against Halaminol E (27) exhibited low micromolar activity with a GI50 value of 6.76 µM against thethethe NCI-60 NCI-60 NCI-60 human human human tumor tumor tumor cell cell cell line line line panel panel panel [ 16[16]. [16].].

5.1.8.5.1.8. Plakortis Plakortis sp. sp. 5.1.8. Plakortis sp. ThisThis specimenspecimen waswas collectedcollected usingusing SCUBASCUBA fromfrom thethe ceilingceiling ofof anan underwaterunderwater cavecave This specimen was collected using SCUBA from the ceiling of an underwater cave (depth(depth of of 12–15 12–15 m) m) off off the the coast coast of of ‘Eua ‘Eua Isla Islandnd [18]. [18]. This This dark dark purplish purplish brown brown sponge sponge was was (depth of 12–15 m) off the coast of ‘Eua Island [18]. This dark purplish brown sponge was identified as a species of Plakortis (order Homosclerophorida), which are commonly found identifiedidentified as as a a species species of ofPlakortis Plakortis(order (order Homosclerophorida), Homosclerophorida), which which are are commonly commonly found found in warm waters. inin warm warm waters. waters. Chemistry/Bioactivity: Spectroscopy-guided chemical analysis of this sponge speci- Chemistry/Bioactivity:Chemistry/Bioactivity: Spectroscopy-guidedSpectroscopy-guided chemicalchemical analysisanalysis ofof thisthis spongesponge speci- speci- men,men,men, afforded afforded afforded seven seven seven new new new metabolites metabolites metabolites of of of polyketide polyketide polyketide origin, origin, origin, lehualides lehualides lehualides E–K E–K E–K (28 ( (2828–34––3434),), four), four four of of of whichwhichwhich incorporate incorporateincorporate various variousvarious sulfur sulfursulfur functionalities functionalitiesfunctionalities [18 ]. [18].[18]. The The compounds’The compoundscompounds structures′ ′ structuresstructures were were elu-were cidatedelucidatedelucidated by interpretation byby interpretationinterpretation of spectroscopic ofof spectroscopicspectroscopic data and datadata spectral andand spectralspectral comparison comparisoncomparison with compounds withwith com-com- modellingpoundspounds modelling modelling the sulfur-containing the the sulfur-containing sulfur-containing functional functional groups.functional Lehualides groups. groups. Lehualides Lehualides F (29) and GFF ( ((293029))) and exhibitedand G G ( (3030)) exhibitedexhibited growth growth inhibition inhibition of of HL-60 HL-60 cells cells with with IC IC5050 values values of of 6.2 6.2 and and 5.4 5.4 μΜ μΜ, ,respectively, respectively, growth inhibition of HL-60 cells with IC50 values of 6.2 and 5.4 µM, respectively, whereas thewhereaswhereas thioacetate thethe thioacetatethioacetate and sulfide andand metabolites sulfsulfideide metabolites lehualidesmetabolites H lehualideslehualides (31) and I H (H32 ()(3131 displayed)) andand II ((32 weaker32)) displayeddisplayed inhi- weaker inhibition with IC5050 values of 14.6 and 10.8 μΜ, respectively [18]. bitionweaker with inhibition IC50 values with of IC 14.6 values and 10.8 of 14.6µM, and respectively 10.8 μΜ, [respectively18]. [18].

5.1.9.5.1.9. Strongylodesma Strongylodesma tongaensis tongaensis 5.1.9. Strongylodesma tongaensis BothBoth the the interior interior and and exterior exterior of of this this massive massive and and soft soft sponge sponge is is black black and and produced produced Both the interior and exterior of this massive and soft sponge is black and produced a aa deep deep greenish-black greenish-black mucus mucus on on coll collectionection (Vava‘u, (Vava‘u, 2009). 2009). To To date, date, S. S. tongaensis tongaensis has has only only deep greenish-black mucus on collection (Vava‘u, 2009). To date, S. tongaensis has only been beenbeen reported reported from from three three countries countries (Tonga, (Tonga, Pa Palaulau and and the the Federated Federated States States of of Micronesia) Micronesia) reported from three countries (Tonga, Palau and the Federated States of Micronesia) [59]. [59].[59]. MoreMore concerning,concerning, spongessponges ofof thethe genusgenus StrongylodesmaStrongylodesma havehave previouslypreviously beenbeen taxo-taxo- More concerning, sponges of the genus Strongylodesma have previously been taxonomically nomicallynomically misidentified misidentified as as Batzella Batzella, ,Damiria Damiria, ,Histodermella Histodermella, ,Negombata Negombata, ,Prianos, Prianos, and and Zyzzya Zyzzya, , misidentified as Batzella, Damiria, Histodermella, Negombata, Prianos, and Zyzzya, all reported allall reported reported as as sources sources of of pyrroloiminoquinone pyrroloiminoquinone secondary secondary metabolites metabolites [59]. [59]. as sources of pyrroloiminoquinone secondary metabolites [59]. Chemistry/Bioactivity:Chemistry/Bioactivity: InitialInitial investigatioinvestigationn ofof thisthis specimenspecimen affordedafforded twotwo knownknown Chemistry/Bioactivity: Initial investigation of this specimen afforded two known pyrroloquinolinepyrroloquinoline derivativesderivatives [60],[60], makaluvaminemakaluvamine GG ((3535)) [61][61] andand prianosinprianosin BB ((3636)) [62].[62]. pyrroloquinoline derivatives [60], makaluvamine G (35)[61] and prianosin B (36)[62]. MakaluvamineMakaluvamine G G ( (3535)) was was originally originally reported reported in in 1993 1993 by by Scheuer Scheuer et et al. al. from from an an Indonesian Indonesian Makaluvamine G (35) was originally reported in 1993 by Scheuer et al. from an Indonesian ZyzzyaZyzzya fuliginosa fuliginosa (previously (previously identified identified as as Histodermella Histodermella sp.) sp.) [61,63], [61,63], and and exhibited exhibited general general cytotoxicitycytotoxicity against against a a panel panel of of tumor tumor cell cell lines lines (IC (IC5050 1.2–1.5 1.2–1.5 μ μM)M) while while displaying displaying no no anti- anti- fungalfungal oror antiviralantiviral activitiesactivities [61].[61]. PrianosinPrianosin BB ((3636),), aa sulfur-containingsulfur-containing alkaloidalkaloid firstfirst ob-ob- tainedtained fromfrom anan OkinawanOkinawan PrianosPrianos melanosmelanos, , displayeddisplayed cytotoxiccytotoxic activityactivity againstagainst murinemurine

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cytotoxicity against a panel of tumor cell lines (IC50 1.2–1.5 µM) while displaying no anti- fungallymphoma or antiviral cell lines activities L1210 [61 and]. Prianosin L5178Y Bin ( 36vitro), a sulfur-containingwith IC50 values alkaloidof 6.0 and first 5.4 obtained μM, but fromonly an weakly Okinawan againstPrianos and the melanos human, displayed epidermoid cytotoxic carcinoma activity KB against cell line murine with an lymphoma IC50 > 15.0 lymphoma cell lines L1210 and L5178Y in vitro with IC50 values of 6.0 and 5.4 μM, but cellμM lines [62]. L1210 In addition, and L5178Y it was inshown vitro towith possess IC50 valuesmoderate of 6.0cytotoxicity and 5.4 µ againstM, but onlythe HL-60 weakly cell only weakly against and the human epidermoid carcinoma KB cell line with an IC50 > 15.0 againstline with and an the IC human50 value epidermoid of 2.2 μM [60]. carcinoma KB cell line with an IC50 > 15.0 µM[62]. In μM [62]. In addition, it was shown to possess moderate cytotoxicity against the HL-60 cell addition,Re-examination it was shown of to the possess same moderate species from cytotoxicity the Vava’u against collection the HL-60 yielded cell two line withnew pyr- an line with an IC50 value of 2.2 μM [60]. ICroloquinoline50 value of 2.2 alkaloids,µM[60]. 6-bromodamirone B (37) and makaluvamine W (38) [21,64], along Re-examination of the same species from the Vava’u collection yielded two new pyr- withRe-examination the known compounds of the same makaluvamines species from A the(39), Vava‘u C (40), collectionE (41), F (42 yielded) [65], I ( two43), newK (44) roloquinoline alkaloids, 6-bromodamirone B (37) and makaluvamine W (38) [21,64], along pyrroloquinoline[63], makaluvone alkaloids, (45) [65], 6-bromodamirone damirone B (46) [66], B (37 makaluvic) and makaluvamine acid A (47) W[67], (38 and)[21 ,tsitsi-64], with the known compounds makaluvamines A (39), C (40), E (41), F (42) [65], I (43), K (44) alongkammamine with the B known (48) [68]. compounds Makaluvamine makaluvamines W (38) contains A (39), an C (oxazole40), E (41 moiety,), F (42 )[which65], I is (43 rare), [63], makaluvone (45) [65], damirone B (46) [66], makaluvic acid A (47) [67], and tsitsi- K(in44 this)[63 large], makaluvone group of natural (45)[ 65products,], damirone and is B the (46 )[first66 ],example makaluvic of a acidpyrroloquinoline A (47)[67], and with kammamine B (48) [68]. Makaluvamine W (38) contains an oxazole moiety, which is rare tsitsikammaminenitrogen substitution B (48 at)[ 68C-8.]. MakaluvamineNeither 37 nor 38 W were (38) containsactive against an oxazole the human moiety, promyelo- which in this large group of natural products, and is the first example of a pyrroloquinoline with iscytic rare leukemia in this large cell group line HL-60 of natural [21]. This products, observation and is thewas first in accordance example of with a pyrroloquino- the iminoqui- nitrogen substitution at C-8. Neither 37 nor 38 were active against the human promyelo- linenone with structural nitrogen requirement substitution necessary at C-8. Neither for cytotoxicity37 nor 38 inwere the activepyrroloiminoquinone against the human alka- cytic leukemia cell line HL-60 [21]. This observation was in accordance with the iminoqui- promyelocyticloids as reported leukemia in the literature cell line HL-60 [61,67]. [21 ]. This observation was in accordance with thenone iminoquinone structural requirement structural requirement necessary for necessary cytotoxicity for cytotoxicityin the pyrroloiminoquinone in the pyrroloimino- alka- quinoneloids as alkaloidsreported in as the reported literature in the [61,67]. literature [61,67].

Historically, a series of pyrroloiminoquinone alkaloids were isolated from a Fijian specimenHistorically, of Z. fuliginosa a series of (formerly pyrroloiminoquinone identified as Z. alkaloids massalis were) in 1993, isolated including from a makaluvam- Fijian spec- Historically, a series of pyrroloiminoquinone alkaloids were isolated from a Fijian imenines ofAZ. (39 fuliginosa), C (40),(formerly E (41), F identified(42), and asmakaluvoneZ. massalis) ( in45 1993,) [63,65]. including Two years makaluvamines later, maka- specimen of Z. fuliginosa (formerly identified as Z. massalis) in 1993, including makaluvam- A(luvamines39), C (40 ),I ( E43 (41) and), F (K42 (),44 and) were makaluvone obtained (from45)[ 63a ,Micronesian65]. Two years specimen later, makaluvamines of Z. fuliginosa, ines A (39), C (40), E (41), F (42), and makaluvone (45) [63,65]. Two years later, maka- I(including43) and K makaluvamines (44) were obtained H, J, from L, and aMicronesian M [63]. Damirone specimen B (46 of) wasZ. fuliginosa first reported, including from a luvamines I (43) and K (44) were obtained from a Micronesian specimen of Z. fuliginosa, makaluvaminesPalauan Z. fuliginosa H, J, L, (previously and M [63 ].identified Damirone as BDamiria (46) was sp.) first [66], reported while makaluvic from a Palauan acid A including makaluvamines H, J, L, and M [63]. Damirone B (46) was first reported from a Z.(47 fuliginosa) was obtained(previously from identifieda Micronesian as Damiria Z. fuliginosasp.) [66 (misspelled], while makaluvic in the original acid A manuscript (47) was Palauan Z. fuliginosa (previously identified as Damiria sp.) [66], while makaluvic acid A obtainedas Z. fuliginosus from a)Micronesian [67]. TsitsikammamineZ. fuliginosa B ((misspelled48) was isolated in the from original the related manuscript South African as Z. (47) was obtained from a Micronesian Z. fuliginosa (misspelled in the original manuscript fuliginosusLatrunculid)[67 sponge,]. Tsitsikammamine Tsitsikamma favus B (48 )[68]. was Compounds isolated from 39 the, 41 related, and 42 South were Africanfound to La- ex- as Z. fuliginosus) [67].Tsitsikamma Tsitsikammamine favus B (48) was isolated39 41 from 42the related South African trunculidhibit cytotoxicity sponge, towards the HCT-116[68]. Compounds cell line with IC, 50 ,values and ofwere 1.3, found1.2, and to 0.17 exhibit μM, Latrunculid sponge, Tsitsikamma favus [68]. Compounds 39, 41, and 42 were found to ex- cytotoxicityrespectively, towards while the45 HCT-116and 46 were cell linebiologically with IC50 inactivevalues of in 1.3, the 1.2, same and assay 0.17 µ [61].M, respec- Maka- hibit cytotoxicity towards the HCT-116 cell line with IC50 values of 1.3, 1.2, and 0.17 μM, tively,luvamines while A45 (39and), E46 (41were), and biologically K (44) exhibited inactive cytotoxicity in the same towa assayrds [P38861]. Makaluvamines murine leukemia A(respectively,39), E (41), andwhile K (4544 )and exhibited 46 were cytotoxicity biologically towards inactive P388 in murinethe same leukemia assay [61]. cells Maka- (IC cells (IC50 2.0–2.2 μM) [67], whilst makaluvamine C (40) had an IC50 value of 2.6 μM50 to- luvaminesµ A (39), E (41), and K (44) exhibited cytotoxicity towards P388µ murine leukemia 2.0–2.2wards HL-60M) [67 ],cells whilst [64]. makaluvamine Makaluvic acid C (A40 )(47 had) displayed an IC50 value no cytotoxicity of 2.6 M towards against HL-60murine cells (IC50 2.0–2.2 μM) [67], whilst makaluvamine C (40) had an IC50 value of 2.6 μM to- cellsleukemia [64]. Makaluvic P388 cellsacid [67], A whereas (47) displayed tsitsikammamine no cytotoxicity B (48 against) exhibited murine cytotoxicity leukemia against P388 cellswards [67 ],HL-60 whereas cells tsitsikammamine [64]. Makaluvic Bacid (48 )A exhibited (47) displayed cytotoxicity no cytotoxicity against the against human murine colon the human colon tumor cell line HCT-116 with an IC50 value of 2.4 μM [68]. tumorleukemia cell lineP388 HCT-116 cells [67], with whereas an IC 50tsitsikammaminevalue of 2.4 µM[ B68 (].48) exhibited cytotoxicity against the human colon tumor cell line HCT-116 with an IC50 value of 2.4 μM [68].

5.1.10. Cacospongia mycofijiensis 5.1.10This. Cacospongia species is mycofijiensis found throughout the Indo-Pacific with a variable morphology from mushroom to tubular-like shapes, depending on the geographical source location and the This species is found throughout the Indo-Pacific with a variable morphology from mushroom to tubular-like shapes, depending on the geographical source location and the

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5.1.10. Cacospongia mycofijiensis This species is found throughout the Indo-Pacific with a variable morphology from mushroomsurrounding to environment tubular-like shapes,[69]. Three depending collections on of the this geographical sponge were source made location by VUW and re- thesearchers surrounding from different environment geographical [69]. Three location collectionss; two of from this spongethe island were of made‘Eua (2008 by VUW and researchers2016) and one from from different the Vava‘u geographical group (2009). locations; two from the island of ‘Eua (2008 and 2016)Chemistry/Bioactivity: and one from the Vava‘u An group initial (2009). investigation into secondary metabolites of the spongeChemistry/Bioactivity: provided a number of An known initial bioactiv investigatione and structurally into secondary diverse metabolites compounds of the[17] spongeincluding provided latrunculin a number A (49 of) [70], known 6,7-epoxylatrunculin bioactive and structurally A (50) [71], diverse dendrolasin compounds (51) [[72],17] includingmycothiazole latrunculin (52) [73], A (49 fijianolide)[70], 6,7-epoxylatrunculin A/isolaulimalide A ( (5350),)[ fijianolide71], dendrolasin B/laulimalide (51)[72], my-(54) cothiazole[74,75], neolaulimalide (52)[73], fijianolide (55) [76], A/isolaulimalide and zampanolide (53), (56 fijianolide) [77]. B/laulimalide (54)[74,75], neolaulimalideLatrunculin (55 A)[ (7649],) andis a 16-membered zampanolide (macrolide56)[77]. with an appended 2-thiazolidinone ring,Latrunculin originally reported A (49) is from a 16-membered the Red Sea macrolidesponge Negombata with an appendedmagnifica (previously 2-thiazolidinone identi- ring,fied originallyas Latrunculia reported magnifica from) [70]. the Red Latrunculin Sea sponge A (Negombata49) is an ichthyotoxic magnifica (previously compound iden- and tifiedwas later as Latrunculia found to be magnifica an actin)[ 70polymerization]. Latrunculin inhibitor, A (49) is anand ichthyotoxic consequently compound 49 is the most and waswidely later used found tool to for be inhibition an actin polymerization of actin polymerization inhibitor, in and cell consequently biological studies49 is [78,79]. the most In widely used tool for inhibition of actin polymerization in cell biological studies [78,79]. 1989, 6,7-epoxylatrunculin A (50) was also reported from N. magnifica (previously L. mag- In 1989, 6,7-epoxylatrunculin A (50) was also reported from N. magnifica (previously L. nifica) [71]. The biological activity reported for this compound includes cytotoxicity magnifica)[71]. The biological activity reported for this compound includes cytotoxicity against P388 murine leukemia (IC50 = 4.1 μM) and human lung cancer A549 (IC50 = 0.5 μM) against P388 murine leukemia (IC = 4.1 µM) and human lung cancer A549 (IC = 0.5 µM) cells [80]. Dendrolasin (51) is a simple50 furano-sesquiterpene that was originally50 reported cells [80]. Dendrolasin (51) is a simple furano-sesquiterpene that was originally reported in in 1957 from the ant Dendrolasius fuliginosus [72], and was found to exhibit extremely weak 1957 from the ant Dendrolasius fuliginosus [72], and was found to exhibit extremely weak cytotoxic activity against the human epithelial type 2 cell line HEp-2 [81]. cytotoxic activity against the human epithelial type 2 cell line HEp-2 [81].

MycothiazoleMycothiazole ( 52(52)) is is an an unusual unusual heterocyclic heterocyclic polyketide polyketide first first obtained obtained from from a specimen a speci- ofmenC. mycofijiensisof C. mycofijiensiscollected collected from Vanuatu, from Vanuatu, and was and the firstwas disubstitutedthe first disubstituted thiazole reported thiazole fromreported a marine from spongea marine [73 sponge]. The original[73]. The chemical original structurechemical structure of 52 was of later 52 was found later to befound in- correct, and a corrected structure (the ∆14,15 E geometry initially proposed was revised to Z) to be incorrect, and a corrected structure (the Δ14,15 E geometry initially proposed was re- was subsequently published in 2006 [82]. Mycothiazole (52) displays anthelminthic activity vised to Z) was subsequently published in 2006 [82]. Mycothiazole (52) displays anthel- (in vitro) and high toxicity towards mice [72]. Further bioactivity study indicated that it minthic activity (in vitro) and high toxicity towards mice [72]. Further bioactivity study has selective cytotoxicity towards lung cancer cells [82] and also proved it to be a valuable indicated that it has selective cytotoxicity towards lung cancer cells [82] and also proved lead mitochondrial complex I inhibitor [83]. A recent article revealed that 52 possesses it to be a valuable lead mitochondrial complex I inhibitor [83]. A recent article revealed picomolar potency against PANC-1 (pancreatic), HepG2 (liver), and HCT-116 (colon) cell that 52 possesses picomolar potency−4 against−4 PANC-1 (pancreatic),−4 HepG2 (liver), and lines with IC50 values of 1.6 × 10 , 2.7 × 10 , and 3.5 × 10 µM, respectively [84]. HCT-116 (colon) cell lines with IC50 values of 1.6 × 10−4, 2.7 × 10−4, and 3.5 × 10−4 μM, re- From the same Vanuatu collection where they originally reported mycothiazole, Crews spectively [84]. and co-workers also identified two cytotoxic macrolides; fijianolides A (53) and B (54)[74]. From the same Vanuatu collection where they originally reported mycothiazole, These isomers were simultaneously reported as isolaulimalide (53) and laulimalide (54), Crews and co-workers also identified two cytotoxic macrolides; fijianolides A (53) and B respectively, from an Indonesian marine sponge Hyatella sp. by Scheuer and colleagues from(54) [74]. the University These isomers of Hawaii; were thesimultaneo latter twously names reported are theas moreisolaulimalide generally ( accepted53) and lau- by thelimalide MNP (54 community), respectively, [75]. from Compound an Indonesian54 is a marine potent sponge inhibitor Hyatella of mammalian sp. by Scheuer cellular and colleagues from the University of Hawaii; the latter two names are the more generally proliferation with low nanomolar IC50 values, while 53 is considerably less potent with accepted by the MNP community [75]. Compound 54 is a potent inhibitor of mammalian IC50 values in the low micromolar range. Both compounds interact with tubulin at a similar butcellular distinct proliferation binding site with relative low nanomolar to that of paclitaxel IC50 values, [85 ,while86]. The 53 is macrolide considerably neolaulimalide less potent (55with) was IC50 first values isolated in the from low a micromolar Japanese marine range. sponge Both compoundsFasciospongia interact rimosa, andwith its tubulin structure at a wassimilar determined but distinct from binding NMR datasite relative and by to chemical that of paclitaxel correlation [85,86]. with known The macrolide congeners neolau- [76]. limalide (55) was first isolated from a Japanese marine sponge Fasciospongia rimosa, and its structure was determined from NMR data and by chemical correlation with known

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Thecongenerscongeners total synthesis [76].[76]. TheThe andtotaltotal mode synthesynthe ofsissis action andand modemode was ofof established actionaction waswas by esestablished Gollnertablished et byby al. GollnerGollner with 55etet al.beingal. demonstratedwithwith 5555 beingbeing demonstrateddemonstrated as a potent microtubule-stabilizing asas aa potentpotent microtubule-stabilizingmicrotubule-stabilizing agent [87,88 agent].agent [87,88].[87,88].

Zampanolide (56) was originally reported from the Japanese marine sponge Fas- ZampanolideZampanolide ((5656)) waswas originallyoriginally reportedreported fromfrom thethe JapaneseJapanese marinemarine spongesponge Fascio-Fascio- ciospongia rimosa, and although it exhibited potent cytotoxicity against several cell lines spongiaspongia rimosarimosa,, andand althoughalthough itit exhibitedexhibited potentpotent cytotoxicitycytotoxicity againstagainst severalseveral cellcell lineslines (IC(IC5050 (IC = 2–10 nM), the mode of action responsible was not determined during the initial == 2–102–1050 nM),nM), thethe modemode ofof actionaction responsibleresponsible waswas notnot determineddetermined duringduring thethe initialinitial investi-investi- investigationgationgation [77].[77]. Re-isolaRe-isola [77]. Re-isolationtiontion ofof compoundcompound of compound 5656 fromfrom aa 56 TonganTonganfrom CacospongiaCacospongia a Tongan Cacospongia mycofijiensismycofijiensis mycofijiensis allowedallowed allowedinvestigationinvestigation investigation ofof itsits modemode of of itsof action,action, mode which ofwhich action, showedshowed which itit toto showed bebe aa novelnovel it to andand be a potentpotent novel covalentcovalent and potent covalentbinding,binding, binding,microtubule-stabilizingmicrotubule-stabilizing microtubule-stabilizing compoundcompound compound [17].[17]. ZampanolideZampanolide [17]. Zampanolide ((5656)) isis cytotoxiccytotoxic (56) at isat nano- cytotoxicnano- atmolarmolar nanomolar concentrations,concentrations, concentrations, andand arrestsarrests and cellscells arrests inin thethe cells G2/MG2/M in phasephase the G2/M ofof thethe cellcell phase cyclecycle of byby the irreversibleirreversible cell cycle by irreversiblecovalentcovalent bindingbinding covalent toto thethe binding luminalluminal to sitesite the ofof luminalββ-tubulin,-tubulin, site thereforetherefore of β-tubulin, disruptingdisrupting therefore thethe functionfunction disrupting ofof thethe the functionmicrotubulemicrotubule of the [89].[89]. microtubule ThisThis placesplaces 5656 [89 inin]. anan This importantimportant places groupgroup56 in ofof an anti-canceranti-cancer important compoundscompounds group of anti-cancer thatthat in-in- compoundscludescludes thethe clinicallyclinically that includes valuablevaluable the paclitaxel.paclitaxel. clinically AA valuable continuedcontinued paclitaxel. NMR-guidedNMR-guided A continued investigationinvestigation NMR-guided ofof thethe investigationsamesame spongesponge offromfrom the aa same differentdifferent sponge TonganTongan from collectioncollection a different (`Eua)(`Eua) Tongan yieldedyielded collection fourfour newnew (‘Eua) zampanolidezampanolide yielded four an-an- new zampanolidealogues,alogues, zampanolideszampanolides analogues, B–EB–E zampanolides ((5757––6060)) [22].[22]. B–E TheThe (isolation57isolation–60)[22 ofof]. thesethese The isolation zampanolidezampanolide of these analoguesanalogues zampano- lidegavegave analogues insightinsight intointo gave thethe insight structure-activitystructure-activity into the structure-activity relatirelationshiponship (SAR)(SAR) relationship ofof thisthis familyfamily (SAR) ofof ofcompounds.compounds. this family of compounds.ZampanolidesZampanolides Zampanolides B–DB–D ((5757––5959)) exhibitedexhibited B–D (57– 59potentpotent) exhibited antiproliferativeantiproliferative potent antiproliferative activityactivity towardstowards activity thethe HL-60HL-60 towards thecellcell HL-60 lineline inin cell thethe line lowlow in nanomolarnanomolar the low nanomolar rangerange (3–5(3–5 range nMnM),), andand (3–5 werewere nM), determineddetermined and were determined toto bebe potentpotent to micro-micro- be potent microtubule-stabilizingtubule-stabilizingtubule-stabilizing agentsagents agents atat levelslevels at levels comparabcomparab comparablelele toto zampanolidezampanolide to zampanolide [22].[22]. Conversely,Conversely, [22]. Conversely, zampa-zampa- zam- nolide E (60), where the key double bond (Δ8,9) involved in covalent binding is saturated, panolidenolide E E(60 (60), ),where where the the key key double double bond bond (Δ (8,9∆)8,9 involved) involved in covalent in covalent binding binding is saturated, is saturated, was significantly less potent with an IC50 value of 306 nM. Surprisingly, zampanolide C waswas significantlysignificantly less potent with with an an IC IC5050 valuevalue of of 306 306 nM. nM. Surprisingly, Surprisingly, zampanolide zampanolide C C ((58(5858))) showed showedshowed similar similar activityactivity toto to thethe the parentparent parent compoundcompound compound despitedespite despite thethe the alterationalteration alteration toto thethe to thegeometrygeometry geometry of the Michael-accepting Δ8,9 double bond pharmacophore. ofof thethe Michael-acceptingMichael-accepting Δ∆8,98,9 doubledouble bond bond pharmacophore. pharmacophore.

InInIn addition,addition,addition, the the re-isolationre-isolation re-isolation ofof of dactylolidedactylolide dactylolide ((6161 (61)) fromfrom) from thethe the samesame same collectioncollection collection establishedestablished established aa a firmfirmfirm conclusion conclusionconclusionregarding regardingregarding its itsits controversial controversiacontroversia absolutell absoluteabsolute configuration, configuration,configuration, where wherewhere Tongan-sourced Tongan-Tongan- sourced 61 possesses the same absolute configuration as (−)-zampanolide (56) and has a 61sourcedpossesses 61 possesses the same the absolute same absolute configuration configuration as (−)-zampanolide as (−)-zampanolide (56) and (56 has) and a levorota-has a levorotatory specific rotation [22], opposite to that for (+)-61 originally reported from a torylevorotatory specific rotationspecific rotation [22], opposite [22], opposite to that forto that (+)- 61fororiginally (+)-61 originally reported reported from afrom Vanuatu a Vanuatu Dactylospongia source [90]. (–)-Dactylolide (61) is a microtubule-stabilizing agent DactylospongiaVanuatu Dactylospongiasource [ 90source]. (− [90].)-Dactylolide (–)-Dactylolide (61) is(61 a) is microtubule-stabilizing a microtubule-stabilizing agent agent and and was shown to be slightly more active than 60 despite missing the N-acyl hemiaminal wasand shownwas shown to be to slightly be slightly more more active active than than60 despite60 despite missing missing the theN -acylN-acyl hemiaminal hemiaminal side side chain, which plays a dramatic role in the activities of these compounds. Alterations chain,side chain, which which plays plays a dramatic a dramatic role inrole the in activitiesthe activities of these of these compounds. compounds. Alterations Alterations to the to the geometry of the double bonds within the macrocyclic core and side chain of 57–59 geometryto the geometry of the of double the double bonds bonds within within the macrocyclic the macrocyclic core core and and side side chain chain of of57 –5759–59have havehave nono effecteffect onon biologicalbiological activity,activity, suggessuggestingting thatthat thethe sideside chainchain andand doubledouble bondbond ((ΔΔ8,98,9)) no effect on biological activity, suggesting that the side chain and double bond (∆8,9) are areare bothboth essentialessential forfor thethe highhigh potencypotency andand microtubulemicrotubule polymerizationpolymerization activity,activity, respec-respec- both essential for the high potency and microtubule polymerization activity, respectively, tively,tively, ofof thesethese newnew analoguesanalogues [89].[89].

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of these new analogues [89].

5.1.11. Fascaplysinopsis sp. 5.1.11.5.1.11.Fascaplysinopsis Fascaplysinopsissp. sp. This massive globular sponge with a shiny red-brown appearance was collected from ThisThis massive massive globular globular sponge sponge with with a a shiny shiny red-brown red-brown appearance appearance was was collected collected from from an underwater cave off the southwestern coast of ‘Eua in 2008. The genus Fascaplysinopsis anan underwater underwater cave cave off off the the southwestern southwestern coast coast of of ‘Eua ‘Eua in in 2008. 2008. The The genus genusFascaplysinopsis Fascaplysinopsis has strong and thick primary fibers and is collagenous throughout the mesophyl of the hashas strong strong and and thick thick primary primary fibers fibers and and is is collagenous collagenous throughout throughout the the mesophyl mesophyl of of the the sponge; specimens are found throughout the Indo-Pacific [91]. sponge;sponge; specimens specimens are are found found throughout throughout the the Indo-Pacific Indo-Pacific [ 91[91].]. Chemistry/Bioactivity: Three known compounds, homofascaplysin A (62), isodehy- Chemistry/Bioactivity:Chemistry/Bioactivity: Three Three know knownn compounds, compounds, homofascaplysin homofascaplysin A A (62 (62), ),isodehy- isode- hydroisoluffariellolidedroisoluffariellolidedroisoluffariellolide ((6363 ()63) [92],[92],)[92 andand], and luffariellolideluffariellolide luffariellolide ((6464 ())64 [93][93])[ 93 werewere] were isolatedisolated isolated fromfrom from thisthis this specimenspecimen spec- imen[60].[60]. BothBoth [60]. 6262 Both andand62 6363and werewere63 originallyoriginallywere originally reportedreported reported inin 19911991 from infrom 1991 thethe from FijianFijian the spongesponge Fijian Fascaplysinop-Fascaplysinop- sponge Fas- caplysinopsississis reticulatereticulate [91]. reticulate[91]. HomofascaplysinHomofascaplysin[91]. Homofascaplysin AA ((6262)) waswas A shownshown (62) was toto bebe shown aa potentpotent to be inin avitrovitro potent inhibitorinhibitorin vitro ofof inhibitorchloroquine-susceptiblechloroquine-susceptible of chloroquine-susceptible (NF54)(NF54) andand (NF54)chloroquine-resistantchloroquine-resistant and chloroquine-resistant PlasmodiumPlasmodium Plasmodiumfalciparumfalciparum strainsstrains falci- with an IC50 value of 4.3 × 10−−22 μM, implying−2 62 as a promising antimalarial candidate for parumwith anstrains IC50 value with an of IC4.350 ×value 10 μ ofM, 4.3 implying× 10 µ62M, as implying a promising62 as antimalarial a promising candidate antimalarial for candidatefuturefuture drugdrug for developmentdevelopment future drug development [94].[94]. IsodehydroisoluffariellolideIsodehydroisoluffariellolide [94]. Isodehydroisoluffariellolide ((6363)) waswas foundfound (63) wastoto exhibitexhibit found cy- tocy- totoxicity against the HL-60 human promyeloid leukemia cell line with an IC50 value of exhibittotoxicity cytotoxicity against the against HL-60 the human HL-60 promyeloid human promyeloid leukemia leukemia cell line cellwith line anwith IC50 anvalue IC50 of value12.212.2 μμ ofMM 12.2 [60].[60].µ LuffariellolideM[Luffariellolide60]. Luffariellolide ((6464)) waswas ( 64 initiallyinitially) was initially obtainedobtained obtained fromfrom aa Palauan fromPalauan a Palauan LuffariellaLuffariellaLuffariella spongesponge sponge[93].[93]. ShortlyShortly [93]. Shortly thereafter,thereafter, thereafter, compoundcompound compound 6464 waswas64 was independentlyindependently independently reportedreported reported fromfrom from a a FijianFijianFijian FascaplysinopsisFascaplysinopsisFascaplysinopsis sp. sp.sp. andandand shown shownshown to toto display displaydisplay cytotoxicity cytotoxicitycytotoxicity against againstagainst murine murinemurine lymphoma lymphomalymphoma L1210 L1210L1210 50 andandand L5178Y L5178YL5178Y (both (both(both IC ICIC5050 == 8.5 8.5 μµμM)M) cellcell lineslines [[95,96].[95,96].95,96].

5.1.12.5.1.12.5.1.12. Order OrderOrder Dictyoceratida, Dictyoceratida,Dictyoceratida, Specimen SpecimenSpecimen I II AnAnAn unidentified unidentifiedunidentified sponge spongesponge from fromfrom order orderorder Dictyoceratida DictyoceratidaDictyoceratida was waswas initially initiallyinitially collected collectedcollected in 2008 inin from 20082008 anfromfrom unlit anancave unlitunlit on cavecave ‘Eua, onon at ‘Eua,‘Eua, a depth atat aa depth ofdepth ca. 12–15ofof ca.ca. 12–15 m12–15 while mm while awhile second aa secondsecond collection collectioncollection was made waswas frommademade thefromfrom Vava‘u thethe Vava‘uVava‘u group groupgroup in 2009 inin [ 1920092009,97 ].[19,97].[19,97]. The sponge TheThe spsp isongeonge porous isis porousporous and firm, andand firm, withfirm, bothwithwith abothboth reticulated aa reticu-reticu- surfacelatedlated surfacesurface and oscules. andand oscules.oscules. It contains ItIt containscontains no siliceous nono siliceoussiliceous spicules spiculesspicules and there andand therethere is little isis littlelittle difference differencedifference in the inin pigmentationthethe pigmentationpigmentation of its ofof pinky-beige itsits pinky-beigepinky-beige exterior exteriorexterior and interiorandand interiorinterior [97]. [97]. Dictyoceratid[97]. DictyoceratidDictyoceratid sponges spongessponges do not dodo possessnotnot possesspossess siliceous siliceoussiliceous spicules, spicules,spicules, which whichwhich makes makesmakes their thth taxonomiceireir taxonomictaxonomic identification identificationidentification more moremore difficult. difficult.difficult. Chemistry/Bioactivity:Chemistry/Bioactivity:Chemistry/Bioactivity: LuakuliidesLuakuliides A–CA–C ( (6565––6767)) were were newnew labdanelabdanelabdane diterpenesditerpenesditerpenes iso-iso-iso- latedlatedlated from fromfrom two twotwo samples samplessamples of ofof the thethe Dictyoceratid DictyoceratidDictyoceratid sponge spspongeonge collected collectedcollected from fromfrom ‘Eua, ‘Eua,‘Eua, together togethertogether with withwith the thethe methyl-acetalmethyl-acetalmethyl-acetal of ofof luakuliide luakuliideluakuliide A AA ( (68(6868)[)) [19].19[19].]. These TheseThese compounds compoundscompounds are areare characterized characterizedcharacterized by byby a aa bridging bridgingbridging hemi-acetalhemi-acetal functionfunction onon thethe BB-ring-ring ofof thethe labdanelabdane bicycle.bicycle. BothBoth 6565 andand 6868 displayeddisplayed veryvery weakweak inhibitioninhibition ofof HL-60HL-60 humanhuman promyeloidpromyeloid leukemialeukemia cellscells [19].[19].

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Molecules 2021, 26, x FOR PEER REVIEW 12 of 26 Molecules Molecules 2021 2021, 26, ,26 x ,FOR x FOR PEER PEER REVIEW REVIEW 12 12of of26 26 hemi-acetal function on the B-ring of the labdane bicycle. Both 65 and 68 displayed very weak inhibition of HL-60 human promyeloid leukemia cells [19].

5.1.13. Order Dictyoceratida, Specimen II 5.1.13.5.1.13. Order Order Dictyoceratida, Dictyoceratida, Specimen Specimen II II 5.1.13.This Order undescribed Dictyoceratida, sponge Specimen was collected II from an underwater cave at the southwest of ThisThis undescribed undescribed sponge sponge was was collected collected from from an an underwater underwater cave cave at atthe the southwest southwest of of ‘EuaThis that undescribed was encrusting sponge with was upright collected fingers from with an underwatersoft slippery cave texture at the [60]. southwest It was pale of ‘Eua‘Eua that that was was encrusting encrusting with with upright upright fingers fingers with with soft soft slippery slippery texture texture [60]. [60]. It Itwas was pale pale ‘Euagrey that on the was surface encrusting with withmid–brownish upright fingers interior with. It contained soft slippery no siliceous texture [ 60spicules]. It was and pale was greygrey on on the the surface surface with with mid–brownish mid–brownish interior interior. It. containedIt contained no no siliceous siliceous spicules spicules and and was was greytentatively on the surface identified with as mid–brownish belonging to the interior. order ItDictyoceratida. contained no siliceous spicules and was tentativelytentatively identified identified as asbelonging belonging to tothe the order order Dictyoceratida. Dictyoceratida. tentativelyChemistry/Bioactivity: identified as belonging Chemical to the investigat order Dictyoceratida.ion of the methanolic extract of an un- Chemistry/Bioactivity:Chemistry/Bioactivity: Chemical Chemical investigat investigationion of ofthe the methanolic methanolic extract extract of ofan an un- un- describedChemistry/Bioactivity: Dictyoceratid sponge Chemical [60] reve investigationaled the known of the compound methanolic thorectolide extract of an (69 unde-) [98]. describeddescribed Dictyoceratid Dictyoceratid sponge sponge [60] [60] reve revealedaled the the known known compound compound thorectolide thorectolide (69 (69) [98].) [98]. scribedCompound Dictyoceratid 69 was first sponge reported [60] from revealed a New the Caledonian known compound sponge Hyrtios thorectolide sp. in ( 691996)[98 and]. CompoundCompound 69 69 was was first first reported reported from from a Newa New Caledonian Caledonian sponge sponge HyrtiosHyrtios Hyrtios sp. sp. in in1996 1996 and and Compoundhas shown cytotoxicwas first activity reported against from ahuman New Caledonianepidermoid sponge carcinoma KB sp.(IC50 in = 1996 12.7 and μM) hashas shownshown shown cytotoxiccytotoxic cytotoxic activity activity activity against against against human human human epidermoid epidermoid epidermoid carcinoma carcinoma carcinoma KB (ICKB KB (IC= (IC 12.750 =50 12.7=µ M)12.7 μ [96 M)μ]M) [96] and ovarian cancer (1A9) (IC50 = 3.7 μM) cell lines [60]. 50 [96] and ovarian cancer (1A9) (IC50 = 3.7 μM) cell lines [60]. and[96] ovarian and ovarian cancer cancer (1A9) (IC(1A9)50 = (IC 3.750µ =M) 3.7 cell μM) lines cell [ 60lines]. [60].

5.1.14.5.1.14. Order Order Dictyoceratida, Dictyoceratida, Specimen Specimen III III 5.1.14.5.1.14. Order Order Dictyoceratida, Dictyoceratida, Specimen Specimen III III This unidentified Dictyoceratid sponge was collected in 2009 from Vava`u in 2009, ThisThis unidentified unidentified Dictyoceratid Dictyoceratid sponge sponge was was collected collected in in2009 2009 from from Vava`u Vava`u in in2009, 2009, andThis it was unidentified described as Dictyoceratid firm but elastic sponge with was a dark collected brown in exterior, 2009 from a green-brown Vava‘u in 2009, interior and andand it wasit was described described as asfirm firm but but elastic elastic with with a dark a dark brown brown exterior, exterior, a green-brown a green-brown interior interior itand was an described odor slightly as firm reminiscent but elastic of with garlic a dark [97]. brown exterior, a green-brown interior and andand an an odor odor slightly slightly reminiscent reminiscent of ofgarlic garlic [97]. [97]. an odorChemistry/Bioactivity: slightly reminiscent ofLuffariellolide garlic [97]. (64) [93] was also isolated from this specimen Chemistry/Bioactivity:Chemistry/Bioactivity: Luffariellolide Luffariellolide (64 (64) [93]) [93] was was also also isolated isolated from from this this specimen specimen [97],Chemistry/Bioactivity: along with the known Luffariellolidediterpenoid ambliol (64)[ 93B ](70 was) [99]. also Compound isolated from 70 was this first speci- re- [97],[97], along along with with the the known known diterpenoid diterpenoid ambliol ambliol B B(70 (70) [99].) [99]. Compound Compound 70 70 was was first first re- re- menported [97 ],by along Faulkner with and the knownWalker diterpenoidfrom the sponge ambliol Dysidea B (70 amblia)[99]. in Compound 1981 and contains70 wasfirst a cis- portedported by by Faulkner Faulkner and and Walker Walker from from the the sponge sponge Dysidea Dysidea amblia amblia in in1981 1981 and and contains contains a cisa cis- - reportedfused bicyclic by Faulkner ring system and Walker [99], which from the was sponge revisedDysidea later to amblia a transin-fused 1981 and decalin contains following a cis- fusedfused bicyclic bicyclic ring ring system system [99], [99], which which was was revised revised later later to toa transa trans-fused-fused decalin decalin following following fusedX-ray bicyclic diffraction ring analysis system [[100].99], which was revised later to a trans-fused decalin following X-rayX-ray diffraction diffraction analysisanalysis analysis [[100].100 [100].].

5.1.15. Order Dictyoceratida, Specimen IV 5.1.15.5.1.15. Order Order Dictyoceratida, Dictyoceratida, Specimen Specimen IV IV The texture of this sponge, sourced from Vava‘u, was rough, and hard, highly retic- TheThe texture texture of ofthis this sponge, sponge, sourced sourced from from Vava‘u, Vava‘u, was was rough, rough, and and hard, hard, highly highly retic- retic- ulated with a honey-comb shape [101]. The exterior was lilac in color and appeared whit- ulatedulated with with a honey-comba honey-comb shape shape [101]. [101]. The The ex exteriorterior was was lilac lilac in incolor color and and appeared appeared whit- whit- ish blue underwater. ishish blue blue underwater. underwater.

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5.1.15. Order Dictyoceratida, Specimen IV MoleculesMolecules 2021 2021, 26, 26, x, FORx FOR PEER PEER REVIEW REVIEW 1313 of of 26 26 The texture of this sponge, sourced from Vava‘u, was rough, and hard, highly reticu- lated with a honey-comb shape [101]. The exterior was lilac in color and appeared whitish blue underwater. Chemistry/Bioactivity:Chemistry/Bioactivity:Chemistry/Bioactivity: Three ThreeThree known knownknown hexahy hexahydroxy-9,11-secosteroids,hexahydroxy-9,11-secosteroids,droxy-9,11-secosteroids, euryspongiols euryspongi-euryspongiols olsA1,A1, A1, A2, A2, A2, and and and B1 B1 B1( 71(71 (–7173–73–)73 )[102] )[[102]102 were ]were were isolated isolated isolated [101]. [101]. [101 These]. These These compounds compounds compounds were were were originally originally originally iso- iso- isolatedlatedlated from from from a a New New Caledonian CaledonianCaledonian Euryspongia EuryspongiaEuryspongia sp.,sp., sp., along along along with with with seven seven other other euryspongioleuryspongiol euryspongiol con-con- con- genersgenersgeners [ 102[102]. [102].]. Compounds Compounds Compounds71 71 71and and and72 72 72were were were found found found to to to strongly strongly strongly inhibit inhibit inhibit the the the release release release of of of histamine histamine histamine fromfromfrom rat rat rat mastocysts. mastocysts. mastocysts.

5.1.16.5.1.16. Order Order Dictyoceratida, Dictyoceratida, Specimen Specimen V V 5.1.16. Order Dictyoceratida, Specimen V ThisThis dark dark brown brown unidentified unidentified sponge sponge was was co collectedllected from from an an underwater underwater cave cave (depth (depth This dark brown unidentified sponge was collected from an underwater cave (depth ofof ca. ca. 20–22 20–22 m) m) on on ‘Eua ‘Eua in in 2016 2016 [64]. [64]. This This was was an an encrusting encrusting sponge sponge with with large large prominent prominent of ca. 20–22 m) on ‘Eua in 2016 [64]. This was an encrusting sponge with large prominent osculaoscula and and a apale-yellow pale-yellow interior. interior. oscula and a pale-yellow interior. Chemistry/Bioactivity:Chemistry/Bioactivity: Examination Examination of of this this specimen specimen [64] [64] yielded yielded the the known known com- com- Chemistry/Bioactivity: Examination of this specimen [64] yielded the known com- poundpound 6-bromohypaphorine 6-bromohypaphorine ( 74(74) )[103]. [103]. This This metabolite metabolite was was first first identified identified from from the the pound 6-bromohypaphorine (74)[103]. This metabolite was first identified from the sponge spongesponge Pachymatisma Pachymatisma johnstoni johnstoni [103], [103], although although it ithas has also also been been reported reported from from both both a ama- ma- Pachymatisma johnstoni [103], although it has also been reported from both a marine tuni- rinerine tunicate tunicate [104] [104] and and a anudibranch nudibranch [105]; [105]; it itis is an an agonist agonist of of the the human human α α7 7nicotinic nicotinic ace- ace- cate [104] and a nudibranch [105]; it is an agonist of the human α7 nicotinic acetylcholine tylcholine receptor [105]. receptortylcholine [105 receptor]. [105].

5.1.17.5.1.17.5.1.17. Order Order Order Dictyoceratida/Dendroceratida, Dictyoceratida/Dendroceratida, Dictyoceratida/Dendroceratida, SpecimenSpecimen Specimen II I LessLessLess thanthan than 11 1 g gof of of this this this sponge spongesponge was was collected collected fr from fromom the the the southwestern southwestern southwestern part part part of of ‘Eua of‘Eua ‘Eua in in 2008 2008 in 2008[106].[106]. [106 The The]. sponge The sponge sponge was was small, was small, small, globular, globular, globular, and and intensely and intensely intensely blue blue bluein in color. color. in color. This This sponge This sponge sponge was was tenta- was tenta- tentativelytivelytively assigned assigned assigned to to either toeither either the the theorder order order Dictyocera Dictyocera Dictyoceratidatidatida or or Dendroceratida, or Dendroceratida, Dendroceratida, as as these as these these sponges sponges sponges are are areknownknown known producers producers producers of of sesquiterpenes ofsesquiterpenes sesquiterpenes that that thatlack lack lacksiliceous siliceous siliceous spicules, spicules, spicules, but but the butthe size thesize of size of the the of speci- speci- the specimenmenmen precluded precluded precluded further further further ta taxonomicxonomic taxonomic identification. identification. identification. Chemistry/Bioactivity:Chemistry/BioactivitChemistry/Bioactivity:y: Guaiazulene Guaiazulene ( 75(75) was)was was obtainedobtained obtained fromfrom from thisthis this spongesponge sponge [ 106[106], [106],], and and and althoughalthoughalthough this this this incredibly incredibly incredibly blue blue blue compound compound compound has has has previously previously previously been been been encountered encountered encountered in in in gorgonians gorgonians gorgonians andandand terrestrial terrestrial terrestrial plants plants plants [ 107[107], [107],], this this this was was was its its its first fi rstfirst reported reported reported occurrence occurrence occurrence from from from a a marine amarine marine sponge. sponge. sponge.

5.1.18.5.1.18.5.1.18. Order Order Order Dictyoceratida/Dendroceratida, Dictyoceratida/Dendroceratida, Dictyoceratida/Dendroceratida, SpecimenSpecimen Specimen IIII II ThisThisThis ginger-rootginger-root ginger-root likelike like spongesponge sponge waswas was collectedcollected collected fromfrom froman an an underwater underwater underwatercave cave cavein in in the the the Vava‘u Vava‘u Vava‘u groupgroupgroup [ 64[64]. [64].]. Chemistry/Bioactivity:Chemistry/Bioactivity:Chemistry/Bioactivity: TwoTwo Two knownknown known bisabolene-typebisabolene-type bisabolene-type aromatic aromatic aromatic sesquiterpenes sesquiterpenes sesquiterpenes ( 76(76 (76and and and 7777)[77) 108)[108,109] [108,109],109] were were were identified identified identified from from from this this this specimen specimen specimen [ 64[64]. [64].]. Compound Compound Compound76 76 76was was was first first first reported reported reported fromfromfrom the the the sponge sponge spongeHalichondria Halichondria Halichondriasp. sp. collectedsp. collected collected off off the off the Western the Western Western Australian Australian Australian coast, coast, alongcoast, along withalong twowith with twotwo other other aromatic aromatic sesqui sesquiterpenesterpenes [108], [108], while while 77 77 was was first first reported reported from from the the sponge sponge DidiscusDidiscus flavus flavus and and displayed displayed cytotoxic cytotoxic activities activities ag againstainst P388 P388 murine murine leukemia leukemia and and hu- hu- manman tumor tumor A549 A549 cell cell lines, lines, and and also also inhibited inhibited the the growth growth of of the the fungus fungus Candida Candida albicans albicans [109].[109].

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Molecules 2021, 26, x FOR PEER REVIEW 14 of 26 MoleculesMolecules 20212021,, 2626,, xx FORFOR PEERPEER REVIEWREVIEWother aromatic sesquiterpenes [108], while 77 was first reported from the sponge Didiscus1414 ofof 2626

flavus and displayed cytotoxic activities against P388 murine leukemia and human tumor A549 cell lines, and also inhibited the growth of the fungus Candida albicans [109].

5.1.19. Order Homosclerophorida, Specimen I 5.1.19.5.1.19. OrderOrder Homosclerophorida,Homosclerophorida, SpecimenSpecimen II 5.1.19.This Order undescribed Homosclerophorida, soft and blood-red Specimen colore I d sponge was collected in 2008 from ‘Eua, ThisThis undescribedundescribed softsoft andand blood-redblood-red colorecoloredd spongesponge waswas collectedcollected inin 20082008 fromfrom ‘Eua,‘Eua, andThis tentatively undescribed identified soft as and Plakortis blood-red quasiamphiaster colored sponge based on was morphological collected in 2008and chemo- from andand tentativelytentatively identifiedidentified asas PlakortisPlakortis quasiamphiasterquasiamphiaster basedbased onon morphologicalmorphological andand chemo-chemo- ‘Eua,taxonomic and tentatively characteristics identified [106,110]. as Plakortis quasiamphiaster based on morphological and taxonomictaxonomic characteristicscharacteristics [106,110].[106,110]. chemotaxonomicChemistry/Bioactivity: characteristics Chemical [106,110 analysis]. of this sponge yielded the pyrroloacridine Chemistry/Bioactivity:Chemistry/Bioactivity: ChemicalChemical analysisanalysis ofof thisthis spongesponge yieldedyielded thethe pyrroloacridinepyrroloacridine compoundsChemistry/Bioactivity: plakinidines A Chemical(78) and B analysis (79) [111,112] of this as sponge the major yielded components the pyrroloacridine [102]. Both compoundscompounds plakinidinesplakinidines AA ((7878)) andand BB ((7979)) [111,112][111,112] asas thethe majormajor componentscomponents [102].[102]. BothBoth compoundscompounds plakinidines were originally A (78 isolated) and B from (79)[ Vanuatu111,112] asand the Fiji major collections components of the [sponge102]. Both Pla- compoundscompounds werewere originallyoriginally isolatedisolated fromfrom VanuatuVanuatu andand FijiFiji collectionscollections ofof thethe spongesponge Pla-Pla- compoundskortis sp. [111,112], were originally and both isolated exhibited from cytotoxi Vanuatucity and towards Fiji collections L1210 murine of the sponge leukemiaPlakor- cells kortiskortis sp.sp. [111,112],[111,112], andand bothboth exhibitedexhibited cytotoxicytotoxicitycity towardstowards L1210L1210 murinemurine leukemialeukemia cellscells tiswithsp. [IC11150 ,values112], and of 0.3 both and exhibited 0.9 μM, cytotoxicity respectively towards [112]. L1210 murine leukemia cells with withwith ICIC5050 valuesvalues ofof 0.30.3 andand 0.90.9 μμM,M, respectivelyrespectively [112].[112]. IC50 values of 0.3 and 0.9 µM, respectively [112].

5.1.20.5.1.20. Order Order Homosclerophorida, Homosclerophorida, Specimen Specimen II II 5.1.20.5.1.20. OrderOrder Homosclerophorida,Homosclerophorida, Specimen Specimen II II The black encrusting sponge was collected at a depth of 12–15 m from an underwater TheThe blackblack encrustingencrusting spongesponge waswas collectedcollected atat aa depthdepth ofof 12–1512–15 mm fromfrom anan underwaterunderwater caveThe on black‘Eua in encrusting 2008 [97]. sponge was collected at a depth of 12–15 m from an underwater cavecave onon ‘Eua‘Eua inin 20082008 [97].[97]. cave onChemistry/Bioactivity: ‘Eua in 2008 [97]. Two known 5α,8α-epidioxy sterols (80 and 81) [113–116] were Chemistry/Bioactivity:Chemistry/Bioactivity: TwoTwo knownknown 55αα,8,8αα-epidioxy-epidioxy sterolssterols ((8080 andand 8181)) [113–116][113–116] werewere isolatedChemistry/Bioactivity: from this undescribed Two sponge known 5[97].α,8α These-epidioxy metabolites sterols (80 wereand initially81)[113 –reported116] were by isolatedisolated fromfrom thisthis undescribedundescribed spongesponge [97].[97]. TheseThese metabolitesmetabolites werewere initiallyinitially reportedreported byby isolatedGunatilaka from et thisal. and undescribed have consequently sponge [been97]. encountered These metabolites in a number were initiallyof different reported sponge GunatilakaGunatilaka etet al.al. andand havehave consconsequentlyequently beenbeen encounteredencountered inin aa numbernumber ofof differentdifferent spongesponge byspecies Gunatilaka [113–115], et al. the and gorgonian have consequently Eunicell cavolini been and encountered the ascidian in Trididemnum a number of inarmatum different speciesspecies [113–115],[113–115], thethe gorgoniangorgonian EunicellEunicell cavolinicavoliniEunicell andand cavolini thethe ascidianascidian TrididemnumTrididemnumTrididemnum inarmatuminarmatum sponge[116]. These species compounds [113–115], were the gorgonian evaluated for growth inhibitoryand the effects ascidian against MCF-7 hu- inarmatum[116].[116]. TheseThese[116 compoundscompounds]. These compounds werewere evaluatedevaluated were for evaluatedfor growthgrowth for inhibitoryinhibitory growth effects inhibitoryeffects againstagainst effects MCF-7MCF-7 against hu-hu- man breast cancer cells [116]. MCF-7manman breastbreast human canccanc breasterer cellscells cancer [116].[116]. cells [116].

5.1.21. Order Haplosclerida 5.1.21.5.1.21.5.1.21. OrderOrderOrder Haplosclerida HaploscleridaHaplosclerida This sponge was collected from three different locations along the southern coast of ThisThisThis sponge spongesponge was waswas collected collectedcollected from fromfrom three threethree different differedifferentnt locations locationslocations along alongalong the thethe southern southernsouthern coast coastcoast of ofof ‘Eua in 2008 and 2016. The strong similarity in the morphological and chemotaxonomic ‘Eua‘Eua‘Eua in inin 2008 20082008 and andand 2016. 2016.2016. The TheThe strong strongstrong similarity similaritysimilarity in inin the thethe morphological morphologicalmorphological and andand chemotaxonomic chemotaxonomicchemotaxonomic profile of these specimens [64,97] and the Fijian sponge Xestospongia carbonaria [117,118] profileprofileprofile of ofof these thesethese specimens specimensspecimens [64 [6[6,974,97]4,97]] and andand the thethe Fijian FijianFijian sponge spongespongeXestospongia XestospongiaXestospongia carbonaria carbonariacarbonaria[117 ,[117,118][117,118]118] led led to a tentative identification of the Tongan organisms. However, the sponge X. carbo- toledled a to tentativeto aa tentativetentative identification identificationidentification of the ofof Tongan thethe TonganTongan organisms. organisms.organisms. However, However,However, the sponge thethe spongespongeX. carbonaria X.X. carbo-carbo- naria was later revised to Neopetrosia carbonaria [44]. wasnarianaria later waswas revised laterlater revisedrevised to Neopetrosia toto NeopetrosiaNeopetrosia carbonaria carbonariacarbonaria[44]. [44].[44]. Chemistry/Bioactivity: Chemical analysis of this specimen from the first collection Chemistry/Bioactivity:Chemistry/Bioactivity:Chemistry/Bioactivity: ChemicalChemicalChemical analysis analysisanalysis of ofof this thisthis specimen specimenspecimen from fromfrom the firstthethe first collectionfirst collectioncollection [97] [97] led to the isolation of the polyketide halenaquinone (82) [119,120]. The closely related led[97][97] to ledled the toto isolation thethe isolationisolation of the ofof polyketide thethe polyketidepolyketide halenaquinone halenaquinonehalenaquinone (82)[ 119 ((8282,))120 [119,120].[119,120].]. The closely TheThe closelyclosely related relatedrelated hale- halenaquinol sulfate (83) [119] was identified as the major component of the methanolic naquinolhalenaquinolhalenaquinol sulfate sulfatesulfate (83)[ 119((8383)]) was[119][119] identified waswas identifiedidentified as the as majoras thethe componentmamajorjor componentcomponent of the methanolic ofof thethe methanolicmethanolic extract extract from the collection in 2016 [64]. The absolute configurations of the two compounds fromextractextract the fromfrom collection thethe collectioncollection in 2016 inin [64 20162016]. The [64].[64]. absolute TheThe absoluteabsolute configurations configurationsconfigurations of the ofof two thethe twotwo compounds compoundscompounds82 82 and 83 have previously been established by interpretation of circular dichroism (CD) and8282 andand83 have 8383 havehave previously previouslypreviously been beenbeen established establishedestablished by interpretation byby interpretationinterpretation of circular ofof circularcircular dichroism dichroismdichroism (CD) spec- (CD)(CD) spectra [119]. Halenaquinone (82) is a pentacyclic polyketide first isolated from the marine spectraspectra [119].[119]. HalenaquinoneHalenaquinone ((8282)) isis aa pentacyclicpentacyclic polyketidepolyketide fifirstrst isolatedisolated fromfrom thethe marinemarine sponge Xestospongia exigua and shown to possess in vitro antibiotic activity against Staph- spongesponge XestospongiaXestospongia exiguaexigua andand shownshown toto possesspossess inin vitrovitro antibioticantibiotic activityactivity againstagainst Staph-Staph- ylococcus aureus and Bacillus subtillis [120]. A recent study, by Takaku et al. described 82 as ylococcusylococcus aureusaureus andand BacillusBacillus subtillissubtillis [120].[120]. AA recentrecent study,study, byby TakakuTakaku etet al.al. describeddescribed 8282 asas

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Molecules 2021, 26, x FOR PEER REVIEW 15 of 26 tra [119]. Halenaquinone (82) is a pentacyclic polyketide first isolated from the marine Xestospongia exigua Staphy- spongea novel RAD51 inhibitor andthat shownspecifically to possess inhibitsin vitroRAD51-dsDNAantibiotic activity binding against [121]. Com- lococcus aureus and Bacillus subtillis [120]. A recent study, by Takaku et al. described 82 as a pounda novel 83 RAD51 inhibited inhibitor eukaryotic that DNAspecifically polymerases inhibits to RAD51-dsDNA varying degrees binding [122]. [121]. Com- novel RAD51 inhibitor that specifically inhibits RAD51-dsDNA binding [121]. Compound pound 83 inhibited eukaryotic DNA polymerases to varying degrees [122]. 83 inhibited eukaryotic DNA polymerases to varying degrees [122]

5.1.22. Order Verongiida, Specimen I 5.1.22.5.1.22.The OrderOrder lack Verongiida, Verongiida,of mineral Specimen spiculesSpecimen in I I sponges of the order Verongiida makes their taxo- nomic identification more difficult. Verongiid sponges show a common and marked oxi- TheThe lack lack of of mineral mineral spicules spicules in spongesin sponges of the of orderthe order Verongiida Verongiida makes makes their taxonomictheir taxo- dative color change at death or upon exposure to air, and they are extremely distinct bio- identificationnomic identification more difficult. more difficult. Verongiid Verongiid sponges sponges show a show common a common and marked and marked oxidative oxi- chemically, known to be a rich source of bromotyrosine-derived secondary metabolites colordative change color atchange death at or death upon exposureor upon exposure to air, and to they air, areand extremely they are extremely distinct biochemically, distinct bio- [24]. An unidentified Verongiid sponge, which oxidized rapidly to dark black at death, knownchemically, to be aknown rich source to be of a bromotyrosine-derivedrich source of bromotyrosine-derived secondary metabolites secondary [24]. Anmetabolites uniden- tifiedwas[24]. collected VerongiidAn unidentified from sponge, shallow Verongiid which waters oxidized sponge, using rapidly snorkel which to oxidizedfrom dark a black beach rapidly at in death, the to Vava‘u dark was collectedblack group at in death, from 2009 shallow[60].was collectedUnderwater, waters from using the shallow snorkel sponge waters from was ausingmassive, beach snorkel in with the from Vava‘ua yellow-green a beach group in in the pigmented 2009 Vava‘u [60]. group Underwater, surface in 2009and theyellow[60]. sponge Underwater, interior. was massive, the sponge with awas yellow-green massive, with pigmented a yellow-green surface and pigmented yellow interior. surface and yellowChemistry/Bioactivity:Chemistry/Bioactivity: interior. NMR-guided NMR-guided investigation investigation of ofthis this sponge sponge resulted resulted in the in theiso- isolationlationChemistry/Bioactivity: of oftwo two known known bromotyrosine-de bromotyrosine-derived NMR-guidedrived investigation compounds compounds of [60], this [60 aplysamine-2 sponge], aplysamine-2 resulted (84) (in 84[123] the)[123 andiso-] andaerophobin-1lation aerophobin-1 of two known (85) [124]. (85 bromotyrosine-de)[ 124Compound]. Compound 84 rivedwas 84originally compoundswas originally reported [60], aplysamine-2 reported in 1989 from in 1989 an(84 Australian) from[123] and an Australianmarineaerophobin-1 sponge marine (85 Aplysina) [124]. sponge Compoundsp.Aplysina [123]. Although sp.84 was [123 originally].84 Althoughwas reported reported84 wasto inbe reported 1989inactive from against to an be Australian inactive several againstGram-positivemarine several sponge Gram-positive Aplysinaand Gram-negative sp. [123]. and Gram-negative Although bacteria 84 [123], was bacteria reportedit revealed [123 ],to it be revealedweak inactive inhibitory weak against inhibitory activityseveral activityagainstGram-positive againstthe human theand human tumorGram-negative tumorcell lines cell MCF-7bacteria lines MCF-7 (b reast[123], (breast cancer), it revealed cancer), NCI-H4 weak NCI-H46060 (humaninhibitory (human non-small activity non- smallcellagainst lung cell the cancer) lung human cancer) and tumor SF268 and cell SF268(glioblastoma) lines (glioblastoma) MCF-7 [125]. (breast Compound [125 cancer),]. Compound NCI-H4 85 was 60first85 (humanwas isolated first non-small isolatedfrom the frommarinecell lung the sponge marinecancer) Verongia spongeand SF268 Verongiaaerophoba (glioblastoma) aerophoba (later revised [125].(later Compoundto revised Aplysina to Aplysina aerophoba85 was first aerophoba [44]) isolated [124],[44 from ])and [124 theex-], andhibitedmarine exhibited severalsponge several biologicalVerongia biological aerophoba activities activities (laterincluding including revised weak to weak inhibitionAplysina inhibition aerophoba against against Factor [44]) Factor [124], Xia Xia[126], and [126 ex-ac-], acetylcholinesteraseetylcholinesterasehibited several biological inhibition inhibition activities (IC (IC5050 value includingvalue of of 1.3 1.3 weak μµM)M) inhibitionand antiproliferative against Factor activityactivity Xia [126], againstagainst ac- MCF-7MCF-7etylcholinesterase cellscells (IC(IC5050 value inhibition of 0.8 µμ(ICM)50 [[127].value127]. of 1.3 μM) and antiproliferative activity against MCF-7 cells (IC50 value of 0.8 μM) [127].

5.1.23. Order Verongiida, Specimen II 5.1.23. Order Verongiida, Specimen II 5.1.23.This Order unidentified Verongiida, yellow Specimen colored, II rubble-like sponge belonging to the order Verongi- This unidentified yellow colored, rubble-like sponge belonging to the order Verongiida ida was collected from the coastline of ‘Eua in 2008. was collectedThis unidentified from the coastlineyellow colored, of ‘Eua rubble-like in 2008. sponge belonging to the order Verongi- Chemistry/Bioactivity: Aerothionin (86) [128] is a bromotyrosine-derived compound ida wasChemistry/Bioactivity: collected from the coastline Aerothionin of ‘Eua (86)[ in128 2008.] is a bromotyrosine-derived compound obtainedobtainedChemistry/Bioactivity: fromfrom this sponge [64]. [Aerothionin64]. This This comp compound (86ound) [128] was wasis afirst bromotyrosine-derived first obtained obtained from from the the sponges compound sponges Ap- Aplysinalysinaobtained aerophoba aerophoba from this andand sponge VerongiaVerongia [64]. thiona thiona This (revised (revisedcompound to to Aiolochroia Aiolochroiawas first thiona obtained thiona [44])[44 from ])[128]. [128 the ].Compound Compoundsponges Ap- 86 86displayedlysinadisplayed aerophoba an anantifeedant and antifeedant Verongia chemical chemicalthiona defe(revised defensense role to Aiolochroia roleagainst against the thiona predatory the [44]) predatory [128]. fish Blennius Compound fish Blennius sphinx 86 [129].displayed an antifeedant chemical defense role against the predatory fish Blennius sphinx [129].

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sphinx [129].

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5.1.24. Unidentified Sponge 5.1.24. Unidentified Sponge This undescribed creamy-pink sponge with thin spreading crusts was collected in This undescribed creamy-pink sponge with thin spreading crusts was collected in Vava‘u. Interestingly, upon exposure to air or at death, no change in pigmentation was Vava‘u. Interestingly, upon exposure to air or at death, no change in pigmentation was observed [60]. The sponge was tentatively identified as a Verongiid sponge based on its observed [60]. The sponge was tentatively identified as a Verongiid sponge based on its 5.1.24.lack of Unidentified spicules and Sponge its chemical constituents. However, it should be noted that these bro- lack of spicules and its chemical constituents. However, it should be noted that these bromi- minatedThis undescribed tyrosine metabolites creamy-pink spongehave beenwith thinrepo spreadingrted from crusts other was orderscollected such in as Agelasida nated tyrosine metabolites have been reported from other orders such as Agelasida [130], Vava‘u.[130], Dictyoceratida Interestingly, upon [131], exposure Tetractinellida to air or at death, [132], no and change Haplosclerida in pigmentation [133] was which also may Dictyoceratidaobserved [60]. The [ 131sponge], Tetractinellida was tentatively iden [132tified], and as a HaploscleridaVerongiid sponge [ based133] whichon its also may not not have spicules. These few counter-examples are a reminder of the complication of using havelack of spicules. spicules and These its chemical few counter-examples constituents. However, are it should a reminder be noted of that the these complication bro- of using chemotaxonomicminatedchemotaxonomic tyrosine metabolites markersmarkers have forfor spongebeensponge repo classificationclassificationrted from other due dueorders to to their suchtheir as lack lack Agelasida of of consistency. consistency. [130],Chemistry/Bioactivity: Chemistry/Bioactivity:Dictyoceratida [131], Tetractinellida Fistularin-3 Fistularin-3 [132], and( (8787 Haplosclerida))[ [134],134], aeroplysinin-1aeroplysinin-1 [133] which also ((8888 may)[) [135],135 ], LL-PPA216LL-PPA216 not have spicules. These few counter-examples are a reminder of the complication of using ((8989)[) [136],136], threethree known known bromotyrosine bromotyrosine compounds, compounds, were were obtained obtained from from this this undescribed undescribed chemotaxonomicspecimen [60]. markers A bioassay-directed for sponge classification isolation due procedureto their lack offirst consistency. yielded 87 from the marine specimenChemistry/Bioactivity: [60]. A bioassay-directed Fistularin-3 (87 isolation) [134], aeroplysinin-1 procedure (88 first) [135], yielded LL-PPA21687 from the marine sponge(sponge89) [136],Aplysina Aplysina three known fistularisfistularis bromotyrosinein in 19791979 compounds, [[134],134], howeverhowever were obtained itsits absoluteabsolute from configurationthisconfiguration undescribed waswas onlyonly estab-estab- lishedspecimenlished inin [60]. aa recentlyrecently A bioassay-directed publishedpublished articleisolationarticle [ [137].137procedure]. ItIt waswas first alsoalso yielded shownshown 87 from totodisplay displaythe marine cytotoxiccytotoxic activityactivity againstspongeagainst Aplysina aa panelpanel fistularis ofof acuteacute in 1979 myeloidmyeloid [134], however leukemialeukemia its absolute (AML)(AML) configuration cellcell lines.lines.Compound wasCompound only estab-88 88was was obtainedobtained lished in a recently published article [137]. It was also shown to display cytotoxic activity fromfrom thethe methanolicmethanolic extractextract ofof thethe NewNew CaledonianCaledonian spongesponge VerongiaVerongia aerophobaaerophoba (later(later re-re- againstvised to a panelV. cavernicola of acute myeloid [138] andleukemia then (AML) to Aplysina cell lines. cavernicola Compound [44]) 88 was and obtained was the first reported visedfrom the to V.methanolic cavernicola extract[138 of] the and New then Caledonian to Aplysina sponge cavernicola Verongia [aerophoba44]) and (later was re- the first reported membervisedmember to V. of ofcavernicola thisthis groupgroup [138]of andof alkaloidsalkaloids then to Aplysina [[135].135]. cavernicola Aeroplysinin-1Aeroplysinin-1 [44]) and (was(8888) )the showedshowed first reported antibacterialantibacterial activityactivity againstmemberagainst Staphylococcus ofStaphylococcus this group of alkaloids albus albus, Bacillus, [135].Bacillus Aeroplysinin-1 cereus cereus, and, and B.(88 B. subtilis) showed subtilis[ 135antibacterial [135],], and and subsequently activity subsequently shown shown to haveagainstto have antiproliferative Staphylococcus antiproliferative albus activity, Bacillus activity incereus small in, and small micromolar B. subtilis micromolar [135], doses and dosessubsequently against against several shown several tumor tumor cell lines, cell to have antiproliferative activity in small micromolar doses against several tumor cell includinglines, including human human cervix uterine, cervix uterine, Ehrlich ascitesEhrlich tumor ascites (EAT), tumor and (EAT), HeLa and cell linesHeLa [ 139cell– 142lines]. lines, including human cervix uterine, Ehrlich ascites tumor (EAT), and HeLa cell lines LL-PPA216[139–142]. LL-PPA216 LL-PPA216 (89) was ( the89) was( first89 )the bromo-compoundwas first the bromo-compound first bromo-compound containing containing two two containing oxazolidone oxazolidone two rings, oxazolidone obtained fromrings, aobtained obtainedVerongia from lacunosefrom a Verongia a Verongia(revised lacunose lacunose to(revisedAplysina to(revised Aplysina lacunose to lacunose Aplysina[44]), [44]), collected lacunose collected off [44]),off the the collected coast of Puerto off the Ricocoast of in of Puerto 1974 Puerto Rico [136 Rico in]. 1974 Compound in 1974[136]. Compound[136].89 Compoundwas 89found was found 89 to wasbeto be inactive foundinactive to against be inactive several several against pathogenic several bacteriapathogenic [136 bacteria bacteria] and [136] human [136] and human cancerand human cancer cell linescell cancer lines [143 [143].cell]. lines [143].

5.2. Tunicate (Ascidian) Derived MNPs 5.2. Tunicate (Ascidian) Derived MNPs Didemnum ternerratum

DidemnumThe genus ternerratum Didemnum belongs to the family Didemnidae, which is strongly associated with Theinteresting genus secondaryDidemnum metabolitesbelongs [144]. to the A specimen family Didemnidae, of this ascidian which was collected is strongly associated 5.2. Tunicate (Ascidian) Derived MNPs with interesting secondary metabolites [144]. A specimen of this ascidian was collected fromDidemnum an underwater ternerratum cave (depth of ca. 20–22 m) in ‘Eua in 2016 and is the only tunicate sourceThe of Tongangenus Didemnum MNPs reported belongs to to date the [family145]. Didemnidae, which is strongly associated

with interesting secondary metabolites [144]. A specimen of this ascidian was collected

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Molecules 2021, 26, x FOR PEER REVIEW 17 of 26 from an underwater cave (depth of ca. 20–22 m) in ‘Eua in 2016 and is the only tunicate sourceChemistry/Bioactivity: of Tongan MNPs reported From to date this [145]. Tongan specimen, six new lamellarin sulfates (90–95) were reportedChemistry/Bioactivity: [145]. NMR From and this MS Tongan experiments specimen, were six used new tolamellarin elucidate sulfates the planar (90– structures from an underwater cave (depth of ca. 20–22 m) in ‘Eua in 2016 and is the only tunicate of95 these) were compounds, reported [145]. while NMRtheir and MS atropisomeric experiments were absolute used configurationsto elucidate the planar were determined sourcestructures of Tongan of these MNPs compounds, reported while to date their [145]. atropisomeric absolute configurations were bydetermined comparisonChemistry/Bioactivity: by comparison of experimental ofFrom experimental this and Tongan calculated and specimen, calculated ECD six ECD spectra new spectra lamellarin [145 [145].]. All sulfates All the the compounds com-(90– were tested95pounds) were against werereported tested the [145]. human against NMR the colon and human carcinomaMS coloexperimentsn carcinoma cell linewere cell HCT-116, used line toHCT-116, elucidate where where lamellarinthe planar lamel- D-8-sulfate (94structureslarin) showed D-8-sulfate of these some (94 compounds,) cytotoxicity showed some while with cytotoxicity their an atropisomeric IC50 withvalue an IC of absolute50 9.7 valueµM, configurationsof while9.7 μM, the while other were the compounds showeddeterminedother compounds only by weakcomparison showed activity ofonly experimental [ 145weak]. activity and [145]. calculated ECD spectra [145]. All the com- pounds were tested against the human colon carcinoma cell line HCT-116, where lamel- larin D-8-sulfate (94) showed some cytotoxicity with an IC50 value of 9.7 μM, while the other compounds showed only weak activity [145].

5.3. Bryozoan Derived MNPs 5.3. Bryozoan Derived MNPs Nelliella nelliiformis Nelliella nelliiformis Bryozoans, also known as sea mats or sea mosses, belong to the phylum Bryozoa 5.3. Bryozoan Derived MNPs withBryozoans, an estimated also 8000 known described as species sea mats [146]. or Despite sea mosses, the few belong bryozoan to the species phylum having Bryozoa with anNelliellabeen estimated studied nelliiformis for 8000 natural described products, species these organisms [146]. Despite have proven the few to be bryozoan an excellent species source having been studiedof novelBryozoans, forand/or natural alsobiological known products, active as sea compound these mats organismsor seas [147]. mosses, This have belong brown proven tobryozoan the to phylum be was an Bryozoacollected excellent source of novelwithfrom an an and/or estimated underwater biological 8000 cave described at active a depth species compounds of ca. [146]. 23 m Despiteusing [147 ].SCUBA the This few brown(‘Eua, bryozoan 2016) bryozoan species [148]. washaving collected from been studiedChemistry/Bioactivity: for natural products, A comprehensive these organisms chem haveical examinationproven to be ofan this excellent bryozoan source af- anofforded underwaternovel two and/or new biologicalnucleosides, cave at a active depth nelliellosides compound of ca. 23 As m([147].96 using) and This B SCUBA( 97brown) [148]. bryozoan (‘Eua, Their planar 2016) was structures [collected148]. fromand Chemistry/Bioactivity: absolutean underwater configurations cave at a were depth Adetermined of comprehensive ca. 23 m by using interpretation SCUBA chemical (‘Eua, of spectroscopicexamination 2016) [148]. and of chro- this bryozoan affordedmatographicChemistry/Bioactivity: two data new and nucleosides, confirmed A comprehensive by nelliellosides total synthesis chemicalA [148]. (examination96) Compound and B (of97 this )[96148 wasbryozoan]. screened Their af- planar struc- turesfordedagainst and two 485 absolute new human nucleosides, disease-relevant configurations nelliellosides kinases were A at determined(96 a) concentration and B (97) by [148]. interpretationof 10Their μM, planar revealing structures of spectroscopicpotent and chromatographicand(>80%) absolute and selective configurations data inhibition and were confirmed against determined 13 kinases, by by total interpretation while synthesis 97 was of [ assessed148 spectroscopic]. Compound against and seven chro-96 ofwas screened againstmatographicthese kinases 485 humandata at 10 andμM, disease-relevant confirmedshowing similar by total levels kinases synthesis of kinase at [148]. a concentrationinhibition Compound to 96 [148].96 of was 10 Conversely,µ screenedM, revealing potent againstthe two 485 compounds human disease-relevant showed no antibacterial kinases at or a antifungalconcentration activities of 10 μagainstM, revealing Staphylococcus potent (>80%) and selective inhibition against 13 kinases, while 97 was assessed against seven of (>80%)aureus andor Saccharomyces selective inhibition cerevisiae against, respectively, 13 kinases, and while neither 97 was possessed assessed cytotoxic against seven activity of thesetheseagainst kinases the HL-60 at at 10 10 μ humanM,µM, showing showingcancer similar cell similar line levels [148]. of levels kinase It is ofnoteworthy inhibition kinase inhibition to that 96 [148].this is toConversely, the96 first[148 re-]. Conversely, thetheported twotwo chemicalcompounds compounds investigation showed showed no of antibacterial noa bryozoan antibacterial orcollected antifungal or from antifungal activities the Kingdom activitiesagainst of Staphylococcus Tonga, against andStaphylococcus is aureusaureusthe first or from SaccharomycesSaccharomyces this bryozoan cerevisiaecerevisiae family., respectively, , respectively, and neither and possessed neither possessed cytotoxic activity cytotoxic activity againstagainst the HL-60 HL-60 human human cancer cancer cell cell line line [148]. [148 It ].is Itnoteworthy is noteworthy that this that is thisthe first is the re- first reported chemicalported chemical investigation investigation of a of bryozoan a bryozoan collected collected fromfrom the the Kingdom Kingdom of Tonga, of Tonga, and andis is the first fromthe first this from bryozoan this bryozoan family. family.

5.4. Red Algae-Derived MNPs Callophycus serratus

Red algae of the genus Callophycus are widely distributed across Australia, Eastern and Southern Africa, the Philippines, and the South Pacific [149], and are known to be Molecules 2021, 26, x FOR PEER REVIEW 18 of 26

5.4. Red Algae-Derived MNPs Callophycus serratus Molecules 2021, 26, 4534 18 of 26 Red algae of the genus Callophycus are widely distributed across Australia, Eastern and Southern Africa, the Philippines, and the South Pacific [149], and are known to be prolific producers of structurally diverse meroditerpenoids [150–153]. This fern-like red prolificalga was producers collected of from structurally ‘Eua by diversehand with meroditerpenoids SCUBA, at a depth [150 of–153 ca.]. 15–20 This fern-likem. red alga wasChemistry/Bioactivity: collected from ‘Eua byA handtotal withof six SCUBA, new halogenated at a depth ofmeroditerpenoids ca. 15–20 m. (98–103) wereChemistry/Bioactivity: isolated from this red alga A total [20], of alon sixg new with halogenated two known macrolides, meroditerpenoids bromophycolides (98–103) wereA (104 isolated) [152] from and this T ( red105) alga [153]. [20 ],The along relative with twoconfigurat knownions macrolides, of the six bromophycolides new compounds A(across104)[ the152 flexible] and T methylene (105)[153 ].linker The were relative deduced configurations from detailed of the analyses six new of compounds1D NOE data acrossand 1H– the1H flexible scalar methylene coupling constants. linker were Compounds deduced from 100– detailed102 incorporate analyses iodine of 1D within NOE data their 1 1 100 102 andstructure,H– H scalarwhich coupling is rare in constants. this family Compounds of natural product.– incorporate Compounds iodine 100, within104, and their 105 structure, which is rare in this family of natural product. Compounds 100, 104, and 105 showed moderate cytotoxicity against the HL-60 cell line with IC50 values of 5.1, 6.2, and showed moderate cytotoxicity against the HL-60 cell line with IC values of 5.1, 6.2, and 6.0 μM, respectively [20]. 50 6.0 µM, respectively [20].

BromophycolideBromophycolide A A (104 (104) was) was first first isolated isolated from from a Fijiana Fijian collection collection of ofC. C. serratus serratus, along, along withwith two two other other related related compounds compounds [152 [152].]. The The relative relative configuration configuration for this for compound this compound was determinedwas determined from NMR from dataNMR while data X-raywhile crystallographicX-ray crystallographic analysis analysis provided provided the absolute the ab- configuration.solute configuration. Compound Compound104 displayed 104 displayed cytotoxicity cytotoxicity against against several several human human tumor tumor cell linescell vialines specific via specific apoptotic apoptotic cell death. cell death. Bromophycolide Bromophycolide T (105 T )(105 was) was also also isolated isolated from from a Fijiana FijianC. serratus C. serratusand and was identifiedwas identified by analysis by analysis of 1D of and 1D 2D and NMR 2D spectroscopyNMR spectroscopy and mass and spectrometrymass spectrometry data [153 data]. Compound [153]. Compound105 exhibited 105 exhibited modest modest cytotoxicity cytotoxicity toward toward selected se- humanlected cancerhuman cell cancer lines. cell lines. 5.5. Bacteria-Derived MNPs 5.5. Bacteria-Derived MNPs Actinomycetospora chlora Strain SNC-032 Actinomycetospora chlora Strain SNC-032 This marine-derived bacterium was isolated from a sediment sample collected from a mangroveThis marine-derived swamp in Vava‘u bacterium [154]. Analysiswas isolated of its from 16S a rDNA sediment sequence sample indicated collected that from thea mangrove strain was swamp more than in Vava‘u 99% identical [154]. Analysis to Actinomycetospora of its 16S rDNA chlora. sequenceMarine indicated actinomycetes that the arestrain prolific wasproducers more than of99% biologically identical to active Actinomycetospora natural products; chlora. more Marine than actinomycetes half of the ma- are rineprolific microbial producers secondary of biological metabolitesly active reported natural in the products; literature more were than sourced half of from the actino- marine mycetesmicrobial [155 secondary]. It should metabolites be noted thatreported the sample in the wasliterature collected were under sourced permits from fromactinomy- the Tonga’scetes [155]. Ministry It should of Agriculture be noted and that Food, the Forests,sample andwas Fisheries,collected inunder conjunction permits with from the the Northcote and Keyzers group. Chemistry/Bioactivity: Bioassay-guided chemical investigation revealed three new compounds, thiasporines A–C (106–108)[154], together with the known compound thi- olutin (109)[156]. Thiasporine A (106) possesses a unique 5-hydroxy-2-phenyl-4H-1,3-

thiazin-4-one core, the first natural metabolite to possess this motif. Compound 106 displayed cytotoxicity against non-small-cell lung cancer cell line H2122 with an IC50 Molecules 2021, 26, x FOR PEER REVIEW 19 of 26

Tonga’s Ministry of Agriculture and Food, Forests, and Fisheries, in conjunction with the Northcote and Keyzers group. Chemistry/Bioactivity: Bioassay-guided chemical investigation revealed three new compounds, thiasporines A–C (106–108) [154], together with the known compound thio- Molecules 2021, 26, 4534 lutin (109) [156]. Thiasporine A (106) possesses a unique 5-hydroxy-2-phenyl-4H-1,3-thia-19 of 26 zin-4-one core, the first natural metabolite to possess this motif. Compound 106 displayed cytotoxicity against non-small-cell lung cancer cell line H2122 with an IC50 value of 5.4 μM, but no activity against the A549, HCC366, and HCC44 cell lines [154]. However, 107 value of 5.4 µM, but no activity against the A549, HCC366, and HCC44 cell lines [154]. and 108 were inactive against all the four tested cell lines. Thiolutin (109) was originally However, 107 and 108 were inactive against all the four tested cell lines. Thiolutin (109) was obtained from the soil bacterium Streptomyces albus [156] and shown to inhibit bacterial originally obtained from the soil bacterium Streptomyces albus [156] and shown to inhibit and eukaryotic transcription in vivo and also used to investigate mRNA stability in sev- bacterial and eukaryotic transcription in vivo and also used to investigate mRNA stability eral species [157–159]. These compounds represent the first secondary metabolites to be in several species [157–159]. These compounds represent the first secondary metabolites to reported from marine-sourced bacteria from the South Pacific nation. be reported from marine-sourced bacteria from the South Pacific nation.

6. Conclusions 6. Conclusions This review highlights a comprehensive literature survey covering the chemical and This review highlights a comprehensive literature survey covering the chemical and biological aspects of secondary metabolites isolated from Tongan marine organisms. A biological aspects of secondary metabolites isolated from Tongan marine organisms. A total of 109 compounds were obtained from 24 sponges (81.7%), one ascidian (5.5%), one total of 109 compounds were obtained from 24 sponges (81.7%), one ascidian (5.5%), one bryozoan (1.8%), one red alga (7.3%), and one bacterium (3.7%), of which 48 were new bryozoan (1.8%), one red alga (7.3%), and one bacterium (3.7%), of which 48 were new MNPs and 61 were previously known metabolites. Known compounds found from MNPs and 61 were previously known metabolites. Known compounds found from Tongan Tongan sources were originally reported predominantly from other Pacific nations in- sources were originally reported predominantly from other Pacific nations including Fiji, cluding Fiji, Vanuatu, New Caledonia, Palau, and Australia. Of the 59 compounds re- Vanuatu, New Caledonia, Palau, and Australia. Of the 59 compounds reported from ported from specimens collected in Vava’u, 40 (67.8%) were known prior to the Tongan specimens collected in Vava‘u, 40 (67.8%) were known prior to the Tongan investigation, investigation, whereas only 21 of 50 (42.0%) of ‘Eua-derived compounds were known. The whereas only 21 of 50 (42.0%) of ‘Eua-derived compounds were known. The phylum phylum Porifera (sponges), the main source of Tongan MNPs, was dominated by investi- Porifera (sponges), the main source of Tongan MNPs, was dominated by investigations of thegations class of Demospongiae the class Demospongiae with the largest with number the largest of metabolites number of (71.6%), metabolites followed (71.6%), by thefol- classlowed Homoscleromorpha by the class Homoscleromorpha (10.1%), and no (10.1%), reported and compounds no reported from compounds the Hexactinellida from the orHexactinellida Calcareous sponges. or Calcareous Based onsponges. their structural Based on types,their structural there were types, 42 terpenoids there were (38.5%), 42 ter- 36penoids alkaloids (38.5%), (33.0%) 36, 21alkaloids polyketides (33.0%), (19.3%), 21 po sixlyketides polyacetylenes (19.3%), six (5.5%), polyacetylenes two nucleosides (5.5%), (1.8%),two nucleosides one amino (1.8%), alcohol one (0.9%), amino and alcohol one glyceride(0.9%), and (0.9%). one glyceride The significant (0.9%). The biological signifi- activitycant biological of Tongan activity MNPs of was Tongan dominated MNPs by was cytotoxicity dominated (70.6%), by cytotoxicity followed by(70.6%), anti-microbial followed activityby anti-microbial (4.6%). activity (4.6%). ItIt should should also also be be noted noted that that more more than than 60% 60% of of the the new new isolated isolated MNPs MNPs were were obtained obtained fromfrom organisms organisms collected collected from from the the island island of of ‘Eua, ‘Eua, despite despite the the fact fact that that the the majority majority of of the the specimensspecimens from from these these marine marine natural natural products products studies studies were were collected collected from from the the Vava‘u Vava‘u is- landsislands group. group. ‘Eua ‘Eua is the is the most most ancient ancient island island in the in Kingdomthe Kingdom and itand is geologicallyit is geologically unrelated unre- tolated the restto the of therest islands of the islands and is believed and is believed to be 30 to million be 30 million years older years [160 older]. ‘Eua [160]. therefore ‘Eua there- has afore unique has a marine unique environment marine environment that could that harbor could organisms harbor organisms that produce that produce interesting interest- and noveling and chemistry. novel chemistry. This became This evident became during evident the during chemical the investigationchemical investigation of C. mycofijiensis of C. my-, withcofijiensis significant, with geographicsignificant geographic variability in variability the chemistry in the between chemistry the between Vava‘uand the Vava‘u ‘Eua speci- and mens.‘Eua specimens. The ‘Eua specimens The ‘Eua hadspecimens detectable had quantitiesdetectableof quantities zampanolide of zampanolide and possessed and new pos- analogues,sessed new whereas analogues, Vava‘u whereas specimens Vava‘u were specimens significantly were less significantly productive less in zampanolideproductive in withzampanolide no sign of with the no new sign analogues. of the new Thus, analogue bioprospectings. Thus, bioprospecting ancient island ancient sites withinisland sites the Southwithin Pacific the South could Pacific lead tocould the discoverylead to the of di novelscovery compounds of novel compou with therapeuticnds with therapeutic potential. potential.To a large extent the review also perceived the environmental similarity across the Indo-Pacific region on the chemistry of the isolated metabolites, however the change in geographical location induced subtle chemical differences. Chemical analysis of C. mycofijiensis specimens collected from Fiji, Vanuatu, and Papua New Guinea yielded similar compounds, however no zampanolide or its analogues were reported, thus revealing

the impact of geographic variation upon the chemical composition of these organisms. However, it is also apparent that the Tongan marine organisms have been under-studied from a natural products perspective, considering the large number of marine macro- and Molecules 2021, 26, 4534 20 of 26

microorganisms still remaining to be explored, which may provide viable sources and inspiration for many chemical entities to come.

Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Acknowledgments: The Ministry of Agriculture and Food, Forests, and Fisheries, Kingdom of Tonga, is acknowledged for allowing us (VUW, Wellington, New Zealand) to collect and export samples from Tonga. We also like to thank the late Sam Tatafu of Deep Blue Cruises, Paul and Karen Stone of Dive Vava‘u, and Jeff Laurie of Whale Swim, Fish, and Dive for their assistance in our collections in Tonga. Conflicts of Interest: The authors declare no conflict of interest.

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