marine drugs

Review Natural Product Repertoire of the Genus

Nourhan Hisham Shady 1, Mostafa A. Fouad 2, Mohamed Salah Kamel 1, Tanja Schirmeister 3,* and Usama Ramadan Abdelmohsen 2,* 1 Department of Pharmacognosy, Faculty of Pharmacy, Deraya University, Universities Zone, P.O. Box 61111 New Minia City, 61519 Minia, Egypt; [email protected] (N.H.S.); [email protected] (M.S.K.) 2 Department of Pharmacognosy, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt; [email protected] 3 Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudingerweg 5, 55128 Mainz, Germany * Correspondence: [email protected] (T.S.); [email protected] (U.R.A.); Tel.: +49-6131-39-25742 (T.S.); +2-86-2347759 (U.R.A.); Fax: +49-6131-39-23062 (T.S.); +2-86-2369075 (U.R.A.)  Received: 25 November 2018; Accepted: 24 December 2018; Published: 30 December 2018 

Abstract: Marine are a very attractive and rich source in the production of novel bioactive compounds. The sponges exhibit a wide range of pharmacological activities. The genus Amphimedon consists of various species, such as viridis, compressa, complanata, and terpenensis, along with a handful of undescribed species. The Amphimedon genus is a rich source of secondary metabolites containing diverse chemical classes, including alkaloids, ceramides, cerebrososides, and terpenes, with various valuable biological activities. This review covers the literature from January 1983 until January 2018 and provides a complete survey of all the compounds isolated from the genus Amphimedon and the associated microbiota, along with their corresponding biological activities, whenever applicable.

Keywords: marine natural products; sponges; Amphimedon; alkaloids; ceramides; bacteria

1. Introduction The broadness in the discovery of natural marine products have increased over the last two decades with the number of new compounds discovered per year similarly increasing [1]. One of the richest sources of marine natural products, among all the marine organisms investigated in literature, are the marine sponges. Nearly thirty percent of all marine natural products discovered in history come from marine sponges [2–4]. Sponges have been considered an important source of new bioactive natural products [5], although the role of microbial symbionts as the producers of metabolites needs more further research in the future. The number of metabolites reported from sponges varies from year to year, e.g., in 2014, 283 new structures were described from the phylum Porifera. By 2015, the number of metabolites (291) remained similar to 2014 and constant in comparison to previous years [6]. In 2016, 224 new compounds were reported from sponges. This reduction may represent the focus changing from studying sponges to studying microorganisms. However, sponges remain one of the important groups in the discovery of new bioactive compounds [7]. Wide ranges of microbes are associated with sponges, these include heterotrophic bacteria, cyanobacteria, dinoflagellates, and diatoms [8]. These microbes all play several roles in the sponges and affect sponge health, growth rates, and the ability to defend against predators [9]. The interaction between sponges and the associated microorganism could help in the nutrition of the sponge [10], or in the fixation of nitrogen [11]. The most important role, however, is the production of secondary metabolites as antifungals and antibiotics [12]. The genus Amphimedon (Kingdom: Animalia; phylum: Porifera; class: Demospongiae; sub class: Heteroscleromorpha; order: ; family: ) is reported to be a very rich source of bioactive metabolites.

Mar. Drugs 2019, 17, 19; doi:10.3390/md17010019 www.mdpi.com/journal/marinedrugs Mar. Drugs 2018, 16, x FOR PEER REVIEW 2 of 21 of secondary metabolites as antifungals and antibiotics [12]. The genus Amphimedon (Kingdom: Animalia; phylum: Porifera; class: Demospongiae; sub class: Heteroscleromorpha; order: Haplosclerida; family: Niphatidae) is reported to be a very rich source of bioactive metabolites. Various chemical and biological investigations, particularly for the different extracts of the undescribed species of the genus Amphimedon, can be found in previous literature. These investigations confirmed that the genus, Amphimedon, is rich in different classes of natural products Mar. Drugs 2019, 17, 19 2 of 20 such as alkaloids, and rich in different subclasses such as manzamine alkaloids [13,14], purine-based alkaloids [15], pyridine-based alkaloids [16], 3-alkylpyridine glycosides [17], and macrocyclic lactones/lactamsVarious chemical [18]. In and addition, biological ceramides investigations, and cerebrosoides particularly forwere the isol differentated from extracts the marine of the undescribedsponges of the species genus of Amphimedon the genus Amphimedon [19]. Moreover,, can be fatty found acids in previous were also literature. reported These from investigations Amphimedon confirmedsp [20]. that the genus, Amphimedon, is rich in different classes of natural products such as alkaloids, and richThe inmarine different sponge subclasses Amphimedon such as sp. manzamine has been alkaloidscollected[ 13from,14], different purine-based regions, alkaloids including [15], pyridine-basedOkinawa and Fukuoka alkaloids in [16 Japan], 3-alkylpyridine [19,21]. Biological glycosides investigations [17], and macrocyclic of the alkaloids lactones/lactams and fatty acids [18]. Inisolated addition, from ceramides Amphimedon and have cerebrosoides shown that were some isolated of these from compounds the marine possess sponges antimicrobial of the genus [22], Amphimedonantitrypanosomal[19]. Moreover,[23], and fatty anticancer acids were [24] also properties. reported fromIn addition,Amphimedon discoverysp. [20]. of the natural metabolitesThe marine from spongethe fourAmphimedon sponges viridis,sp. compressa, has been complanata, collected from and differentterpenensis regions, were reported including in Okinawaprevious literature. and Fukuoka In this in review, Japan [ 19we,21 present]. Biological an overview investigations on the chemical of the alkaloids structures and of the fatty marine acids isolatedmetabolites from fromAmphimedon the marinehave sponges shown of that the somegenus of Amphimedon these compounds, their associated possess antimicrobial microorganisms [22],, antitrypanosomalbiological activities, [23 and], and their anticancer places of [24 collection] properties. whenever In addition, applicable. discovery of the natural metabolites from the four sponges viridis, compressa, complanata, and terpenensis were reported in previous literature. In2. Amphimedon this review, we compressa present an overview on the chemical structures of the marine metabolites from the marineCyclostellettamine sponges of the [25] genus is consideredAmphimedon an ,impo theirrtant associated precursor microorganisms, of the manzamine biological alkaloids. activities, Its andrelated their compound places of collection8,8’-dienecyclostellettamine whenever applicable. 1 is an alkyl pyridine alkaloid, as shown in Figure 1, and was isolated from the marine sponge , which was collected in Florida. 2. Amphimedon compressa Compound 1 shows potent antibacterial and antifungal activities against six of the seven tested microorganisms,Cyclostellettamine Candida [ 25albicans,] is considered Escherichia an coli, important Pseudomonas precursor aeruginosa of the, Cryptococcus manzamine neoformans alkaloids., 0 ItsMethicillin-resistance related compound 8,8staphylococcus-dienecyclostellettamine aureus, and Aspergillus1 is an alkyl fumigatus pyridine with alkaloid, IC50 values as shown of 0.4, in Figure 1.3, 2.1,1, and2.5, 0.25, was isolatedand 0.3 mg from mL the−1, marinerespectively. sponge Amphimedon compressa, which was collected in Florida.

0 Figure 1. The chemical structure of 8,88,8’-dienecyclostellettamine-dienecyclostellettamine (1).

Compound 1 shows potent antibacterial and antifungal activities against six of the seven tested Amphitoxin [26] was isolated from different marine sponges belonging to the order microorganisms, Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Cryptococcus neoformans, Haplosclerida, which is found in relatively high quantities in extracts of Amphimedon compressa, Methicillin-resistance staphylococcus aureus, and Aspergillus fumigatus with IC values of 0.4, 1.3, 2.1, collected near the coast of San Salvador Island. Amphitoxin is a polymeric compound50 containing 3- 2.5, 0.25, and 0.3 mg mL−1, respectively. alkyl- and 3-alkenyl pyridinium units and contains a mixture of high-molecular-weight pyridinium Amphitoxin [26] was isolated from different marine sponges belonging to the order Haplosclerida, salts. It is similar in structure to a polymeric pyridinium alkaloid, which has recently been isolated which is found in relatively high quantities in extracts of Amphimedon compressa, collected near the from a sponge belonging to the genus Callyspongia (C. fibrosa). However, the amphitoxin of coast of San Salvador Island. Amphitoxin is a polymeric compound containing 3-alkyl- and 3-alkenyl Amphimedon compressa lacks the carbon–carbon double bond in the side-chain and its molecular pyridiniumweight has not units yet and been contains established a mixture precisely. of high-molecular-weight The amphitoxin showed pyridinium ichthyotoxic salts. activity It is similar towards in structureXiphophorus to a variatus polymeric (moon pyridinium fish) and alkaloid, insecticidal which activity has recently against been Cylas isolated formicarius from a elegantulus sponge belonging (sweet Callyspongia C. fibrosa Amphimedon compressa topotato the genusweevil) in concentrations( of 0.2,). However, 0.8, and 0.4 the ppm amphitoxin and corresponding of mortality rateslacks of 30, the 20 carbon–carbonand 10%, respectively, double with bond a in life the span side-chain of 72 h. andThe itstoxicity molecular towards weight the moon has not fish yet was been evidenced established by Xiphophorus variatus precisely.the high mortality The amphitoxin rates. In showed amphitoxin ichthyotoxic concentratio activityns of towards 1000 and 100 ppm, the lifespan(moon of the fish) moon and Cylas formicarius elegantulus insecticidalfish is <30 min activity and <60 against min, respectively, thus demonstrating(sweet a potato mortality weevil) rate in of concentrations 100%. [27]. of 0.2, 0.8, and(Z)-17-tricosenal 0.4 ppm and corresponding2, 19-hexacosenal mortality 3, 16-tricosenoic rates of 30, 20acid and 4, 10%,18-tricosenoic respectively, acid with 5, 16-tricosenoic a life span of 72acid h. 6 The, 19-pentacosenal toxicity towards 7, 19-pentacosenoic the moon fish was acid evidenced 8, 20-hepacosenoic by the high acid mortality 9, and rates.21-octacosenoic In amphitoxin acid concentrations of 1000 and 100 ppm, the lifespan of the moon fish is <30 min and <60 min, respectively, thus demonstrating a mortality rate of 100%. [27]. (Z)-17-tricosenal 2, 19-hexacosenal 3, 16-tricosenoic acid 4, 18-tricosenoic acid 5, 16-tricosenoic acid 6, 19-pentacosenal 7, 19-pentacosenoic acid 8, 20-hepacosenoic acid 9, and 21-octacosenoic acid 10, as shown in Figure2, are mono-unsaturated phospholipid fatty acids isolated from Amphimedon compressa [28]. Mar. Drugs 2018, 16, x FOR PEER REVIEW 3 of 21 Mar. Drugs 2018, 16, x FOR PEER REVIEW 3 of 21 10, as shown in Figure 2, are mono-unsaturated phospholipid fatty acids isolated from Amphimedon 10compressa, as shown [28]. in Figure 2, are mono-unsaturated phospholipid fatty acids isolated from Amphimedon compressaIn addition [28]. to the previously isolated fatty acids, methyl 2-methoxyhexadecanoate 11 (Figure 3), In addition to the previously isolated fatty acids, methyl 2-methoxyhexadecanoate 11 (Figure 3), Mar.2-hydroxydocosanoic Drugs 2019, 17, 19 acid 12 and 2-hydroxytricosanoic acid 13 [29] have been isolated 3from of 20 2-hydroxydocosanoicAmphimedon compressa [30].acid 12 and 2-hydroxytricosanoic acid 13 [29] have been isolated from Amphimedon compressa [30].

Figure 2. The chemical structures of the compounds (22–10–10). Figure 2. The chemical structures of the compounds (2–10). InAcetamidoglucosyl addition to the previously ceramide isolated14, as shown fatty acids,in Figure methyl 3, was 2-methoxyhexadecanoate isolated from Amphimedon11 (Figure compressa3), 2-hydroxydocosanoiccollectedAcetamidoglucosyl from the coast acid ofceramide Key12 Largo,and 14,2-hydroxytricosanoic asFlorida shown [31]. in Figure 3, was acid isolated13 [29] from have Amphimedon been isolated compressa from Amphimedoncollected from compressa the coast[30 of]. Key Largo, Florida [31].

Figure 3. The chemical structures of the compounds (12–14). Figure 3. The chemical structures of the compounds (1212–14–14). 3. Amphimedon viridis 3. AmphimedonAcetamidoglucosyl viridis ceramide 14, as shown in Figure3, was isolated from Amphimedon compressa collected1,3-Dimethylisoguanine from the coast of Key 15 Largo, [32] is Florida a purine-based [31]. alkaloid, as shown in Figure 4, which was isolated1,3-Dimethylisoguanine from Amphimedon viridis 15 [32]. The is alkaloid a purine-based induces contractionsalkaloid, as whenshown obtained in Figure by 4, a whichtransmural was 3.isolatedelectricalAmphimedon from stimulation Amphimedon viridis in a guineaviridis. Thepigs’ alkaloid longitudin inducesal muscle/myenteric contractions when plexus obtained in a dose-dependentby a transmural electrical stimulation in a guinea pigs’ longitudinal muscle/myenteric plexus in a dose-dependent manner1,3-Dimethylisoguanine [33]. 15 [32] is a purine-based alkaloid, as shown in Figure4, which was manner [33]. isolated from Amphimedon viridis. The alkaloid induces contractions when obtained by a transmural electrical stimulation in a guinea pigs’ longitudinal muscle/myenteric plexus in a dose-dependent manner [33]. Mar. Drugs 20192018, 1716,, 19x FOR PEER REVIEW 44 of of 21 20 Mar. Drugs 2018, 16, x FOR PEER REVIEW 4 of 21

Figure 4. The chemical structures of the compounds (15, 16). Figure 4. TheThe chemical chemical structures of the compounds ( 15,15, 16).

Theophylline 16 [32] is another purine-based alkaloid isolated fromAmphimedon Amphimedon viridis viridis, which Theophylline 1616 [[32]32] is is another another purine-based purine-based alkaloid alkaloid isolated isolated from from Amphimedon viridis,, which which was was previously isolated from the plant sourceCamellia Camellia sinensis sinensis [34]. Furthermore, cerebrosoides waspreviously previously isolated isolated from from the the plant plant source source Camellia sinensis[34 [34].]. Furthermore,Furthermore, cerebrosoides amphicerebroside B-F 17–21, as shown in Figure 5, [35] were obtained from this sponge and were amphicerebroside B-F B-F 17–2117–21,, as as shown shown in in Figure Figure 55,,[ [35]35] were obtained from this sponge and were collected from the Red Sea. collected from the Red Sea.

Figure 5. The chemical structures of the compounds (1717–21–21). Figure 5. The chemical structures of the compounds (17–21). 4. Amphimedon complanata 4. Amphimedon complanata Amphimedon complanatacomplanatais is a a species species of of sponge sponge rich rich in in fatty fatty acids, acids, such such as as 11,l5-icosadienoic 11,l5-icosadienoic acid acid22, Amphimedon complanata is a species of sponge rich in fatty acids, such as 11,l5-icosadienoic acid 7-methyl-6-hexadecenoic22, 7-methyl-6-hexadecenoic acid acid23, and23, 6,11-icosadienoicand 6,11-icosadienoic acid 24acid[36 24], and [36], was and isolated was isolated from a spongefrom a 22, 7-methyl-6-hexadecenoic acid 23, and 6,11-icosadienoic acid 24 [36], and was isolated from a collectedsponge collected near the near shelf the edge shelf of Laedge Parguera of La Pargue at a depthra at a of depth 80 ft, asof 80 shown ft, as in shown Figure in6 .Figure 6. spongeFor collected the near first the shelf time edge in of La nature Parguera 2-methoxy-13-methyltetradecanoic at a depth of 80 ft, as shown in Figure acid6. 25, 2-methoxy-14-methylpentadecanoic acid 26, 2-methoxy-13-methylpentadecanoic acid 27, and ethyl 2-methoxy-13-methyltetradecanoate 28 were identified and isolated from the marine sponge Amphimedon complanata, collected in Puerto Rico, as shown in Figure6[37].

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Mar. Drugs 2019, 17, 19 5 of 20 Mar. Drugs 2018, 16, x FOR PEER REVIEW 5 of 21

Figure 6. The chemical structures of the compounds (22–28).

For the first time in nature 2-methoxy-13-methyltetradecanoic acid 25, 2-methoxy-14- methylpentadecanoic acid 26, 2-methoxy-13-methylpentadecanoic acid 27, and ethyl 2-methoxy-13- methyltetradecanoate 28 were identified and isolated from the marine sponge Amphimedon complanata, collected in Puerto Rico, as shown in Figure 6 [37]. Figure 6. The chemical structures of the compounds (2222–28–28). 5. Amphimedon terpenensis For the first time in nature 2-methoxy-13-methyltetradecanoic acid 25, 2-methoxy-14- methylpentadecanoic6-Bromo-5E,9,9Z-pentacosadienoic acid 26, 2-methoxy-13-methylpentadecanoic acidacid 29 and 6-bromo-5E,9,9Z-tetracosadienoic acid 27, and ethyl acidacid 2-methoxy-13- 30,, as shown methyltetradecanoatein Figure7 7,, are are brominated brominated 28 were acids acids and identifiedand were were isolated isolatedand isolated from from AmphimedonAmphimedon from the terpenensisterpenensis.marine sponge. Amphimedon complanata, collected in Puerto Rico, as shown in Figure 6 [37].

5. Amphimedon terpenensis 6-Bromo-5E,9Z-pentacosadienoic acid 29 and 6-bromo-5E,9Z-tetracosadienoic acid 30, as shown in Figure 7, are brominated acids and were isolated from Amphimedon terpenensis.

Figure 7. The chemical structures of the compounds (2929,, 30). 6. Undescribed Marine Sponges of the Genus Amphimedon 6. Undescribed Marine Sponges of the Genus Amphimedon One of the classes repeatedly isolated from Amphimedon sp. is the manzamine alkaloids. One of the classes repeatedly isolated from Amphimedon sp. is the manzamine alkaloids. In 1986, In 1986, Higa and coworkers isolated the manzamine A prototype for this group, a novel cytotoxic Higa and coworkers isolated the manzamine A prototype for this group, a novel cytotoxic β-carboline β-carboline alkaloid from marine sponge Haliclona sp. collected from Manzamo, Okinawa [38]. alkaloid from marine spongeFigure 7.Haliclona The chemical sp. collected structures from of the Manzamo, compounds Okinawa (29, 30). [38]. The isolation of The isolation of manzamines (B–D), from the marine sponge Haliclona sp. subsequently followed [39], manzamines (B–D), from the marine sponge Haliclona sp subsequently followed [39], as well as as well as ircinals (A–B) from an ircinia sponge [40]. In the last two decades more than 80 β 6.ircinals Undescribed (A–B) from Marine an ircinia Sponges sponge of the[40]. Genus In the lastAmphimedon two decades more than 80 β -carboline-containing -carboline-containing manzamine alkaloids and manzamine-related alkaloids have been isolated from manzamine alkaloids and manzamine-related alkaloids have been isolated from marine sponges marineOne sponges of the classes following repeatedly manzamine isolated A discoveryfrom Amphimedon [41]. Manzamines sp. is the manzamine are very attractive alkaloids. bioactive In 1986, Higanatural and metabolites coworkers isolated due to theirthe manzamine wide range A ofprototype biological for applications this group, a asnovel well cytotoxic as insecticidal β-carboline [42], alkaloidcytotoxic from [43], marine and anti-inflammatory sponge Haliclona properties sp. collected [44]. from Manzamo, Okinawa [38]. The isolation of manzamines (B–D), from the marine sponge Haliclona sp subsequently followed [39], as well as ircinals (A–B) from an ircinia sponge [40]. In the last two decades more than 80 β -carboline-containing manzamine alkaloids and manzamine-related alkaloids have been isolated from marine sponges

Mar. Drugs 2018, 16, x FOR PEER REVIEW 6 of 21 Mar. Drugs 2019, 17, 19 6 of 20 following manzamine A discovery [41]. Manzamines are very attractive bioactive natural metabolites due to their wide range of biological applications as well as insecticidal [42], cytotoxic [43], and anti- Theinflammatory first example properties is [44]. zamamiphidin A 31 (Figure8)[ 13] which was obtained from the AmphimedonThe firstsp. example collected is zamamiphidin at Zamami, Okinawa.A 31 (Figure 8) The [13] compound which was obtained exhibited from antibacterial the Amphimedon activity againstsp. Staphylococcuscollected at Zamami, aureus (MIC, Okinawa. 32 µg/mL) The compound but did not exhibited show any antibacterial activity against activityEscherichia against coli, Staphylococcus aureus (MIC, 32 μg/mL) but did not show any activity against Escherichia coli, Bacillus Bacillus subtilis, or Micrococcus luteus (MIC, >32 µg/mL). The compound also displayed antifungal subtilis, or Micrococcus luteus (MIC, >32 μg/mL). The compound also displayed antifungal activities Aspergillus niger Trichophyton mentagrophytes Candida albicans Cryptococcus activitiesagainst against Aspergillus niger, Trichophyton, mentagrophytes, Candida albicans,, and Cryptococcus, and neoformans neoformans µ (IC50 > (IC32 50μg/mL).> 32 g/mL).The compound The compound did not show did notcytotoxicity show cytotoxicity against L1210 against murine L1210 leukemia murine or leukemia KB or KBhuman human epidermoid epidermoid carcinoma carcinoma cells cells(IC50 > (IC 1050 μg/mL).> 10 µ g/mL).

FigureFigure 8. 8.The The chemical chemical structurestructure of of the the compound compound (31 ().31 ).

ZamamidineZamamidine A-C A-C32– 3432–34(Figure (Figure9)[ 45 9),46 [45,46]] are other are other manzamine manzamine alkaloids alkaloids with with inhibitory inhibitory activities againstactivitiesTrypanosoma against Trypanosoma brucei brucei brucei(IC brucei50 values (IC50 values of 1.04 of 1.04 mg/mL, mg/mL, 1.05 1.05 mg/mL,mg/mL, and and 0.27 0.27 mg/mL, mg/mL, respectively) and against Plasmodium falciparum with IC50 values of 7.16 mg/mL, 12.20 mg/mL, 0.58 respectively) and against Plasmodium falciparum with IC50 values of 7.16 mg/mL, 12.20 mg/mL, 0.58 mg/mL,mg/mL, respectively. respectively. Zamamidine Zamamidine D D35 35[22],[22 as], asshown shown in Figure in Figure 9, is9 ,the is thefirst first manzamine manzamine alkaloid alkaloid possessing a 2,2′-methylene bis-tryptamine unit as the aromatic moiety instead of a β-carboline unit. possessing a 2,20-methylene bis-tryptamine unit as the aromatic moiety instead of a β-carboline It showed antibacterial activity against Escherichia coli, Stapylococcus aureus, Bacillus subtilis, and unit. It showed antibacterial activity against Escherichia coli, Stapylococcus aureus, Bacillus subtilis, Micrococcus luteus with MIC values of 32, 8, 8, and 8 μg/μL, respectively. In addition, it showed and antifungalMicrococcus activity luteus againstwith MICAspergillus values niger, of 32,Trichophyton 8, 8, and me 8ntagrophytes,µg/µL, respectively. Candida albicans In addition,and it showedCryptococcus antifungal neoformans activity with against IC50 valuesAspergillus of 16, 8, niger 16, ,andTrichophyton 2 μg/μL, respectively. mentagrophytes , Candida albicans and Cryptococcus neoformans with IC values of 16, 8, 16, and 2 µg/µL, respectively. Mar. Drugs 2018, 16, x FOR PEER 50REVIEW 7 of 21

FigureFigure 9. The 9. The chemical chemical structures structures of of the the compounds compounds (32–35 (32). –35).

Keramaphidin B 36 and keramaphidin C 37 [21,47,48], as shown in Figure 10, were isolated from Amphimedon sp. which was collected from the Kerama Islands, Okinawa.

Figure 10. The chemical structures of the compounds (36, 37).

Among the manzamine derivatives 3,4-dihydromanzamine A 38, 6-hydroxymanzamine A 39 [43], 3,4 dihydro-6 hydroxy-10,11-epoxymanzamine A 40, and 3,4-dihydromanzamine J N-oxide 41 [46], as shown in Figure 11, the 3,4-dihydromanzamine J N-oxide 41 compound showed anti- parasitic activity against T. b. brucei with an IC50 value of 4.44 (μg/mL) and against P. falciparum with an IC50 value of 7.02 (μg/mL) [23].

Mar. Drugs 2018, 16, x FOR PEER REVIEW 7 of 21

Mar. Drugs 2019, 17, 19 7 of 20 Figure 9. The chemical structures of the compounds (32–35).

Keramaphidin B 36 and keramaphidin C 37 [21,47,48],[21,47,48], as shown in Figure Figure 10,10, were were isolated isolated from from Amphimedon sp. which was collected from the Kerama Islands,Islands, Okinawa.Okinawa.

Figure 10. The chemical structures of the compounds (3636,, 37).

Among thethe manzamine manzamine derivatives derivatives 3,4-dihydromanzamine 3,4-dihydromanzamine A 38 ,A 6-hydroxymanzamine 38, 6-hydroxymanzamine A 39 [43 A], 3,439 [43], dihydro-6 3,4 dihydro-6 hydroxy-10,11-epoxymanzamine hydroxy-10,11-epoxymanzamine A 40, and A 40, 3,4-dihydromanzamine and 3,4-dihydromanzamine J N-oxide J N41-oxide[46], Mar. Drugs 2018, 16, x FOR PEER REVIEW 8 of 21 as41 shown[46], as inshown Figure in 11 Figure, the 3,4-dihydromanzamine 11, the 3,4-dihydromanzamine J N-oxide J N41-oxidecompound 41 compound showed anti-parasiticshowed anti- activity against T. b. brucei with an IC value of 4.44 (µg/mL) and against P. falciparum with an IC parasitic activity against T. b. brucei with50 an IC50 value of 4.44 (μg/mL) and against P. falciparum with50 Mar.value Drugs of 7.022018, (16µg/mL), x FOR PEER [23]. REVIEW 8 of 21 an IC50 value of 7.02 (μg/mL) [23].

Figure 11. The chemical structures of the compounds (38–41). Figure 11. The chemical structures of the compounds (38–41).

Ircinol A 42, ircinol B 43 [14], and ircinic acid A 44 (which is the 1-O-methyl carboxylic acid Ircinol A 42, ircinolFigure B 43 11.[14 The], and chemical ircinic structures acid A 44 of(which the compounds is the 1-O -methyl(38–41). carboxylic acid analog ofanalog ircinal of A)ircinal [13], A) as shown[13], as inshown Figure in 12 Figure, were 12, isolated were isolated from Amphimedon from Amphimedonsp. collected sp. collected from the from Kerama the Islands,KeramaIrcinol Okinawa.Islands, A 42 ,Okinawa. ircinol B 43 [14], and ircinic acid A 44 (which is the 1-O-methyl carboxylic acid analog of ircinal A) [13], as shown in Figure 12, were isolated from Amphimedon sp. collected from the Kerama Islands, Okinawa.

Figure 12. The chemical structures of the compounds (4242–44–44).).

Keramamine C 45 [47], manzamine H 46, and manzamine L 47 displayed cytotoxicity against Figure 12. The chemical structures of the compounds (42–44). murine lymphoma LI210 cells and human epidermoid carcinoma KB cells with IC50 values of 3.7 and 11.8lKeramamine μg/mL, respectively. C 45 [47], Antibacterialmanzamine H activity 46, and against manzamine the bacteria L 47 displayed Sarcina cytotoxicitylutea, Staphylococcus against murineaureus, lymphomaBacillus subtilis, LI210 cellsand andMycobacterium human epidermoid 607 with carcinoma MICs values KB cells of 10,with 10, IC 5010, values and of5 3.7μg/mL, and 11.8lrespectively μg/mL, [21].respectively. Antibacterial activity against the bacteria Sarcina lutea, Staphylococcus aureus,New Bacillus manzamine-related subtilis, and Mycobacterium tetrahydro-carboline 607 with alkaloidsMICs values with ofa 10,methylene 10, 10, andcarbon 5 μbridgeg/mL, respectivelybetween N-2 [21]. and N-27 such as manzamine M 48 [49], manzamine D 49 [21], ma'eganedin A 50, and nakadomarinNew manzamine-related A 51 are novel tetrahydro-carbolinecytotoxic alkaloids fromalkaloids Amphimedon with a methylenesp. collected carbon in Okinawa. bridge betweenNakadomarin N-2 and A 51N-27 showed such ascytotoxicity manzamine against M 48 murine [49], manzamine lymphoma D L1210 49 [21], cells ma'eganedin (IC50 1.3 μg/ A mL) 50, andand nakadomarinexhibited activity A 51 against are novelcyclin cytotoxicdependent alkaloids kinase 4 (ICfrom50 9.9 Amphimedon μg/mL) [50], sp. as showncollected in Figurein Okinawa. 13. Nakadomarin A 51 showed cytotoxicity against murine lymphoma L1210 cells (IC50 1.3 μg/ mL) and exhibited activity against cyclin dependent kinase 4 (IC50 9.9 μg/mL) [50], as shown in Figure 13.

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Keramamine C 45 [47], manzamine H 46, and manzamine L 47 displayed cytotoxicity against murine lymphoma LI210 cells and human epidermoid carcinoma KB cells with IC50 values of 3.7 and 11.8l µg/mL, respectively. Antibacterial activity against the bacteria Sarcina lutea, Staphylococcus aureus, Bacillus subtilis, and Mycobacterium 607 with MICs values of 10, 10, 10, and 5 µg/mL, respectively [21]. New manzamine-related tetrahydro-carboline alkaloids with a methylene carbon bridge between N-2 and N-27 such as manzamine M 48 [49], manzamine D 49 [21], ma’eganedin A 50, and nakadomarin A 51 are novel cytotoxic alkaloids from Amphimedon sp. collected in Okinawa. Nakadomarin A 51 showed cytotoxicity against murine lymphoma L1210 cells (IC50 1.3 µg/ mL) and exhibitedMar. Drugs 2018 activity, 16, x againstFOR PEER cyclin REVIEW dependent kinase 4 (IC50 9.9 µg/mL) [50], as shown in Figure 139 of. 21

Mar. Drugs 2018, 16, x FOR PEER REVIEW 9 of 21

Figure 13. The chemical structures of the compounds (4545–51–51).). Figure 13. The chemical structures of the compounds (45–51). Another compound class class isolated isolated from from AmphimedonAmphimedon sp.sp. are are purine-based purine-based alkaloids alkaloids such such as as6- 6-imino-1,9-dimethyl-7,9-dihydro-1Another compound class isolatedH-purine-2,8(3 from AmphimedonH,6H)-dione sp. are52 purine-based, 6-imino-1,3-dimethyl-7,9-dihydro alkaloids such as 6- imino-1,9-dimethyl-7,9-dihydro-1imino-1,9-dimethyl-7,9-dihydro-1HH-purine-2,8(3-purine-2,8(3H,6HH)-dione)-dione 52 52, 6-imino-1,3-dimethyl-7,9-dihydro-, 6-imino-1,3-dimethyl-7,9-dihydro- -1H-purine-2,8(3H,6H)-dione 53, 6-imino-3,9-dimethyl-7,9-dihydro-1H-purine-2,8(3H,6H)-dione 54, 1H-purine-2,8(31H-purine-2,8(3H,6H,6)-dioneH)-dione 53 53, 6-imino-3,9-dimethyl-7,9-dihydro-1, 6-imino-3,9-dimethyl-7,9-dihydro-1H-purine-2,8(3H-purine-2,8(3H,6HH)-dione,6H)-dione 54, 54, H H H 55 and 6-imino-9-methyl-7,9-dihydro-1and 6-imino-9-methyl-7,9-dihydro-1 6-imino-9-methyl-7,9-dihydro-1HH-purine-2,8(3-purine-2,8(3-purine-2,8(3H,6,6,6HH)-dione)-dione)-dione 55 55 [15], [15], [as15 as],shown shown asshown in Figure in Figure in 14. Figure The 14. The 14. The compounds showed neuropharmacological activities with CD values of 2.4, 54, 18, 18 nmol, compoundscompounds showed showed neuropharmac neuropharmacologicalological activitiesactivities withwith CD CD50 50values values50 of of2.4, 2.4, 54, 54,18, 1818, nmol,18 nmol, respectively,respectively, inin mousemouse in mouse viavia via thethe the modulationmodulation modulation ofof of inhibitory inhibiinhibitory transmission transmission actions actions in the in themammalian mammalian CNS. CNS.

FigureFigure 14. 14.The The chemical chemical structuresstructures of of the the compounds compounds (52–55 (52–).55 ).

Pyridine-basedFigure alkaloid 14. compoundsThe chemical we structuresre isolated of thewith compounds high yield ( 52–55from ).Amphimedon sp. An example is pyrinodemin A 56 [51], which showed potent cytotoxicity against the murine leukemia Pyridine-basedLI210 with an IC50 alkaloidvalue of 0.058 compounds μg/mL and we againstre isolated KB epidermoid with high carcinoma yield from cells withAmphimedon an IC50 value sp. An exampleof 0.5 is μpyrinodeming/mL. The related A 56 compounds [51], which pyrinodemin showed potent B–D 57–59cytotoxicity [16] exhibited against potent the murine cytotoxicity leukemia LI210against with an murine IC50 value leukemia of 0.058 with μ ICg/mL50 values and againstof 0.07, KB0.06, epidermoid and 0.08 μg/mL, carcinoma respectively. cells with The ananalogs IC50 value of 0.5pyrinodemin μg/mL. The E, relatedF 60, 61 [52],compounds pyrinodemin pyrinodemin G, H 62, and B– 63D [53]57–59 exhibited [16] exhibited cytotoxicity potent against cytotoxicity P388 50 againstand murine L1210 murine leukemia leukemia with ICcells50 valueswith IC of values0.07, 0.06,of 5.7 and and 0.08 8.8 μμg/mL,g/mL, and respectively. 9.6 and 2.5 Theμg/mL, analogs pyrinodeminrespectively, E, Fin 60 vitro., 61 Finally,[52], pyrinodemin pyrinodemin G,I 64 H was 62 ,also and isolated 63 [53] from exhibited Amphimedon cytotoxicity sp., as shown against in P388 Figure 15. and L1210 murine leukemia cells with IC50 values of 5.7 and 8.8 μg/mL, and 9.6 and 2.5 μg/mL, respectively, in vitro. Finally, pyrinodemin I 64 was also isolated from Amphimedon sp., as shown in Figure 15.

Mar. Drugs 2019, 17, 19 9 of 20

Pyridine-based alkaloid compounds were isolated with high yield from Amphimedon sp. An example is pyrinodemin A 56 [51], which showed potent cytotoxicity against the murine leukemia LI210 with an IC50 value of 0.058 µg/mL and against KB epidermoid carcinoma cells with an IC50 value of 0.5 µg/mL. The related compounds pyrinodemin B–D 57–59 [16] exhibited potent cytotoxicity against murine leukemia with IC50 values of 0.07, 0.06, and 0.08 µg/mL, respectively. The analogs pyrinodemin E, F 60, 61 [52], pyrinodemin G, H 62, and 63 [53] exhibited cytotoxicity against P388 and L1210 murine leukemia cells with IC50 values of 5.7 and 8.8 µg/mL, and 9.6 and 2.5 µg/mL, respectively, in vitro. Finally, pyrinodemin I 64 was also isolated from Amphimedon sp., as shown in FigureMar. Drugs 15 .2018, 16, x FOR PEER REVIEW 10 of 21

Figure 15. The chemical structures of the compounds (56–64).

Nakinadine A 65 [54] which was isolated from a sponge collected in Nakijin, Okinawa, is an example of a bis-3-alkyl pyridine alkaloid with a β-amino acid moiety. The compound showed cytotoxicity against L1210 murine leukemia (IC50 1.3 μg/mL) and KB human epidermoid carcinoma cells (IC50 2.5 μg/mL) in-vitro, as shown in Figure 16. The related nakinadine B–F 66–70 [55], were also isolated from a sponge collected in Nakijin, Okinawa. Nakinadine B 66 and nakinadine C 67 were shown to exhibit cytotoxicity against L1210 murine leukemia with IC50 values of 3.0 and 5.0 μg/mL, respectively, and against KB human epidermoid carcinoma cells with IC50 values of 7.0 and >10 μg/mL, respectively, in-vitro, while nakinadines D–F 68–70 did not show these activities (IC50 > 10 μg /mL).

Mar. Drugs 2019, 17, 19 10 of 20

Nakinadine A 65 [54] which was isolated from a sponge collected in Nakijin, Okinawa, is an example of a bis-3-alkyl pyridine alkaloid with a β-amino acid moiety. The compound showed cytotoxicity against L1210 murine leukemia (IC50 1.3 µg/mL) and KB human epidermoid carcinoma cells (IC50 2.5 µg/mL) in-vitro, as shown in Figure 16. The related nakinadine B–F 66–70 [55], were also isolated from a sponge collected in Nakijin, Okinawa. Nakinadine B 66 and nakinadine C 67 were shown to exhibit cytotoxicity against L1210 murine leukemia with IC50 values of 3.0 and 5.0 µg/mL, respectively, and against KB human epidermoid carcinoma cells with IC50 values of 7.0 and >10 µg/mL, Mar.respectively, Drugs 2018, in-vitro, 16, x FOR whilePEER REVIEW nakinadines D–F 68–70 did not show these activities (IC50 > 10 µg11 /mL). of 21

Figure 16. TheThe chemical structures of the compounds ( 65–70).

Hachijodine E–G 71–73 [24][24] are also 3-alkylpyridine alkaloids isolated from Amphimedon sp. collected off the coast of Hachijo-jima Hachijo-jima Island. They They also also showed showed cytotoxic cytotoxic activity activity against against P388 murine murine leukemia cells with IC 50 valuesvalues of of 2.3, 2.3, 1.0, 1.0, 1.0 1.0 μµg/mL,g/mL, respectively, respectively, as as shown shown in in Figure Figure 17.17.

Figure 17. The chemical structures of the compounds (71–73).

(1E,11Z)-N-Hydroxy-14-(pyridin-3-yl) tetradec-11-en-1-imine 74, (1E,5Z)-N-hydroxy-14- (pyridin-3-yl) tetradec-5-en-1-imine 75, (1E)-N-hydroxy-13-(pyridin-3-yl) tridecan-1-imine 76, and

Mar. Drugs 2018, 16, x FOR PEER REVIEW 11 of 21

Figure 16. The chemical structures of the compounds (65–70).

Hachijodine E–G 71–73 [24] are also 3-alkylpyridine alkaloids isolated from Amphimedon sp.

Mar.collected Drugs 2019off the, 17, coast 19 of Hachijo-jima Island. They also showed cytotoxic activity against P388 murine11 of 20 leukemia cells with IC50 values of 2.3, 1.0, 1.0 μg/mL, respectively, as shown in Figure 17.

Figure 17. The chemical structures of the compounds (71–73). Mar. Drugs 2018, 16, x FOR PEERFigure REVIEW 17. The chemical structures of the compounds (71–73). 12 of 21

Mar. Drugs(1E,11 2018Z)-N, 16-Hydroxy-14-(pyridin-3-yl), x FOR PEER REVIEW tetradec-11-en-1-imine 74, (1E,5Z)-N-hydroxy-14-(pyridin-3-yl)12 of 21 (1E)-N-hydroxy-12-(pyridin-3-yl)(1E,11Z)-N-Hydroxy-14-(pyridin-3-yl) dodecan-1-imine tetradec-11-en-1-imine 77 [16], as shown in74 Figure, (1E 18,,5Z )-areN-hydroxy-14- compounds tetradec-5-en-1-imine 75, (1E)-N-hydroxy-13-(pyridin-3-yl) tridecan-1-imine 76, and (1E)-N-hydroxy-12- which(pyridin-3-yl) possess tetradec-5-en-1-imineantifungal and antimicrobial 75, (1E activities.)-N-hydroxy-13-(pyridin-3-yl) tridecan-1-imine 76, and (pyridin-3-yl)(1E)-N-hydroxy-12-(pyridin-3-yl) dodecan-1-imine 77 [ 16dodecan-1-imine], as shown in Figure 77 [16], 18, areas shown compounds in Figure which 18, possess are compounds antifungal andwhich antimicrobial possess antifungal activities. and antimicrobial activities.

.

Figure 18. The chemical structures of the compounds (74–77).. FigureFigure 18.18. TheThe chemicalchemical structuresstructures ofof thethe compoundscompounds ((7474––7777).). Tetrahydrohalicyclamine A 78 and 22-hydroxyhalicyclamine A 79 (Figure 19) [56], are 3- 78 79 alkylpiperidineTetrahydrohalicyclamineTetrahydrohalicyclamine alkaloids isolated A 78from andand the 22-hydroxyhalicyclamine 22-hydroxyhalicyclamineAmphimedon sp. in Southern A A 79 Japan. (Figure(Figure These 19) 19 compounds[56],)[56 ],are are 3- Amphimedon displayed3-alkylpiperidinealkylpiperidine cytotoxic alkaloids alkaloids activity isolated inhibiting isolated from from the the growth the Amphimedon of P388 cells spsp.. within in Southern IC50 values Japan.Japan. of 2.2 TheseThese and compounds0.45compounds μg/mL, respectively.displayed cytotoxic Amphimedine activity inhibiting 80 [57] is thea pentacyclic growth of P388aromatic cells alkaloid with IC50 isolatedvalues offrom 2.2 andthe Amphimedon 0.45 µg/mL, displayed cytotoxic activity inhibiting the growth of P388 cells with IC50 values of 2.2 and 0.45 μg/mL, 80 Amphimedon sp.respectively.respectively. Amphimedine Amphimedine 80[ 57[57]] is is a a pentacyclic pentacyclic aromatic aromatic alkaloid alkaloid isolated isolated from from the the Amphimedonsp. sp.

Figure 19. TheThe chemical chemical structures of the compounds ( 78–80). A group of brominatedFigure 19. alkaloids, The chemical namely structures amphimedonoic of the compounds acid (7881–80,). psammaplysene E 82, A group of brominated alkaloids, namely amphimedonoic acid 81, psammaplysene E 82, and and 3,5-dibromo-4-methoxybenzoic acid 83 were isolated from Amphimedon sp. collected from the 3,5-dibromo-4-methoxybenzoic acid 83 were isolated from Amphimedon sp. collected from the Mitsio MitsioA Islands,group of Madagascar, brominated as alkaloids, shown in namely Figure 20amphimedonoic[58]. acid 81, psammaplysene E 82, and Islands,3,5-dibromo-4-methoxybenzoic Madagascar, as shown in acid Figure 83 were 20 [58]. isolated from Amphimedon sp. collected from the Mitsio Islands, Madagascar, as shown in Figure 20 [58].

Mar. Drugs 2019, 17, 19 12 of 20 Mar. Drugs 2018, 16, x FOR PEER REVIEW 13 of 21 Mar. Drugs 2018, 16, x FOR PEER REVIEW 13 of 21

OO

HOHO

ONON BrBr 81 BrBr 81 BrBr OO NHNH OO NN BrBr 8282 OO BrBr OO

BrBr BrBr

HOHO OO 83 83 FigureFigure 20. 20. TheThe chemical chemical structures structures ofof thethe compoundscompounds ((8181––8383).).

AmphimedosideAmphimedoside AA A 848484,, ,amphimedosideamphimedoside amphimedoside BB B858585,, amphimedosideamphimedoside, amphimedoside CC 8686 C,, 86amphimedosideamphimedoside, amphimedoside DD 87,87, D andand87, andamphimedosideamphimedoside amphimedoside EE 8888 E [17][17]88 [ 17 areare] are 3-alkylpyridine3-alkylpyridine 3-alkylpyridine glycosidesglycosides glycosides isolatedisolated isolated fromfrom from thethe the AmphimedonAmphimedonAmphimedon spsp.sp.. collected fromfrom thethe Hachijo-jimaHachijo-jimaHachijo-jima Island,Island, asas shownshownshown ininin FigureFigureFigure 2121.21.. AmphimelibiosideAmphimelibiosideAmphimelibioside AA 8989,,, amphimelibiosideamphimelibiosideamphimelibioside BB 9090,, amphimelibiosideamphimelibioside CC 9191,, amphimelibiosideamphimelibioside DD 9292,, amphimelibiosideamphimelibioside EE 9393,93,, and and amphimelibioside amphimelibioside FF 9494 [19],[[19],19], as as shown shown in in Figure Figure 22,2222,, areare newnew ceramideceramide dihexosidesdihexosides andand werewere isolatedisolated fromfrom from AmphimedonAmphimedon spspsp... collectedcollected nearnear Fukuoka,Fukuoka, Japan.Japan.

FigureFigure 21. 21. TheThe chemical chemical structures structures ofof thethe compoundscompounds ((8484––8888).).

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FigureFigure 22. 22. TheThe The chemicalchemical chemical structuresstructures structures ofof of thethe the compounds compounds compounds (89 ( (–8994–).94 ).

IsolatedIsolated macrocyclic macrocyclic lactone/lactams lactone/lactams are are amphilactamamphilactam amphilactam A–D A–D A–D 95 95–9598––98 98[18], [18],[18 as], asshown as shown shown in Figure in in Figure Figure 23. 23.23. TheseThese four fourcompounds compounds were were found found to to be be ac activetive against against nematodesnematodes in in vitro vitro with with LD LD99 activities99 activities of 7.5, of 7.5, These four compounds were found to be activeactive against nematodes inin vitro with LD9999 activitiesactivities of of 7.5, 7.5, 47, 8.5, and 0.39 μg/mL, respectively. 47, 8.5, and 0.39 μµg/mL, respectively. respectively.

Figure 23. The chemical structures of the compounds (95–98). Figure 23. The chemical structures of the compounds (95–98). Amphimic acidFigure A, B 23.99 , The100 chemicaldisplayed structures inhibitory of activity the compounds against DNA (95–98 to). poisomerase I with IC50 values of 0.47 and 3.2 μM, respectively Amphimic acid C 102 and 5Z,9Z,21Z-triacontatrienoic Amphimicacid were isolated acidacid A,A, from B B99 99the, 100, 100Amphimedondisplayed displayed sp. inhibitory inhibitory103 [59], as activity shownactivity against in againstFigure DNA 24. DNA to poisomerase to poisomerase I with I with IC50 ICvalues50 values of 0.47 of 0.47 and 3.2andµ 3.2M, respectivelyμM, respectively Amphimic Amphimic acid acid C 102 Cand 102 5Z,9Z,21Z-triacontatrienoicand 5Z,9Z,21Z-triacontatrienoic acid IC50 values of 0.47 and 3.2 μM, respectively Amphimic acid C 102 and 5Z,9Z,21Z-triacontatrienoic acidwere were isolated isolated from from the Amphimedon the Amphimedonsp. 103 sp.[ 59103], [59], as shown as shown in Figure in Figure 24. 24.

Figure 24. The chemical structures of the compounds (99–102).

Figure 24. The chemical structures of the compounds (99–102). Figure 24. TheThe chemicalchemical structuresstructures ofof thethe compoundscompounds ((99–102).

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The terpene diisocyanoadociane 103103 [60],[60], as shown in Figure 2525,, is an exampleexample of aa compoundcompound from another substance class isolatedisolated fromfrom AmphimedonAmphimedon sp.sp.

Figure 25. The chemical structure of the compound (103). 7. Bacteria Associated with the Genus Amphimedon 7. Bacteria Associated with the Genus Amphimedon Marine sponges contain a huge diversity of fatty acids which are hypothesized to be composed Marine sponges contain a huge diversity of fatty acids which are hypothesized to be composed from bacterial origin. Regarding Amphimedon terpenensis, the brominated long-chain fatty acids 29 from bacterial origin. Regarding Amphimedon terpenensis, the brominated long-chain fatty acids 29 and 30, were more distributed in the sponge and its associated bacterial symbionts [61]. However, and 30, were more distributed in the sponge and its associated bacterial symbionts [61]. However, the role of these fatty acids in marine sponges is unclear, but they may be involved in the relationship the role of these fatty acids in marine sponges is unclear, but they may be involved in the relationship between the sponge and their associated bacteria and in protecting the bacterial symbionts from between the sponge and their associated bacteria and in protecting the bacterial symbionts from sponge phagocytosis. Amphitoxin [62] is a pyridinium alkaloid isolated from Amphimedon chloros, sponge phagocytosis. Amphitoxin [62] is a pyridinium alkaloid isolated from Amphimedon chloros, which was previously described as Amphimedon viridis. The amphitoxin exhibited broad-spectrum which was previously described as Amphimedon viridis. The amphitoxin exhibited broad-spectrum activity against bacteria derived from seawater. Furthermore, the sponge-associated bacteria alpha activity against bacteria derived from seawater. Furthermore, the sponge-associated bacteria alpha proteobacteria were resistant against this compound, as well as six different bacterial strains associated proteobacteria were resistant against this compound, as well as six different bacterial strains with the sponge A. viridis [63]. This inhibition may explain the ability of the bacteria to live in close associated with the sponge A. viridis [63]. This inhibition may explain the ability of the bacteria to live association with their host sponge while having a chemical defense against other microbial pathogens. in close association with their host sponge while having a chemical defense against other microbial Moreover, actinomycetes such as Kocuria, Microbacterium, and Micrococcus were cultivated from the pathogens. Moreover, actinomycetes such as Kocuria, Microbacterium, and Micrococcus were cultivated Amphimedon sp. that had been collected offshore of the Red Sea, Egypt, but were never chemically from the Amphimedon sp. that had been collected offshore of the Red Sea, Egypt, but were never investigated [64]. chemically investigated [64]. Several types of mycobacteria, including a strain closely related to M. tuberculosis, have been Several types of mycobacteria, including a strain closely related to M. tuberculosis, have been isolated from . The strain Salinispora arenicola was also isolated from isolated from Amphimedon queenslandica. The strain Salinispora arenicola was also isolated from Amphimedon queenslandica. This strain can synthesize antimycobacterial compounds [65]. Amphimedon queenslandica. This strain can synthesize antimycobacterial compounds [65]. As the polyketide class is well-known for their antibiotic activities, the polyketide synthetase As the polyketide class is well-known for their antibiotic activities, the polyketide synthetase genes of the sponge-derived mycobacteria were examined [66] and found to catalyze the synthesis of genes of the sponge-derived mycobacteria were examined [66] and found to catalyze the synthesis of mycobacterial outer membrane lipids. mycobacterial outer membrane lipids. The diversity in the regions in which Amphimedon and its different species were collected, play The diversity in the regions in which Amphimedon and its different species were collected, play a role in the production of manzamine alkaloids 30–50. They are widely believed to be produced a role in the production of manzamine alkaloids 30–50. They are widely believed to be produced by by a symbiotic relationship between the sponge and common or closely related microorganism(s), a symbiotic relationship between the sponge and common or closely related microorganism(s), which which may account for the generation of the manzamine alkaloids [67]. Furthermore, there is may account for the generation of the manzamine alkaloids [67]. Furthermore, there is evidence that evidence that sponge-associated microbes have a significant role in the bioconversion of manzamines sponge-associated microbes have a significant role in the bioconversion of manzamines to the to the growing number of alkaloids found in sponges producing manzamines and is provided growing number of alkaloids found in sponges producing manzamines and is provided by the by the biotransformation of 8-hydroxymanzamine A and its enantiomer to manzamine A and biotransformation of 8-hydroxymanzamine A and its enantiomer to manzamine A and ent-12,34- ent-12,34-oxamazamine F, respectively [41]. oxamazamine F, respectively [41]. Classes of chemical compounds, such as fatty acids, were used as markers for the the Classes of chemical compounds, such as fatty acids, were used as markers for the the chemodiversity in the genus Amphimedon. Several unique fatty acids were isolated from this genus chemodiversity in the genus Amphimedon. Several unique fatty acids were isolated from this genus as 17, 18, and 19-hexacosenoic acids. Commonly, there were two biosynthetic pathways that were as 17, 18, and 19-hexacosenoic acids. Commonly, there were two biosynthetic pathways that were reported in marine sponges such as 18: ln-7 to 26: ln-7, and the 18: ln-9 to 26: ln-9 routes. While the reported in marine sponges such as 18: ln-7 to 26: ln-7, and the 18: ln-9 to 26: ln-9 routes. While the 18: ln-8 to 26: ln-8 pathway has only recently existed in these invertebrates [28,68] the long chain 18: ln-8 to 26: ln-8 pathway has only recently existed in these invertebrates [28,68] the long chain monounsaturated fatty acids were rare in nature due to their existence in small amounts, especially in monounsaturated fatty acids were rare in nature due to their existence in small amounts, especially microgram quantities [28]. The biosynthesis of the long chain brominated fatty acids in Amphimedon in microgram quantities [28]. The biosynthesis of the long chain brominated fatty acids in terpenensis has previously been explained in past literature. The substituent of bromine was introduced Amphimedon terpenensis has previously been explained in past literature. The substituent of bromine following chain elongation and desaturation of a 16:0 precursor. The formation of 24:2 brominated was introduced following chain elongation and desaturation of a 16:0 precursor. The formation of and 26:2 brominated acids might have been predicted, however, the isolation of a 25:2 brominated 24:2 brominated and 26:2 brominated acids might have been predicted, however, the isolation of a acid suggests that sponges may additionally have the capacity to extend chains, desaturate, and 25:2 brominated acid suggests that sponges may additionally have the capacity to extend chains, desaturate, and functionalize an odd carbon chain length fatty acid. Odd carbon chain fatty acids,

Mar. Drugs 2019, 17, 19 15 of 20 functionalize an odd carbon chain length fatty acid. Odd carbon chain fatty acids, such as 15:0 and 17:0, generally have a branched structure rather than straight chain structure which were usually found in bacteria. Amphimedon terpenensis contains both cyanobacterial and bacterial symbionts and thus an additional consideration is which of the three cell types, sponge, bacteria, or cyanobacteria contains the brominated fatty acids [69]. Terpenes biosynthesis is under investigation as a rearranged diterpenoid diisocyanoadociane and was isolated from the Amphimedon sp. that was collected at the Great Barrier Reef in Australia [60]. Terpenes biosynthesis could be explained by the sponge-associated microorganisms which enable the enzymes to synthesize isoprenoids or alternatively, from the modification in a sponge mediated cell of a symbiont-produced precursor such as isoagelaxanthin [70]. Cyanide incorporation by the Amphimedon sp. was first established by Karuso and Scheuer [71] and demonstrated that these sponges utilize carbon and nitrogen from the cyanide precursor. The role of the symbionts may be incorporated in the biosynthesis of isonitriles as the production of diisocyanoadociane from Amphimedon sp. in high rates is due to the cyanide production by the symbionts utilization in the sponges or, a metabolic process which can proceed without symbionts. An important class of metabolites that were reported from the genus Amphimedon are manzamine alkaloids owing to their fascinating biological activities. Manzamine alkaloids were biogenetically synthesized from the condensation of ircinals A or B from the icrinia sponge [48]. Keramaphidin B, isolated from Amphimedon sp., might be the biogenetic precursor of the ircinals and may be produced by hydrolysis of the N2/C3 bond of the 2, 3-imino form of keramaphidin B. In the continuous search for biogenetic precursors of manzamine alkaloids keramaphidin C and keramamine C might be plausible biogenetic precursors of manzamine C, especially considering that keramaphidin C is an important intermediate in the biogenetic pathway of manzamine C generation. Several Amphimedon metabolites were targets for chemical synthesis such as nakadomarin A, owing to its interesting biological applications including antibacterial, cytotoxic and antimicrobial properties [72]. Synthesis was carried out by using a thioamide based strategy [73]. Marine diterpenoid diisocyanoadociane is another example that was synthesized by using intramolecular Michael reaction due to its potent antimalarial activity [74].

8. Conclusions Marine sponges contain treasures of undiscovered natural metabolites by having a wide spectrum of pharmacological activities. Among the several Amphimedon species discovered, A. viridis, A. compressa, A. complanata, and A. terpenensis are the richest producers of natural products with various pharmaceutically relevant bioactivities. The research on this genus is interesting and has made variable progression over the years. However, in recent years there is increasing interest in studying sponge-associated microorganisms in order to explain this complex relationship and in order to reveal the facts of whether metabolites originate mainly from the sponge or from their associated microorganism(s). One hundred and four natural products from various marine sponges belonging to the genus Amphimedon were reported in literature as well as in the Marinlit databases until 2018. Undescribed species of the sponge represent the highest source of secondary metabolites and thus, the discovery of new species of this sponge indicate that there are still possibilities in isolating new secondary metabolites with predicted strong pharmacological activities. The genus Amphimedon and its associated microorganism(s) showed their potential to produce great diversity of chemical leads from the different chemical classes. Alkaloids showed the highest distribution among the different chemical classes followed by fatty acids and then ceramides and cerebrosoides and finally, the lowest percent were the macrocyclic lactones/lactams, as shown in Figure 26. Among the various types of alkaloids pyridine type alkaloids and manzamine alkaloids were the highest followed by purine alkaloids and finally 3-alkyl pyridine glycosides, as shown in Figure 27. These chemical leads exhibited a huge diversity of bioactivities such as antibacterial, antifungal, and anticancer activities. Mar. Drugs 20192018,, 1716,, 19x FOR PEER REVIEW 1716 of of 2021 Mar. Drugs 2018, 16, x FOR PEER REVIEW 17 of 21

4 11 4 4% 1111% 4% 11% Alkaloids 24% 61% Alkaloidsfatty acids 24% 61% fattyCeramides/cerebrosides acids 23 59 Ceramides/cerebrosides 23 59 Macrocyclic lactone/lactams Macrocyclic lactone/lactams

Figure 26. The distribution of different chemical classes of compounds isolated from the genus FigureFigureAmphimedon 26. TheThe. distribution distribution of differentof different chemical chemical classes classes of compounds of compounds isolatedfrom isolated the genus fromAmphimedon the genus. Amphimedon.

Figure 27. The distribution of different chemical subclasses of the alkaloids compounds isolated from Figurethe genusgenus 27. TheAmphimedon distribution.. of different chemical subclasses of the alkaloids compounds isolated from the genus Amphimedon. AuthorAmphimedon Contributions:and its N.H.S. associated collected microorganisms a complete survey have a broadof all compounds range of pharmacological isolated from the activities genus Authorand,Nocardiopsis; therefore, Contributions: N.H.S. we and must M.A.FN.H.S. carry wrote collected out the manuscript; furthera complete investigations U.R. surveyA. interpreted of all for compounds and the revised genus isolated the and results, theirfrom and associatedthe wrote genus the Nocardiopsis;microorganismsmanuscript; M.A.F., N.H.S. as T.S.and they andM.A.F play M.S.K. wrote an important discussed the manuscript; the role results in U.R. the scientificallyA. discovery interpreted ofand newand contributed revised natural the products.to results, editing and of the wrote paper the manuscript; M.A.F., T.S. and M.S.K. discussed the results scientifically and contributed to editing of the paper AuthorFunding: Contributions: This work wasN.H.S. funded collected by Minia a complete University survey. of all compounds isolated from the genus Nocardiopsis; Funding:N.H.S. and This M.A.F work wrote was funded the manuscript; by Minia U.R.A.University interpreted. and revised the results, and wrote the manuscript; M.A.F.,Acknowledgments: T.S. and M.S.K.We discussedthank Eman the Zekry results (Minai scientifically Univer andsity) contributedfor her helpful to editing discussion.. of the paper. Acknowledgments:We thank Eman Zekry (Minai University) for her helpful discussion.. Funding:Conflicts Thisof Interest: work was The funded authors by declare Minia no University. conflict of interest. ConflictsAcknowledgments: of Interest:We The thank authors Eman declare Zekry no (Minai conflict University) of interest. for her helpful discussion. References Conflicts of Interest: The authors declare no conflict of interest. References 1. Hu, G.-P.; Yuan, J.; Sun, L.; She, Z.-G.; Wu, J.-H.; Lan, X.-J.; Zhu, X.; Lin, Y.-C.; Chen, S.-P. Statistical research 1. Hu,on marine G.-P.; Yuan, natural J.; Sun,products L.; She, based Z.-G.; on Wu, data J.-H.; obtained Lan, betweenX.-J.; Zhu, 1985 X.; Lin, and Y.-C.; 2008. Chen,Mar. Drugs S.-P. Statistical 2011, 9, 514–525. research 2. onBlunt, marine J.W.; natural Copp, productsB.R.; Keyzers, based R.A.; on data Munro, obtained M.H.; between Prinsep, 1985 M.R. and Marine 2008. natural Mar. Drugs products. 2011 ,Nat. 9, 514–525. Prod. Rep . 2. Blunt,2013, 30J.W.;, 237–323. Copp, B.R.; Keyzers, R.A.; Munro, M.H.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2013, 30, 237–323.

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