Secondary Metabolites from the Marine Sponge Genus Phyllospongia

marine drugs

Review Secondary Metabolites from the Marine Sponge Genus Phyllospongia

Huawei Zhang 1,*, Menglian Dong 1, Hong Wang 1 and Phillip Crews 2

1 School of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China; [email protected] (M.D.); [email protected] (H.W.) 2 Department of Chemistry & Biochemistry, University of California-Santa Cruz, Santa Cruz, CA 95064, USA; [email protected] * Correspondence: [email protected]; Tel.: +86-571-8832-0903

Academic Editor: Vassilios Roussis Received: 15 November 2016; Accepted: 29 December 2016; Published: 6 January 2017

Abstract: Phyllospongia, one of the most common marine sponges in tropical and subtropical oceans, has been shown to be a proliﬁc producer of natural products with a broad spectrum of biological activities. This review for the ﬁrst time provides a comprehensive overview of secondary metabolites produced by Phyllospongia spp. over the 37 years from 1980 to 2016.

Keywords: marine sponge; Phyllospongia sp.; secondary metabolites; bioactivity

1. Introduction Marine sponges, as very primitive animals, are widely distributed in the oceans from tropic to polar regions. Growing evidence indicates that these animals are the most prolific source of natural products as pharmaceutical leads [1–3]. Marine sponges possess a large variety of secondary metabolites with diverse chemical structures, such as terpenoids [4], macrolides [5], and sterols [6]. Therefore, it has greatly attracted the attention of natural product chemists and pharmaceutical experts around the world to carry out chemical research for the new drug discovery. Phyllospongia (Porifera, Demospongiae, Dictyoceratida, Thorectidae) is one of the most common marine sponges in tropical and subtropical areas, including the Indian Ocean, the Great Barrier Reef, Papua New Guinea, the South China Sea, the South Pacific, and the Red Sea. Chemical investigation of Phyllospongia spp. has been extensively carried out and has given rise to a great array of bioactive secondary metabolites. In order to better understand and rationally exploit the marine sponge genus Phyllospongia, relevant research references reported between 1980 and 2016 are summarized in this review for the first time.

2. Natural Products from Phyllospongia spp. By 2016, a total of 132 various secondary metabolites (1–132) had been isolated and characterized from the marine sponge genus Phyllospongia, including P. dendyi, P. (syn. Carteriospongia) foliascens, P. lamellosa, P. madagascarensis, P. papyracea, Carteriospongia (syn. Phyllospongia) flabellifera, and other unidentified Phyllospongia spp. (Table1). In terms of their chemical structures, most Phyllospongia sponge-derived natural products are sesterterpenoids, especially scalaranes [7], which are classified as C25 (scalarane), C26 (homoscalarane), and C27 (bishomoscalarane) [8]. Bioassay results indicated that some chemicals have pronounced biological activities and can be used as lead drugs. These secondary metabolites are summarized below according to biological origin.

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Table 1. Phyllospongia sponge‐derived natural products. Table 1. Phyllospongia sponge-derived natural products. Organism Locality Compound References Organismthe Great Barrier Locality Reef furodendin (1), sesterterpenes Compound (2, 3) References[9] Andaman and Phyllospongia dendyi the Great Barrier Reefscalaranes furodendin (4–6), (sesterterpene1), sesterterpenes (7) (2, 3)[[10] 9] Phyllospongia dendyi AndamanNicobar and Islands Nicobar Islands scalaranes (4–6), sesterterpene (7)[10] Palau Islands bromophenols (8–12bromophenols) and diphenyl (8–12 ethers) and (13–22) [11,12] Palau Islands [11,12] foliaspongin (23),diphenyl dehydrofoliaspongin ethers (13–22) (24), the Okinawa phyllofoliasponginfoliaspongin (25), (23 dihydrofurospongin), dehydrofoliaspongin‐2 (26 (24), ), [13,14] the Okinawa phyllofoliasponginfurospongin (25‐1), (27 dihydrofurospongin-2) [13,14] (26), furospongin-1 (27) phylloketal (28), phyllofenone A (29), phyllofenonephylloketal B (30), phyllofolactones (28), phyllofenone A–B ( A31 (–2932),), phyllofenone B (30), phyllofolactones A–B phyllohemiketals A (33) and B (34), acetoxy (31–32), phyllohemiketals A (33) and B (34), phyllofolactone A (35), phyllactones A–G (36–42), the South China Sea acetoxy phyllofolactone A (35), phyllactones [7,15–25] P. (syn. Carteriospongia) the South China Sea phyllofolactonesA–G ( 36C–D–42 ),(43 phyllofolactones–44), phyllofolactone C–D ( 43L (–4544),), [7,15–25] foliascens phyllofenone D–Ephyllofolactone (46–47), phyllofolactone L (45), phyllofenone F–G ( D–E48–49), (46–47), phyllofolactone F–G (48–49), P. (syn. Carteriospongia) carteriofenones A‐K (50–60), analogue (61), foliascens carteriofenones A-K (50–60), analogue (61), phyllofolactonephyllofolactone M (62 M), sterol (62), sterol (63) (63) PapuaPapua New New Guinea Guinea 20,24‐dimethylscalaranes 20,24-dimethylscalaranes (64–70 (64) –70)[[26,27]26,27 ] the Indonesiathe Indonesia Sea Seascalaranes scalaranes (71–7 (571) –75)[[28]28 ] the Souththe South Pacific Pacific 12‐epi‐ 12-phyllofolactoneepi-phyllofolactone B (76 B) (76)[[29]29 ] the Greatthe Great Barrier Barrier Reef Reef scalaranes scalaranes (77–79 (77) –79)[[30,31]30,31 ] unknown furanoterpene (80)[32] unknown furanoterpene (80) [32] thethe Indo-West Indo‐West Pacific Ocean phyllolactones A–E (81–85)[33] P. lamellosa phyllolactonesphyllospongins A–E ( A–E81–85 (86) –90), [33] the Egyptian Red Sea [8] P. lamellosa Pacific Ocean sesterterpenes (76, 91, 92) the Egyptian Red Sea phyllospongins A–E (86–90), sesterterpenes (76, 91, 92) [8] P. madagascarensis Northern Madagascar sesterterpenes (93–95)[34] P. madagascarensis Northern Madagascar sesterterpenes (93–95) [34] HainanHainan Island Island scalaranes scalaranes (96–98 (96) –98)[[35]35 ] 99 104 P. papyracea Papua New Guinea bishomoscalarane sesterterpenes ( – )[36] P. papyracea Papua NewSangihe Guinea Island bishomoscalarane phyllactone sesterterpenes H (105 (99)[–104) [36]37 ] Sangihe Island phyllactone H (105) [37] the South Pacific Ocean flabelliferins A (106) and B (107)[38] C. (syn. P.) flabellifera the South Pacific Ocean flabelliferins A (106) and B (107) [38] C. (syn. P.) flabellifera the Great Barrier Reef sesterterpenoid (108)[39] the Great Barrier Reef sesterterpenoid (108) [39] the Indonesia Sea scalaranes (109–114)[40] the Indonesia Sea scalaranes (109–114) [40] Northern Madagascar homoscalarane sesterterpenes (115–119)[41] Northern Madagascar homoscalaranefatty acids sesterterpenes (120, 123), steroids (115– (121119,)122 , [41] the South China Sea [42,43] Unclassified P. spp. fatty acids (120, 124123–),127 steroids), phylloamide (121, 122 A, (124128)–127), Unclassified P. spp. the South China Sea [42,43] Philippines carteriosulfonicphylloamide A acids (128 A–C) (129–131)[44] Fiji sesterterpene (132)[45] Philippines carteriosulfonic acids A–C (129–131) [44] Fiji sesterterpene (132) [45] 2.1. Phyllospongia dendyi 2.1. Phyllospongia dendyi One new C22 furanoterpene, furodendin (1), was characterized from P. dendyi collected near One new C22 furanoterpene, furodendin (1), was characterized from P. dendyi collected near Cairns on the Great Barrier Reef together with two known C26 tetracyclic sesterterpenes (2, 3) in 1980Cairns [9]. on One the specimenGreat Barrier of ReefP. dendyi togethercollected with two from known the coastsC26 tetracyclic of Andaman sesterterpenes and Nicobar (2, 3) in Islands 1980 [9]. in the One specimen of P. dendyi collected from the coasts of Andaman and Nicobar Islands in the Indian Indian Ocean was found to produce three novel scalaranes (4–6) and a known sesterterpene (7)[10]. Ocean was found to produce three novel scalaranes (4–6) and a known sesterterpene (7) [10]. Fifteen Fifteen brominated compounds, bromophenols (8–12)[11] and diphenyl ethers (13–22)[12], were brominated compounds, bromophenols (8–12) [11] and diphenyl ethers (13–22) [12], were detected detected in P. dendyi grown at Palau Islands (Chart1). To the best of our knowledge, P. dendyi is the in P. dendyi grown at Palau Islands (Chart 1). To the best of our knowledge, P. dendyi is the only onlysponge sponge that thatmetabolizes metabolizes brominated brominated compounds compounds among among the Phyllospongia the Phyllospongia genus.genus. Bioassay Bioassay results results suggestedsuggested that that these these bromides bromides have have a broad a spectrumbroad spectrum of biological of biological activities, activities, including antimacroalgalincluding activityantimacroalgal [11], inhibitory activity effects[11], inhibitory on the assembly effects on of microtubulethe assembly proteins, of microtubule and the proteins, meiotic maturation and the of starfishmeiotic oocytes maturation [12]. of starfish oocytes [12].

2: R=CH2CH(OH)CH3 4: R=OH 1 6 3: R=CH3 5: R=H

Chart 1. Cont.

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7 8 9 10 11

13: R1=H, R2=Me, R3=R4=Br 14: R1=H, R2=Me, R3=H, R4=Br 13: R1=H, R2=Me, R3=R4=Br 15: R1=R2=H, R3=R4=Br 14: R1=H, R2=Me, R3=H, R4=Br 16: R1=R2=Me, R3=H, R4=Br 12 15: R1=R2=H, R3=R4=Br 21 22 17: R1=H, R2=Me, R3=R4=H 16: R1=R2=Me, R3=H, R4=Br 12 18: R1=R2=Me, R3=R4=H 21 22 17: R1=H, R2=Me, R3=R4=H 19: R1=R2=H, R3=Br, R4=H 18: R1=R2=Me, R3=R4=H 20: R1=H, R2=Me, R3=Br, R4=H 19: R1=R2=H, R3=Br, R4=H 20: R1=H, R2=Me, R3=Br, R4=H ChartChart 1.1. Chemical structures structures of of secondary secondary metabolites metabolites (1– (221–)22 from) from P. dendyiP. dendyi. . Chart 1. Chemical structures of secondary metabolites (1–22) from P. dendyi. 2.2. Phyllospongia (syn. Carteriospongia) foliascens 2.2. Phyllospongia (syn. Carteriospongia) foliascens 2.2.Marine Phyllospongia sponge (syn. P. foliascens Carteriospongia) is the most foliascens productive maker of secondary metabolites among all Marine sponge P. foliascens is the most productive maker of secondary metabolites among all known Phyllospongia spp. Chemical investigation indicates that most of these compounds belong to known MarinePhyllospongia spongespp. P. foliascens Chemical is the investigation most productive indicates maker that of secondary most of these metabolites compounds among belong all scalaraneknown Phyllospongia sesterterpenoid. spp. P.Chemical foliascens investigation grows in many indicates marine that areas, most suchof these as Okinawa,compounds the belong South to to scalarane sesterterpenoid. P. foliascens grows in many marine areas, such as Okinawa, the South Chinascalarane Sea, Papua sesterterpenoid. New Guinea, P. Indonesia,foliascens grows the South in many Pacific marine near Vanuatu, areas, such and theas Okinawa, Great Barrier the Reef.South China Sea, Papua New Guinea, Indonesia, the South Pacific near Vanuatu, and the Great Barrier Interestingly,China Sea, Papua the same New speciesGuinea, of Indonesia, marine sponge the South collected Pacific nearfrom Vanuatu, different andareas the possesses Great Barrier various Reef. Reef. Interestingly, the same species of marine sponge collected from different areas possesses various scalaraneInterestingly, sesterterpenoids. the same species of marine sponge collected from different areas possesses various scalaranescalaraneAfter sesterterpenoids. Kikuchisesterterpenoids. et al. firstly reported the isolation of one novel anti‐inflammatory scalarane bishomosesterterpeneAfterAfter Kikuchi Kikuchi et et al.foliaspongin al. firstly firstly reported reported (23) from thethe the isolationisolation Okinawan of one P. novel novelfoliascens anti anti-inflammatory in‐inflammatory 1981 [13], two scalarane scalarane new bishomosesterterpenescalaranebishomosesterterpene‐type bishomosesterterpenes, foliaspongin foliaspongin ((23 23dehydrofoliaspongin)) fromfrom thethe Okinawan (24 )P. P.and foliascens foliascens phyllofoliaspongin inin 1981 1981 [13], [13 ( 25],two), two andnew new scalarane-typetwoscalarane new furanoterpenes,‐type bishomosesterterpenes, bishomosesterterpenes, dihydrofurospongin dehydrofoliaspongin dehydrofoliaspongin‐2 (26) and furospongin (24 (24) and) and‐1 phyllofoliaspongin ( 27phyllofoliaspongin), were also characterized (25 (25),), and and two newfromtwo furanoterpenes, Okinawannew furanoterpenes, P. foliascens dihydrofurospongin-2 dihydrofurospongin (Chart 2). Compound (26‐)2 and (2526 )exhibited furospongin-1and furospongin a broad (27 ‐spectrum1), (27 were), were also of pharmacologicalalso characterized characterized from Okinawaneffects,from OkinawansuchP. foliascens as cytotoxic, P. foliascens(Chart anti2 ‐).(Chartthrombocyte, Compound 2). Compound and25 exhibited vasodilative 25 exhibited a broad activities a broad spectrum [14]. spectrum of pharmacological of pharmacological effects, effects, such as cytotoxic, anti‐thrombocyte, and vasodilative activities [14]. such as cytotoxic, anti-thrombocyte, and vasodilativeO activitiesCHO O [14].

O CHO O

O O OH O OH 26: R=O 23 24 25 2726: R=: R=Oα‐Me, β‐H 23 24 25 Chart 2. Chemical structures of secondary metabolites (2327–27: R=) fromα‐Me, P. β foliascens.‐H Chart 2. Chemical structures of secondary metabolites (23–27) from P. foliascens. Natural productsChart 2. Chemical from the structures marine sponge of secondary P. foliascens metabolites collected (23– 27from) from theP. South foliascens China. Sea are abundant.Natural Since products 1989, up from to 36 compoundsthe marine sponge have been P. foliascensreported. collected In 1991, Fu from and the his Southcoworkers China isolated Sea are andabundant.Natural identified Since products 7 compounds:1989, from up to the 36 phylloketal compounds marine sponge ( 28have) [15], beenP. foliascens phyllofenone reported.collected In 1991,A (29 Fu from) [16],and the hisphyllofenone Southcoworkers China Bisolated (30 Sea), are abundant.phyllofolactonesand identified Since 1989, 7A–B compounds: up(31 to–32 36) compounds[17], phylloketal and phyllohemiketal have (28) been[15], reported.phyllofenone A‐B (33 In–34 1991, )A [18]. (29 Fu ) Among[16], and hisphyllofenone these coworkers secondary B isolated (30 ), andmetabolites,phyllofolactones identiﬁed compound 7 compounds: A–B (2931 –showed32) phylloketal[17], weakand phyllohemiketalantifungal (28)[15], activity phyllofenone A‐ Bagainst (33–34 A)Candida [18]. (29)[ Among 16pseudotropicalis], phyllofenone these secondary, while B (30 ), phyllofolactonescompoundmetabolites, 30 compounddisplayed A–B (31 –cytotoxic2932 )[showed17], activity and weak phyllohemiketal againstantifungal the P388activity A-B murine against (33– 34leukemia )[Candida18]. Among cell pseudotropicalis line thesewith an secondary, whileIC50 metabolites,valuecompound of 5 μg/mL. compound 30 displayed Acetoxy29 phyllofolactonecytotoxicshowed weakactivity antifungalA against(35) [19] the and activity P388 phyllactones murine against leukemia A–ECandida (36– cell40 pseudotropicalis) [20]line were with foundan, IC while 50 and characterized in 1992. Compounds 36 and 37 had moderate in vitro cytotoxicity against KB cells compoundvalue of 305 μdisplayedg/mL. Acetoxy cytotoxic phyllofolactone activity against A (35 the) [19] P388 and murine phyllactones leukemia A–E cell (36– line40) with[20] were an IC found50 value ofwith 5andµg/mL. characterizedthe same Acetoxy IC in50 phyllofolactone 1992.value Compounds of 20 μ Ag/mL. (3635 and)[ 19Interestingly, 37] and had phyllactones moderate phyllactones in vitro A–E cytotoxicity ( 36F–G–40 )[(4120– against]42 were) [21] foundKB and cells and phyllofolactones C–D (43–44) [22] were also detected in the same specimen. Phyllofolactone L (45) characterizedwith the same in 1992. IC Compounds50 value of 3620 μandg/mL.37 had Interestingly, moderate in phyllactones vitro cytotoxicity F–G against(41–42) KB [21] cells and with andphyllofolactones phyllofenone D–EC–D ( 46(43––4744) )belong [22] were to ascalarane also detected sesterterpenoids in the same specimen. [23]. Their Phyllofolactone chemical structures L (45 ) the same IC50 value of 20 µg/mL. Interestingly, phyllactones F–G (41–42)[21] and phyllofolactones were elucidated on the basis of spectroscopic analysis. A biological assay showed that only C–Dand (43 phyllofenone–44)[22] were D–E also (46 detected–47) belong in theto ascalarane same specimen. sesterterpenoids Phyllofolactone [23]. Their L ( 45chemical) and phyllofenone structures

D–Ewere (46– 47elucidated) belong toon ascalarane the basis sesterterpenoidsof spectroscopic [analysis.23]. Their A chemical biological structures assay showed were elucidated that only on

Mar. Drugs 2017, 15, 12 4 of 10 theMar. basis Drugs of spectroscopic2017, 15, 12 analysis. A biological assay showed that only compound 47 had moderate4 of 10 cytotoxic activity against the leukemia cell line P388, with an IC50 value of 6.5 µg/mL. Two new compound 47 had moderate cytotoxic activity against the leukemia cell line P388, with an IC50 value sesquiterpenes, phyllofolactone F (48) and phyllofolactone G (49), together with phyllofenone D (46) of 6.5 μg/mL. Two new sesquiterpenes, phyllofolactone F (48) and phyllofolactone G (49), together with and phyllofenone E (47), were isolated and identiﬁed by chromatographic methods and modern phyllofenone D (46) and phyllofenone E (47), were isolated and identified by chromatographic methods analytical methods [7]. Carteriofenones A–C (50–52) were 20,24-bishomo-25-norscalaranes and and modern analytical methods [7]. Carteriofenones A–C (50–52) were 20,24‐bishomo‐25‐norscalaranes carteriofenonesand carteriofenones D–K ( 53D–K–60 (53) and–60) oneand one analogue analogue (61 ()61 belong) belong to to 20,24-bishomoscalaranes 20,24‐bishomoscalaranes [24]. [24 ].Moreover, Moreover, phyllofolactonephyllofolactone M M (62 (62) and) and a a new new sterol, sterol, (24 (24EE)-5)‐5αα,6,6α-epoxystigmasta-7,24(28)-dien-3‐epoxystigmasta‐7,24(28)‐dien‐3β‐olβ-ol (63 (63), together), together withwith a known a known sesterterpene, sesterterpene, phyllofolactone phyllofolactone B B ( (3232),), werewere detected in in the the same same sample sample collected collected from from thethe South South China China Sea Sea [25 [25]] (Chart (Chart3). 3).

O OH O

28 29 30 31 32 OH O O O O OH 26

36: R=H, 26‐α‐Me 39: 26‐α‐Me 33 34 35 37: R=H, 26‐β‐Me 40: 26‐β‐Me 38: R=Ac, 26‐β‐Me

41: 26‐αMe 43 44 45 46 42: 26‐βMe

48: 26‐αMe 47 50 51 52 49: 26‐βMe

54: 25‐α‐OH 56: 25‐α‐OH 53 58 59 55: 25‐β‐OH 57: 25‐β‐OH O OH O

60 61 62 63

ChartChart 3. 3.Chemical Chemical structures structures of of secondary secondary metabolites ( (2828––6363) )from from P.P. foliascens. foliascens .

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Mar. Drugs 2017, 15, 12 5 of 10 Seven 20,24-dimethylscalarane derivatives (64–70) were characterized from P. (syn. Carteriospongia) foliascensSevengathered 20,24‐dimethylscalarane from Papua New derivatives Guinea. ( Compounds64–70) were characterized64 and 70 fromwere P. C-14 (syn. anomersCarteriospongia [26,27) ]. foliascens gathered from Papua New Guinea. Compounds 64 and 70 were C‐14 anomers [26,27]. Chemical investigation of P. (syn. C.) foliascens collected from the Indonesian sea afforded ﬁve Chemical investigation of P. (syn. C.) foliascens collected from the Indonesian sea afforded five scalarane sesterterpenoids (71–75), which possessed Ras Converting Endoprotease (RCE) inhibitory scalarane sesterterpenoids (71–75), which possessed Ras Converting Endoprotease (RCE) inhibitory effect except 72 [28]. Specimens of P. (syn. C.) foliascens from the South Paciﬁc could metabolite effect except 72 [28]. Specimens of P. (syn. C.) foliascens from the South Pacific could metabolite 12‐ 12-epiepi-phyllofolactone‐phyllofolactone B B ( (7676) )[[29],29], while while the the sample sample collected collected from from the the Great Great Barrier Barrier Reef Reef produced produced scalaranescalarane sesterterpenoids sesterterpenoids (77 (–7779–)[7930) [30,31].,31]. Additionally, Additionally, one one furanoterpene furanoterpene (80 ()80 was) was also also isolated isolated from thefrom marine the sponge marine P.sponge(syn. P.C. (syn.) foliascens C.) foliascens[32] (Chart [32] (Chart4). 4).

64 65 66 67 68

73: 26‐α‐Me 69 70 71 72 74: 26‐β‐Me

75 76 77 78 79

ChartChart 4. Chemical 4. Chemical structures structures of of secondary secondary metabolites metabolites ( 64––8080)) from from P.P. (syn.(syn. CarteriospongiaCarteriospongia) foliascens) foliascens. .

2.3. Phyllospongia lamellosa 2.3. Phyllospongia lamellosa Until now, there have only been two reports on the chemical study of the marine sponge P.Until lamellosa now, therein the have database only been Web two of reports Sciences on the[33]. chemical Five 20,24 study‐bishomoscalane of the marine spongesesterterpenes,P. lamellosa in thephyllolactones database Web A–E of (81 Sciences–85), were [33 ].characterized Five 20,24-bishomoscalane from P. lamellosa sesterterpenes,collected in the phyllolactonesIndo‐West Pacific A–E (81–Ocean.85), were Bioassay characterized results indicated from P. lamellosathat thesecollected secondary in metabolites the Indo-West possessed Pacific an Ocean. inhibitory Bioassay effect results on indicatedhuman that immunodeficiency these secondary virus metabolites type 1 (HIV possessed‐1) envelope an inhibitory‐mediated effect fusion on in human vitro with immunodeficiency IC50 values of virusabout type 2 μ 1 (HIV-1)M [34]. From envelope-mediated the same marine fusion spongein vitro derivedwith from IC50 thevalues Egyptian of about Red 2 Sea,µM[ five34]. new From thescalarane same marine sesterterpenes, sponge derived phyllospongins from the A–E Egyptian (86–90), Red were Sea, detected five new together scalarane with sesterterpenes,four known phyllosponginsderivatives (76 A–E, 91 (,86 92– 90and), were99) [8] detected (Chart 5). together Compounds with four 87–91 known had potent derivatives cytotoxic (76 ,activity91, 92 and against99)[ 8] (ChartHCT5).‐116 Compounds as the positive87 –control91 had doxorubicin, potent cytotoxic while activity90 showed against cytotoxic HCT-116 activity as against the positive MCF‐7. control doxorubicin, while 90 showed cytotoxic activity against MCF-7.

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R1 R2 R3 2 2 3 81: OCOCHR1 CH CH R2OH R3H

8182: OCOCH: OCOCH2CH2CH2CH3 3 OHOH HH 86: R1=CH3, R2=α‐OAc 89: β‐OH R1 R2 R3 88 8283: OCOCH: OCOCH2CH3 3 OHOH HH 8687: R: 1R=CH1=CH3, 2RCH2=α3‐, OAcR2=α ‐OAc 8990: β: ‐αOH‐OH 81: OCOCH2CH2CH3 OH H 88 8384: OCOCH: OCOCH3 2CH3 OHOAc HH 87: R1=CH2CH3, R2=α‐OAc 90: α‐OH 82: OCOCH2CH3 OH H 86: R1=CH3, R2=α‐OAc 89: β‐OH 8485: OCOCH: H 2CH3 OAcOH HH 88 83: OCOCH3 OH H 87: R1=CH2CH3, R2=α‐OAc 90: α‐OH 85: H OH H 84: OCOCH2CH3 OAc H 85: H OH H

91 92

91 92 ChartChart 5. Chemical5. Chemical structures structures of of secondary secondary metabolites metabolites ( 81–9292)) from from P.P. lamellosa lamellosa. . Chart 5. Chemical91 structures of secondary metabolites (81–92) from 92P. lamellosa. 2.4. Phyllospongia madagascarensis 2.4. PhyllospongiaChart madagascarensis 5. Chemical structures of secondary metabolites (81–92) from P. lamellosa. 2.4. Phyllospongia madagascarensis To the best of our knowledge, only three natural products (93–95) (Chart 6) have been found in 2.4.theTo Phyllospongia Tomarine the the best best sponge of of our madagascarensis our P. knowledge, madagascarensisknowledge, only only, which threethree was natural grown products products near the (93 ( 93northwest–95–95) (Chart) (Chart coast 6)6 have) of have Madagascar been been found found [35]. in in P. madagascarensis thethe marineInterestingly, marineTo the sponge sponge best the of chemicalP.our madagascarensis knowledge, structure only,, which whichof 94three possesses was natural grown seven products near near‐membered the the ( 93northwest northwest–95) oxacycle.(Chart coast coast 6) ofhave ofMadagascar Madagascarbeen found [35]. in [ 35 ]. Interestingly,Interestingly,the marine thesponge the chemical chemical P. madagascarensis structure structure of of, which94 94possesses possesses was grown seven seven-membered near‐membered the northwest oxacycle. oxacycle. coast of Madagascar [35]. Interestingly, the chemical structure of 94 possesses seven‐membered oxacycle.

93 94 95 93 94 95 Chart 6. Chemical structures of secondary metabolites (93–95) from P. madagascarensis . 93 94 95 ChartChart 6. 6.Chemical Chemical structures structures of secondary metabolites metabolites (93 (93–95–95) from) from P. P.madagascarensis madagascarensis. . 2.5. PhyllospongiaChart 6. papyracea Chemical structures of secondary metabolites (93–95) from P. madagascarensis. 2.5. Phyllospongia papyracea 2.5. PhyllospongiaTen small papyracea molecules (96–105) (Chart 7) were isolated from P. papyracea collected on Hainan 2.5.Island PhyllospongiaTen in small the South molecules papyracea China ( Sea,96–105 Papua) (Chart New 7) Guinea, were isolatedand Sangihe from Island P. papyracea in the Indonesian collected on Sea Hainan [36–38]. Ten small molecules (96–105) (Chart7) were isolated from P. papyracea collected on Hainan IslandCytotoxicTen in thesmall tests South moleculessuggested China Sea, that(96 –Papua compound105) (Chart New 96Guinea, 7) had were an and inisolated vitro Sangihe cytotoxic from Island P. effectpapyracea in the on Indonesian the collected leukemia Sea on cancer [36–38].Hainan cell Island in the South China Sea, Papua New Guinea, and Sangihe Island in the Indonesian Sea [36–38]. CytotoxicIslandline P388 in the tests with South suggested an China IC50 that Sea,value compound Papua of 5 μNewg/mL, 96 Guinea, had and an inand99 vitro– 104Sangihe cytotoxic were Island inactive effect in the onagainst theIndonesian leukemia the β ‐Seacatenin cancer [36–38]. celland Cytotoxic tests suggested that compound 96 had an in vitro cytotoxic effect on the leukemia cancer lineCytotoxictranscription P388 testswith factor suggestedan IC 450 (Tcf4) value that complex.compound of 5 μ g/mL,Phyllactone 96 had and an 99 inH– vitro104(105 ) werecytotoxic was foundinactive effect in against theon the marine leukemiathe spongeβ‐catenin cancer derived and cell cell line P388 with an IC value of 5 µg/mL, and 99–104 were inactive against the β-catenin and transcriptionlinefrom P388 Sangihe with factor Islandan 4IC (Tcf4)and5050 value possessed complex. of 5 μ Phyllactoneing/mL, vitro moderateand H99 (–105104 cytotoxicities) waswere found inactive inagainst theagainst marine cell linesthe sponge β A549,‐catenin derived MCF and‐7, transcriptionfromtranscriptionand SangiheHeLa with factor factorIsland IC 450 4 (Tcf4) valuesand (Tcf4) possessed complex. ofcomplex. no more in PhyllactonePhyllactone vitrothan moderate25 μM. H H ( (105 105cytotoxicities) )was was found found against in in the the cellmarine marine lines sponge A549, sponge MCFderived derived‐7, fromandfrom Sangihe HeLa Sangihe with Island Island IC50 andvalues and possessed possessed of no morein in than vitro vitro 25 moderate μM. cytotoxicities cytotoxicities against against cell cell lines lines A549, A549, MCF MCF-7,‐7, andand HeLa HeLa with with IC IC50 50values values of of no no more more thanthan 25 μµM.

97: R1=OH, R2=Me 99: β‐OH 96 101 102 9798: R: 1R=OH,1=Me, R R2=Me2=OH 99100: β‐:OH α‐OH 96 101 102 98: R1=Me, R2=OH 100: α‐OH 97: R1=OH, R2=Me 99: β‐OH 96 101 102 98: R1=Me, R2=OH 100: α‐OH

Chart 7. Cont.

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Mar. Drugs 2017, 15, 12 7 of 10

103 104 105

103 104 105 ChartChart 7. 7.Chemical Chemical structuresstructures of secondary metabolites metabolites (96 (96–105–105) from) from P. P.papyracea papyracea. .

Chart 1037. Chemical structures of secondary metabolites104 (96–105) from P. papyracea105. 2.6. Carteriospongia (syn. Phyllospongia) flabellifera 2.6. CarteriospongiaChart (syn. 7. Phyllospongia)Chemical structures flabellifera of secondary metabolites (96–105) from P. papyracea. 2.6. CarteriospongiaThe marine sponge (syn. Phyllospongia) C. (syn. P.) flabellifera is usually distributed in a wide corridor of the The marine sponge C. (syn. P.) flabellifera is usually distributed in a wide corridor of the Indo2.6.‐ThePacific Carteriospongia marine Ocean. sponge A ( syn.chemical C. Phyllospongia) (syn. study P.) offlabellifera theflabellifera marine is usuallysponge collecteddistributed in thein Southa wide Pacific corridor Ocean of ledthe Indo-Pacific Ocean. A chemical study of the marine sponge collected in the South Pacific Ocean led to toIndo the‐Pacific isolation Ocean. of two A chemicalnew small study molecules, of the marineflabelliferins sponge A collected (106) and in B the (107 South) [39]. Pacific Compound Ocean 106led The marine sponge C. (syn. P.) flabellifera is usually distributed in a wide corridor of the thehadto isolation the a rareisolation of25‐ twohomocheilanthane of newtwo smallnew small molecules, carbon molecules, skeleton, flabelliferins flabelliferins and 107 A (106 exhibitedA ()106 and) and B inhibitory (107 B ()[10739) ]. [39].effect Compound Compound on the human106 106had a Indo‐Pacific Ocean. A chemical study of the marine sponge collected in the South Pacific Ocean led rarecolonhad 25-homocheilanthane a raretumor 25 ‐cellhomocheilanthane lines KM12 carbon and carbon skeleton, COLO205. skeleton, and A107 andnewexhibited 107 sesterterpenoid exhibited inhibitory inhibitory derivative effect effect on ( the108on )the human was human also colon to the isolation of two new small molecules, flabelliferins A (106) and B (107) [39]. Compound 106 tumorcharacterizedcolon cell tumor lines fromcell KM12 lines C. and flabellifera KM12 COLO205. andcollected COLO205. A new around sesterterpenoid A the new Great sesterterpenoid Barrier derivative Reef [40] derivative (108 (Chart) was 8). also( 108) characterized was also had a rare 25‐homocheilanthane carbon skeleton, and 107 exhibited inhibitory effect on the human fromcharacterizedC. flabellifera fromcollected C. flabellifera around collected the Great around Barrier the ReefGreat [ 40Barrier] (Chart Reef8). [40] (Chart 8). colon tumor cell lines KM12 and COLO205. A new sesterterpenoid derivative (108) was also characterized from C. flabellifera collected around the Great Barrier Reef [40] (Chart 8).

106 107 108

Chart 8. Chemical structures106 of secondary metabolites107 (106–108) from C. (syn. Phyllospongia108 ) flabellifera.

ChartChart 8. 8.Chemical Chemical structures structures106 of of secondary secondary metabolites 107(106 (106–108–108) from) from C.C. (syn.(syn. Phyllospongia108Phyllospongia) flabellifera) flabellifera. . 2.7. Other Phyllospongia spp. 2.7. OtherChart Phyllospongia 8. Chemical structuresspp. of secondary metabolites (106–108) from C. (syn. Phyllospongia) flabellifera. 2.7. OtherUp Phyllospongiato 24 secondaryspp. metabolites (109–132) (Chart 9) were isolated and identified from other unclassified2.7.Up Other to 24 PhyllospongiaPhyllospongia secondary spp.metabolitesspp. Compounds (109– 132109) –(Chart114 from 9) anwere Indonesian isolated andmarine identified sponge from displayed other 30%–95%unclassifiedUp to 24inhibition Phyllospongia secondary of the metabolites spp.growth Compounds of KB (109 cells–132 109 at) 10– (Chart114 μg/mL from9) [41]. werean Indonesian Compounds isolated marine and 115 identified–119 sponge were displayedproduced from other Up to 24 secondary metabolites (109–132) (Chart 9) were isolated and identified from other unclassifiedby30%–95% the Phyllospongia inhibitionPhyllospongia of sp. the spp. collectedgrowth Compounds of from KB cells Northern109 at 10–114 μ g/mLMadagascar.from [41]. an Compounds Indonesian Compounds marine115 –119115 , spongewere 116, producedand displayed 119 unclassified Phyllospongia spp. Compounds 109–114 from an Indonesian marine sponge displayed 30%–95%possessedby the inhibitionPhyllospongia strong in of vitro thesp. growthcytotoxiccollected of activities KBfrom cells Northern against at 10 µ g/mLhumanMadagascar. [ 41ovarian]. Compounds Compounds cancer cell115 line 115–119 A2780, 116were, withand produced IC11950 30%–95% inhibition of the growth of KB cells at 10 μg/mL [41]. Compounds 115–119 were produced byvaluespossessed the Phyllospongia of 0.26, strong 0.28, insp. andvitro collected 0.65 cytotoxic μM, from respectively, activities Northern against while Madagascar. human 117 and ovarian Compounds 118 had cancer moderate115 cell, 116line activities, A2780 and 119 withpossessed ICIC5050 by the Phyllospongia sp. collected from Northern Madagascar. Compounds 115, 116, and 119 strongvaluesin of vitro 0.26,4.5 cytotoxicand 0.28, 8.7 and μ activitiesM, 0.65 respectively. μM, against respectively, Compound human while ovarian 116 117 exhibited and cancer 118 had cella strong linemoderate A2780inhibitory activities with effect IC with50 onvalues ICthe50 of possessed strong in vitro cytotoxic activities against human ovarian cancer cell line A2780 with IC50 0.26,humanvalues 0.28, oflung and 4.5 non 0.65and‐small 8.7µM, μ cellM, respectively, linerespectively. H522‐T1 while withCompound 117an ICand50 value116118 exhibited ofhad 0.61 moderate μ Ma strong [42]. Compounds activities inhibitory with effect120– IC127 on50 [43]valuesthe values of 0.26, 0.28, and 0.65 μM, respectively, while 117 and 118 had moderate activities with IC50 ofandhuman 4.5 andphylloamide lung 8.7 µnonM,‐ small respectively.A (128 cell) [44] line were H522 Compound also‐T1 isolatedwith 116an ICfromexhibited50 value the South of a 0.61 strong China μM [42]. inhibitory Sea Compoundssponge. effect Carteriosulfonic 120 on– the127 human[43] acidsvalues A–C of ( 1294.5 –and131) 8.7[45] μ M,and respectively. 132 [46] were Compound respectively 116 isolated exhibited from a strong two specimens inhibitory collected effect on at the lungand non-small phylloamide cell A line (128 H522-T1) [44] were with also an isolated IC50 value from ofthe 0.61 SouthµM[ China42]. Sea Compounds sponge. Carteriosulfonic120–127 [43] and human lung non‐small cell line H522‐T1 with an IC50 value of 0.61 μM [42]. Compounds 120–127 [43] Philippinesacids A–C (and129– Fiji.131) Bioassay[45] and results132 [46] suggested were respectively that 128–130 isolated had an from inhibitory two specimenseffect on the collected growth ofat phylloamideand phylloamide A (128)[ A44 (]128 were) [44] also were isolated also isolated from the from South the ChinaSouth China Sea sponge. Sea sponge. Carteriosulfonic Carteriosulfonic acids glycogenPhilippines synthase and Fiji. kinase Bioassay‐3β (GSK results‐3β ),suggested with IC50 valuesthat 128 of– 13012.5, had 6.8, an and inhibitory 6.8 μM, respectively.effect on the growth of A–Cacids (129– 131A–C)[ (45129] and–131132) [45][46 and] were 132 respectively [46] were respectively isolated from isolated two specimens from two collectedspecimens at collected Philippines at glycogen synthase kinase‐3β (GSK‐3β), with IC50 values of 12.5, 6.8, and 6.8 μM, respectively. and Fiji.Philippines Bioassay and results Fiji. Bioassay suggested results that suggested128–130 had that an128 inhibitory–130 had an effect inhibitory on the effect growth on the of growth glycogen of synthaseglycogen kinase-3 synthaseβ (GSK-3 kinaseβ),‐3 withβ (GSK IC‐350β),values with IC of50 12.5,values 6.8, of 12.5, and 6.86.8, µandM, 6.8 respectively. μM, respectively.

R1 R2 R3 115: 12‐α‐ OH, 18‐

110: H α‐OH H 113: R=H α‐CHO 109 R1 R2 R3 115: 12‐α‐OH, 18‐ 117: 12‐β‐OH 111: Me α‐OH H 114: R=OH 116: 12‐β‐OH, 18‐ 110 : H α‐OH H 113: R=H α‐CHO 109 112: H α‐OMe α‐OMe β‐CHO 117: 12‐β‐OH 111 : MeR 1 α‐OHR2 H R3 114: R=OH 116115: 12:‐ 12β‐OH,‐α‐OH, 18‐ 18‐ 112110: H: H α‐OMe α‐OH α‐ OMeH 113: R=H β‐CHOα‐CHO 109 117: 12‐β‐OH 111: Me α‐OH H 114: R=OH 116: 12‐β‐OH, 18‐ 112: H α‐OMe α‐OMe β‐CHO

Chart 9. Cont.

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118 119 120 121

122 123 124 125

126 127 128

129 130

131 132

ChartChart 9. 9.Chemical Chemical structures structures of of secondary secondary metabolites ( (109109––132132) )from from other other PhyllospongiaPhyllospongia spp.spp.

3. Conclusions 3. Conclusions Natural products from the marine sponge genus Phyllospongia have been well studied over the lastNatural 37 years. products Their frameworks from the marine are diverse, sponge including genus Phyllospongia terpenoid, macrolide,have been sterol, well and studied ceramide. over the lastMoreover, 37 years. the Their most frameworks common structure are diverse, is sesterterpenoid, including terpenoid, which has macrolide, diverse biological sterol, and activities. ceramide. Moreover,With the the increasing most common development structure of is oceanographic sesterterpenoid, technology which has leading diverse to biological the isolation activities. of new With thePhyllospongia increasing development species from ofmarine oceanographic environments, technology more secondary leading to metabolites the isolation with of newnovelPhyllospongia chemical speciesstructure(s) from marineand/or potent environments, bioactivities more will secondarybe found in metabolites the near future. with novel chemical structure(s) and/orAcknowledgments: potent bioactivities This project will was be found financially in the supported near future. by the Zhejiang Natural Science Foundation of China (LY16H300007). Acknowledgments: This project was financially supported by the Zhejiang Natural Science Foundation of China (LY16H300007).Author Contributions: H.Z. conceived and wrote the review; M.D. searched and collected the references; H.W. Authormade Contributions: an effective analysisH.Z. of conceived the document; and wrote P.C. offered the review; important M.D. advice searched to improve and collected the review. the references; H.W. made an effective analysis of the document; P.C. offered important advice to improve the review. Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest. References References 1. Keyzers, R.A.; Davies‐Coleman, M.T. Anti‐inflammatory metabolites from marine sponges. Chem. Soc. Rev. 1. Keyzers,2005, 34 R.A.;, 355–365. Davies-Coleman, M.T. Anti-inflammatory metabolites from marine sponges. Chem. Soc. Rev. 2. 2005Xu,, 34 W.H.;, 355–365. Ding, [ CrossRefY.; Jacob,][ M.R.;PubMed Agarwal,] A.K.; Clark, A.M.; Ferreira, D.; Liang, Z.; Li, X. Puupehanol, 2. Xu,a W.H.;sesquiterpene Ding, Y.;‐dihydroquinone Jacob, M.R.; Agarwal, derivative A.K.; from Clark,the marine A.M.; sponge Ferreira, Hyrtios D.; Liang,sp. Bioorg. Z.; Li,Med. X. Chem. Puupehanol, Lett. a sesquiterpene-dihydroquinone2009, 19, 6140–6143. derivative from the marine sponge Hyrtios sp. Bioorg. Med. Chem. Lett. 2009, 19, 6140–6143. [CrossRef][PubMed]

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