Bioactive Nitrogenous Secondary Metabolites from the Marine Sponge Genus Haliclona

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Review Bioactive Nitrogenous Secondary Metabolites from the Marine Sponge Genus Haliclona

Jiaying Zhu, Yang Liu, Zijun Liu, Hao Wang and Huawei Zhang * School of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China; [email protected] (J.Z.); [email protected] (Y.L.); [email protected] (Z.L.); [email protected] (H.W.) * Correspondence: [email protected]; Tel.: +86-571-8832-0613

Received: 12 November 2019; Accepted: 2 December 2019; Published: 3 December 2019

Abstract: Marine sponge genus Haliclona, one of the most prolific sources of natural products, contains over 600 species but only a small part of them had been classified and chemically investigated. On the basis of extensive literature search, this review firstly summarizes 112 nitrogenous secondary metabolites from classified and unclassified Haliclona sponges as well as from their symbiotic microorganisms. Most of these substances have only been found in Haliclona sponges, and display diverse bioactive properties with potential applications in new drug discovery.

Keywords: marine sponge; Haliclona; symbiotic microbe; secondary metabolite; alkaloid; bioactivity

1. Introduction The marine environment is the largest treasure trove of creatures, including plants, animals and microorganisms. People never stop conducting chemical studies of marine organisms owing to their potential capability to produce bioactive secondary metabolites that are potential sources of leads for new drug development. So far over 34,000 articles about marine-derived natural products research have been published [1]. Marine sponges, which are immemorial organisms, are widely distributed around the world and comprise over ten thousand species, most of which them live in the sea, while only one percent are freshwater sponges [2]. These creatures are a great source of natural products with a broad spectrum of biological properties. Numerous sponge-derived chemicals, especial alkaloid compounds, display pharmacological effects, such as didemnin B, cytarabine, trabectedin, vidarabine, etc. The marine sponge genus Haliclona belongs to the family Chalinidae, order Haplosclerida, class Demospongiae [3]. Its skeleton is made up of grids of single spines or a network of spongy fibrous branches without an epidermal skeleton [2]. The Haliclona genus consists of over 600 species distributed throughout the world [3]. However, only a few dozen specimens collected from the Pacific Ocean [4], north Indian Ocean [5], Atlantic Ocean [6], and Mediterranean Sea [7] have been chemically investigated. These studies suggest that Haliclona sponges are some of the most prolific producers of bioactive secondary metabolites. On the basis of a extensive literature search using SciFinder, this review firstly summarizes all nitrogenous substances from the marine sponge genus Haliclona and its symbiotic microbes.

2. Bioactive Alkaloids from Haliclona Genus As many as 103 alkaloid secondary metabolites have been isolated and characterized from Haliclona sponges since 1994. However, only 32 of them (compounds 1–32) were from seven classiﬁed Haliclona species including H. baeri, H. cymaeformis, H. densaspicula, H. exigua, H. koremella, H. nigra and H. tulearensis, and are respectively introduced in detail according to their biological sources. Other alkaloids (compounds 33–103) from unclassiﬁed Haliclona sponges are grouped into

Mar. Drugs 2019, 17, 682; doi:10.3390/md17120682 www.mdpi.com/journal/marinedrugs Mar.Mar. Drugs Drugs 2019 2019, ,17 17, ,x x FOR FOR PEER PEER REVIEW REVIEW 22 ofof 1313

HaliclonaMar.Haliclona Drugs 2019 speciesspecies, 17, 682 includingincluding H.H. baeri,baeri, H.H. cymaeformis,cymaeformis, H.H. densaspicula,densaspicula, H.H. exigua,exigua, H.H. koremelkoremella,la, H.H. 2 nigranigra of 13 andand H.H. tulearensis tulearensis,, andand are are respectivelyrespectively introduced introduced in in detail detail according according to to their their biological biological sources sources.. OtherOther alkaloids alkaloids ( (compoundscompounds 3 333--101033)) from from unclassified unclassified Haliclona Haliclona sponge spongess are are grouped grouped into into three three types types three types on basis of their chemical structures, namely 3-alkylpyridine, amide and depsipeptide, onon basis basis of of their their chemical chemical structures, structures, namelynamely 33--alkylpyridine,alkylpyridine, amide amide and and depsipeptide, depsipeptide, andand and miscellaneous alkaloids. miscellaneousmiscellaneous alkaloidalkaloidss.. 2.1. Haliclona Baeri 2.1.2.1. HaliclonaHaliclona BaeriBaeri There is only one report on a chemical study of Haliclona baeri collected from the coast of Jongbrii ThereThere is is only only one one report report on on a a chemical chemical study study of of Haliclona Haliclona baeri baeri collected collected from from the the coast coast of of Jongbrii Jongbrii Province (Thailand) [8]. One new nitrogenated compound maleimide-5-oxime (1) along with one ProvinceProvince (Thailand) (Thailand) [8]. [8]. OneOne newnew nitrogenatednitrogenated compound compound mamaleimideleimide--55--oximeoxime ( (11)) alongalong with with oneone benzoic derivative and two tetillapyrones was separated from this sponge (Figure1). The follow-up benzoicbenzoic derivativederivative andand twotwo tetillapyronestetillapyrones waswas separatedseparated fromfrom thisthis spongesponge ((FigureFigure 11)).. TheThe followfollow--upup bioassay tests suggested that compound 1 had weak cytotoxic activity against the human DAOY bbioassayioassay testtestss suggestsuggesteded thatthat compoundcompound 11 hadhad weakweak cytotoxic cytotoxic activityactivity againstagainst the the humanhuman DAOY DAOY medulloblastoma cell line at 50 µg/mL [9]. medulloblastomamedulloblastoma cellcell lineline atat 5050 μμg/mLg/mL [9][9]..

11 FigureFigureFigure 1. 1 1.Chemical .Chemical Chemical structure structure structure of of of compound compound compound1 1from1 from fromHaliclona Haliclona Haliclona baeri baeri baeri.

2.2.2.2. Haliclona Haliclona CymaeformisCymaeformis FractionationFractionation of of the the ethanol ethanol extract extract of of HaliclonaHaliclona cymaeformis cymaeformis collectedcollected from from a a XuwenXuwen coral coral reefreef (Guangdong,(Guangdong(Guangdong,, China) China) using using silica silica gel gel column column chromatographychromatography led ledled to toto isolationisolation of of of eleveneleven alkaloid alkaloids,alkaloids,s, includingincluding oneone indoleindole alkaloidalkaloid 2 2,,, sixsix nucleosidesnucleosidenucleosidess 3 3––88 and and four four sterols sterols (Figure(Figure2 2) )[2) [10]. [10].10]. SubsequentlySubsequently two two pairspairs ofof 6-oxypurine66--oxypurineoxypurine regioisomersregioisomers substitutedsubstituted atat thethe 77 oror 99 positionposition (compounds(compounds 99––1212)) werewere puriﬁedpurifiedpurified fromfrom thethe samesame specimensspecimenpecimen (Figure(Figure2 2))[2) 11[11].[11].].

22 33 R R = = H H 55 R R = = H H 77 R R = = H H 4 R = CH3 6 R = CH3 8 R = CH3 4 R = CH3 6 R = CH3 8 R = CH3

99 1010 1111 1212 Figure 2. Chemical structures of compounds 2–12 from Haliclona cymaeformis. FigureFigure 2.2. Chemical structures of compounds 22––1212from fromHaliclona Haliclona cymaeformiscymaeformis..

2.3.2.3. Haliclona Haliclona DensaspiculaDensaspicula TwoTwo novel novelnovel alkaloidsalkaloids withwith with sixsix six hexacyclichexacyclic hexacyclic diamines,diamines, diamines, densaninsdensanins densanins AA ((13 A13)) ( and13and) andBB ((1414 B)) (Figure(Figure (14) (Figure 3)3),, werewere3), werefoundfound found in in methanol methanol in methanol extract extract extract ofof the the of sponge sponge the sponge HaliclonaHaliclonaHaliclona densaspicula densaspicula densaspicula from from fromKeomun Keomun Keomun Island Island Island (Korea) (Korea) (Korea) and and their their and absolutetheirabsolute absolute chemical chemical chemical structures structures structures were were were determined determined determined by by by 1D 1D 1D and and and 2D 2D 2D NMR NMR NMR spectral spectral spectral analysis analysis analysis and and Mosher Mosher Mosher reactionreactions.reactionss.. Bio BiologicalBiologicallogical evaluation evaluationevaluation indicatedindicated that that compounds compounds 1313 and and 14 14 possess possess potent potent inhibitory inhibitory effects eeffectsﬀects on lipopolysaccharide-induced nitric oxide production in BV2 microglial cells with IC50 values of 1.05 onon lipopolysaccharide-inducedlipopolysaccharide-induced nitric nitric oxide oxide production production in in BV2 BV2 microglial microglial cells cells with with IC IC5050values values ofof 1.051.05 and 2.14 μM, respectively [4,12]. Mar.andand Drugs 2.142.14 µ2019μM,M,, respectively17respectively, x FOR PEER [ [4,12].4REVIEW,12]. 3 of 13

13 14 densaspicula. FigureFigure 3 3.. ChemicalChemical structures structures of of compounds compounds 1313––14 from Haliclona densaspicula.

2.4. Haliclona Exigua Chemical study of the sponge specimen Haliclona exigua collected from the coastal areas of India and Indonesia afforded nine alkaloid derivatives, including xestospongin D (15), araguspongins C-E (16–18), 3α-methylaraguspongine C (19), neopetrocyclamines A (20) and B (21), papuamine (22) and haliclonadiamine (23) (Figure 4) [5,13–17]. Compound 16 was the most common alkaloid from H. exigua and shown to have strong inhibitory activity against human lymphatic filarial parasite B, promastigote and intracellular amastigote forms of Leishmania donovani, and anti-fouling and competitive inhibition of NOS [5,15–17]. This compound was later purified from an Indonesian sponge Neopetrosia chaliniformis and could inhibit zebrafish embryos with a LD50 value of 4.3 μg/mL [18]. Compound 22 possessed remarkable cytotoxicity toward human glioblastoma cell line SF-295 with a GI50 value of 0.8 μM and 23 could control the transfer of MDA-MB-231 breast cancer cells [14]. Additionally, these alkaloids 22 and 23 obtained from an Okinawan sponge H. panicea and were found to inhibit the growth of Mycobacterium bovis BCG, M. intracellulare and M. smegmatis [19,20].

15 16

17 18 19 20

21 22 23 Figure 4. Chemical structures of compounds 15–23 from Haliclona exigua.

2.5. Haliclona Nigra Fractionation of the aqueous extract of the marine sponge Haliclona nigra collected from northern coast of Papua New Guinea resulted in the discovery of two new hexapeptides, haligramides A (24) and B (25), together with waiakeamide (26) (Figure 5) [21]. Their chemical structures and configurations were elucidated by extensive NMR analyses and oxidative reactions.

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Mar. Drugs 2019, 17, 682 13 14 3 of 13 Figure 3. Chemical structures of compounds 13–14 from Haliclona densaspicula. 2.4. Haliclona Exigua 2.4. Haliclona Exigua Chemical study of the sponge specimen Haliclona exigua collected from the coastal areas of India Chemical study of the sponge specimen Haliclona exigua collected from the coastal areas of India and Indonesia afforded nine alkaloid derivatives, including xestospongin D (15), araguspongins C-E and Indonesia afforded nine alkaloid derivatives, including xestospongin D (15), araguspongins C-E (16–18), 3α-methylaraguspongine C (19), neopetrocyclamines A (20) and B (21), papuamine (22) and (16–18), 3α-methylaraguspongine C (19), neopetrocyclamines A (20) and B (21), papuamine (22) and haliclonadiamine (23) (Figure4)[ 5,13–17]. Compound 16 was the most common alkaloid from H. exigua haliclonadiamine (23) (Figure 4) [5,13–17]. Compound 16 was the most common alkaloid from H. and shown to have strong inhibitory activity against human lymphatic filarial parasite B, promastigote exigua and shown to have strong inhibitory activity against human lymphatic filarial parasite B, and intracellular amastigote forms of Leishmania donovani, and anti-fouling and competitive inhibition promastigote and intracellular amastigote forms of Leishmania donovani, and anti-fouling and of NOS [5,15–17]. This compound was later purified from an Indonesian sponge Neopetrosia chaliniformis competitive inhibition of NOS [5,15–17]. This compound was later purified from an Indonesian and could inhibit zebrafish embryos with a LD50 value of 4.3 µg/mL [18]. Compound 22 possessed sponge Neopetrosia chaliniformis and could inhibit zebrafish embryos with a LD50 value of 4.3 μg/mL remarkable cytotoxicity toward human glioblastoma cell line SF-295 with a GI value of 0.8 µM and [18]. Compound 22 possessed remarkable cytotoxicity toward human glioblastoma50 cell line SF-295 23 could control the transfer of MDA-MB-231 breast cancer cells [14]. Additionally, these alkaloids with a GI50 value of 0.8 μM and 23 could control the transfer of MDA-MB-231 breast cancer cells [14]. 22 and 23 obtained from an Okinawan sponge H. panicea and were found to inhibit the growth of Additionally, these alkaloids 22 and 23 obtained from an Okinawan sponge H. panicea and were Mycobacterium bovis BCG, M. intracellulare and M. smegmatis [19,20]. found to inhibit the growth of Mycobacterium bovis BCG, M. intracellulare and M. smegmatis [19,20].

15 16

17 18 19 20

21 22 23 FigureFigure 4.4. ChemicalChemical structuresstructures ofof compoundscompounds 1515––2323from fromHaliclona Haliclona exigua exigua. .

2.5.2.5. HaliclonaHaliclona NigraNigra FractionationFractionation of of the the aqueousaqueous extractextract ofof thethe marinemarine spongespongeHaliclona Haliclona nigranigracollected collected fromfrom northernnorthern coastcoast ofof PapuaPapua NewNew GuineaGuinea resultedresulted inin thethe discoverydiscovery ofof twotwo newnew hexapeptides,hexapeptides, haligramideshaligramides AA ((2424)) andand B (B25 (),25 together), together with waiakeamide with waiakeamide (26) (Figure (26)5 )[(Figure21]. Their 5) chemical[21]. The structuresir chemical and structures conﬁgurations and wereconfigurationsMar. elucidated Drugs 2019 were by, 17 extensive ,elucidated x FOR PEER NMR by REVIEW analysesextensive and NMR oxidative analyses reactions. and oxidative reactions. 4 of 13

24 R1 = R2 = S-Me 1 2 25 R = S-Me R = SO-Me 26 R1 = R2 = SO-Me FigureFigure 5. Chemical 5. Chemical structures ofstructures compounds of24 compounds–26 from Haliclona 24-26 nigra from. Haliclona nigra.

2.6. Haliclona Tulearensis Five new alkaloids, halitulin (27), halic isolorensin (29), isohaliclorensin (30), haliclorensin B (31) and haliclorensin C (32) together with isohalitulin (28) (Figure 6), were purified from the sponge Haliclona tulearensis collected from Sodwana Bay (South Africa) [22–24]. Compound 29 was a novel diamino derivative possessing an azacyclodecane ring, and exhibited strong cytotoxicity against P- 388 mouse leukemia cells with an IC50 value of 0.1 mg/mL [21]. In vitro biological evaluation results suggested that compounds 27, 29, 31 and 32 had significant cytotoxicity against P-388 with IC50 values of no more than 0.1 μg/mL [23,24].

29 30

27 R1 = H, R2 = OH 28 R1 = OH, R2 = H 31 32 Figure 6. Chemical structures of compounds 27-32 from Haliclona tulearensis.

2.7. Other Haliclona Spps. Until now, up to 71 nitrogenated compounds 33–103 have been discovered from unidentified marine sponge species of Haliclona. According to their chemical structures, these substances can be grouped into three classes, including 3-alkylpyridines, amides and depsipeptides, and miscellaneous alkaloids.

2.7.1. 3-Alkylpyridines 3-Alkylpyridine analogs with linear and cyclic frameworks such as navenones, halitoxins, niphatynes, niphatesines, haminols, viscosamine, etc [25] are the most common alkaloids isolated from the marine sponge genus Haliclona sponges. These substances possess pronounced biological activities. Chemical study of a marine sponge Haliclona sp. from New Zealand led to isolation of haliclocyclin C (33) and two new alkaloids dehydrohaliclocyclins C (34) and F (35) (Figure 7), which were the first examples of cyclic 3-alkylpyridinium alkaloid (3-APA) monomerz with an unsaturated alkyl chain [26]. An anti-fouling mixture of poly 3-alkylpyridinium salts (36) as well as haminols (37- 38) was firstly isolated from the methanol extract of Haliclona sp. collected in Terra Nova Bay, Ross Sea (Antarctica) (Figure 7) [27]. From an Indonesian sponge Haliclona sp. no. 95546, a new alkaloid, 3-dodecyl- pyridine (39) bearing a terminal cyano group, was purified and found to possess moderate in vitro cytotoxicity against tumor cell lines A549, MCF7 and Hela with the IC50 values of 41.8, 48.4, 33.2 μM, respectively. Two new alkaloids 40–41 with dimeric and trimeric 3-APA moieties were isolated from the methanolic extract of the sponge Haliclona sp. collected in the Pacific coast of

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24 R1 = R2 = S-Me 25 R1 = S-Me R2 = SO-Me 26 R1 = R2 = SO-Me Figure 5. Chemical structures of compounds 24-26 from Haliclona nigra. Mar. Drugs 2019, 17, 682 4 of 13 2.6. Haliclona Tulearensis Five new2.6. alkaloids, Haliclona Tulearensis halitulin (27), halic isolorensin (29), isohaliclorensin (30), haliclorensin B (31) and haliclorensinFive C new(32) alkaloids, together halitulin with isohalitulin (27), halic isolorensin (28) (Figure (29), isohaliclorensin 6), were purifi (30),ed haliclorensin from the B (sponge31) Haliclona tulearensisand haliclorensin collected C from (32) together Sodwana with Bay isohalitulin (South (28Africa)) (Figure [226),– were24]. Compound puriﬁed from 29 the was sponge a novel Haliclona tulearensis collected from Sodwana Bay (South Africa) [22–24]. Compound 29 was a novel diamino derivative possessing an azacyclodecane ring, and exhibited strong cytotoxicity against P- diamino derivative possessing an azacyclodecane ring, and exhibited strong cytotoxicity against P-388 388 mouse leukemia cells with an IC50 value of 0.1 mg/mL [21]. In vitro biological evaluation results mouse leukemia cells with an IC50 value of 0.1 mg/mL [21]. In vitro biological evaluation results suggested thatsuggested compounds that compounds 27, 29, 3127 and, 29, 3132and had32 significanthad signiﬁcant cytotoxicity cytotoxicity against against P-388 P-388 with with IC50 ICvalues50 values of no more thanof no 0.1 more μg/mL than 0.1 [23,24]µg/mL. [23,24].

29 30

27 R1 = H, R2 = OH 28 R1 = OH, R2 = H 31 32 Figure 6. ChemicalFigure 6. Chemical structures structures of compounds of compounds 27-3227– from32 from HaliclonaHaliclona tulearensis. .

2.7. Other Haliclona2.7. Other Spps. Haliclona Spps. Until now, up to 71 nitrogenated compounds 33–103 have been discovered from unidentiﬁed Until now,marine up spongeto 71 nitrogenated species of Haliclona compounds. According 33–103 to their have chemical been discovered structures, thesefrom substances unidentified marine spongecan species be grouped of Haliclona into three. According classes, including to their chemical 3-alkylpyridines, structure amidess, these and substances depsipeptides, can be grouped intoand three miscellaneous classes, including alkaloids. 3-alkylpyridines, amides and depsipeptides, and miscellaneous alkaloids. 2.7.1. 3-Alkylpyridines

2.7.1. 3-Alkylpyridines3-Alkylpyridine analogs with linear and cyclic frameworks such as navenones, halitoxins, niphatynes, niphatesines, haminols, viscosamine, etc [25] are the most common alkaloids isolated from 3-Alkylpyridinethe marine sponge analogs genus withHaliclona lineasponges.r and cyclic These substances frameworks possess such pronounced as navenones, biological activities. halitoxins, niphatynes, niphatesines,Chemical study haminols, of a marine viscosamine, sponge Haliclona etcsp. [25 from] are New the Zealand most led common to isolation alkaloids of haliclocyclin isolated C(33) and two new alkaloids dehydrohaliclocyclins C (34) and F (35) (Figure7), which were the first from the marine sponge genus Haliclona sponges. These substances possess pronounced biological examples of cyclic 3-alkylpyridinium alkaloid (3-APA) monomerz with an unsaturated alkyl chain [26]. activities. An anti-fouling mixture of poly 3-alkylpyridinium salts (36) as well as haminols (37-38) was firstly Chemicalisolated study from of the a methanolmarine extract sponge of HaliclonaHaliclonasp. collectedsp. from in TerraNew Nova Zealand Bay, Ross led Sea to (Antarctica) isolation of haliclocyclin(Figure C (337))[ and27]. two From new an Indonesian alkaloid sponges dehydrohaliclocyclinsHaliclona sp. no. 95546, C a ( new34) alkaloid,and F (35 3-dodecyl-) (Figure pyridine 7), which were the first(39 examples) bearing a of terminal cyclic cyano 3-alkylpyridinium group, was purified alkaloid and found (3-APA) to possess monomerz moderate inwith vitro ancytotoxicity unsaturated against tumor cell lines A549, MCF7 and Hela with the IC values of 41.8, 48.4, 33.2 µM, respectively. alkyl chain [26]. An anti-fouling mixture of poly 3-alkylpyridinium50 salts (36) as well as haminols (37- Two new alkaloids 40–41 with dimeric and trimeric 3-APA moieties were isolated from the methanolic 38) was firstlyextract isolate of thed from sponge theHaliclona methanosp. collectedl extract in of the Haliclona Pacific coast sp. of collected Guatemala in (Figure Terra7)[ Nova28]. Bioassay Bay, Ross Sea (Antarctica)results (Figure indicated 7) that[27] compounds. From an 40Indonesianand 41 had lowsponge cytotoxic Haliclona effect on sp. murine no. 95546 macrophage, a new J774.A1 alkaloid, 3-dodecyl- pyridineand fibrosarcoma (39) bearing WEHI-164 a terminal cell lines cyano and human group, epithelial was purified kidney HEK-293 and found with to IC possess50 > 20 µg moderate/mL. in vitro cytotoxicity against tumor cell lines A549, MCF7 and Hela with the IC50 values of 41.8, 48.4, 33.2 μM, respectively. Two new alkaloids 40–41 with dimeric and trimeric 3-APA moieties were isolated from the methanolic extract of the sponge Haliclona sp. collected in the Pacific coast of

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Guatemala (Figure 7) [28]. Bioassay results indicated that compounds 40 and 41 had low cytotoxic effectMar. Drugs on murine2019, 17, 682macrophage J774.A1 and fibrosarcoma WEHI-164 cell lines and human epithelial5 of 13 kidney HEK-293 with IC50 > 20 μg/mL.

33 34 35 36

37 38 39

40 41

42 m = 3, n = 5 44 m = 5, n = 6 47 m = 4, n = 4 43 m = 5, n = 3 45 m = 3, n = 3 48 m = 4, n = 5 46 m = 3, n = 4 49 m = 5, n = 5

50 cyclohaliclonamine A n = 1 55 m = 2, n = 3 59 n = 4, D12, (E) 51 cyclohaliclonamine B n = 2 56 m = 3, n = 4 60 n = 4, D13, (Z) 52 cyclohaliclonamine C n = 3 57 m = 1, n = 3 61 n = 5, D9, (Z) 53 cyclohaliclonamine D n = 4 58 m = 3, n = 3 62 n = 5, D15, (Z) 54 cyclohaliclonamine E n = 5 63 n = 6, D13, (Z) 64 n = 6, D15, (Z)

65 66 67

68 69 70 Figure 7. Chemical structures of compounds 33-70 from unclassified Haliclona sps. Figure 7. Chemical structures of compounds 33–70 from unclassiﬁed Haliclona sps.

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Haliclocyclamines A–C (42–44), three new cyclic bis-1,3-APA derivatives, found together with five analogs cyclostellettamines A–C (45–47), E (48) and F (49), were separated from the EtOH extract of Haliclona sp. collected at Manado in Indonesia (Figure7)[ 29,30]. Compounds 44 and 49 could inhibit vaccinia H-1-related phosphatase (VHR) at 17–18 µM and compound 45 possessed cytotoxic effect on HeLa cells with an IC50 value of 0.9 µg/mL and P388 cells with an IC50 value of 1.06 µg/mL. A heterogeneous and inseparable mixture of five cyclic 3-APAs, cyclohaliclonamines A-E (50-54), was isolated from an Okinawa sponge Haliclona sp., which compounds 52–54 were the first tetrameric, pentameric and hexameric 3-APAs from natural sources (Figure7)[ 25]. By solvent partition, Sephadex LH-20 gel permeation and HPLC, ten cyclic bis-1,3-APA derivatives (55–64) were separated from the MeOH extract of Haliclona sp. collected at the shore of Jeju Island (Korea) and characterized using combined NMR and FAB-MS/MS analyses (Figure7)[ 31]. Compounds 56 and 62–64 had moderate antibacterial activities against Staphylococcus aureus with the same MIC values of 12.5 µg/mL, and compound 63 exhibited the highest cytotoxic against A549 cell-line with a LC50 value of 14.7 µg/mL. Six tetracyclic alkaloids, haliclonacyclamines A-D (65–68) and halicyclamines A (69) and B (70) consisting of two 3-alkyl hexahydropyridine units were separated from Haliclona sp. grown on acroporid coral substrate on the Heron Island (Australia), and compounds 65 and 66 could inhibit the growth of leukemia P-388 cells with IC50 values of 0.8 and 0.6 µg/mL, respectively (Figure7)[ 32,33]. Halicyclamines A (69) derived from the Indonesian sponge Haliclona sp. 05A08 was shown to possess inhibitory effect on inosine-phosphate dehydrogenase at 1 µg/mL and anti-microbial activity against Mycobacterium smegmatis and M. bovis BCG with MIC values of 2.5 and 1.0 µg/mL, respectively [34]. Compound 70 showed cytotoxicity against HeLa cells with an IC50 value of 12 µM and inhibitory effect on chymotrypsin and caspase with IC50 values of 0.42 and 0.48 µM, respectively [35].

2.7.2. Amides and Depsipeptides Three novel amides, 2-palmitamidoethane sulfonic acid (71), N1-(2-aminoethyl)-N2- isopentylphthalamide (72) and N1-isobutyl-N2-tridecylphthalamide (73), were obtained from a Haliclona sp. sponge collected off the coast of Hainan Island (China) (Figure8)[ 36,37]. Haliclonin A (74), a new macrocyclic diamide from the Korean-derived sponge Haliclona sp. exhibited moderate antibacterial activity with a MIC value of 6.25 µg/mL against Bacillus subtilis, and cytotoxicity against the K562 leukemia cell line with an IC50 of 15.9 µg/mL (Figure8)[ 38]. Chemical analysis of a Rottnest Island-derived sponge Haliclona sp. afforded two new olefinic amides, salicylihalamides A(75) and B (76) (Figure8)[ 39]. Chemical investigation of a Haliclona sp. sponge specimen from the Vanuatu Islands afforded three new amides, haliclamide (77), halipeptins A (78) and B (79) (Figure8)[ 40,41]. The structures of compounds 78 and 79 were later revised and corrected by total chemical synthesis [42]. Compound 77 exhibited in vitro anti-tumor activity against human bronchopulmonary non-small-cell-lung-carcinoma line NSCLC-N6 with an IC50 value of 4.0 µg/mL while 78 displays potent anti-inflammatory effect. One new depsipeptide, kendarimide A (80), was isolated and characterized from a Sulawesi Island-derived Haliclona sp. Sponge (Figure8)[ 43]. A MTT assay suggested that this chemical had 87% growth inhibition on multi-drug resistance (MDR) cell line KB-C2 cells in the presence of 0.1 mg/mL colchicine. Two cyclic hexapeptides, waiakeamide (81) and its sulfone derivative 82, and five cyclic heptapeptides, the haliclonamides A-E (83–87) (Figure8), were sequentially purified from a Palau-derived Haliclona sp. sponge [44–46]. Bioassay results showed that these peptides had potent antifouling activity at the concentration of 100 ppm, except for compounds 84 and 86. Mar. Drugs 2019, 17, 682 7 of 13 Mar. Drugs 2019, 17, x FOR PEER REVIEW 7 of 13

71 72

73 74 75; 76 △17 cis 77

78 79

80 81

82 83 84

85 86 87 Figure 8. Chemical structures of compounds 71-87 from unclassified Haliclona sps. Figure 8. Chemical structures of compounds 71–87 from unclassiﬁed Haliclona sps.

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2.7.3.2.7.3. Miscellaneous Miscellaneous Alkaloids Alkaloids 88 AA new new cytotoxic cytotoxic polycyclic polycyclic alkaloid alkaloid njaoamine njaoamine I I ( (88)) containing containing a a quinoline quinoline system system and and a a known known cytotoxic compound njaoamine G (89) were detected in the methanol extract of a Haliclona (Reniera) cytotoxic compound njaoamine G (89) were detected in the methanol extract of a Haliclona (Reniera) spsp.. sponge sponge collected collected from from Okuza Okuza Island Island (Tanzania (Tanzania)) (Figure (Figure 9)9 )[[47].47 Two]. Two isoquinoline isoquinoline alkaloids alkaloids,, 1- 1-hydroxymethyl-7-methoxyisoquinolin-6-ol (90) and mimosamycin (91) (Figure9), were puriﬁed hydroxymethyl-7-methoxyisoquinolin-6-ol (90) and mimosamycin (91) (Figure 9), were purified from Haliclona afrom Haliclona a sp. spongesp. collected sponge at collected Jessie Beazley at Jessie Reef Beazley (Philippines) Reef(Philippines) [48]. Interestingly, [48]. compound Interestingly, 91 91 Cribrochalina wascompound also producedwas by also the produced marine sponge by the Cribrochalina marine sponge and had strong cytotoxicand had effect strong on cytotoxic human eﬀect on human tumor cell lines LOX, OVCAR-3 and HeLa cells with IC50 values of 10, 10, 2.6 µg/mL, tumor cell lines LOX, OVCAR-3 and HeLa cells with IC50 values of 10, 10, 2.6 μg/mL, respectively [48, 92 93 β 49respectively]. Manzamine [48,49s ]. A Manzamines (92) and Y A (93 ( ) )( andFigure Y ( 9)), (Figure two unusual9), two unusual alkaloids alkaloids with withβ-carboline-carboline and N isoquinolineand isoquinoline skeletons skeletons and anda 13 a-element 13-element dense dense,, N-containing-containing polycyclic polycyclic structure structure unit unit,, were were isolated isolated Haliclona andand characterized characterized from from two two specimens specimens of of the the sponge sponge Haliclona sp.,sp., which which w wereere respectively respectively collected collected 92 fromfrom Manzamo Manzamo and and Iriomot Iriomotee Island Island [50,51]. [50,51]. Compound Compound 92 couldcould strongly strongly inhibit inhibit the the growth growth of of mouse P-388 cells with an IC50 value of 0.07 µg/mL while 93 showed weak cytotoxicity on KB cells mouse P-388 cells with an IC50 value of 0.07 μg/mL while 93 showed weak cytotoxicity on KB cells (IC = 7.3 µg/mL). (IC5050 = 7.3 μg/mL).

88 89

90 91 92 93

94 95

96 97

100 101 102 103 Figure 9. Chemical structures of compounds 88–103 from unclassified Haliclona sps. Figure 9. Chemical structures of compounds 88–103 from unclassiﬁed Haliclona sps. Four antifungal amino alcohols, halaminols A-D (94–97) (Figure 9), were purified from a Haliclona sp. sponge grown on the Great Barrier Reef and their relative configurations were deduced

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Four antifungal amino alcohols, halaminols A–D (94–97) (Figure9), were purified Haliclona fromMar. a Drugs 2019, 17, xsp. FOR PEER sponge REVIEW grown on the Great Barrier Reef and their9 relativeof 13 configurations were deduced from the NMR characteristics of oxazolidinone derivatives and absolutefrom configurations the NMR characteristics were determined of oxazolidinone by their derivatives MPA esters and absolute [52]. Two configurations new uncommon were aminodetermined ketones, (6Z,9Z,12Z,15Z)-1-[(2-phenyl-ethyl)amino]octadeca-6,9,12,15-tetraen-3-oneby their MPA esters [52]. Two new uncommon amino ketones, (6Z,9Z,12Z,15Z)- (98)1-[(2 and- (6Z,9Z,12Z,15Z)-1-(diethylamino)octadeca-6,9,12,15-tetraen-3-onephenyl-ethyl)amino]octadeca-6,9,12,15-tetraen-3-one (98) (99) (Figure and 9), were (6Z,9Z,12Z,15Z) separated- from1- an unclassified(diethylamino)octadecaHaliclona sponge-6,9,12,15 collected-tetraen from-3-one Weizhou (99) (Figure Island 9), (Guangci, were separated China) from [53 ].an Chemical unclassified study of theHaliclona EtOH extract sponge of collected a Haliclona from sp. Weizhou sample Island collected (Guangci, from Chi Iriomotena) [53]. Island Chemical (Japan) study afforded of the twoEtOH new extract of a Haliclona sp. sample collected from Iriomote Island (Japan) afforded two new haliclonadiamine derivatives, halichondriamine C (100) and 1-epi-halichondriamine C (101) along with haliclonadiamine derivatives, halichondriamine C (100) and 1-epi-halichondriamine C (101) along papuamine (22) and haliclonadiamine (23) (Figure9)[ 19]. Compounds 100 and 101 could inhibit the with papuamine (22) and haliclonadiamine (23) (Figure 9) [19]. Compounds 100 and 101 could inhibit growth of Mycobacterium bovis BCG with the same MIC values of 0.5 µg/mL and M. intracellulare with the growth of Mycobacterium bovis BCG with the same MIC values of 0.5 μg/mL and M. intracellulare MIC valueswith MIC of 1.0 values and 0.5 of µ 1.0g/ mL, and respectively. 0.5 μg/mL, Additionally,respectively. Additionally, two purine derivatives, two purine 1,3-dimethylpurine derivatives, 1,3- (102)dimethylpurine and 1,3-dimethyl-6-imino (102) and 1,3 (103)-dimethyl (Figure-6-imino9), were (103 separated) (Figure 9) from, were a separatedHaliclona fromsp. sponge a Haliclona grown sp. on Hainansponge Island grown (China) on Hainan [54]. Island (China) [54].

3. Bioactive3. Bioactive Alkaloids Alkaloids from fromHaliclona Haliclona-Derived-Derived Microbes Microbes MarineMarine sponges sponges are are important important hosts hosts for for a a large large community community of microorganisms, microorganisms, which which are are shown shown to beto great be great producers producers of secondary of secondary metabolites metabolites [55 [55].]. However, However, only eight eight alkaloids alkaloids 104104–112–112 havehave been been separatedseparated from fromHaliclona Haliclonasponge-derived sponge-derived microbes microbes until until now now (Figure (Figure 10). 10) Chemical. Chemical analysis analysis of theof the ethyl acetateethyl extract acetate of theextract strain of Bacillusthe strain megaterium Bacillus megateriumLC3CS2 LC3CS2 symbiont symb of theiont sponge of the spongeHaliclona Haliclona oculata oculatacollected fromcollected Son Cha Peninsulafrom Son Cha (Vietnam) Peninsula aff orded(Vietnam) three afforded anti-microbial three anti agents:-microbial 7,7-bis(3-indolyl)- agents: 7,7-bis(3p-cresol-indolyl) (104- ), cyclo-(Pro-Leu)p-cresol (104 (),105 cyclo) and-(Pro cyclo-(Pro-Val)-Leu) (105) and (cyclo106)- (Figure(Pro-Val) 10 (106)[56) ].(Figure These 10) chemicals [56]. These had chemicals antimicrobial had antimicrobial activities against Vibrio vulnificus, V. parahaemolyticus and Trichophyton mentagrophytes activities against Vibrio vulnificus, V. parahaemolyticus and Trichophyton mentagrophytes with MIC values with MIC values ranging from 0.05 to 5.0 µg/mL. Compound 104, formerly obtained from a marine ranging from 0.05 to 5.0 µg/mL. Compound 104, formerly obtained from a marine sponge Hyatell-derived sponge Hyatell-derived microbe Vibrio sp. was shown to inhibit the growth of Bacillus cereus and microbeMicrococcusVibrio sp. luteus was with shown MIC values to inhibit of 0.5 the and growth 0.005 µg/mL, of Bacillus respectively cereus [56,57].and Micrococcus Alantrypinone luteus (107with) MICalong values with of 0.5 lovastatin, and 0.005 meµthylg/mL, ester respectively of lactone ring [56,-57opened]. Alantrypinone monacolin K, ( 107terrein,) along territrems with lovastatin, B and methylergosterol ester of was lactone separated ring-opened from a monacolin F62 fungal K,strain terrein, associated territrems with Bthe and sponge ergosterol Haliclona was simulans separated fromcollected a F62 fungal from strain the South associated China S withea (Figure the sponge 10) [58]Haliclona. Screening simulans of symbioticcollected strains from fro them the South marine China Sea (Figuresponge 10Haliclona)[58]. sp. Screening collected of from symbiotic the sea shore strains of Tateyama from the city marine (Japan) sponge led toHaliclona the discoverysp. of collected four fromnew the seaStreptomyces shore of strains Tateyama [59]. cityLater (Japan) chemical led investigation to the discovery of strains of four GE-23 new GEStreptomyces-26 and SC-24 strainsafforded [59 ]. Laterfive chemical new alkaloids investigation JBIR- of30, strains -34, -35, GE-23 -39 andGE-26 -40 and (108 SC-24–112) a(Figurefforded 10) five. However, new alkaloids noneJBIR-30, of these -34, -35, -39compound and -40s ( 108had– 112 potent) (Figure cytotoxic 10). effectsHowever, on human none of cervical these compounds carcinoma HeLa had potent cells and cytotoxic malignant effects on humanpleural cervical mesothelioma carcinoma ACC HeLa-MESO cells-1 cells and. malignant pleural mesothelioma ACC-MESO-1 cells.

104 105 106 107

108 109 R = CH3 111 R = CH2CH3 110 R = H 112 R = CH3 Figure 10.FigureChemical 10. Chemical structures structures of compounds of compounds104– 104112–from112 fromHaliclona Haliclona-derived-derived microbes. microbes.

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4. Conclusions In summary, 112 nitrogenous secondary metabolites have been isolated and characterized from the marine sponge genus Haliclona and its derived microbes till now. Only five alkaloids (compounds 16, 22, 23, 91 and 104) were separated from other organisms. Therefore, this indicates that Haliclona sponges are some of the most prolific sources of exclusive bioactive alkaloids despite the fact only a handful of classified species had been chemically investigated. It is well-known that marine organisms have served as a primary source of bioactive natural products during the past several decades. Nowadays, however, a rapid decrease in the speed of discovery of new compounds from Nature strongly necessitates new research strategies and approaches. Microorganisms are ubiquitous in the ocean owing to their stronger adaptability. During long co-evolution with marine sponges, symbiotic microbes maybe play important physiological and ecological roles in promoting host growth and increasing the resistance to predators and omnivores by excreting toxic metabolites. Therefore, more efforts should be made to explore and identify unknown Haliclona sponges and their derived symbiotic microbes and to carry out chemical studies for the discovery of novel therapeutical agents.

Author Contributions: J.Z., Y.L., Z.L. and H.W. collected all references. J.Z. and Y.L.wrote the draft. H.Z. conceived and revised this review. Funding: Financial supports from the National Natural Science Foundation of China (41776139 and 81773628) and the Fundamental Research Fund for the Provincial Universities of Zhejiang (RF-C2019002) were greatly appreciated. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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