Marine-Derived Macrolides 1990–2020: an Overview of Chemical and Biological Diversity

marine drugs

Review Marine-Derived Macrolides 1990–2020: An Overview of Chemical and Biological Diversity

Hairong Zhang, Jiabin Zou, Xiaoxue Yan, Junlong Chen, Xiujiao Cao, Jialing Wu, Yinghui Liu and Tingting Wang *

Li Dak Sum Marine Biopharmaceutical Research Center, Department of Marine Pharmacy, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo 315800, China; [email protected] (H.Z.); [email protected] (J.Z.); [email protected] (X.Y.); [email protected] (J.C.); [email protected] (X.C.); [email protected] (J.W.); [email protected] (Y.L.) * Correspondence: [email protected]

Abstract: Macrolides are a significant family of natural products with diverse structures and bioactivities. Considerable effort has been made in recent decades to isolate additional macrolides and characterize their chemical and bioactive properties. The majority of macrolides are obtained from marine organisms, including sponges, marine microorganisms and zooplankton, cnidarians, mollusks, red algae, bryozoans, and tunicates. Sponges, fungi and dinoflagellates are the main producers of macrolides. Marine macrolides possess a wide range of bioactive properties including cytotoxic, antibacterial, antifungal, antimitotic, antiviral, and other activities. Cytotoxicity is their most significant property, highlighting that marine macrolides still encompass many potential antitumor drug leads. This extensive review details the chemical and biological diversity of 505 macrolides derived

from marine organisms which have been reported from 1990 to 2020. Keywords: macrolides; marine organisms; chemical diversity; biological diversity; cytotoxicity Citation: Zhang, H.; Zou, J.; Yan, X.; Chen, J.; Cao, X.; Wu, J.; Liu, Y.; Wang, T. Marine-Derived Macrolides 1990–2020: An Overview of Chemical and Biological Diversity. Mar. Drugs 1. Introduction 2021, 19, 180. https://doi.org/ The term “macrolide” was coined by Woodward in 1957 [1] to describe antibiotics 10.3390/md19040180 which typically consist of 14-, 15- or 16-membered macrolactam rings and feature double bonds and different saccharide and aminosaccharide functional groups. The naturally oc- Academic Editors: Bin Wu and curring 14-membered lactones erythromycin and clarithromycin, 15-membered macrolides Ikuro Abe azithromycin and spiramycin, and the 16-membered avermectin B1a are typical macrolide antibiotics in clinical use [2–4]. The 26-membered macrolide oligomycin A (an inhibitor of Received: 10 March 2021 ATP synthase) [5,6] and the 36-membered macrocyclic lactone amphotericin B (an antifun- Accepted: 21 March 2021 gal agent) are also used clinically [7,8]. In the last thirty years, many studies have described Published: 25 March 2021 the molecular features, structures, and bioactivities of the intriguing macrolides obtained from plants, animals, and microbes in terrestrial and marine ecosystems [9–12]. Macrolides Publisher’s Note: MDPI stays neutral with larger macrocyclic rings have been reported, exemplified by the cytotoxic swinholide with regard to jurisdictional claims in H, with its 40-membered lactone ring, obtained from the New Zealand deep-water marine published maps and institutional affil- sponge Lamellomorpha strongylata (La. strongylata)[13], and the novel 62-membered polyol iations. symbiodinolide from the symbiotic dinoflagellate Symbiodinium sp. [14]. Macrolides, there- fore, can be considered more broadly as a class of uncorrelated compounds containing a ring of twelve or more members. This literature review from 1990 to 2020 highlights 505 new macrolides derived from Copyright: © 2021 by the authors. marine organisms (65.8% of which are from sponges, fungi, and dinoflagellates) (Figure1 ). Licensee MDPI, Basel, Switzerland. Compared with terrestrial environments, the oceans exhibit more wide-ranging hyper- This article is an open access article saline, hyperbaric, hypoxic, cryogenic, and oligotrophic conditions. Marine organisms distributed under the terms and must develop the capacity to produce diverse bioactive metabolites to survive in these conditions of the Creative Commons Attribution (CC BY) license (https:// complex and competitive ecosystems. Marine metabolites have huge potential as new drug creativecommons.org/licenses/by/ leads, with nine approved pharmaceuticals and 31 compounds in clinical pharmaceutical 4.0/). trials [15]. Macrolides are a significant family of natural marine products (Figure2). The

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complex and competitive ecosystems. Marine metabolites have huge potential as new drug leads, with nine approved pharmaceuticals and 31 compounds in clinical pharma- Mar. Drugs 2021, 19,ceuticalcomplex 180 trials and [15].competitive Macrolides ecosystems. are a significa Marinent familymetabolites of natural have marine huge potentialproducts as(Figure new2 of 67 2).drug The leads, marine with macrolides nine approved reviewed pharmaceuticals herein display and cytotoxic, 31 compounds antibacterial, in clinical antifungal, pharma- an- timitotic,ceutical trials antiviral, [15]. Macrolidesantiplasmodial are aand significa other ntbioactivities, family of natural as listed marine in Table products 1. This (Figurereview discusses2). The marine themarine isolation, macrolides macrolides structures, reviewed reviewed and herein hereinchemic disp displayallay and cytotoxic, cytotoxic, bioactive antibacterial, diversity of antifungal, marineantifungal, macro- antimitotic, an- lidestimitotic, from antiviral, 309antiviral, publications. antiplasmodial antiplasmodial and and other bioactivities,bioactivities, as as listed listed in Tablein Table1. This 1. This review review discusses discusses thethe isolation, isolation, structures, structures, and and chemicalchemical and and bioactive bioactive diversity diversity of marineof marine macrolides macro- from lides from 309309 publications. publications.

Figure 1. The Figurepercentage 1. The of percentage macrolides of macrolidesfrom diverse from marine diverse organisms. marine organisms.

Figure 1. The percentage of macrolides from diverse marine organisms.

Figure 2. All new macrolides by source/year, n = 505. Figure 2. All new macrolides by source/year, n = 505. 2. Chemical and Biological Diversity of Marine-Derived Macrolides 2. ChemicalFigure 2.1.2.and All Macrolides Biological new macrolides Extracted Diversity by from source/year, of Marine Marine-Derived Organisms n = 505. Macrolides 2.1. Macrolides2.1.1. Extracted Sponges from Marine Organisms 2. Chemical and Biological Diversity of Marine-Derived Macrolides 2.1.1. Sponges The Okinawan Theonella sp. (T. sp.) sponges produced a series of dimeric macrolides 2.1. Macrolidescalled Extracted swinholides from Marine A–G (1 –Organisms7) and isoswinholide A (8)[16–19]. Four bistheonellide-related The Okinawancompounds—bistheonellide Theonella sp. (T. sp.) C sponges (9), isobistheonellide produced a series A (10 ),of anddimeric bistheonellic macrolides acids A 2.1.1. Sponges called swinholides(11) and A–G B (12 (1)—are–7) and also isoswinholide produced by A Okinawan (8) [16–19].T. sp. Four sponges bistheonellide-related [20]. The structure of compounds—bistheonellideThe Okinawanthe macrolide Theonella miyakolide C sp. (9 ),(T. isobistheonellide sp.) (13), sponges which is produce weakly A (10d), cytotoxic aand series bistheonellic andof dimeric obtained acids macrolides from A Japanese(11) andcalled B (swinholides12)—aresponge also A–GPolyﬁbrospongia produced (1–7) and by Okinawanisoswinholidesp., was elucidated T. sp. A sponges(8) by[16–19]. X-ray [20]. Four single The bistheonellide-related structure crystal diffraction of the mac- [21]. 13- rolidecompounds—bistheonellide miyakolideDeoxytedanolide (13), which (C14 ()is9 was), weakly isobistheonellide isolated cytotoxic from Mycale andA (10 adhaerensobtained), and bistheonellic(M. from adhaerens Japanese) acids and identiﬁedsponge A (11) by and B (12)—arespectroscopic also produced analysis by [ 22Okinawan]. T. sp. sponges [20]. The structure of the macrolide miyakolide (13), which is weakly cytotoxic and obtained from Japanese sponge

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Mar. Drugs 2021, 19, 180 Polyfibrospongia sp., was elucidated by X-ray single crystal diffraction [21]. 13-Deox-3 of 67 ytedanolide (14) was isolated from Mycale adhaerens (M. adhaerens) and identified by spectroscopic analysis [22].

OMe OMe

O O

OH OH

OMe OH OH OOH OR1 OH OH OOH O O O O R2 R R O 1 O 3 2' O O

OH O OH OH OMe OH O OH OH OMe HO HO

O O

OR2 OMe

R =R =Me 1 1 2 4 R1 =R3 =H,R2 =Me R =H,R =Me Mar. Drugs 2021, 19, x FOR PEER REVIEW 2 1 2 5 R1 =R2 =Me,R3 =OH 4 of 70 R =Me,R =H 2' 3 1 2 6 R1 =R2 =Me,R3 =H, = Z 7 R1 =Me,R2 =R3 =H

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TheThe antimitoticantimitotic macrolides macrolides halistatin halistatin 1 (15 1 ()15 and) and halistatin halistatin 2 (16 2) were (16) wereisolated isolated from from PhakelliaPhakellia cartericarteri fromfrom the the Comoros Comoros Islands Islands and and AxinellaAxinella cf. cartericf. carteri (Dendy)(Dendy) from fromthe Western the Western Indian Ocean [23,24]. Halistatin 3 (17) was produced in extremely small quantities by Indian Ocean [23,24]. Halistatin 3 (17) was produced in extremely small quantities by Phakellia sponges collected at Chuuk [25]. Phakellia sponges collected at Chuuk [25].

Independent groups have reported the potent antitumor macrolides spongiastatins 1 (18), 2 (19), and 3 (20), which were isolated from Spongia sp. in the Republic of Maldives and identified via spectral data without stereochemistry [26,27]. Another group isolated spongiastatin congeners 4 (21), 5 (22), 6 (23), 7 (24), 8 (25), and 9 (26) from Spirastrella spinispirulfera (S. spinispirulfera) on the southeast coast of Africa [28,29].

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Independent groups have reported the potent antitumor macrolides spongiastatins 1 (18), 2 (19), and 3 (20), which were isolated from Spongia sp. in the Republic of Maldives Mar. Drugs 2021, 19, x FOR PEER REVIEWand identiﬁed via spectral data without stereochemistry [26,27]. Another group isolated6 of 70

spongiastatin congeners 4 (21), 5 (22), 6 (23), 7 (24), 8 (25), and 9 (26) from Spirastrella spinispirulfera (S. spinispirulfera) on the southeast coast of Africa [28,29].

Three macrolides sphinxolides B (27), C (28), and D (29) have been isolated from the CaledonianThreeThree macrolides macrolides sponge sphinxolides sphinxolidesNeosiphoniu B B ( 27 superstes(27),), C C (28 (28), ),[30]. and and D D (29 (29) have) have been been isolated isolated from from the the CaledonianCaledonian sponge spongeNeosiphoniu Neosiphoniu superstes superstes[30 [30].].

Three new trisoxazole macrolides, jaspisamides A (30), B (31), and C (32), were re- Three new trisoxazole macrolides, jaspisamides A (30), B (31), and C (32), were portedThree without new stereochemical trisoxazole data macrolides, in an Okinawan jaspisamides Juspis sponge A [31].(30), B (31), and C (32), were re- reported without stereochemical data in an Okinawan Juspis sponge [31]. ported without stereochemical data in an Okinawan Juspis sponge [31].

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A new 22-membered macrocyclic lactone named dictyostatin 1 (33) was isolated from AA new new 22-membered 22-membered macrocyclic macrocyclic lactone lactone named named dictyostatin dictyostatin 1 1 (33 (33) was) was isolated isolated from from a Republic of Maldives Spongia sponge and exhibited significant cytotoxicity towards mu- aa Republic Republic ofof Maldives SpongiaSpongia spongesponge and and exhibited exhibited significant signiﬁcant cytotoxicity cytotoxicity towards towards murine P388 lymphocytic leukemia [32]. The relative stereochemistry of dictyostatin 1 was murinerine P388 P388 lymphocytic lymphocytic leukemia leukemia [32]. [32]. The The rela relativetive stereochemistry ofof dictyostatindictyostatin 1 1 was was determined by Murata’s method [33]. Two new 26-membered macrolides, reidispon- determineddetermined by by Murata’s Murata’s method method [33 [33].]. Two Tw newo new 26-membered 26-membered macrolides, macrolides, reidispongi- reidispon- giolides A (34) and B (35), have been produced by the marine sponge Reidispongia coerulea olidesgiolides A (A34 )(34 and) and B ( 35B (),35 have), have been been produced produced by by the the marine marine sponge spongeReidispongia Reidispongia coerulea coerulea (R. coerulea) [34]. The relative and absolute stereochemistries of the C-23–C-35 portion of (R.(R. coerulea coerulea)[) 34[34].]. TheThe relativerelative andand absolute stereochemistries stereochemistries of of the the C-23–C-35 C-23–C-35 portion portion of reidispongiolide A were determined by synthesis of an ozonolysis fragment of the natural ofreidispongiolide reidispongiolide A Awere were determined determined by synthesi by synthesiss of an of ozonolysis an ozonolysis fragment fragment of the ofnatural the product [35], which was later synthesized enantioselectively [36]. The relative stereochem- naturalproduct product [35], which [35], was which later was synthesized later synthesized enantioselectively enantioselectively [36]. The relative [36]. The stereochem- relative istry of the C-7–C-15 fragment was reassigned through a series of diastereomers of a deg- stereochemistryistry of the C-7–C-15 of the C-7–C-15fragment fragmentwas reassigned was reassigned through througha series of a seriesdiastereomers of diastereomers of a degradation fragment synthesis [37]. ofradation a degradation fragment fragment synthesis synthesis [37]. [37].

CytotoxicCytotoxic superstolidesuperstolide AA ((3636)) andand superstolidesuperstolide BB (37(37)) havehave beenbeen isolatedisolated fromfrom thethe Cytotoxic superstolide A (36) and superstolide B (37) have been isolated from the deep-waterdeep-water marinemarine spongespongeNeosiphonia Neosiphonia superstessuperstes( N.(N. superstes superstes)[) 38[38,39].,39]. Another Another cytotoxic cytotoxic deep-water marine sponge Neosiphonia superstes (N. superstes) [38,39]. Another cytotoxic macrolide,macrolide, lasonolide lasonolide A A (38 (38), was), was produced produced by by the the shallow-water shallow-water Caribbean Caribbean sponge spongeForcepia For- macrolide, lasonolide A (38), was produced by the shallow-water Caribbean sponge For- sp.cepia [40 sp.]. Isohomohalichondrin [40]. Isohomohalichondrin B (39 ),B belonging(39), belonging to the to halichondrin the halichondrin family, family, was isolatedwas iso- cepia sp. [40]. Isohomohalichondrin B (39), belonging to the halichondrin family, was iso- fromlated the from New the Zealand New Zealand deep-water deep-water sponge spongeLissodendoryx Lissodendoryxsp. (Li. sp.sp.) ( [Li.41 ].sp.) Phorboxazoles [41]. Phorboxa- A lated from the New Zealand deep-water sponge Lissodendoryx sp. (Li. sp.) [41]. Phorboxa- (40zoles) and A ( B40 (41) and) have B (41 an) unprecedentedhave an unprecedented scaffold scaffold and were and isolated were isolated from the from Indian the Ocean Indian zoles A (40) and B (41) have an unprecedented scaffold and were isolated from the Indian spongeOcean spongePhorbas Phorbassp. (P. sp.sp.), (P. with sp.), completewith complete stereochemistry stereochemistry and absoluteand absolute conﬁguration configura- Ocean sponge Phorbas sp. (P. sp.), with complete stereochemistry and absolute configura- determinedtion determined by spectroscopy by spectroscopy and and partial partial synthesis synthesis [42 [42,43].,43]. The The structures structures and and absolute absolute tion determined by spectroscopy and partial synthesis [42,43]. The structures and absolute

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configurations of latrunculin A (42) and laulimalide B (43) isolated from Okinawan sponge Fasciospongia rimosa were determined by X-ray analysis [44]. Other cytotoxic mac- conﬁgurations of latrunculin A (42) and laulimalide B (43) isolated from Okinawan sponge rolides, latrunculin S (44), neolaulimalide (45) and zampanolide (46), have been produced Fasciospongia rimosa were determined by X-ray analysis [44]. Other cytotoxic macrolides, by the F. rimosa genus [45,46]. Halichlorine (47), isolated from the marine sponge Halicho- latrunculin S (44), neolaulimalide (45) and zampanolide (46), have been produced by the F. dria okadai, exhibited significant inhibition of vascular cell adhesion molecule 1 (VCAM-1) rimosa genus [45,46]. Halichlorine (47), isolated from the marine sponge Halichodria okadai, [47]. exhibited signiﬁcant inhibition of vascular cell adhesion molecule 1 (VCAM-1) [47].

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Leucascandrolide A (48), exhibiting antifungal and cytotoxic activities, was obtained from the sponge Leucascandra caveolata (Le. caveolata) [48]. The marine lithistida sponge CallipeltaLeucascandrolideLeucascandrolide sp. (Cal. sp.) A (A48 (contains),48 exhibiting), exhibiting the antifungal first antifungal member and and cytotoxic of cytotoxic a new activities, activities,class was of obtainedmarine-derivedwas obtained macro- fromfromlides, the the callipeltoside sponge spongeLeucascandra Leucascandra A (49 caveolata), caveolatawhich(Le. caveolataincorporates (Le. caveolata)[48]. The) an[48]. marine unusual The lithistidamarine chlorocyclopropyl lithistida sponge Cal- sponge group and lipeltaCallipeltaan aminosp. (Cal. sp. sugar (sp.)Cal. contains sp.) [49]. contains The the ﬁrstrelative the member first and member of aabsolu new of class ate new stereochemistry of marine-derivedclass of marine-derived macrolides,of the chlorocyclopropyl macro- callipeltoside A (49), which incorporates an unusual chlorocyclopropyl group and an amino lides,side chaincallipeltoside of callipeltoside A (49), which A wasincorporates determined an unusual by stereoselective chlorocyclopropyl synthesis group and[50–52]. Cyto- sugaran amino [49]. Thesugar relative [49]. andThe absolute relative stereochemistryand absolute stereochemistry of the chlorocyclopropyl of the chlorocyclopropyl side chain of callipeltosidetoxic macrolides A was determined altohyrtins by stereoselectiveA–C (50–52) synthesis and 5-desacetylaltohyrtin [50–52]. Cytotoxic macrolides A (53) were isolated side chain of callipeltoside A was determined by stereoselective synthesis [50–52]. Cyto- altohyrtinsfrom the A–Csponge (50–52 Hyrtios) and 5-desacetylaltohyrtin altum and their absolute A (53) were stereochemistries isolated from the sponge were determined by toxic macrolides altohyrtins A–C (50–52) and 5-desacetylaltohyrtin A (53) were isolated Hyrtios altum and their absolute stereochemistries were determined by spectroscopy [53,54]. fromspectroscopy the sponge [53,54]. Hyrtios Screeningaltum and their of extrac absolutets fromstereochemistries a New Zealand were determined deep-water by sponge La. Screeningstrongylata of extracts for cytotoxicity from a NewZealand towards deep-water the P388 sponge cell lineLa. strongylata yielded forswinholide cytotoxicity H (54) [13]. towardsspectroscopy the P388 [53,54]. cell line Screening yielded swinholide of extracts H from (54)[ a13 New]. Zealand deep-water sponge La. strongylata for cytotoxicity towards the P388 cell line yielded swinholide H (54) [13].

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Another deep-water (> 100 m) sponge of the genus Li. produced the antitumor mac- AnotherAnother deep-water deep-water (> (> 100100 m)m) sponge of of the the genus genus Li.Li. producedproduced the the antitumor antitumor macrolides neonorhalichondrin B (55), neohomohalichondrin B (56), 55-methoxyisohomoha- macrolidesrolides neonorhalichondrin neonorhalichondrin B ( B55 (),55 neohomohalichondrin), neohomohalichondrin B (56 B), (56 55-methoxyisohomoha-), 55-methoxyisoho- lichondrin (57), 53-methoxyneoisohomohalichondrin B (58a) and 53-epi-53-methoxyneo- mohalichondrinlichondrin (57), ( 5753-methoxyneoisohomohalichondrin), 53-methoxyneoisohomohalichondrin B (58a B ()58a and) and53-epi-53-methoxyneo- 53-epi-53-metho- isohomohalichondrin B (58b) [55]. xyneoisohomohalichondrinisohomohalichondrin B (58b B ()58b [55].)[ 55 ].

MacrolideMacrolide salicylihalamides salicylihalamides A (A59 )( and59) and B (60 )B were(60) isolatedwere isolated from the fromHaliclona the Haliclonasponge, Macrolide salicylihalamides A (59) and B (60) were isolated from the Haliclona representingsponge, representing a potentially a potentially important important new class ofnew antitumor class of leadsantitumor [56]. Theleads absolute [56]. The conﬁg- abso- sponge, representing a potentially important new class of antitumor leads [56]. The abso- urationslute configurations of salicylihalamides of salicylihalamides A and B have A beenand B revised have been by a revised reinterpretation by a reinterpretation of Mosher lute configurations of salicylihalamides A and B have been revised by a reinterpretation esterof Mosher derivatives ester and derivatives enantioselective and enantioselec synthesestive of both syntheses enantiomers of both [57 enantiomers–59]. Cytotoxic [57–59]. cal- of Mosher ester derivatives and enantioselective syntheses of both enantiomers [57–59]. lipeltosideCytotoxic Bcallipeltoside (61) and C (62 B), (61 two) and members C (62), of two a novel members class of marinea novel glycosideclass of marine macrolides, glyco- Cytotoxic callipeltoside B (61) and C (62), two members of a novel class of marine glyco- wereside isolatedmacrolides, from were the spongeisolatedCal. fromsp. the [60 sponge]. Cal. sp. [60]. side macrolides, were isolated from the sponge Cal. sp. [60].

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Another deep-water (> 100 m) sponge of the genus Li. produced the antitumor macrolides neonorhalichondrin B (55), neohomohalichondrin B (56), 55-methoxyisohomoha- lichondrin (57), 53-methoxyneoisohomohalichondrin B (58a) and 53-epi-53-methoxyneoisohomohalichondrin B (58b) [55].

Macrolide salicylihalamides A (59) and B (60) were isolated from the Haliclona sponge, representing a potentially important new class of antitumor leads [56]. The absolute configurations of salicylihalamides A and B have been revised by a reinterpretation Mar. Drugs 2021, 19, 180 of Mosher ester derivatives and enantioselective syntheses of both enantiomers [57–59].10 of 67 Cytotoxic callipeltoside B (61) and C (62), two members of a novel class of marine glycoside macrolides, were isolated from the sponge Cal. sp. [60].

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FourFour newnew oxazole-containing oxazole-containing compounds, compounds, halishigamides halishigamides A–D A–D (63– (6663),–66 were), were isolated iso- fromlated an from Okinawan an Okinawan marine marine sponge, sponge,Halichondria Halichondriasp. [61 sp.]. [61].

AA PalauPalau DysideaDysidea sp.sp. spongesponge containedcontained aa 14-membered14-membered macrolide,macrolide, arenolidearenolide ((6767),), showingshowing modestmodest cytotoxicity [62]. [62]. Three Three macrolides, macrolides, 30-hydroxymycalolide 30-hydroxymycalolide A ( A68 (),68 32-hy-), 32- hydroxymycalolidedroxymycalolide A A (69 (69),), and and 38-hydroxymycalolide 38-hydroxymycalolide B B ( (7070),), were were isolated fromfrom thethe marinemarine spongespongeM. M. magellanicamagellanicaand and showedshowed cytotoxicitycytotoxicitytowards towardsL1210 L1210 cells cells [ 63[63].].

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Pateamine 1 (71), a thiazole-containing macrolide with an unique dilactone function- Pateamine 1 (71), a thiazole-containing macrolide with an unique dilactone func- ality,Pateamine was isolated 1 (71 from), a thiazole-containing M. sp. sponge [64]. macrolide Four new with macr anocyclic unique lactones/lactams, dilactone function- am- tionality, was isolated from M. sp. sponge [64]. Four new macrocyclic lactones/lactams, ality,philactams was isolated A–D ( 72from–75 ),M. were sp. producedsponge [64]. by Fourthe marine new macr spongeocyclic Amphimedon lactones/lactams, spp. collected am- amphilactams A–D (72–75), were produced by the marine sponge Amphimedon spp. col- philactamsin the Great A–D Australian (72–75), Bightwere produced[65]. by the marine sponge Amphimedon spp. collected lectedin the inGreat the Australian Great Australian Bight [65]. Bight [65].

CytotoxicCytotoxic macrolides macrolides haterumalides haterumalides NA NA (76 (76),), NB NB (77 (77),), NC NC (78 (78),), ND ND (79 (79) and) and NE NE (80 (80) ) werewereCytotoxic isolated isolated from macrolidesfrom the the New New haterumalides Caledonian Caledonian Litbistida NA Litbistida (76), sponges NB sponges (77),N. NC superstes N. (78 superstes), NDand (79R. and) Coerulea and R. NECoerulea[ (6680].) Sphinxolideswere[66]. isolatedSphinxolides E–G from (81 E–Gthe–83 New)(81 and–83 Caledonian reidispongiolide) and reidispongiolide Litbistida C (84 sponges) areC (84 new) areN. cytotoxic superstesnew cytotoxic macrolides and R. macrolides Coerulea from Okinawan[66].from Sphinxolides Okinawan species species ofE–GIrcinia (81 of–[ 6783Ircinia].) and Leucascandrolide [67]. reidispongiolide Leucascandrolide B (85 C) ( is84 aB) 16-memberedare(85 )new is a cytotoxic16-membered macrolide macrolides macro- from thefromlide calcareous Okinawanfrom the spongecalcareous speciesLe. of sponge caveolata Ircinia [67].Le.from caveolata Leucascandrolide the northeastern from the northeastern B waters (85) is ofa 16-membered New waters Caledonia of New macro- [Cale-68]. Thelidedonia Newfrom [68]. Zealandthe The calcareous New marine Zealand sponge sponge marine Le.M. caveolatasp. sponge contained from M. sp. the the contained northeastern polyoxygenated, the polyoxygenated, waters pyranose of New Cale- ring- pyra- containing,donianose ring-containing,[68]. The 16-membered New Zealand 16-membered macrolide marine peloruside macrolidesponge M. Apelorusidesp. (86 contained)[69], A which ( the86) [69],polyoxygenated, was synthesizedwhich was synthe- pyra- via a Mitsunobu-typenosesized ring-containing, via a Mitsunobu-type lactonization 16-membered lactonization [70]. macrolide [70]. peloruside A (86) [69], which was synthesized via a Mitsunobu-type lactonization [70].

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CytotoxicCytotoxic spongidepsin spongidepsin ( 87(87)) has has been been isolated isolated from from the the VanuatuVanuatu marine marine sponge spongeSpon- Spon- giagiasp. sp. [ 71[71].]. A A new new cytotoxic cytotoxic 20-membered 20-membered macrolide, macrolide, dactylolide dactylolide (88 (),88 was), was isolated isolated from from a marinea marine sponge sponge of the of genusthe genusDactylospongia Dactylospongia. This. This has been has been synthesized synthesized and the and relative the relative stere- ochemistrystereochemistry of the of acyloxymethine the acyloxymethine andthe and absolute the absolute conﬁguration configuration of the of whole the whole molecule mole- havecule beenhave determinedbeen determined [72]. The[72]. Vanuatu The Vanuatu marine marine sponge spongeHa. sp. Ha. was sp. foundwas found to contain to contain the cyclicthe cyclic metabolite metabolite haliclamide haliclamide (89)[ (7389].) [73]. Clavosolides A–D (90–93) have been found in sponge Myriastra clavosa [74,75]. The absolute configurations of clavosides A and B were determined by total synthesis [74–76].

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90 93 Myriastra clavosa SpirastrellolidesClavosolides A–G A–D (94 ( ––100)) haveare antimitotic been found macrolides in sponge isolated from the Caribbean[74,75]. The ma- absolute conﬁgurations of clavosides A and B were determined by total synthesis [74–76]. rineSpirastrellolides sponge S. coccinea A–G ( 94[77–80].–100) are Spirastrellolide antimitotic macrolides A exhibited isolated selective from inhibition the Caribbean of protein ma- Spirastrellolides A–G (94–100) are antimitotic macrolides isolated from the Caribbean phosphataserine sponge S. 2A coccinea [80]. [77–80]. Spirastrellolide A exhibited selective inhibition of protein S. coccinea marinephosphatase sponge 2A [80]. [77–80]. Spirastrellolide A exhibited selective inhibition of protein phosphatase 2A [80].

The sponge Chondrosia corticata produced two oxazole-containing macrolides, neoha- lichondramideTheThe sponge sponge (Chondrosia101 Chondrosia) and (19 corticata corticataZ)-halichondramideproduced produced two two ( oxazole-containing102 oxazole-containing), and the open ringed macrolides, macrolides, secohalichon- neohali- neoha- chondramidedramide.lichondramide Neohalichondramide (101 (101) and) and (19 (19Z)-halichondramideZ)-halichondramide and (19Z)-halichondramide (102 (102),), and and the the exhibited open open ringed ringed significant secohalichon- secohalichon- cytotox- dramide.icitydramide. and Neohalichondramideantifungal Neohalichondramide activity toward and and (19 the(19Z)-halichondramide Zhuman)-halichondramide leukemia cell-line exhibited exhibited K562 signiﬁcant significant and Candida cytotoxic- cytotox- albi- itycansicity and (andC. antifungal albicans antifungal) activity[81]. activity toward toward the humanthe human leukemia leukemia cell-line cell-line K562 K562 and Candidaand Candida albicans albi- (C.cans albicans (C. albicans)[81]. ) [81].

ThreeThree cytotoxic cytotoxic mycalolides, mycalolides, 30-hydroxymycalolide 30-hydroxymycalolide A (A103 (103), 32-hydroxymycalolide), 32-hydroxymycalolide A (104A ()104 andThree) and 38-hydroxymycalolide cytotoxic 38-hydroxymycalolide mycalolides, B (30-hydroxymycalolide105 B (),105 have), have been been isolated isolated A from (103 from), a Japanese32-hydroxymycalolide a JapaneseM. magellan-M. magel- icalanicaA [(82104]. [82].) The and The ﬁve 38-hydroxymycalolide antiproliferativefive antiproliferativ lasonolide Be (lasonolide105), congenershave congenersbeen C–Gisolated (106C–G from– 110(106) a were– Japanese110) isolatedwere M. isolated frommagel- Forcepiafromlanica Forcepia[82].sponge The sponge collectedfive antiproliferativ collected in the U.S.in the Gulfe lasonolideU.S. of Gulf Mexico of congeners Mexico [83]. Exiguolide [83]. C–G Exiguolide (106 (111–110),) isolated (were111), isolated from thefrom marine theForcepia marine sponge sponge spongeGeodia collected exiguaGeodia , inexigua was the reported U.S., was Gulf reported to of inhibit Mexico to fertilizationinhibit [83]. fertilizationExiguolide of sea urchin( of111 sea), isolated ( Hemi-urchin (fromHemicentrotus the marine pulcherrimus sponge Geodia) gametes exigua but, was not reported embryogenesis to inhibit [84]. fertilization The absolute of configura-sea urchin tion(Hemicentrotus of exiguolide pulcherrimus was determined) gametes by but total not synthesis embryogenesis of the enantiomer [84]. The absolute [85]. configuration of exiguolide was determined by total synthesis of the enantiomer [85].

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Mar. Drugs 2021, 19, x FOR PEER REVIEW 15 of 70 centrotus pulcherrimus) gametes but not embryogenesis [84]. The absolute conﬁguration of exiguolide was determined by total synthesis of the enantiomer [85].

CytotoxicCytotoxic macrolides macrolides leiodolides leiodolides A A (112 (112) and) and B B (113 (113) were) were obtained obtained from from a deep-water a deep-wa- (>200ter (> m) 200Leiodermatium m) Leiodermatiumsponge sponge [86,87 ].[86,87]. Tedanolide Tedanolide C (114 ),C isolated (114), isolated from Ircinia fromsp. Ircinia (Papua sp. New(Papua Guinea), New Guinea), was found was to found be potently to be potent cytotoxic,ly cytotoxic, causing causing S-phase S-phase arrest, arrest, suggestive sugges- of proteintive of synthesisprotein synthesis inhibition inhibition [88]. Cytotoxic [88]. Cytotoxic kabiramides kabiramides F–I (115– F–I118 )(115 were–118 produced) were pro- by Pachastrissaduced by Pachastrissa nux (P. nux nux) (Gulf (P. ofnux Thailand)) (Gulf of [ 89Thailand)]. [89].

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An antiplasmodial macrolide, kabiramide L (119), was isolated from P. nux sponge [90].An SwinholideAn antiplasmodial antiplasmodial I (120 macrolide,) andmacrolide, the related kabiramide kabiramide hurghadolide L (119 L (),119 was ),A was isolated(121 ),isolated with from cytotoxicity fromP. nux P.sponge nux towards sponge [90]. Swinholidehuman[90]. Swinholide colon I (120 cancer) andI (120 cells, the) and related were the produced hurghadoliderelated hurghadolide by T. A swinhoei (121), withA (Hurghada, (121 cytotoxicity), with Egypt)cytotoxicity towards [91]. humantowards colonhuman cancer colon cells, cancer were cells, produced were produced by T. swinhoei by T.(Hurghada, swinhoei (Hurghada, Egypt) [91 Egypt)]. [91].

OxalatrunculinOxalatrunculin BB ( 122(122)) was was isolated isolated from from Red Red Sea Sea sponge spongeNegombata Negombata corticata corticataand and showedshowedOxalatrunculin significant significant antifungal antifungal B (122) andwas and anticancer isolated anticancer from activities, activities, Red suggestingSea suggesting sponge it Negombata as it aas potential a potential corticata member mem- and ofbershowed the of bioactivethe significant bioactive latrunculin antifungallatrunculin family and family [anticancer92]. [92]. A LithistidA activities,Lithistid sponge spongesuggesting of of the the it family asfamily a potential neopeltidae neopeltidae mem- containedcontainedber of the the thebioactive macrolide macrolide latrunculin neopeltolide neopeltolide family (123 (123 )[92]. with) with A potential Lithistid potential cytotoxic sponge cytotoxic andof the and antifungal family antifungal neopeltidae activities. activi- Thisties.contained compound This compound the macrolide was synthesized was neopeltolidesynthesized to determine to(123 determine) with its absolutepotential its absolute configurationcytotoxic configuration and andantifungal the and relative the activi- rel- stereochemistryativeties. Thisstereochemistry compound of C-13 wasof [93 C-13 ].synthesized Candidaspongiolides [93]. Candidaspongiolides to determine (124 its), absolute a ( complex124), a configuration complex mixture mixture of acyland estersofthe acyl rel- ofestersative a macrolide stereochemistryof a macrolide related torelated of tedanolide, C-13 to [93]. tedanolide, wasCandidaspongiolides isolated was fromisolatedCandidaspongia from (124 Candidaspongia), a complexsp. (Can. mixture sp.sp.) (Can. (Papua of sp.)acyl New(Papuaesters Guinea) of New a macrolide Guinea) and Can. related and flabellata Can. to tedanolide,flabellata(Great Barrier(Great was isolatedBarrier Reef, Australia) Reef,from AustCandidaspongia [94ralia)]. Fijianolides [94]. sp.Fijianolides (Can. D–I sp.) (125D–I(Papua– 130(125) –New were130) Guinea)were produced produced and by spongeCan. by flabellataspongeCacospongia Cacospongia (Great mycofijiensis Barrier mycofijiensis Reef,(Cac. Aust mycofijiensis(Cac.ralia) mycofijiensis [94].) (MeleFijianolides) (Mele Bay, Vanuatu)Bay,D–I (Vanuatu)125 [–95130]. Phorbasides) were [95]. producedPhorbasides A–E by (131 spongeA–E–135 ()131 are Cacospongia– chlorocyclopropane135) are chlorocyclopropanemycofijiensis macrolides (Cac. mycofijiensis macrolides isolated) from (Mele iso- marinelatedBay, fromVanuatu) sponge marineP. [95].sp. sponge [ 96Phorbasides,97]. P. sp. [96,97]. A–E ( 131 –135) are chlorocyclopropane macrolides isolated from marine sponge P. sp. [96,97].

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Latrunculin analogs, latrunculol A–C (136–138), 18-epi-latrunculol (139) and latrun- culonesLatrunculin A (140 analogs,) and B latrunculol (141), were A–C obtained (136–138 ),from 18-epi-latrunculol Cac. mycofijiensis (139) and[98]. latruncu- Salarin A (142), lonessalarin A (140 B ()143 and) Band (141 tulearin), were obtained A (144) from wereCac. obtained mycoﬁjiensis from[98 repeated]. Salarin collections A (142), salarin of the Mada- B(143) and tulearin A (144) were obtained from repeated collections of the Madagascan gascan sponge Fascaplysinopsis sp. (F. sp.) [99]. sponge Fascaplysinopsis sp. (F. sp.) [99].

AA further further collection collection led toled the to isolation the isolation of salarin of salarin C (145), C which (145), was which considered was considered to be to be thethe precursor precursor of salarins of salarins A and A Band [100 B]. [100]. Marine Marine sponge spongeSiliquariaspongia Siliquariaspongia mirabilis containedmirabilis contained anan antitumor antitumor macrolide macrolide lactam lactam named named mirabilin mirabilin (146)[101 (146].) The [101]. nitrogenous The nitrogenous bismacrolide bismacrolide 147 F. tausalarintausalarin C (C (147) was) was isolated isolated from from the Madagascarthe Madagascar sponge spongesp. F. and sp. was and found was found to to in- inhibit proliferation of K562 leukemia cells [102]. Muironolide A (148), containing a rare hibit proliferation of K562 leukemia cells [102]. Muironolide A (148), containing a rare hexahydro-1H-isoindolone and trichlorocarbinol ester, was isolated from marine sponge of thehexahydro-1 genus PhorbasH-isoindolone[103]. and trichlorocarbinol ester, was isolated from marine sponge of the genus Phorbas [103].

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Four variants of halichondrin B, B-1140 (149), B-1092 (150), B-1020 (151) and B-1076 Four variants of halichondrin B, B-1140 (149), B-1092 (150), B-1020 (151) and B-1076 (152), wereFour extractedvariants offrom halichondrin the Poecilosclerid B, B-1140 sponge (149), B-1092Li. sp. in(150 microgram), B-1020 (quantities151) and B-1076 and (152), were extracted from the Poecilosclerid sponge Li. sp. in microgram quantities and their(152 structures), were extracted were elucidated from the byPoecilosclerid capillary NMR sponge spectroscopy Li. sp. in [104].microgram quantities and theirtheir structures structures were were elucidated elucidated by by capillary capillary NMR NMR spectroscopy spectroscopy [104 [104].].

Cytotoxic phosphate-containingphosphate-containing macrolide macrolide enigmazole enigmazole A A (153 (153) and) and two two analogs, analogs, 15- 15-O- methylenigmazoleO-methylenigmazoleCytotoxic phosphate-containing A ( 154A ()154 and) and 13-hydroxy-15- 13-hydroxy-15- macrolideO-methylenigmazole Oenigmazole-methylenigmazole A (153 A ()155 and A), ( weretwo155), analogs, extractedwere ex- 15- fromtractedO-methylenigmazole the from marine the spongemarine ACinachyrella sponge (154) and Cinachyrella 13-hydroxy-15- enigmatica enigmaticacollectedO-methylenigmazole collected in Papua Newin Papua Guinea A New(155 [105), Guineawere] and ex- their[105]tracted structuresand fromtheir structuresthe were marine conﬁrmed were sponge co bynfirmed totalCinachyrella synthesis by total enigmatica [synthesis106]. collected [106]. in Papua New Guinea [105]Seven and scalarintheir structures analogs were D–J co( 156nfirmed–162) wereby total obtained synthesis from [106]. the Madagascan F. sp. sponge.sponge.Seven Scalarins scalarin D, E, analogs H, and JD–J inhibited (156– 162 cell) proliferationwere obtained inin aafrom dose-dose- the andand Madagascan time-dependenttime-dependent F. sp. mannersponge. [[107].107 Scalarins]. Theonezolides D, E, H, and A–C J inhibited (163–165 cell) werewere proliferation obtainedobtained in fromfrom a dose- thethe OkinawanandOkinawan time-dependent marinemarine spongespongemanner T. sp.sp.[107]. and Theonezolides absolute configurations conﬁgurations A–C (163 were–165) determinedwere obtained by combining from the Okinawan a JBCA method, marine 13 a universalsponge T. NMRNMR sp. and database,database, absolute andand configurations aa 13C-acetonide were method determined [108,109]. [108, 109by combining]. a JBCA method, a universal NMR database, and a 13C-acetonide method [108,109].

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TheThe Indonesian Indonesian sponge spongeT. T. swinhoei swinhoeiyielded yielded the the dimeric dimeric macrolides macrolides isoswinholideisoswinholide B (166(166) and) and swinholide swinholide K K (167 (167)[)110 [110].]. An An unusual unusual carbamate, carbamate, callyspongiolide callyspongiolide ((168168),), withwith strongstrong cytotoxicity cytotoxicity towards towards human human Jurkat Jurkat J16 J16 T T and and Ramos Ramos B B lymphocytes, lymphocytes, waswas isolatedisolated fromfrom marine marine sponge spongeCal. Cal. sp.sp. [111]. [111]. Cytotoxic Cytotoxic polyketide polyketide macrolides macrolides phormidolides phormidolides B (169 B) (169and) and C (170 C ()170 were) were isolated isolated from from PetrosiidaePetrosiidae spongesponge with stereochemical with stereochemical assignment assignment via en- viaantioselective enantioselective synthesis synthesis of the of macrocyclic the macrocyclic core [112]. core [Cytotoxic112]. Cytotoxic chondropsin-type chondropsin-type macro- macrolideslides poecillastrins poecillastrins E (171 E (171), F), ( F172 (172), and), and G G(173 (173) were) were isolated isolated from from the the marine marine sponge PoecillastraPoecillastrasp. sp. [113 [113].].

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2.1.2. Microorganisms and Zooplankton 2.1.2. Microorganisms and Zooplankton Fungi Fungi The fungus Periconia byssoides (Per. byssoides), obtained from the sea hare Aplysia The fungus Periconia byssoides (Per. byssoides), obtained from the sea hare Aplysia ku- kurodai (Ap. sp.), was reported to produce the cytotoxic triols pericosides A and B, and rodai (Ap. sp.), was reported to produce the cytotoxic triols pericosides A and B, and four four new macrolides, macrosphelides E–H (174–177)[114]. Macrosphelide I (178) and new macrolides, macrosphelides E–H (174–177) [114]. Macrosphelide I (178) and macro- macrosphelides E–H from Per. byssoides isolated from Ap. kurodai were also reported else- sphelides E–H from Per. byssoides isolated from Ap. kurodai were also reported elsewhere where [115]. Macrosphelide E was synthesized at a high yield via a key chemoenzymatic [115]. Macrosphelide E was synthesized at a high yield via a key chemoenzymatic reaction reaction [116]. The synthesis of macrosphelides H and G has also been described [117,118]. Absolute[116]. The conﬁgurations synthesis of macrosphelides determined by H spectroscopy and G has also and been chemical described transformation [117,118]. Abso- have beenlute configurations reported for macrosphelides determined by L( 179spectrosco) and Hpy produced and chemical by Per. transformation byssoides from Ap. have kurodai been, reported for macrosphelides L (179) and H produced by Per. byssoides from Ap. kurodai,

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and the cytotoxic macrosphelide M (180) [114,119,120]. Penicillum verruculosum and the cytotoxic macrosphelide M (180)[114,119,120]. Penicillum verruculosum (IMI352119) (IMI352119) was reported to produce three macrolides with antifungal activity: BK223-A was reported to produce three macrolides with antifungal activity: BK223-A (181), BK223-B (181), BK223-B (182) and BK223-C (183) [121]. The mitosporic fungus Varicosporina ramu- (182) and BK223-C (183)[121]. The mitosporic fungus Varicosporina ramulosa has been losa has been reported to produce (6R,11S,12S,14R)-colletodiol (184), (6R,11R,12R,14R)- reported to produce (6R,11S,12S,14R)-colletodiol (184), (6R,11R,12R,14R)-colletodiol (185) colletodiol (185) and colletoketol (186) [122,123]. The 12-membered macrolides pandan- and colletoketol (186)[122,123]. The 12-membered macrolides pandangolide 1 (187) and golide 1 (187) and pandangolide 2 (188) were extracted from an unidentified fungus iso- pandangolide 2 (188) were extracted from an unidentiﬁed fungus isolated from marine lated from marine sponge collected in Indonesia [124]. sponge collected in Indonesia [124].

PandangolidePandangolide 3 3 (189 (189),), macrolide macrolide dimer dimer pandangolide pandangolide 4 ( 1904 (190), and), and a new a new acetyl acetyl deriva- de- tiverivative of 5-hydroxymethylfuran-2-carboxylic of 5-hydroxymethylfuran-2-carboxylic acid were acid produced were byproduced the fungus by Cladosporiumthe fungus herbarumCladosporium(Cla. herbarum herbarum ),(Cla. associated herbarum with), associated the sponge withCallyspongia the sponge aerizusa Callyspongia(Cal. aerizusa aerizusa) and(Cal. collected aerizusa) in and Bali collected [125]. The in Bali cytotoxic [125]. macrocyclicThe cytotoxic trichothecene macrocyclic trichothecene 12,13-deoxyroridin 12,13- E(deoxyroridin191) was obtained E (191) from was anobtained extract from of the an marine extract fungus of theMyrothecium marine fungus roridum Myrothecium(M. ror- idumroridum)[126 (M.]. The roridum 14-membered) [126]. The resorcylic 14-membered macrolides resorcylic aigialomycins macrolides A–E aigialomycins (192–196) were A–E isolated(192–196 from) were the isolated mangrove from fungus the mangroveAigialus fungus parvus AigialusBCC 5311 parvus [127 ].BCC Potential 5311 [127]. antifungal Poten- ğ macrocyclictial antifungal polyesters macrocyclic 15G256 polyesters(197) and 15G256 15G256wɩ (197 (198) and) were 15G256 obtainedѡ (198 from) were the obtained marine fungusfrom theHypoxylon marine fungus oceanicum HypoxylonLL-15G256 oceanicum [128]. LL-15G256 Two cytotoxic [128]. macrolides,Two cytotoxic sporiolides macrolides, A (199sporiolides) and B ( 200A (),199 were) and produced B (200), were by the produced fungus Cladosporium by the fungusisolated Cladosporium from the isolated brown from alga Actinotrichiathe brown alga fragilis Actinotrichia(Okinawa, fragilis Japan) (Okinawa, [129]. Japan) [129].

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AnAn unidentiﬁed unidentified endophytic endophytic fungus fungus from from the brown the brown alga Sargassumalga Sargassumsp. (Zhanjiang sp. (Zhanjiang Sea, China)Sea, wasChina) the sourcewas the of twosource 12-membered of two 12-membered ring lactones ring (201 lactones–202)[130 (201]. 12-Hydroxyroridin–202) [130]. 12-Hy- E(203droxyroridin), roridin Q E (204(203)), and roridin 2,3-deoxyroritoxin Q (204) and 2,3-deoxyroritoxin D (205) were obtained D (205 from) wereM. obtained roridum fromon submergedM. roridum wood on submerged in Palau [131 wood]. Gliocladium in Palau [131].sp. isolated Gliocladium from sp. the isolated alga Durvillaea from the antarctica alga Dur- (Taurangavillaea antarctica Bay, New (Tauranga Zealand) Bay, yielded New 4-ketoclonostachydiol Zealand) yielded 4-ketoclonostachydiol (206)[132]. (206) [132].

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OH O OMe O H O OH O OMe O H O O O O OO O HO HO O O O O HO HO O O O O O HOO 201 202 H HO O 201 202 H O HO HO 203 203

H H O O H H O O O O O O O O O O O O O O O O O O O O O O O O O HO O HOO HO O H HO O O H O O O O HOOC O O O O OH HOOC O O O O OH 206 204 205 206 204 205 The 14-membered resorcylic acid lactone derivatives 8′-hydroxyzearalanone (207) The 14-membered resorcylic acid lactone derivatives 80-hydroxyzearalanone (207) and The2′-hydroxyzearalanol 14-membered resorcylic (208) were acid isolated lactone from derivatives the marine-derived 8′-hydroxyzearalanone fungus Penicillium (207) and 20-hydroxyzearalanol (208) were isolated from the marine-derived fungus Penicillium andsp. (2Pen.′-hydroxyzearalanol sp.) [133]. β-resorcylic (208) were macrolide isolated 5′-hydroxyzearalenol from the marine-derived (209) wasfungus obtained Penicillium from sp. (Pen. sp.) [133]. β-resorcylic macrolide 50-hydroxyzearalenol (209) was obtained from sp.the ( Pen.culture sp.) broth [133]. of β -resorcylicthe fungus macrolideFusarium sp.5′-hydroxyzearalenol 05ABR26 [134]. The (209 cytotoxic) was obtained 14-membered from the culture broth of the fungus Fusarium sp. 05ABR26 [134]. The cytotoxic 14-membered themacrolides culture broth aspergillide of the fungusA–C (210 Fusarium–212) were sp. 05ABR26isolated from [134]. the The culture cytotoxic broth 14-membered of the marine macrolides aspergillide A–C (210–212) were isolated from the culture broth of the marine macrolidessponge-derived aspergillide fungus A–C Aspergillus (210–212 ostianus) were ( isolatedAs. ostianus from) (Pohnpei, the culture Micronesia) broth of the [135]. marine sponge-derivedsponge-derived fungus fungusAspergillus Aspergillus ostianus ostianus( As.(As. ostianus ostianus)) (Pohnpei, (Pohnpei, Micronesia) Micronesia) [ 135[135].].

TheThe marine-derived marine-derived fungus fungusAs. As.sp. sp. SCSGAF SCSGAF 0076 0076 was was reported reported to to produce produce the the 16- 16- memberedmemberedThe marine-derived macrolide macrolide aspergillide aspergillide fungus DAs. D (213 sp.(213)[ SCSGAF)136 [136].]. Apralactone Apralactone 0076 was Areported A (214 (214) and) andto enantiomersproduce enantiomers the of16- of curvularinmemberedcurvularin ( 215 macrolide(215–220–220) were) wereaspergillide isolated isolated fromD from (213Curvularia )Curvularia [136]. Apralactonesp. sp. (Cur. (Cur.sp.) sp.)A [(137 214[137,138].,)138 and]. Theenantiomers The macrolide macrolide of curvulonecurvularincurvulone A (A (215221 (221–)220 was) was) were produced produced isolated by by Cur.from Cur.sp. Curvulariasp. isolated isolated fromsp. from (Cur. the the marinesp.) marine [137,138]. alga algaGracilaria Gracilaria The macrolide folifera folifera andcurvuloneand inhibited inhibited A ( the221 the growth) growthwas produced of ofB. B. subtilis subtilis by Cur., Microbotryum, Microbotryum sp. isolated violaceum fromviolaceum the, marineSeptoria, Septoria alga tritici tritici Gracilaria, and, andChlorella Chlorella folifera fusca [139]. andfusca inhibited [139]. the growth of B. subtilis, Microbotryum violaceum, Septoria tritici, and Chlorella fusca [139].

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Three decalactones, xestodecalactones D–F (222–224), were purified from an ethyl acetate extract of Corynespora cassiicola isolated from leaf tissues of the Chinese mangrove Three decalactones, xestodecalactones D–F (222–224), were puriﬁed from an ethyl medicinalThree decalactones,plant Laguncularia xestodecalactones racemose [140]. D–F Seiricuprolide (222–224), were pestalotioprolides purified from an ethylA (225 ) and acetateacetate extract extract of ofCorynespora Corynespora cassiicola cassiicolaisolated isolated from from leaf tissues leaf tissues of the Chineseof the Chinese mangrove mangrove medicinalB (226) (as plant theLaguncularia diacetate) racemose were [isolated140]. Seiricuprolide from the pestalotioprolides fungus Pestalotiopsis A (225) andspp., B which is asso- medicinal plant Laguncularia racemose [140]. Seiricuprolide pestalotioprolides A (225) and (ciated226) (as thewith diacetate) mangrove were isolated twigs fromof Rhizophora the fungus Pestalotiopsis mucronataspp., [141]. which Calcarides is associated A–C (227–229), B (226) (as the diacetate) were isolated from the fungus Pestalotiopsis spp., which is asso- with15G256 mangroveα (230 twigs), and of 15G256Rhizophoraβ mucronata(231) were[141 obtained]. Calcarides from A–C crude (227–229 extracts), 15G256 ofα the fungus Cal- ciated with mangroveβ twigs of Rhizophora mucronata [141]. Calcarides A–C (227–229), (carisporium230), and 15G256 sp. KF525(231) were isolated obtained from from German crude extracts Wadden of the Sea fungus waterCalcarisporium samples [142]. sp.15G256 KF525α isolated(230), and from 15G256 Germanβ Wadden(231) were Sea obtained water samples from [ 142crude]. extracts of the fungus Cal- carisporium sp. KF525 isolated from German Wadden Sea water samples [142]. O O O O HO O O HO O O HO HO MeO R MeO OnBu MeO OH O R MeO OH OnBu OH O OH 222 R= OH 222 R= OHOnBu 224 223 R= 224 223 R= OnBu

OH OH OH O OH O OH O O OH OHOH O OHOH O OO HOHO OO 225 226 225 226

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Thirteen new 12-membered macrolides, dendrodolides A–M (232–244), were ob- Thirteen new 12-membered macrolides, dendrodolides A–M (232–244), were obtained from the fungus Dendrodochium sp. derived from sea cucumber Holothuria nobilis tainedThirteenThirteen from the new new fungus 12-membered 12-membered Dendrodochium macrolides, macrolides, sp. dendrodolidesderived dendrodolidesfrom sea A–M cucumber (232 –A–M244 Holothuria), were(232 obtained–244 nobilis), were ob- fromSelenka the in fungus the SouthDendrodochium China Seasp. [143]. derived Dendrodolide from sea cucumber K was obtainedHolothuria from nobilis a commercially Selenka in tainedSelenka fromin the theSouth fungus China Dendrodochium Sea [143]. Dendrodolide sp. derived K was from obtained sea cucumber from a commercially Holothuria nobilis theavailable South Chinasubstrate Sea by [143 a]. convergent Dendrodolide strategy, K was and obtained the dendrolides from a commercially F, G, I, J, and available L were Selenkaavailable in substrate the South by China a convergent Sea [143]. strategy, Dendrodolide and the dendrolides K was obtained F, G, I, fromJ, and a L commercially were substratesynthesized by a via convergent a unified strategy,strategy andemploying the dendrolides ring-closing F, G, metathesis I, J, and L [144,145]. were synthesized availablesynthesized substrate via a unified by a strategy convergent employing strategy, ring-closing and the metathesis dendrolides [144,145]. F, G, I, J, and L were via a uniﬁed strategy employing ring-closing metathesis [144,145]. synthesizedOR O via a unifiedOR O strategy employingO ring-closingOH metathesis [144,145].OH OR O OR O O OH OH OR O OR O O OH OH O O O O O O O O O O O OH O OH O OH O OH O OH O O OH O O OH O O OH O OOH O OHO 232 R=Me 233 R=Me 236 237 238 O R=MeOH O OH O OH 237O OH O OH 232234 R=H 233235R=MeR=H 236 239 238240 234 R=H 235 R=H 239 240 232 R=Me 233 R=Me 236 237 238 H OH OH OH O O H234O OHR=H OH235OHR=H O O 239 240 O H H O HOH OOH OH O O O OMeO O O O O O OMe O OH O OH O OH O OH O OH O OH O OH O OH H O O O O OMe 241 242 243 244 241 242 243 244 O CochliomycinOH CO (245) wasOH producedO by theOH gorgonian-derivedO OH fungus Cochliobolus CochliomycinCochliomycin CC (245(245)) was was produced produced by by the the gorgonian-derived gorgonian-derived fungus fungusCochliobolus Cochliobolus lunatus (Coc. lunatus) [146], its absolute configuration was corrected in a later study [147]. lunatuslunatus( Coc.(Coc. lunatuslunatus)[) [146],146], its its absolute absolute conﬁguration configuration was was corrected corrected in in a a later later study study [ 147[147].]. 241 242 243 244 Cochliomycin C (245) was produced by the gorgonian-derived fungus Cochliobolus lunatus (Coc. lunatus) [146], its absolute configuration was corrected in a later study [147].

The fungus Pen. sumatrense MA-92, associated with the mangrove Lumnitzera race- The fungus Pen. sumatrense MA-92, associated with the mangrove Lumnitzera racemose, yielded the sulfur-containing curvularin derivatives sumalarins A−C (246–248) mose, yielded the sulfur-containing curvularin derivatives sumalarins A−C (246–248) [148]. Chemical epigenetic manipulation of the marine-derived fungus Coc. lunatus (TA26- [148]. Chemical epigenetic manipulation of the marine-derived fungus Coc. lunatus (TA26-

The fungus Pen. sumatrense MA-92, associated with the mangrove Lumnitzera race-

mose, yielded the sulfur-containing curvularin derivatives sumalarins A−C (246–248) [148]. Chemical epigenetic manipulation of the marine-derived fungus Coc. lunatus (TA26-

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The fungus Pen. sumatrense MA-92, associated with the mangrove Lumnitzera racemose, yielded the sulfur-containing curvularin derivatives sumalarins A−C(246–248)[148]. Chemical46) with histone epigenetic deacetylase manipulation inhibitors of the led marine-derivedto the elucidation fungus of twoCoc. 14-membered lunatus (TA26-46) resor- withcylic histone acid lactones: deacetylase 5-bromozeaenol inhibitors led (249 to the) and elucidation 3,5-dibromozeaenol of two 14-membered (250) [149]. resorcylic Glio- acidmasolides lactones: A–E 5-bromozeaenol (251–255) were ( 249obtained) and 3,5-dibromozeaenolfrom a sponge-derived (250 fungus)[149]. Gliomastix Gliomasolides sp. A–EZSDS1-F7-2, (251–255 )their were structures obtained being from determined a sponge-derived by spectroscopy fungus Gliomastix and singlesp. crystal ZSDS1-F7-2, X-ray theirdiffraction structures [150]. being Two determined 13-membered by spectroscopymacrolides (256 and–257 single) were crystal isolated X-ray from diffraction the marine- [150]. Twoderived 13-membered fungus Pen. macrolides meleagrinum (256 var.–257 viridiflavum) were isolated [151]. Application from the marine-derived of published proce- fungus Pen.dures meleagrinum for experimentalvar. viridiflavum design and[151 chemometri]. Applicationc analysis of published to enhance procedures the production for experi- of mentalcurvularin-related design and chemometriccompounds by analysis marine-derived to enhance Penicillium the production sp. DRF2 of led curvularin-related to the isolation of cyclothiocurvularins (258–260) and cyclosulfoxicurvularins (261–262) [152]. Thio- compounds by marine-derived Penicillium sp. DRF2 led to the isolation of cyclothiocurvu- cladospolide E (263) was produced by the mangrove endophytic fungus Cladosporium sp. larins (258–260) and cyclosulfoxicurvularins (261–262)[152]. Thiocladospolide E (263) was (Cla. sp.) SCNU-F0001 and its absolute configuration was determined by X-ray diffraction produced by the mangrove endophytic fungus Cladosporium sp. (Cla. sp.) SCNU-F0001 and [153]. Thiocladospolides F–J (264–268) were isolated from another mangrove-derived en- its absolute configuration was determined by X-ray diffraction [153]. Thiocladospolides F–J dophytic fungus species in the same Cla. genus [154]. The macrolide 6,7,9,10-tetrahy- (264–268) were isolated from another mangrove-derived endophytic fungus species in the dromutolide (269) was isolated from endophytic fungus Aplosporella javeedii [155]. Two same Cla. genus [154]. The macrolide 6,7,9,10-tetrahydromutolide (269) was isolated from trichothecene macrolides, myrothecines H and I (270–271), were obtained from the endo- endophytic fungus Aplosporella javeedii [155]. Two trichothecene macrolides, myrothecines phytic fungus Paramyrothecium roridum isolated from the medicinal plant Morinda offici- H and I (270–271), were obtained from the endophytic fungus Paramyrothecium roridum nalis [156]. isolated from the medicinal plant Morinda officinalis [156].

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BacteriaBacteria TheThe 24-membered 24-membered macrolide maduralide maduralide (272 (272) was) was isolated isolated from from a marine a marine bacterium bacterium inin the the orderorder Actinomycetales [157]. [157 Halichomycin]. Halichomycin (273 () 273was) produced was produced by Streptomyces by Streptomyces hygroscopicus (S. hygroscopicus) isolated from the marine fish Halichoeres bleekeri [158]. 7-O- Mar. Drugs 2021, 19, x FOR PEER REVIEWhygroscopicus (S. hygroscopicus) isolated from the marine ﬁsh Halichoeres bleekeri [30158 of]. 70 7- O- SuccinylSuccinyl macrolactinmacrolactin F ( 274)) and and 7- 7-OO-succinyl-succinyl macrolactin macrolactin A A(275 (275) were) were isolated isolated from from a a culture of marine Bacillus sp. (B. sp.) Sc026 [159]. culture of marine Bacillus sp. (B. sp.) Sc026 [159].

Cytotoxic macrolide IB-96212 (276) was obtained from marine actinomycete L-25- ES25-008 [160]. Chalcomycin B (277) was isolated from marine Streptomycete isolate B7064 and was bioactive in both microorganisms and microalgae [161]. Lobophorins A and B (278–279) have been extracted from culture broths of bacteria isolated from the surface of the Caribbean brown alga Lobophora variegata (Dictyotales) [162]. Micromonospolides A– C (280–282) were produced by Micromonospora sp. (M. sp.) and demonstrated inhibition of gastrulation in starfish embryos [163,164].

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Cytotoxic macrolide IB-96212 (276) was obtained from marine actinomycete L-25- Mar. Drugs 2021, 19, x FOR PEER REVIEWES25-008 [160]. Chalcomycin B (277) was isolated from marine Streptomycete isolate B7064 31 of 70

and was bioactive in both microorganisms and microalgae [161]. Lobophorins A and B (278–279) have been extracted from culture broths of bacteria isolated from the surface of Mar. Drugs 2021, 19, x FOR PEER REVIEWthe Caribbean brown alga Lobophora variegata (Dictyotales) [162]. Micromonospolides31 A–Cof 70 (280–282) were produced by Micromonospora sp. (M. sp.) and demonstrated inhibition of gastrulation in starﬁsh embryos [163,164].

Marinomycins A–D (283–286) were isolated from actinomycete “Marinispora ”. These marinomycinsMarinomycinsMarinomycins showed A–DA–D ((283283 antibacterial––286286)) werewere isolatedisolated activity fromfrom actinomycetetowardsactinomycete methicillin-resistant “ “MarinisporaMarinispora”.”. TheseThese S. aureus marinomycinsmarinomycins(MRSA), while showed showed marinomycin antibacterial antibacterial A activity in hibitedactivity towards vancomycin-resistanttowards methicillin-resistant methicillin-resistant S. aureusfaecium S.(MRSA), (VREF)aureus and C. while(MRSA),albicans marinomycin while(weakly). marinomycin AMarinomyci inhibited A in vancomycin-resistanthibitedns A–C vancomycin-resistant demonstratedS. faecium cytotoxic S.(VREF) faecium activity and (VREF)C. against albicans and C. a panel of (weakly).albicans60 tumor (weakly). Marinomycins cell lines, Marinomyci including A–C demonstratedns A–Csix of demonstrated the cytotoxiceight melanoma cytotoxic activity against cellactivity lines a panelagainst [165]. of a 60 panel tumor of cell60 tumor lines, includingcell lines, including six of the eightsix of melanoma the eight melanoma cell lines [ 165cell]. lines [165].

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Marinomycins A–D (283–286) were isolated from actinomycete “Marinispora”. These marinomycins showed antibacterial activity towards methicillin-resistant S. aureus (MRSA), while marinomycin A inhibited vancomycin-resistant S. faecium (VREF) and C. albicans (weakly). Marinomycins A–C demonstrated cytotoxic activity against a panel of 60 tumor cell lines, including six of the eight melanoma cell lines [165].

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Marine actinomycete Salinispora arenicola yielded the three macrolide polyketides ar- Marine actinomycete Salinispora arenicola yielded the three macrolide polyketides areni- enicolides A–C (287–289), with arenicolides A showing moderate cytotoxicity [166]. Mac- colides A–C (287–289), with arenicolides A showing moderate cytotoxicity [166]. Macro- rolactin S (290) has been reported in a culture of marine Bacillus sp. [167]. The actinomy- lactin S (290) has been reported in a culture of marine Bacillus sp. [167]. The actinomycete cete strain CNQ-140 in the genus “Marinispora” yielded polyene macrolides marin- strain CNQ-140 in the genus “Marinispora” yielded polyene macrolides marinisporolides A (291isporolides) and B ( 292A (),291 which) and photoisomerizedB (292), which photoisomerized to the geometric to isomers the geometric marinisporolides isomers marin- C–E, suggestingisporolides that C–E, they suggesting may be artefactsthat they [168may]. beS. hygroscopicusartefacts [168].(associated S. hygroscopicus with the(associated marine ﬁshwithHalichoeres the marine bleekeri fish )Halichoeres produced halichoblelidesbleekeri) produced B (293 halichoblelides) and C (294), B which (293) areand cytotoxic C (294), towhich tumor are cells cytotoxic [169]. to tumor cells [169].

TwoTwo 36-membered 36-membered macrolides, macrolides, bahamaolides bahamaolides A A and and B B ( (295295––296296),), werewere obtainedobtained fromfrom thethe culture culture of of a a marine marine actinomycete actinomyceteS. S.sp. sp. isolated isolated fromfrom aa sedimentsediment samplesample collectedcollected atat NorthNorth Cat Cat Cay Cay in in the the Bahamas Bahamas [ 170[170].].

O OH 12 O OH

OH OH OH OH OH OH OH

295 (12E) 296 (12Z) B. subtilis isolated from marine sediment collected at Gageocho (Republic of Korea) was a source of three new glycosylated methoxy-macrolactins (297–299) [171]. Three new 24-membered macrolactones, macrolactins X–Z (300–302), featuring an oxetane, an epoxide, and a tetrahydropyran ring, were isolated from an ethyl acetate extract of a marine B. sp. [172]. Cytotoxic juvenimicin C (303) was produced by a marine-derived actinomycete strain (CNJ-878) [173]. The M. strain FIM07-0019 isolated from shallow coastal waters near the island of Chiloe (Chile) produced a 20-membered macrolide, levantilide C (304) [174].

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Marine actinomycete Salinispora arenicola yielded the three macrolide polyketides arenicolides A–C (287–289), with arenicolides A showing moderate cytotoxicity [166]. Mac- rolactin S (290) has been reported in a culture of marine Bacillus sp. [167]. The actinomycete strain CNQ-140 in the genus “Marinispora” yielded polyene macrolides marinisporolides A (291) and B (292), which photoisomerized to the geometric isomers marinisporolides C–E, suggesting that they may be artefacts [168]. S. hygroscopicus (associated with the marine fish Halichoeres bleekeri) produced halichoblelides B (293) and C (294), which are cytotoxic to tumor cells [169].

Mar. Drugs 2021, 19, 180 Two 36-membered macrolides, bahamaolides A and B (295–296), were obtained31 from of 67 the culture of a marine actinomycete S. sp. isolated from a sediment sample collected at North Cat Cay in the Bahamas [170].

O OH 12 O OH

OH OH OH OH OH OH OH

295 (12E) 296 (12Z) B.B. subtilissubtilis isolatedisolated fromfrom marinemarine sedimentsediment collectedcollected atat GageochoGageocho (Republic(Republic ofof Korea)Korea) waswas aa sourcesource ofof threethree newnew glycosylatedglycosylated methoxy-macrolactinsmethoxy-macrolactins ((297297––299299)[) [171].171]. ThreeThree newnew 24-membered24-membered macrolactones, macrolactones, macrolactins macrolactins X–Z X–Z (300 (300–302–302), featuring), featuring an an oxetane, oxetane, an epoxide,an epox- andide, aand tetrahydropyran a tetrahydropyran ring, ring, were were isolated isolated from from an an ethyl ethyl acetate acetate extract extract of of a amarine marine B.B. Mar. Drugs 2021, 19, x FOR PEER REVIEWsp. [172 ]. Cytotoxic juvenimicin C (303) was produced by a marine-derived actinomycete33 of 70 sp. [172]. Cytotoxic juvenimicin C (303) was produced by a marine-derived actinomycete strainstrain (CNJ-878)(CNJ-878) [[173].173]. TheThe M.M. strainstrain FIM07-0019FIM07-0019 isolatedisolated fromfrom shallowshallow coastalcoastal waterswaters nearnear thethe islandisland ofof ChiloeChiloe (Chile)(Chile) producedproduced aa 20-membered20-membered macrolide,macrolide, levantilidelevantilide CC ((304304)[) [174].174].

InvestigationInvestigation ofof a aS. S.sp. sp. ininsediment sediment from from Heishijiao Heishijiao Bay Bay (Dalian, (Dalian, China) China) yielded yielded 0 0 0 0 0 1111,12′,12-dehydroelaiophylin′-dehydroelaiophylin (305 (305) and) and 11,11 11,11-O-dimethyl-14′-O-dimethyl-14-deethyl-14′-deethyl-14-methylelaiophylin′-methylelaiophy- (306lin )—both(306)—both 6-deoxyhexose-containing 6-deoxyhexose-containing antibiotics—with antibiotics—with the formerthe former exhibiting exhibiting inhibition inhibi- oftion MRSA of MRSA and and vancomycin-resistant vancomycin-resistantEnterococci Enterococcipathogens pathogens [175 [175].]. A A rare rare 18-membered 18-membered macrolide,macrolide, macplocimine macplocimine A A ( 307(307),), was was produced produced by by a a marine-derived marine-derived filamentous filamentous sulfur sulfur bacteria,bacteria,Thioploca Thioplocasp. sp. [ 176[176].]. A A potent potent anthrax anthrax antibiotic, antibiotic, anthracimycin anthracimycin ( 308(308),), was was isolated isolated fromfrom marine marine sediment-derived sediment-derived actinomycete actinomyceteS. sp. S. (Santasp. (Santa Barbara, Barbara, California, California, U.S.A.) U.S.A.) [177]. Fijiolides[177]. Fijiolides A (309) A and (309 B) ( 310and) B were (310 identified) were identified in marine-derived in marine-derived bacteria bacteria of the genus of theNocar- genus diopsis α κ Nocardiopsisand demonstrated and demonstrated inhibition inhibition towards TNF-towards-induced TNF-α NF-inducedB activation NFκB (fijiolideactivation A to(fijiolide A to a greater extent than fijiolide B) [178]. Astolides A (311) and B (312) were obtained from S. hygroscopicus in the alkaline soil of the Saratov region of Russia. They exhibited significant cytotoxicity towards doxorubicin-resistant human leukemia cells [179]. Two hygrolidin macrolides, catenulisporidins A (313) and B (314), were isolated from the actinobacterium Catenulispora sp. KCB13F192 [180].

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a greater extent than ﬁjiolide B) [178]. Astolides A (311) and B (312) were obtained from S. hygroscopicus in the alkaline soil of the Saratov region of Russia. They exhibited signiﬁcant cytotoxicity towards doxorubicin-resistant human leukemia cells [179]. Two hygrolidin Mar. Drugs 2021, 19, x FOR PEER REVIEW 34 of 70 macrolides, catenulisporidins A (313) and B (314), were isolated from the actinobacterium Catenulispora sp. KCB13F192 [180].

CyanobacteriaCyanobacteria CyanobacteriaCyanobacteriaScytonema Scytonema mirabile mirabileBY-8-1, BY-8-1,S. S. burmanicum burmanicumDO-4-1, DO-4-1, and andS. S. ocellatum ocellatumDD-8- DD- 1,8-1, FF-65-1 FF-65-1 and and FF-66-3 FF-66-3 have have been been reported reported to produce to produce tolytoxin tolytoxin (315 ().315S.). burmanicum S. burmanicumDO-4-1 DO- also4-1 yielded also yielded scytophycin scytophycin B (316 B), ( 6-hydroxyscytophycin316), 6-hydroxyscytophycin B (317 ),B 19-O-demethylscytophycin(317), 19-O-demethylscyto- C(phycin318), 6-hydroxy-7-O-methylscytophycinC (318), 6-hydroxy-7-O-methylscytophycin E (319 E), ( and319), scytophycinand scytophycin E (320 E ()[320181) [181].]. A macrolide,A macrolide, oscillatoriolide oscillatoriolide (321 (321), was), was isolated isolated from from Japanese JapaneseOscillatoria Oscillatoriasp. sp. andand demon- stratedstrated inhibition inhibition towards towards fertilized fertilized echinoderm echinoderm eggs eggs [ 182[182].]. TheThe marinemarine cyanobacteriumcyanobacterium LyngbyaLyngbya bouillonii bouillonii(L. (L. bouillonii bouillonii)) collected collected on on Laing Laing Island Island (Papua (PapuaNew New Guinea)Guinea) producedproduced lyngbyalosidelyngbyaloside (322 (322)[)183 [183]] in in addition addition to to the the macrolides macrolides laingolide laingolide ( 323(323),), madangolide madangolide ( (324324),), and laingolide A (325) [184,185], and the glycosidic macrolide lyngbouilloside (326), for which the configuration of C-11 was later revised [186,187].

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Mar. Drugs 2021, 19, x FOR PEER REVIEW 35 of 70 and laingolide A (325)[184,185], and the glycosidic macrolide lyngbouilloside (326), for which the conﬁguration of C-11 was later revised [186,187]. O OMe

O OMe OMe CHO R1 N O OH O OMe Me

OR2 O

315 R1 =OH,R2 =Me 316 R1 =H,R2 =H 317 R1 =OH,R2 =H

OR4

O OMe OMe CHO R1 N O OH O OMe Me

OR2 O

318 R1 =R2 =R3 =R4 =H 319 R1 =R3 =OH,R2 =R4 =Me 320 R1 =R2 =H,R3 =OH,R4 =Me

Br OH OH OH OH OH OH O OMe O OH O 321

O OH Me O O O O O O N N O O Br O Me MeO OMe O OH OMe R

322 323 324 R=H 325 R=Me TwoTwo glycosylatedglycosylated swinholides,swinholides, ankaraholidesankaraholides A (327) and B (328), together with with swinholideswinholide A A previously previously obtainedobtained fromfrom thethe marinemarine sponge T. swinhoei [91],[91], were were isolated isolated fromfrom cyanobacterium cyanobacterium GeitlerinemaGeitlerinema sp.sp. collectedcollected in Madagascar [188]. [188]. Cyanolide Cyanolide A A ( (329329),), demonstratingdemonstrating signiﬁcantsignificant molluscicidal molluscicidal activity activity towards towards the the snail snail vector vector BiomphalariaBiomphalaria gla- glabratabrata, was, was also also isolated isolated from from L.L. bouillonii bouillonii fromfrom Papua Papua New New Guinea Guinea [189]. [189]. Biselyngbyolide Biselyngbyolide A(A 330(330)) was was isolated isolated from fromL. L.sp. sp. and and showed showed strong strong apoptosis-inducing apoptosis-inducing activity activity in in HeLa HeLa S3 andS3 and HL60 HL60 cells cells [190 [190],], while while its analogs,its analogs, biselyngbyolide biselyngbyolide B–D B–D (331 (331–333–333), were), were produced produced by anotherby anotherL. cyanobacterium L. cyanobacteriumsampled sampled on Tokunoshimaon Tokunoshima Island Island (Japan) (Japan) [191 [191].]. Biselyngbyolide Biselyngbyo- Blide exhibited B exhibited inhibition inhibition and and apoptosis-inducing apoptosis-inducing activity activity in in HeLa HeLa S3 S3 and and HL60HL60 cells and and 2+ increasedincreased the the cytosolic cytosolic Ca Ca2+ concentration in HeLa S3 S3 cells cells [191]. [191].

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TheThe Caribbean Caribbean OkeaniaOkeania cyanobacteriumcyanobacterium VQR28MAR11-2VQR28MAR11-2 has has been been reported reported to to pro- pro- duceduce polycavernoside polycavernoside DD ((334334)[) [192],192], whilewhile fourfour cytotoxiccytotoxic macrolides,macrolides, leptolyngbyolidesleptolyngbyolides A–DA–D ( 335(335––338338),), have have been been isolated isolated fromfromLeptolyngbya Leptolyngbya sp.sp. collectedcollected in Okinawa [193]. [193].

DinoflagellatesDinoflagellates AmphidinolideAmphidinolide E ( 339)) was was isolated isolated from from the the Okinawan Okinawan flatworm flatworm AmphiscolopsAmphiscolops sp. sp.(Amphis. (Amphis. sp.) sp.)and exhibited and exhibited cytotoxicity cytotoxicity towards towards murine murine leukemia leukemia cells L1210 cells and L1210 L5178Y and L5178Y[194]. The [194 absolute]. The absolute stereochemistry stereochemistry of amphidinolide of amphidinolide E was Edetermined was determined by NMR by spec- NMR spectroscopy,troscopy, modified modified Mosher’s Mosher’s method method and the and exciton the exciton chirality chirality method method [195]. The [195 potent]. The Mar. Drugs 2021, 19, x FOR PEER REVIEW 38 of 70 potentcytotoxic cytotoxic macrolides macrolides amphidinolides amphidinolides F (340), FG ((340341),) and G (341 H ()342 and) were H (342 produced) were produced by dino- byflagellate dinoflagellate AmphidiniumAmphidinium sp. (Amphid.sp. (Amphid. sp.) associatedsp.) associated with thewith Okinawan the Okinawan flatworm flatworm Amphis. Amphis.breviviridis breviviridis [196,197].[196 ,197].

Amphidinolides G and H were elucidated by X-ray diffraction analysis and interconversion [198]. Amphidinolides J (343) and K (344) were isolated from symbiotic dinoflagellate Amphid. sp. and later synthesized [199,200]. Amphidinolides B1 (345), B2 (346) and B3 (347) were also isolated from Amphid. sp. [201–203], as were amphidinolides L (348), M (349) and N (350) [204–206].

The structure of amphidinolide N was later revised and stereochemistry assigned [207]. Cytotoxic 15-membered macrolides, amphidinolides O (351) and P (352), were also

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AmphidinolidesAmphidinolidesAmphidinolides GG G andand and H H were were elucidated elucidated elucidated by by byX-ray X-ray X-ray diffraction diffraction diffraction analysis analysis analysis and andintercon- and intercon- intercon- versionversionversion [198 [198].]. Amphidinolides AmphidinolidesAmphidinolides JJ ((J343 (343) and ) and K K (K (344344 (344)) were were) were isolated isolated isolated from from from symbiotic symbiotic symbiotic dinoflag- dinoﬂagel- dinoflagellate Amphid. sp. and later synthesized [199,200]. Amphidinolides B1 (345), B2 (346) and lateellateAmphid. Amphid.sp. sp. and and later later synthesized synthesized [199 [199,200].,200]. Amphidinolides Amphidinolides B1 B1 (345 (345),), B2 B2 (346 (346) and) and B3 (347) were also isolated from Amphid. sp. [201–203], as were amphidinolides L (348), M B3B3 (347 (347) were) were also also isolated isolated from fromAmphid. Amphid.sp. sp. [201 [201–203],–203], as as were were amphidinolides amphidinolides L L (348 (348),), M M (349) and N (350) [204–206]. (349(349) and) and N N (350 (350)[)204 [204–206].–206].

TheThe structure structure of of amphidinolide amphidinolide N N was was later later revised revised and and stereochemistry stereochemistry assigned assigned [207 ]. [207]. Cytotoxic 15-membered macrolides, amphidinolides O (351) and P (352), were also Cytotoxic 15-membered macrolides, amphidinolides O (351) and P (352), were also isolated from Amphis. sp. [208]. The absolute stereochemistry of amphidinolide P was confirmed The structure of amphidinolide N was later revised and stereochemistry assigned by convergent total synthesis [209]. The 12-membered macrolide amphidinolide Q (353), [207]. Cytotoxic 15-membered macrolides, amphidinolides O (351) and P (352), were also showing moderate cytotoxicity towards murine lymphoma L1210 cells in vitro (IC50 6.4 µg/mL), was obtained from the symbiotic flatworm Amphis. sp. of dinoflagellate Amphid.

sp. [210]. Amphidinolide Q was synthesized stereoselectively by combined Julia coupling, Myers alkylation, and Yamaguchi lactonization [211]. The absolute conﬁgurations at ﬁve chiral centers in amphidinolide Q were determined as 4R, 7R, 9S, 11R, and 13R on the

basis of NMR analysis and a modified Mosher’s method [212]. Cytotoxic macrolides amphidinolides R (354) and S (355) were also isolated from Amphid. sp. [213]. The 20- membered macrolide amphidinolide U (356) was obtained from a cultured Amphid. sp. Y-56 isolated from the flatworm Amphis. sp. in Okinawa [214]. A 25-membered macrolide, amphidinolide C3 (357), was also obtained from the Y-56 dinoflagellate strain and exhib- Mar. Drugs 2021, 19, 180 37 of 67

ited cytotoxicity towards P388, L1210 and KB cells [215]. Y-56 has also been reported to yield the 19-membered macrolide amphidinolide T (T1) (358)[216], while the A. sp. Y-5 produced the 14-membered polyene amphidinolide V (359)[217]. Total synthesis of amphidinolide V was accomplished and the absolute stereochemistry assigned [218]. Analogs of amphidinolides T2 (360), T3 (361), T4 (362), and T5 (363) were produced by Amphid. sp. [219,220]. Amphidinolides H2 (364), H3 (365), H4 (366), H5 (367), G2 (368), and G3 (369) were produced by Amphid. sp. strain Y-42 isolated from marine acoel flatworms Amphis. sp. The absolute configurations of these compounds were determined by coupling constant data, distance geometry calculations, and chemical means [221]. Amphidinolide T2 was synthesized using methyl (S)-lactate via a 16-step linear sequence [222]. Amphidinolide W (370) was isolated from an Amphid. sp. and the absolute stereochemistry determined by a combination of J-based configuration analysis and modified Mosher’s method [223]. Total synthesis was later achieved and its C-6 stereochemistry revised [224]. Amphidinolides X (371) and Y (372) were produced by symbiotic dinoflagellate Amphid. sp. strain Y-42 from Okinawan Amphis. species. Amphidinolide Y exists as a 9:1 equilibrium mixture of the 6-keto- and 6(9)-hemiacetal forms (373). Both amphidinolides X and Y showed significant cytotoxicity against murine lymphoma L1210 and human epidermoid carcinoma KB cells in vitro [225,226]. Two 26-membered macrolides, amphidinolides B6 (374) and B7 (375), Mar. Drugs 2021, 19, x FOR PEER REVIEWwere isolated from a culture of a symbiotic dinoflagellate Amphid. sp. from Amphis.40 of 70 sp. and

demonstrated cytotoxicity against human B lymphocyte DG-75 cells [227]. Amphidinolide C2 (376) was isolated from dinoﬂagellate Amphid. sp. (Y-71 strain) [228]. R

O H H O O O O HO H O O OH

351 R=O 353

352 R=CH2

HO O OH OH

O O O O

C3H7 C3H7

354 355 O O OH O O O O OH O O HO OH O O O 356 OH O 357

OH O O O H HO H

O C H HO 3 7 O O O O R O O O 358 359 360 R=OH 361 R = H

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TheTheAmphid. Amphid.strain strain S1-36-5 S1-36-5 yielded yielded the the highly highly cytotoxic cytotoxic 26-membered 26-membered caribenolide caribenolide II (377(377)[229) [229].]. TheThe 13-membered 13-membered macrolide macrolide amphidinolactone amphidinolactone A ( 378A (378) and) and a 26-membered a 26-membered macrolide macro- amphidinolactonelide amphidinolactone B (379 )B have (379) beenhave isolatedbeen isolated from from cultures cultures of Amphid. of Amphid.sp. sp. Amphidino- Amphidi- lactonenolactone A was A synthesizedwas synthesized totally totally via a via ring-closing a ring-closing metathesis metathesis reaction reaction and and the absolutethe abso- configurationlute configuration was elucidated was elucidated [8,230, 231[8,230,231]]. The vasoconstrictors. The vasoconstrictors zooxanthellatoxins zooxanthellatoxins A (380 A) and(380 B ()381 and) were B (381 isolated) were fromisolated a symbiotic from a symbiotic dinoflagellate dinoflagellateSymbiodinium Symbiodiniumsp. (Y-6 sp. strain), (Y-6 whichstrain), was which associated was associated with Amphis. with Amphis.sp. [232 sp.,233 [232,233].]. Bioassay-guided Bioassay-guided fractionation fractionation of of a butanola butanol extract extract of the of the tropical tropical dinoflagellate dinoflagellateProrocentrum Prorocentrum maculosum maculosumFaust Faust yielded yieldedthe the fast-acting toxin prorocentrolide B (382)[234]. Hoffmanniolide (383) was identified in the

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fast-acting toxin prorocentrolide B (382) [234]. Hoffmanniolide (383) was identified in the marine dinoflagellate P. hoffmannianum [235]. The 20-membered iriomoteolide-1a (384), - marine1b (385 dinoﬂagellate) and -1c (386P. hoffmannianum) were isolated[235 from]. The a 20-memberedmarine benthic iriomoteolide-1a dinoflagellate (384 Amphid.), -1b sp. (385(strain) and HYA024) -1c (386) were[236,237]. isolated from a marine benthic dinoﬂagellate Amphid. sp. (strain HYA024) [236,237]. O OH OH OH O HO O OH O O

OH O 378 379

OH OH OH O O OH

HO OH OH OH OH HO NaO SO R1 3 OH OH OH

O O OH OH OH OH OH HO

HO OH R2 OH O O O OH OH OH OH HO OH HO OH R3 O HO OH O NH OH OH HO O

HO OH OH HO OH OH

380 R1 =H;R2 =R3 =OH 381 R1 =OH;R2 =R3 =H

OH OH OH O HO HO OH N O O OH OH O

OH OH O OH OSO3 HO OH OH O O O OSO3H 383 HO OH OH OH 382

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The cytotoxic 23-membered iriomoteolide-2a (387) was also obtained from Amphid. sp. [238]. The 15-membered macrolide iriomoteolide-3a (388) containing an allyl epoxide wasThe obtainedThe cytotoxic cytotoxic from 23-membered Amphid.23-membered sp. iriomoteolide-2a strain iriomoteolide-2a HYA024( 387and) waswas(387 also)potently was obtained also cytotoxic obtained from Amphid. to fromhuman Amphid. B sp. [238]. The 15-membered macrolide iriomoteolide-3a (388) containing an allyl epoxide lymphocytesp. [238]. The DG-75 15-membered cells and Epstein–Barr macrolide iriomoteolide-3a virus (EBV)-infected (388 )Raji containing cells [239]. an Iriomote-allyl epoxide wasolide-4a obtained (389 from) andAmphid. -5a (390sp.) were strain isolated HYA024 from and wasa benthic potently dinoflagellate cytotoxic to humanAmphid. B sp. lym- (strain phocytewas obtained DG-75 cells from and Amphid. Epstein–Barr sp. virusstrain (EBV)-infected HYA024 and Raji was cells potently [239]. Iriomoteolide-4a cytotoxic to human B HYA024) and showed moderate cytotoxicity towards human B lymphocytes DG-75 [240]. (389lymphocyte) and -5a (390 DG-75) were cells isolated and from Epstein–Barr a benthic dinoﬂagellate virus (EBV)-infectedAmphid. sp. Raji (strain cells HYA024) [239]. Iriomote- The 15- and 19-membered iriomoteolide-9a (391) and -11a (392) were cytotoxic towards andolide-4a showed (389 moderate) and -5a cytotoxicity (390) were towards isolated human from Ba lymphocytesbenthic dinoflagellate DG-75 [240 Amphid.]. The 15- sp. (strain human cervix adenocarcinoma HeLa and murine hepatocellular carcinoma MH134 cells andHYA024) 19-membered and showed iriomoteolide-9a moderate (cytotoxicity391) and -11a towards (392) were human cytotoxic B lymphocytes towards human DG-75 [240]. cervix[241].The 15- adenocarcinoma and 19-membered HeLa and iriomoteolide-9a murine hepatocellular (391) and carcinoma -11a ( MH134392) were cells cytotoxic [241]. towards human cervix adenocarcinoma HeLa and murine hepatocellular carcinoma MH134 cells [241].

Iriomoteolide-10aIriomoteolide-10a (393 (393) and) and -12a -12a (394 (394)) were were isolated isolated from from a a marine marine dinoﬂagellatedinoflagellate Am- Amphid.phid. sp.sp. (KCA09053 (KCA09053 strain) strain) with with iriomoteolide-10a iriomoteolide-10a being being cytotoxic cytotoxic to human cervixcervix adenocarcinoma HeLa and murine hepatocellular carcinoma MH134 cells [242]. The 62-mem- Iriomoteolide-10a (393) and -12a (394) were isolated from a marine dinoflagellate Am- phid. sp. (KCA09053 strain) with iriomoteolide-10a being cytotoxic to human cervix adenocarcinoma HeLa and murine hepatocellular carcinoma MH134 cells [242]. The 62-mem-

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bered novel polyol macrolide symbiodinolide (395) was isolated from the symbiotic dino- adenocarcinoma HeLa and murine hepatocellular carcinoma MH134 cells [242]. The 62- flagellate Symbiodinium sp. (S. sp.) and showed significant voltage-dependent N-type Ca2+ membered novel polyol macrolide symbiodinolide (395) was isolated from the symbiotic channel-opening activity at 7 nM and immediately ruptured the surface tissue of the acoel dinoflagellate Symbiodinium sp. (S. sp.) and showed significant voltage-dependent N-type Caflatworm2+ channel-opening Amphis. sp. at activity 2.5 mM at 7[14]. nM The and stereochemistries immediately ruptured of C-23–C-34 the surface were tissue revised of by thestereoselective acoel flatworm synthesisAmphis. andsp. the at 2.5 (17 mMS,18 [14R,21]. TheR) configurations stereochemistries were of C-23–C-34determined were by syn- revisedthesis [243,244]. by stereoselective The synthesis synthesis of andthe C-33–C-42 the (17S,18 Rfragment,21R) configurations elucidated were(36S,40 determinedS) and (C-1′– byC-25 synthesis′) [243–245]. [243, 244The]. dinoflagellate-der The synthesis of theived C-33–C-42 macrolide fragment acuminolide elucidated A (396 (36)S caused,40S) and potent (C-1stimulation0–C-250)[ of243 actomyosin–245]. The dinoflagellate-derived ATPase activity [246]. macrolide The 25-membered acuminolide polyketide-derived A (396) caused potentmacrocycle stimulation belizentrin of actomyosin (397) was ATPaseisolated activity from cultures [246]. The of the 25-membered marine dinoflagellate polyketide- Pro- derivedrocentrum macrocycle belizeanum belizentrin [247]. Gymnodimine (397) was isolated D (398 from) was cultures extracted of the marineand purified dinoflagellate from a cul- Prorocentrumture of dinoflagellate belizeanum Alexandrium[247]. Gymnodimine ostenfeldii Dfrom (398 the) was Baltic extracted Sea [248]. and purifiedSymbiodinolactone from a cultureA (399) of was dinoflagellate isolated fromAlexandrium a culture ostenfeldii of the symbioticfrom the Baltic marine Sea dinoflagellate [248]. Symbiodinolactone S. sp. [249]. A(399) was isolated from a culture of the symbiotic marine dinoflagellate S. sp. [249]. OH

O O O O H H O O O HO HO O O

393 394

OH OH OH O O OH

HO OH OH OH OH HO

HO NaO3SO OH OH OH

O O OH OH OH OH OH

HO OH OH OH O O HO O OH OH OH OH HO OH HO OH OH O HO OH O NH OH OH HO O

HO OH OH HO OH OH

395

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2.1.3. Red algae

2.1.3.Polycavernosa Red algae tsudai (Gracilaria edulis) contained the macrolide polycavernoside A 2.1.3. Red algae (400), which led to human illness and death in Guam [250]. The relative configuration of PolycavernosaPolycavernosa tsudai tsudai(Gracilaria (Gracilaria edulis edulis) contained) contained the macrolidethe macrolide polycavernoside polycavernoside A A polycavernosolide A was assigned and the sugar substructure was synthesized [251,252]. (400(400),), which which led led to humanto human illness illness and and death death in Guam in Guam [250 ].[250]. The relativeThe relative conﬁguration configuration of of polycavernosolideItspolycavernosolide structure was A wasAconfirmed was assigned assigned andby andtotal the the sugar synthesi suga substructurer substructures in a wasstereocontrolled synthesizedwas synthesized [251 manner,252 [251,252].]. [253]. Poly- ItscavernosidesIts structure structure was was conﬁrmedA2 confirmed (401), by A3 total by (402 total synthesis), Bsynthesi (403 in) a ands stereocontrolled in aB2 stereocontrolled (404) were manner also manner [253 obtained]. Polycav- [253]. fromPoly- Polycaver- ernosidesnosacavernosides red A2algae (401 A2 ),[254]. ( A3401 (),402 A3), B(402 (403), )B and (403 B2) and (404 )B2 were (404 also) were obtained also obtained from Polycavernosa from Polycaver- rednosa algae red [ 254algae]. [254].

Two analogs of polycavernosolide A, polycavernosides C (405) and C2 (406), were isolated from the red alga Gracilaria edulis (G. edulis) [255]. Manauealides A–C (407–409) wereTwo isolated analogs from extractsof polycavernosol of red alga G.ide coronopifolia A, polycavernosides [256]. Anhydrodebromoaplysia- C (405) and C2 (406), were isolatedtoxin (410 from) and themanauealide red alga C Gracilaria were extracted eduli froms (G. Hawaiianedulis) [255]. G. coronopifolia Manauealides [257]. Inves- A–C (407–409) tigation of Fijian red alga Callophycus serratus (C. serratus) led to the isolation of three diter- were isolated from extracts of red alga G. coronopifolia [256]. Anhydrodebromoaplysia- pene-benzoate natural products: bromophycolides A (411) and B (412), and a nonhalogen- toxinated compound(410) and manauealide(413). Bromophycolides C were extracted A and B exhibited from Hawaiian moderate G. antibacterial coronopifolia and [257]. Inves- tigation of Fijian red alga Callophycus serratus (C. serratus) led to the isolation of three diterpene-benzoate natural products: bromophycolides A (411) and B (412), and a nonhalogenated compound (413). Bromophycolides A and B exhibited moderate antibacterial and

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Two analogs of polycavernosolide A, polycavernosides C (405) and C2 (406), were isolated from the red alga Gracilaria edulis (G. edulis)[255]. Manauealides A–C (407–409) were isolated from extracts of red alga G. coronopifolia [256]. Anhydrodebromoaplysiatoxin Mar. Drugs 2021, 19, x FOR PEER REVIEW(410) and manauealide C were extracted from Hawaiian G. coronopifolia [257]. Investigation46 of 70

of Fijian red alga Callophycus serratus (C. serratus) led to the isolation of three diterpene- benzoate natural products: bromophycolides A (411) and B (412), and a nonhalogenated compoundantifungal (properties413). Bromophycolides while bromophycolides A and B exhibited A demonstrated moderate potent antibacterial anti-HIV andand anti-mod- fungalerate propertiescytotoxic activities while bromophycolides [258]. Bromophycolides A demonstrated C–I (414 potent–420) anti-HIVwere also and isolated moderate from cytotoxicextracts activitiesof C. serratus [258.]. All Bromophycolides the bromophycolides C–I (414 exhibited–420) were modest also isolatedantineoplastic from extracts activity oftowardsC. serratus a range. All theof human bromophycolides tumor cell exhibitedlines while modest bromophycolides antineoplastic F and activity I showed towards weak a rangeantifungal of human activity tumor [259]. cell lines while bromophycolides F and I showed weak antifungal activity [259].

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Further investigation of the C. serratus extract yielded a series of unusual antimalarial diterpene-benzoateFurtherFurther investigation investigation macrolid of the ofes, the C.bromophycolides serratusC. serratusextract extract yieldedJ–Q yielded (421 a– series428 a series), with of unusualof a unusualrange antimalarial of antimalarialmoderate diterpene-benzoateto diterpene-benzoatestrong antimicrobial macrolides, macrolid and anticancer bromophycolideses, bromophycolides propertiesJ–Q [260]. J–Q (421 C. (–421 serratus428–),428 with), was with a rangealso a range a ofsource moderate of moderate of the toditerpene-benzoate strongto strong antimicrobial antimicrobial macrolides and and anticancer anticancer bromophycolides properties properties [ 260 R–U[260].]. C. (C.429 serratus serratus–432). waswasThese alsoalso demonstrated a source of of the themodestditerpene-benzoate diterpene-benzoate cytotoxicity toward macrolides selected bromophycolidesbromophycolides human cancer cell R–U R–U lines (429 ( 429while–432–432 ).bromophycolide These). These demonstrated demonstrated S was modestactivemodest (at cytotoxicity submicromolarcytotoxicity toward toward concentrations) selected selected human human against cancer cancer the cell humancell lines lines while malaria while bromophycolide bromophycolideparasite Plasmodium S was S was activefalciparumactive (at (at submicromolar (Pla. submicromolar falciparum concentrations)) [261]. concentrations) against against the the human human malaria malaria parasite parasitePlasmodium Plasmodium falciparumfalciparum(Pla. (Pla. falciparum falciparum)[261) [261].].

TheTheα α-pyrone-pyrone macrolidesmacrolides neurymenolidesneurymenolides AA ((433433)) andand BB ( 434(434)) were were obtained obtained from from thethe FijianFijianThe redred α-pyrone alga algaNeurymenia Neurymenia macrolidesfraxinifolia fraxinifolia neurymenolides[ 262[262].]. TheThe A brown(brown433) and algaalga B Ecklonia(Ecklonia434) were stoloniferastolonifera obtained pro-pro- from ducedducedthe Fijian ecklonialactonesecklonialactones red alga Neurymenia CC ((435435)) andand fraxinifolia DD ((436436)) containing[262].containing The brown aa 14-membered14-membered alga Ecklonia lactonelactone stolonifera moiety,moiety, pro- andandduced ecklonialactones ecklonialactones ecklonialactones E E ( 437(437 C)) and and(435 F )F ( and438(438), ),D with with(436 a )a 16-membered containing16-membered a 14-membered moiety moiety [ 263[263].]. The lactoneThe absolute absolute moiety, and ecklonialactones E (437) and F (438), with a 16-membered moiety [263]. The absolute

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configurationsconfigurations of of ecklonialactones ecklonialactones A, A, B andB and E were E were determined determined from from chiroptical chiroptical data [data264]. Eight[264]. oxylipins Eight oxylipins (439–446 ()439 with–446 a) macrolide with a macrolide scaffold andscaffold one cymathere-typeand one cymathere-type oxylipin with ox- anylipin open with ring an were open isolated ring were from isolated the brown from algathe brownEisenia alga bicyclis Eisenia. The bicyclis absolute. The configura- absolute tionsconfigurations of compounds of compounds439–443 and 439446–443were and determined446 were determined by NMR by spectroscopy NMR spectroscopy with the relativewith the stereochemistry relative stereochemistry at C-9 in at446 C-9remaining in 446 remaining unassigned unassigned [265].The [265]. metamorphosis- The metamor- enhancingphosis-enhancing macrodiolide macrodiolide luminaolide luminaolide (447) was (447 isolated) was isolated from thefrom crustose the crustose coralline coralline alga Hydrolithonalga Hydrolithon reinboldii reinboldiiand its and absolute its absolute relative relative configuration configuration was determined was determined by NMR by NMR spec- troscopyspectroscopy with with the relationships the relationships of the of the two two side side chains chains to to the the macrolide macrolide ringring remaining unassignedunassigned [ 266[266,267].,267].

2.1.4.2.1.4. Cnidarians Cnidarians TwoTwo avermectin avermectin congeners, congeners, avermectins avermectins B1c B1c ((448448)) andand B1eB1e (449), exhibiting moderate moderate antifoulingantifouling activity activity were were obtained obtained fromfromAnthrogorgia Anthrogorgia caeruleacaerulea collectedcollected in the South China China SeaSea [ 268[268].].

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2.1.5. Bryozoans 2.1.5.2.1.5. Bryozoans Bryozoans Large-scale isolation of bryostatin 1 (450) from the marine bryozoan Bugula neritina Large-scale isolation of bryostatin 1 (450) from the marine bryozoan Bugula neritina (L.) wasLarge-scale carried out isolationto provide of material bryostatin for clinical 1 (450 study) from [269]. the Bryostatinmarine bryozoan 2 (451) has Bugula been neritina (L.) was carried out to provide material for clinical study [269]. Bryostatin 2 (451) has been converted(L.) was carriedto bryostatin out to 1 provideand bryostatin material 12 ( 452for )clinical by selective study protection [269]. Bryostatin and deprotection 2 (451) has been converted to bryostatin 1 and bryostatin 12 (452) by selective protection and deprotection involvingconverted the to C-26 bryostatin hydroxyl 1 and group bryostatin [270]. The 12 stereochemistries (452) by selective of protection bryostatins and 1 and deprotection 2 involving the C-26 hydroxyl group [270]. The stereochemistries of bryostatins 1 and 2 wereinvolving assigned the by C-26 X-ray hydroxyl analysis of group p-bromobenzoate [270]. The (453stereochemistries) [271], while the ofassignments bryostatins of 1 and 2 were assigned by X-ray analysis of p-bromobenzoate (453)[271], while the assignments bryostatinwere assigned 1 from by 1H- X-ray and analysis13C-NMR of were p-bromobenzoate later revised [272]. (453 Bryostatin) [271], while 3 was the isolated assignments of of bryostatin 1 from 1H- and 13C-NMR were later revised [272]. Bryostatin 3 was isolated from B. neritina and reinvestigation1 13 of 2D NMR spectroscopic data revised the structure frombryostatinB. neritina 1 andfrom reinvestigation H- and C-NMR of 2D NMR were spectroscopic later revised data [272]. revised Bryostatin the structure 3 was of isolated of bryostatin 3 to structure 454 [273]. bryostatinfrom B. 3neritina to structure and 454reinvestigation[273]. of 2D NMR spectroscopic data revised the structure of bryostatin 3 to structure 454 [273].

FurtherFurther investigation investigation ofof B. neritina neritina ledled to to the the identification identiﬁcation of ofbryostatins bryostatins 14 ( 14455 (455) and) and15 ( 15456 (456) [274].)[274 The]. The structures structures of bryostatin of bryostatin 3 and 3 and 20-epi-bryostatin 20-epi-bryostatin 3 (457 3 (457) have) have been been elu-

elucidatedcidated by by NMR NMR spectroscopy spectroscopy [271,273,275]. [271,273,275 Bryostatin]. Bryostatin 3 was 3 was then then synthesized synthesized in inan anen- enantioselectiveantioselectiveFurther manner mannerinvestigation [276]. [276]. Bryostatin Bryostatin of B. neritina 10 10 ( 458 led) wasto the determineddetermined identification toto bebe the theof majorbryostatins major cytotoxic cytotoxic 14 ( 455) and componentcomponent15 (456) [274]. of ofB. B.neritina Theneritina structures[ 277[277].]. Three Three of bryostatin additional additional antileukemic 3antileukemic and 20-epi-bryostatin macrolides, macrolides, bryostatins 3bryostatins (457) have 16 16 been elu- (459(459cidated),), 17 17 (460 ( 460by), ),NMR and and 18 18spectroscopy (461 (461), were), were isolated isolated [271,273,275]. in in trace trace amounts amountsBryostatin from fromB. 3 neritinawasB. neritina thenfrom synthesizedfrom the the Gulf Gulf of in an en- Mexicoofantioselective Mexico [278 [278].]. Antineoplastic mannerAntineoplastic [276]. bryostatin bryostatinBryostatin 19 (462 19 10) ( was462 (458) isolated was) was isolated determined from B.from neritina B. toneritinacollected be the collected major from cytotoxic the South China Sea [279]. A further member of the bryostatins, bryostatin 20 (463), was fromcomponent the South of China B. neritina Sea [279]. [277]. A further Three memberadditional of the antileukemic bryostatins, macrolides,bryostatin 20 bryostatins(463), 16 produced by the larvae of B. neritina and its structure determined by spectral comparison was(459 produced), 17 (460 by), and the 18larvae (461 of), B.were neritina isolated and itsin tracestructure amounts determined from byB. neritinaspectral fromcom- the Gulf withparison previously with previously described described bryostatins bryostatins [280]. Bioassay-guided [280]. Bioassay-guided isolation elucidatedisolation elucidated the ﬁrst of Mexico [278]. Antineoplastic bryostatin 19 (462) was isolated from B. neritina collected memberthe first ofmember a new familyof a new of macrocycles,family of macrocycles, neristatin neristatin 1 (464), which 1 (464 was), which cytotoxic was towardscytotoxic thetowardsfrom P388 the lymphocytic the South P388 lymphocyticChina leukemia Sea [279]. cellleukemia line A [further281 cell]. line member [281]. of the bryostatins, bryostatin 20 (463), was produced by the larvae of B. neritina and its structure determined by spectral comparison with previously described bryostatins [280]. Bioassay-guided isolation elucidated the first member of a new family of macrocycles, neristatin 1 (464), which was cytotoxic towards the P388 lymphocytic leukemia cell line [281].

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2.1.6.2.1.6. MollusksMollusks AplysiatoxinAplysiatoxin (465 (465) was) was isolated isolated from from an extract an extract of the of sea the hare seaStylocheilus hare Stylocheilus longicauda longicauda andand synthesizedsynthesized [282 [282,283].,283]. The The sea sea hare hareAplysia Aplysia kurodai kurodai Baba containedBaba contained the novel the and novel po- and po- tentlytently cytotoxic cytotoxic macrolides macrolides aplyronines aplyronines A (466 A), (466 B (467), B) and(467 C) (and468). C The (468 absolute). The absolute conﬁgu- config- rationuration of aplyronineof aplyronine A was A assignedwas assigned following following enantioselective enantioselective synthesis synthesis of its degradation of its degrada- productstion products and total and synthesis total synthesis was also was reported also [re284ported,285]. Five[284,285]. cytotoxic Five macrolides, cytotoxic aply- macrolides, ronines D–H (469–473), were also isolated from the Japanese sea hare Aplysia kurodai [286]. aplyronines D–H (469–473), were also isolated from the Japanese sea hare Aplysia kurodai [286]. The 22-membered macrolide dolabelide A (474) and the diacetyl derivative dolabelide B (475), both cytotoxins, were obtained from the Japanese sea hare Dolobella auricularia [287]. Cytotoxic 24-membered macrolides dolabelides C (476) and D (477) were also isolated from Dolabella auricularia, the originally assigned structure of dolabelide D being confirmed by total synthesis [288,289]. Five unprecedented C-16 and C-18 fatty acid

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Mar. Drugs 2021, 19, x FOR PEER REVIEWThe 22-membered macrolide dolabelide A (474) and the diacetyl derivative dolabelide51 of B 70 (475), both cytotoxins, were obtained from the Japanese sea hare Dolobella auricularia [287]. Cytotoxic 24-membered macrolides dolabelides C (476) and D (477) were also isolated from Dolabella auricularia, the originally assigned structure of dolabelide D being confirmed by totallactones synthesis named [288 aplyolides,289]. Five A–E unprecedented (478–482) were C-16 found and in C-18 the fattyskin acidof the lactones marine namedmollusk aplyolidesAplysia depilans A–E (,478 and–482 were) were ichthyotoxic found in to the the skin mosquito of the marinefish Gambusia mollusk affinisAplysia [290]. depilans The ste-, andreochemistry were ichthyotoxic of (-)-aplyolide to the mosquito A was confirmed fish Gambusia by synthesis affinis [290 [291]]. The and stereochemistry the absolute stereo- of (-)-aplyolidechemistries Aof wasaplyolides confirmed B–E bywere synthesis confirmed [291 by] andtotal the synthesis absolute [292,293]. stereochemistries Pectenotoxins of aplyolides4 (483) and B–E 7 (484 were) were confirmed isolated by from total Patinopecten synthesis [ 292yessoensis,293]. Pectenotoxinsscallops [294]. 4LC–MS (483) and analy- 7 (484sis) of were shellfish isolated extracts from identifiedPatinopecten PTX-12 yessoensis (485scallops) as a pectenotoxin [294]. LC–MS accumulating analysis of in shellfish Norwe- extractsgian blue identified mussels PTX-12 (Mytilus (485 )edulis as a pectenotoxin) and cockles accumulating (Cerastoderma in edule Norwegian) [295]. blueDolastatin mussels 19 (Mytilus(486), containing edulis) and a cockles14-membered (Cerastoderma macrocyclic edule)[ lactone295]. Dolastatin linked to 19a 2,4-di- (486),O containing-methyl-L- aR- 14-memberedrhamnopyranoside, macrocyclic was lactonefound in linked the Gulf to a of 2,4-di- CaliforniaO-methyl-L- in theR shell-less-rhamnopyranoside, mollusk Dolabella was foundauricularia in the [296]. Gulf The of California stereochemistry in the of shell-less (+)-dolast molluskatin 19 wasDolabella confirmed auricularia by total[296 synthesis]. The stereochemistry[297]. of (+)-dolastatin 19 was confirmed by total synthesis [297].

2.1.7.2.1.7. Tunicates Tunicates TwoTwo 24-membered 24-membered macrolide macrolide sulfates sulfates showing showing antineoplastic antineoplastic activity, activity, iejimalides iejimalides C C (487(487) and) and D D (488 (488),), were were isolated isolated from from the the Okinawan Okinawan tunicate tunicateEudistoma Eudistomacf. cf.rigida rigida[ 298[298].]. TwoTwo cytotoxic cytotoxic macrolides, macrolides, lobatamides lobatamides A A (489 (489) and) and B B (490 (490),), were were reported reported in in the the tunicate tunicate AplidiumAplidium lobatum lobatum[ 299[299].]. A.A. lobatum from shallow shallow waters waters in in Australia, Australia, A.A. sp.sp. from from deep deep wa- water,ter, and and an an unidentified unidentiﬁed Philippine Philippine ascidian ascidian have have been been reported reported as as sources sources of of aa series series of ofmacrolides, macrolides, lobatamides lobatamides C–F C–F (491 (491–494–494), ),demonstrating demonstrating cytotoxicity cytotoxicity towards towards human human tu- tumormor cell cell lines lines [300]. [300 ].The The absolute absolute stereochem stereochemistryistry of lobatamide of lobatamide C was C determined was determined by stereospecific synthesis [301]. The chlorinated macrolide haterumalide B (495) was obtained from an Okinawan ascidian L. sp. by bioassay-guided isolation and was shown to inhibit the first cleavage of fertilized sea urchin eggs at 0.01 μg/mL [302]. The Okinawan ascidian Didemnidae sp. was the source of the macrolides biselides A (496) and B (497) [303]. Further

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by stereospecific synthesis [301]. The chlorinated macrolide haterumalide B (495) was Mar. Drugs 2021, 19, x FOR PEER REVIEW 52 of 70 obtained from an Okinawan ascidian L. sp. by bioassay-guided isolation and was shown to inhibit the first cleavage of fertilized sea urchin eggs at 0.01 µg/mL [302]. The Okinawan ascidian Didemnidae sp. was the source of the macrolides biselides A (496) and B (497)[303]. Furtherinvestigation investigation of the ofD. thesp. ledD. sp. to the led isolation to the isolation of biselides of biselides C (498), D C ( (499498)), and D (E499 (500) and) which E (500exhibited) which exhibitedcytotoxicity cytotoxicity against human against cancer human cells cancer NCI-H460 cells and NCI-H460 MDA-MB-231 and MDA-MB- [304]. Cy- 231totoxic [304]. Cytotoxicpalmerolide palmerolide A (501) was A (obtained501) was obtainedfrom the fromAntarctic the Antarctic tunicate Synoicum tunicate Synoicum adareanum adareanum[305] and[305 its] stereochemistry and its stereochemistry was revised was revisedand confirmed and confirmed by synthesis by synthesis [306,307]. [306 ,307].

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Mar. Drugs 2021, 19, 180 51 of 67 Mar. Drugs 2021, 19, x FOR PEER REVIEW 55 of 70

GlycosylatedGlycosylated macrolides macrolides mandelalides mandelalides A−D(502 A−–D505 (502) were–505 isolated) were fromisolatedLissoclinum from Lissoclinum ascidianascidiancollected collected in Algoa in Algoa Bay near Bay Portnear Elizabeth Port Elizabeth and the and surrounding the surrounding Nelson Mandela Nelson Mandela Metropole in South Africa [308]. Metropole in South Africa [308]. 2.2. Bioactivities of Marine-Derived Macrolides 2.2.The Bioactivities biological activitiesof Marine-Derived of marine-derived Macrolides macrolides have been studied extensively. As listedThe in biological Table1, marine activities macrolides of marine-derived harbor a broad macrolides range of have bioactive been properties studied extensively. includingAs listed cytotoxicity, in Table 1, antibacteria, marine macrolides antifungi, antimitotic,harbor a broad antiviral, range and of other bioactive activities, properties in- withcluding cytotoxicity cytotoxicity, being their antibacteria, most signiﬁcant antifungi, bioactivity. antimitotic, antiviral, and other activities, with cytotoxicity being their most significant bioactivity.

Table 1. Biological activities of marine-derived macrolides.

Drug Class Compounds Pharmacology Activities Ref. IC50: 0.041, 0,052, 1.1 Cytotoxic a swinholides A–C (1–3) KB cells [16] μg/mL miyakolide (13) P388 cells IC50: 17.5 μg/mL [21] HL-60, NCI-116, DMS 114 et spongiastatin 1 (18) GI50: 2.5–3.5 × 10−11 M [26] al. dictyostatin 1 (33) P388 cells undetermined [32] KB, P388, IC50: 0.005, 0.003, superstolide B (37) [38] NSCLC-N6-L16 cells 0.039 μg/mL lasonolide A (38) A-549, P388 cells IC50: 40, 2 ng/mL [40] latrunculin S (44), neolaulimalide P388, A549, HT29, MEL28 IC50: 0.5–1.2 μg/mL, [46] (45) cells IC50: 0.01–0.05 μg/mL

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Table 1. Biological activities of marine-derived macrolides.

Drug Class Compounds Pharmacology Activities Ref. a Cytotoxic swinholides A–C (1–3) KB cells IC50: 0.041, 0,052, 1.1 µg/mL [16] miyakolide (13) P388 cells IC50: 17.5 µg/mL [21] HL-60, NCI-116, DMS 114 spongiastatin 1 (18) GI : 2.5–3.5 × 10−11 M [26] et al. 50 dictyostatin 1 (33) P388 cells undetermined [32] KB, P388, superstolide B (37) IC : 0.005, 0.003, 0.039 µg/mL [38] NSCLC-N6-L16 cells 50 lasonolide A (38) A-549, P388 cells IC50: 40, 2 ng/mL [40] latrunculin S (44), P388, A549, HT29, MEL28 IC : 0.5–1.2 µg/mL, 50 [46] neolaulimalide (45) cells IC50: 0.01–0.05 µg/mL leucascandrolide A (48) KB, P388 cells undetermined [48] altohyrtins B–C (51–52) IC : 0.02, 0.4; 0.3 ng/mL; KB cell;L1210 cells 50 [53] 5-desacetylaltohytrin A (53) IC50: 0.03, 1.3, 2.3 ng/mL swinholide H (54) P388 cells undetermined [13] neonorhalichondrin B (55), neohomohalichondrin B (56), 55- methoxyisohomohalichon-drin P388 cells IC : 0.4, 0.8, 10, 0.1 ng/mL [55] (57), 53- 50 methoxyneoisohomohalichondrin B(58a) salicylihalamides A (59), B (60) NCI 60 cells GI50: 7 ± 2 nM; 60 ± 25 nM [56] callipeltoside B (61), C (62) NSCLC-N6 cells IC50: 15.1, 30.0 µg/mL [60] HCT-116, arenolide (67) IC : 21, 9.8 mM [62] A2780 cells 50 30-hydroxymycalolide A (68), 32-hydroxymycalolide A (69), L1210 cells IC50: 0.019, 0.013, 0.015 µg/mL [63] 38-hydroxymycalolide B (70) NA (76), NB (77), NC (78), ND P388, P388dox, KB tumor undetermined [66] (79) and NE (80) cells J774.A1, HEK-392, spongidepsin (87) IC : 0.56, 0.66, 0.42 µg/mL [71] WEHI-164 cells 50 dactylolide (88) L1210,SK-OV-3 cells IC50: 3.2 µg/mL [72] neohalichondramide (101), K562 cells LC : 4.9 µg/mL [81] (19Z)-halichondramide (102) 50 IC : 0.13, 4.5, 0.31 µM; 0.38. lasonolides C–E (106–108) A-549,PANE-1 cells 50 [83] 4.89, 0.57, 15.6 µM leiodolides A (112) and B (113) HCT-116 cells IC50: 1.4, 3.8 µg/mL [86,87] tedanolide C (114) HCT-116 cells IC50: 0.057 µg/mL [88] kabiramide F–I (115–118) NCI cells undetermined [89] swinholide I (120), HCT-116 cells IC : 5.6, 365 nM [91] hurghadolide A (121) 50 oxalatrunculin B (122) HepG2, HCT-116,1301 cells undetermined [92] A-549, NCI-ADR-RES, neopeltolide (123) IC : 1.2, 5.1, 0.56 µg/mL [93] P388 cell lines 50 phorbaside C (134) HCT-116 cells IC50: 2 µM[97] tausalarin C (147) K562 cells IC50: 1 µg/mL [102] enigmazole A (153) IC-2 IC50: 0.37 µg/mL [105] Jurkat J16 T, Ramos B callyspongiolide (168) IC : 70, 60 nM [111] lymphocytes 50 A-549, HT-29, phormidolides B (169), C (170) undetermined [112] MDA-MB-231 cells poecillastrins E (171), F (172), G 3Y1 cells IC : 6.7, 1.2, 5.0 ng/mL [113] (173) 50 macrosphelide M (180) HL-60 cell IC50: 33.2 µM[120] 12,13-deoxyroridin E (191) HL-60, L1210 cells IC50: 25, 15 µg/mL [126] myrothecines H, I (270–271) HepG-2 cells IC50: 8, 0.4 µM[156] marinomycins A–D (283–286) 60 cell line panel LC50: 0.005–50 µM[165] Mar. Drugs 2021, 19, 180 53 of 67

Table 1. Cont.

Drug Class Compounds Pharmacology Activities Ref.

arenicolide A (287) KB cells IC50: 30 µg/mL [166] halichoblelide B (293) P388 cell line ED50 0.63 [169] juvenimicin C (303) Hepa 1c1c7 cells undetermined [173] K-562, Pgp-positive MDR astolides A (311), B (312) IC : 1.2–1.4 µM[179] subline K-562/4 50 biselyngbyolide A (330), IC : 0.22, 0.027 µM[190] HeLa S3, HL60 cells 50 biselyngbyolide B (331) IC50: 3.5, 0.82 µM[191] amphidinolide E (339) L1210, L5178Y cells undetermined [194] IC : 0.0054, 0.00048 µg/mL; amphidinolide G,H (341–342) L1210, KB cells 50 [197] 0.0059, 0.00052 µg/mL amphidinolides O (351), IC : 1.7, 1.6 µg/mL; L1210, KB cells 50 [208] P(352) IC50: 3.6, 5.8 µg/mL. amphidinolide Q (353) L1210 cells IC50: 6.4 µg/mL [210] amphidinolides R (354), IC : 1.4, 4.0 µg/mL; L1210, KB cells 50 [213] S(355) IC50: 0.67, 6.5 µg/mL amphidinolide C3 (357) P388, L1210, KB cells undetermined [215] amphidinolide X (371) L1210, KB cells IC50: 0.6, 7.5 µg/mL [226] amphidinolides B6 (374), DG-75 cells IC : 0.02, 0.4 µg/mL [227] B7 (375) 50 amphidinolide C2 (376) L1210, KB cells IC50: 0.8, 3 µg/mL [228] HCT-116, HCT 116/VM IC : 1.6 nM, 1.6 nM, 0.03 caribenolide I (377) 50 [229] 46,P388 mg/kg iriomoteolide-2a (387) DG-75, cells IC50: 0.006, 0.03 µg/mL [238] iriomoteolide-3a (388) DG-75 cells IC50: 0.08 µg/mL [239] iriomoteolide-4a (389), -5a (390) DG-75 cells IC50: 0.8, 1.0 µg/mL [240] iriomoteolide-9a (391), -11a (392) HeLa cells IC50: 15, 2 µM[241] iriomoteolide-10a (393) HeLa, DG-75, MH134 cells IC50: 1.5, 1.2, 3.3 µM[242] iriomoteolide-12a (394) DG-75 cells IC50: 50 µM[242] bromophycolide A (411) A2780 cells IC50: 6.7 µM[258] bromophycolide H (419) DU4475 cell line IC50: 3.88 µM[259] BT-549, DU4475, bromophycolides J–Q (421–428) IC : 2.1–7.2 µM[260] MDA-MD-468 et al. 50 bromophycolide K (425) DU4475 cell line IC50: 1.5 µM[260] bryostatin 10 (458) P388 cell line ED50: 0.33 µg/mL [277] bryostatins 16 (459), ED : 0.0093, 0.019, 0.033 P388 cell line 50 [282] 17 (460), 18 (461) µg/mL IC : 0.075, 0.18, 0.19, 0.12, 9.8 aplyronines D–H (469–473) HeLa S cells 50 [286] 3 nM dolabelide A (474), dolabelide B HeLa S cells IC : 6.3, 1.3 µg/mL [287] (475) 3 50 dolabelides C (476), D (477) HeLa S3 cells IC50: 1.9, 1.5 µg/mL [288,289] IC : 4.7, 0.2 µg/mL; 10, 0.58 iejimalides C (487) and D (488) KB, L1210 cells 50 [298] µg/mL lobatamides A–F (489–494) NCT’S 60 cells mean panel GI50’s 1.6 nM [301,302] NCI-H460, MDA-MB-231 IC : 3.53, 3.72 µM; biselides A (496), C (497) 50 [303] cells IC50: 18.0, 25.5 µM palmerolide A (501) HCC-2998, RXF 393 LC50: 18, 6.5, 6.5 µM[305] B. subtilis, Microbotryum, violaceum, Antibacteria a curvulone A (221) undetermined [139] Septoria tritici, Chlorella fusca thiocladospolides F–J (264–268) Edwardsiella tarda MIC: 4 µg/mL [154] marinomycins A–D (283–286) MRSA, VREF MIC: 0.1–0.6 µM[165] MRSA, 110,120-dehydroelaiophylin (305) vancomycin-resistant MIC: 1–4 µg/mL [175] Enterococci pathogens Mar. Drugs 2021, 19, 180 54 of 67

Table 1. Cont.

Drug Class Compounds Pharmacology Activities Ref. Bacillus anthracis (strain anthracimycin (308) MIC: 0.031 µg/mL [177] UM23C1–1) bromophycolides A (411), B MIC: 5.9, 5.9 µM; MRSA and VREF [258] (412) 5.9, 3.0 µM MIC: 1.4, 13 µM; bromophycolides P–Q (427–428) MRSA and VREF [260] 1.8, 5.8 µM Antifugal a leucascandrolide A (48) C. albicans undetermined [48] neohalichondramide (101), C. albicans 12.5 mm at 25 µg/disk [81] (19Z)-halichondramide (102) neopeltolide (123) C. albicans MIC: 0.62 µg/mL [93] Botrytis cinerea, Phoma lingam, Phoma bataem, BK223-A (181) BK223-B (182), Pyrenophora teres, undetermined [121] BK223-C (183) Sclerotinia sclerotiorum, Moilinia fructigena, Ascochyta pisi and Alternaria alternata 15G256ğ(197),15G256w; (198) Neuropora crassa OS-1 undetermined [128] C. albicans, A. niger 219, C. Astolides A (311), B (312) MIC: 4, 8 µg/mL [179] tropicales bromophycolides A (411), B C. albicans MIC: 6.7, 27.7 µM[258] (412) amphotericin B-resistant C. bromophycolides F, I (417, 420) undetermined [259] albicans Inhibition of tubulin Antimitotic halistatin 1, 2 (15–16) undetermined [23,24] polymerization accelerating the entry of spirastrellolide A (94) IC : 100 ng/mL [79] cells into mitosis 50 HIV strains 96USHIPS7 Antiviral bromophycolides A (411) IC : 9.1,9.8 µg/mL [258] and UG/92/029 inhibition 50 Antiplasmodial kabiramide L (119) Against P. ﬂaciparum K1 IC50: 2.6 µM[90] Antiparasite bromophycolides R–U (429–432) Against Pla. falciparum. IC50: 0.9–8.4 µM[261] VCAM b halichlorine (47) Inhibition to VCAM-1 IC : 7 µg/mL [47] inhibition 50 Prevent Inhibited fertilization of exiguolide (111) IC : 21 µM[84] fertilization sea urchin gametes 50 Reducing TNF-α-inducing NFκB inhibition ﬁjiolides A (309) IC : 0.57 µM[178] NFκB activation 50 Prevent Inhibited fertilization of oscillariolide (321) IC : 0.5 µg/mL [182] fertilization echinoderm eggs 50 Molluscicidal Against the snail vector B. cyanolide A (329) LC : 1.2 µM[189] activity glabrata 50 Vasoconstrict- zooxanthellatoxins A (380), B undetermined [232,233] ors (381) Fast-acting Rapid toxic response in the prorocentrolide B (382) undetermined [234] toxin mouse bioassay Voltage-dependent N-type 2+ symbiodinolide (395) Ca channel-opening IC50: 7 nM [14] activity −6 acuminolide A (396) IC50: 10 M [246] Prevent Inhibited fertilization of haterumalide B (495) IC : 0.01 µg/mL [302] fertilizatoin sea urchin eggs 50 a In the pharmacology column, cytotoxic, antibacteria and antifungal parts present species to which the compounds show inhibition bioactivities. b Vascular cell adhesion molecule. Mar. Drugs 2021, 19, 180 55 of 67

3. Conclusions and Outlook This review presents a summary of 505 marine-derived macrolides reported from 1990 to 2020 and highlights their chemical and biological diversity. As shown in Figure1, sponges are the dominant producer of marine macrolides, yielding 173 of these 505 compounds (34.3%). Fungi and dinoflagellates are also important sources, producing 19.4% and 12.1%, respectively, of the macrolides reviewed. Marine animals (cnidarians, bryozoans, tunicates, and mollusks) produced significantly fewer macrolides with a combined percentage of 11.6%, while marine plants (red algae) yielded 9.5%. Marine microbes (including fungi, bacteria, cyanobacteria) produced 32.7% of 505 macrolides. Notably, macrolides obtained from sponges have fallen since 2010, while microbes, especially fungi, have grown to be important producers (Figure2). This phenomenon suggests that biochemists are acknowledging that sampling slow-growing sessile organisms to identify natural products is not an eco-friendly practice. More attention is now being given to microbes due to their capacity for unlimited reproduction and the ease with which their genome can be mined for targeted metabolites. Marine macrolides have a broad range of properties, including cytotoxic, antifungal, antimitotic, and some other activities (Table1). Cytotoxicity is their most significant bioactivity, highlighting that marine macrolides include many potential antitumor drug leads. For macrolides with larger macrocyclic rings, such as reidispongiolides A and B [34], symbiodinolide [14] and zooxanthellatoxins A and B [232,233], the flexible ring structures make stereochemistry identification more difficult. Novel configuration determination technologies, such as sponge crystals [309], are needed to solve this problem. Although they possess diverse bioactivities, few marine macrolides have been developed into approved antitumor drugs or even for clinical trials during the last thirty years. Limited production from natural biomaterials and difficulties in synthesis may be hindering new drug discovery. High throughput screening and investigation of target prediction and additional bioactivity mechanisms must be employed to increase the successful discovery of lead compounds from marine macrolides. This should include mining for more structurally unusual macrolides with broader bioactivities.

Author Contributions: J.Z., X.Y., J.C., X.C., J.W. and Y.L. searched and collected literature; T.W. and H.Z. carried out the writing work. All authors have read and agreed to the published version of the manuscript. Funding: The National Natural Science Foundation of China (NSFC; grant 41906093 to T.W.), the Natural Science Foundation of Zhejiang Province (grant LGF21D060003 to T.W.), Research Fund for Science in Ningbo University (XYL20021 to T.W.), the Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Development Fund of Ningbo University. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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