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

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.

1. Introduction

The term “class="Chemical">macrolide” was coined by Woodward in 1957 [1] to describe antibiotics which typically consist of 14-, 15- or <class="Gene">span class="Chemical">16-membered macrolactam rings and feature double bonds and different saccharide and aminosaccharide functional groups. The naturally occurring 14-membered lactones erythromycin and clarithromycin, 15-membered macrolides azithromycin and spiramycin, and the 16-membered avermectin B1a are typical macrolide antibiotics in clinical use [2,3,4]. The 26-membered macrolide oligomycin A (an inhibitor of ATP synthase) [5,6] and the 36-membered macrocyclic lactone amphotericin B (an antifungal agent) are also used clinically [7,8]. In the last thirty years, many studies have described the molecular features, structures, and bioactivities of the intriguing macrolides obtained from plants, animals, and microbes in terrestrial and marine ecosystems [9,10,11,12]. Macrolides with larger macrocyclic rings have been reported, exemplified by the cytotoxic swinholide H, with its 40-membered lactone ring, obtained from the New Zealand deep-water marine sponge Lamellomorpha strongylata (La. strongylata) [13], and the novel 62-membered polyol symbiodinolide from the symbiotic dinoflagellate Symbiodinium sp. [14]. Macrolides, therefore, 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 class="Chemical">macrolides derived from marine organisms (65.8% of which are from class="Gene">sponges, fungi, <class="Gene">span class="Chemical">and dinoflagellates) (Figure 1). Compared with terrestrial environments, the oceans exhibit more wide-ranging hypersaline, hyperbaric, hypoxic, cryogenic, and oligotrophic conditions. Marine organisms must develop the capacity to produce diverse bioactive metabolites to survive in these complex and competitive ecosystems. Marine metabolites have huge potential as new drug leads, with nine approved pharmaceuticals and 31 compounds in clinical pharmaceutical trials [15]. Macrolides are a significant family of natural marine products (Figure 2). The marine macrolides reviewed herein display cytotoxic, antibacterial, antifungal, antimitotic, antiviral, antiplasmodial and other bioactivities, as listed in Table 1. This review discusses the isolation, structures, and chemical and bioactive diversity of marine macrolides from 309 publications.

Figure 1

The percentage of macrolides from diverse marine organisms.

Figure 2

All new macrolides by source/year, n = 505.

Table 1

Biological activities of marine-derived macrolides.

Drug Class	Compounds	Pharmacology	Activities	Ref.
Cytotoxic a	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]
	spongiastatin 1 (18)	HL-60, NCI-116, DMS 114 et al.	GI50: 2.5–3.5 × 10−11 M	[26]
	dictyostatin 1 (33)	P388 cells	undetermined	[32]
	superstolide B (37)	KB, P388,NSCLC-N6-L16 cells	IC50: 0.005, 0.003, 0.039 μg/mL	[38]
	lasonolide A (38)	A-549, P388 cells	IC50: 40, 2 ng/mL	[40]
	latrunculin S (44), neolaulimalide (45)	P388, A549, HT29, MEL28 cells	IC50: 0.5–1.2 μg/mL, IC50: 0.01–0.05 μg/mL	[46]
	leucascandrolide A (48)	KB, P388 cells	undetermined	[48]
	altohyrtins B–C (51–52) 5-desacetylaltohytrin A (53)	KB cell;L1210 cells	IC50: 0.02, 0.4; 0.3 ng/mL;IC50: 0.03, 1.3, 2.3 ng/mL	[53]
	swinholide H (54)	P388 cells	undetermined	[13]
	neonorhalichondrin B (55), neohomohalichondrin B (56), 55-methoxyisohomohalichon-drin (57), 53-methoxyneoisohomohalichondrin B (58a)	P388 cells	IC50: 0.4, 0.8, 10, 0.1 ng/mL	[55]
	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]
	arenolide (67)	HCT-116,A2780 cells	IC50: 21, 9.8 mM	[62]
	30-hydroxymycalolide A (68), 32-hydroxymycalolide A (69), 38-hydroxymycalolide B (70)	L1210 cells	IC50: 0.019, 0.013, 0.015 μg/mL	[63]
	NA (76), NB (77), NC (78), ND (79) and NE (80)	P388, P388dox, KB tumor cells	undetermined	[66]
	spongidepsin (87)	J774.A1, HEK-392, WEHI-164 cells	IC50: 0.56, 0.66, 0.42 μg/mL	[71]
	dactylolide (88)	L1210,SK-OV-3 cells	IC50: 3.2 μg/mL	[72]
	neohalichondramide (101), (19Z)-halichondramide (102)	K562 cells	LC50: 4.9 μg/mL	[81]
	lasonolides C–E (106–108)	A-549,PANE-1 cells	IC50: 0.13, 4.5, 0.31 μM; 0.38. 4.89, 0.57, 15.6 μM	[83]
	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),hurghadolide A (121)	HCT-116 cells	IC50: 5.6, 365 nM	[91]
	oxalatrunculin B (122)	HepG2, HCT-116,1301 cells	undetermined	[92]
	neopeltolide (123)	A-549, NCI-ADR-RES, P388 cell lines	IC50: 1.2, 5.1, 0.56 μg/mL	[93]
	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]
	callyspongiolide (168)	Jurkat J16 T, Ramos B lymphocytes	IC50: 70, 60 nM	[111]
	phormidolides B (169), C (170)	A-549, HT-29, MDA-MB-231 cells	undetermined	[112]
	poecillastrins E (171), F (172), G (173)	3Y1 cells	IC50: 6.7, 1.2, 5.0 ng/mL	[113]
	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]
	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]
	astolides A (311), B (312)	K-562, Pgp-positive MDR subline K-562/4	IC50: 1.2–1.4 μM	[179]
	biselyngbyolide A (330),	HeLa S3, HL60 cells	IC50: 0.22, 0.027 μM	[190]
	biselyngbyolide B (331)		IC50: 3.5, 0.82 μM	[191]
	amphidinolide E (339)	L1210, L5178Y cells	undetermined	[194]
	amphidinolide G,H (341–342)	L1210, KB cells	IC50: 0.0054, 0.00048 μg/mL; 0.0059, 0.00052 μg/mL	[197]
	amphidinolides O (351),P (352)	L1210, KB cells	IC50: 1.7, 1.6 μg/mL;IC50: 3.6, 5.8 μg/mL.	[208]
	amphidinolide Q (353)	L1210 cells	IC50: 6.4 μg/mL	[210]
	amphidinolides R (354),S (355)	L1210, KB cells	IC50: 1.4, 4.0 μg/mL;IC50: 0.67, 6.5 μg/mL	[213]
	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),B7 (375)	DG-75 cells	IC50: 0.02, 0.4 μg/mL	[227]
	amphidinolide C2 (376)	L1210, KB cells	IC50: 0.8, 3 μg/mL	[228]
	caribenolide I (377)	HCT-116, HCT 116/VM 46,P388	IC50: 1.6 nM, 1.6 nM, 0.03 mg/kg	[229]
	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]
	bromophycolides J–Q (421–428)	BT-549, DU4475, MDA-MD-468 et al.	IC50: 2.1–7.2 μM	[260]
	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),17 (460), 18 (461)	P388 cell line	ED50: 0.0093, 0.019, 0.033 μg/mL	[282]
	aplyronines D–H (469–473)	HeLa S3 cells	IC50: 0.075, 0.18, 0.19, 0.12, 9.8 nM	[286]
	dolabelide A (474), dolabelide B (475)	HeLa S3 cells	IC50: 6.3, 1.3 μg/mL	[287]
	dolabelides C (476), D (477)	HeLa S3 cells	IC50: 1.9, 1.5 μg/mL	[288,289]
	iejimalides C (487) and D (488)	KB, L1210 cells	IC50: 4.7, 0.2 μg/mL; 10, 0.58 μg/mL	[298]
	lobatamides A–F (489–494)	NCT’S 60 cells	mean panel GI50’s 1.6 nM	[301,302]
	biselides A (496), C (497)	NCI-H460, MDA-MB-231 cells	IC50: 3.53, 3.72 μM;IC50: 18.0, 25.5 μM	[303]
	palmerolide A (501)	HCC-2998, RXF 393	LC50: 18, 6.5, 6.5 μM	[305]
Antibacteria a	curvulone A (221)	B. subtilis,Microbotryum, violaceum,Septoria tritici,Chlorella fusca	undetermined	[139]
	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]
	11′,12′-dehydroelaiophylin (305)	MRSA, vancomycin-resistant Enterococci pathogens	MIC: 1–4 μg/mL	[175]
	anthracimycin (308)	Bacillus anthracis (strain UM23C1–1)	MIC: 0.031 μg/mL	[177]
	bromophycolides A (411), B (412)	MRSA and VREF	MIC: 5.9, 5.9 μM;5.9, 3.0 μM	[258]
	bromophycolides P–Q (427–428)	MRSA and VREF	MIC: 1.4, 13 μM;1.8, 5.8 μM	[260]
Antifugal a	leucascandrolide A (48)	C. albicans	undetermined	[48]
	neohalichondramide (101), (19Z)-halichondramide (102)	C. albicans	12.5 mm at 25 μg/disk	[81]
	neopeltolide (123)	C. albicans	MIC: 0.62 μg/mL	[93]
	BK223-A (181) BK223-B (182), BK223-C (183)	Botrytis cinerea,Phoma lingam,Phoma bataem,Pyrenophora teres,Sclerotinia sclerotiorum, Moilinia fructigena, Ascochyta pisi and Alternaria alternata	undetermined	[121]
	15G256ɩ (197),15G256w; (198)	Neuropora crassa OS-1	undetermined	[128]
	Astolides A (311), B (312)	C. albicans, A. niger 219, C. tropicales	MIC: 4, 8 μg/mL	[179]
	bromophycolides A (411), B (412)	C. albicans	MIC: 6.7, 27.7 μM	[258]
	bromophycolides F, I (417, 420)	amphotericin B-resistant C. albicans	undetermined	[259]
Antimitotic	halistatin 1, 2 (15–16)	Inhibition of tubulin polymerization	undetermined	[23,24]
	spirastrellolide A (94)	accelerating the entry of cells into mitosis	IC50: 100 ng/mL	[79]
Antiviral	bromophycolides A (411)	HIV strains 96USHIPS7 and UG/92/029 inhibition	IC50: 9.1,9.8 μg/mL	[258]
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 inhibition	halichlorine (47)	Inhibition to VCAM-1	IC50: 7 μg/mL	[47]
Prevent fertilization	exiguolide (111)	Inhibited fertilization of sea urchin gametes	IC50: 21 μM	[84]
NFκB inhibition	fijiolides A (309)	Reducing TNF-α-inducing NFκB activation	IC50: 0.57 μM	[178]
Prevent fertilization	oscillariolide (321)	Inhibited fertilization of echinoderm eggs	IC50: 0.5 μg/mL	[182]
Molluscicidal activity	cyanolide A (329)	Against the snail vector B. glabrata	LC50: 1.2 μM	[189]
Vasoconstrict-ors	zooxanthellatoxins A (380), B (381)		undetermined	[232,233]
Fast-acting toxin	prorocentrolide B (382)	Rapid toxic response in the mouse bioassay	undetermined	[234]
	symbiodinolide (395)	Voltage-dependent N-type Ca2+ channel-opening activity	IC50: 7 nM	[14]
	acuminolide A (396)		IC50: 10−6 M	[246]
Prevent fertilizatoin	haterumalide B (495)	Inhibited fertilization of sea urchin eggs	IC50: 0.01 μg/mL	[302]

a In the pharmacology column, cytotoxic, antibacteria and antifungal parts present species to which the compounds show inhibition bioactivities. b Vascular cell adhesion molecule.

2. Chemical and Biological Diversity of Marine-Derived Macrolides

2.1. Macrolides Extracted from Marine Organisms

2.1.1. Sponges

The Okinawan class="Species">Theonella sp. (T. class="Gene">sp.) class="Gene">sponges produced a series of <class="Gene">span class="Chemical">dimeric macrolides called swinholides A–G (1–7) and isoswinholide A (8) [16,17,18,19]. Four bistheonellide-related compounds—bistheonellide C (9), isobistheonellide A (10), and bistheonellic acids A (11) and B (12)—are also produced by Okinawan T. sp. sponges [20]. The structure of the macrolide miyakolide (13), which is weakly cytotoxic and obtained from Japanese sponge Polyfibrospongia sp., was elucidated by X-ray single crystal diffraction [21]. 13-Deoxytedanolide (14) was isolated from Mycale adhaerens (M. adhaerens) and identified by spectroscopic analysis [22].

The antimitotic class="Chemical">macrolides <class="Gene">span class="Chemical">halistatin 1 (15) and halistatin 2 (16) were isolated from Phakellia carteri from the Comoros Islands and Axinella cf. carteri (Dendy) from the Western Indian Ocean [23,24]. Halistatin 3 (17) was produced in extremely small quantities by Phakellia sponges collected at Chuuk [25].

Iclass="Disease">ndepe<class="Gene">span class="Disease">ndent 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].

Three class="Chemical">macrolides <class="Gene">span class="Chemical">sphinxolides B (27), C (28), and D (29) have been isolated from the Caledonian sponge Neosiphoniu superstes [30].

Three new class="Chemical">trisoxazole macrolides, <class="Gene">span class="Chemical">jaspisamides A (30), B (31), and C (32), were reported without stereochemical data in an Okinawan Juspis sponge [31].

A new 22class="Chemical">-membered macrocyclic <class="Gene">span class="Chemical">lactone named dictyostatin 1 (33) was isolated from a Republic of Maldives Spongia sponge and exhibited significant cytotoxicity towards murine P388 lymphocytic leukemia [32]. The relative stereochemistry of dictyostatin 1 was determined by Murata’s method [33]. Two new 26-membered macrolides, reidispongiolides A (34) and B (35), have been produced by the marine sponge Reidispongia coerulea (R. coerulea) [34]. The relative and absolute stereochemistries of the C-23–C-35 portion of reidispongiolide A were determined by synthesis of an ozonolysis fragment of the natural product [35], which was later synthesized enantioselectively [36]. The relative stereochemistry of the C-7–C-15 fragment was reassigned through a series of diastereomers of a degradation fragment synthesis [37].

Cytotoxic class="Chemical">superstolide A (36) <class="Gene">span class="Chemical">and superstolide B (37) have been isolated from the deep-water marine sponge Neosiphonia superstes (N. superstes) [38,39]. Another cytotoxic macrolide, lasonolide A (38), was produced by the shallow-water Caribbean sponge Forcepia sp. [40]. Isohomohalichondrin B (39), belonging to the halichondrin family, was isolated from the New Zealand deep-water sponge Lissodendoryx sp. (Li. sp.) [41]. Phorboxazoles A (40) and B (41) have an unprecedented scaffold and were isolated from the Indian Ocean sponge Phorbas sp. (P. sp.), with complete stereochemistry and absolute configuration determined by spectroscopy and partial synthesis [42,43]. The structures and absolute configurations of latrunculin A (42) and laulimalide B (43) isolated from Okinawan sponge Fasciospongia rimosa were determined by X-ray analysis [44]. Other cytotoxic macrolides, latrunculin S (44), neolaulimalide (45) and zampanolide (46), have been produced by the F. rimosa genus [45,46]. Halichlorine (47), isolated from the marine sponge Halichodria okadai, exhibited significant inhibition of vascular cell adhesion molecule 1 (VCAM-1) [47].

class="Chemical">Leucascandrolide A (48), exhibiting antifungal <class="Gene">span class="Chemical">and cytotoxic activities, was obtained from the sponge Leucascandra caveolata (Le. caveolata) [48]. The marine lithistida sponge Callipelta sp. (Cal. sp.) contains the first member of a new class of marine-derived macrolides, callipeltoside A (49), which incorporates an unusual chlorocyclopropyl group and an amino sugar [49]. The relative and absolute stereochemistry of the chlorocyclopropyl side chain of callipeltoside A was determined by stereoselective synthesis [50,51,52]. Cytotoxic macrolides altohyrtins A–C (50–52) and 5-desacetylaltohyrtin A (53) were isolated from the sponge Hyrtios altum and their absolute stereochemistries were determined by spectroscopy [53,54]. Screening of extracts from a New Zealand deep-water sponge La. strongylata for cytotoxicity towards the P388 cell line yielded swinholide H (54) [13].

Another deep-class="Chemical">water (> 100 m) class="Gene">sponge of the genus Li. produced the anti<class="Gene">span class="Disease">tumor macrolides neonorhalichondrin B (55), neohomohalichondrin B (56), 55-methoxyisohomohalichondrin (57), 53-methoxyneoisohomohalichondrin B (58a) and 53-epi-53-methoxyneoisohomohalichondrin B (58b) [55].

class="Chemical">Macrolide <class="Gene">span class="Chemical">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 of Mosher ester derivatives and enantioselective syntheses of both enantiomers [57,58,59]. 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].

Four new class="Chemical">oxazole-containing compou<class="Gene">span class="Disease">nds, halishigamides A–D (63–66), were isolated from an Okinawan marine sponge, Halichondria sp. [61].

A Palau Dysidea sclass="Species">p. sponge contained a <class="Gene">span class="Chemical">14-membered macrolide, arenolide (67), showing modest cytotoxicity [62]. Three macrolides, 30-hydroxymycalolide A (68), 32-hydroxymycalolide A (69), and 38-hydroxymycalolide B (70), were isolated from the marine sponge M. magellanica and showed cytotoxicity towards L1210 cells [63].

class="Chemical">Pateamine 1 (71), a <class="Gene">span class="Chemical">thiazole-containing macrolide with an unique dilactone functionality, was isolated from M. sp. sponge [64]. Four new macrocyclic lactones/lactams, amphilactams A–D (72–75), were produced by the marine sponge Amphimedon spp. collected in the Great Australian Bight [65].

Cytotoxic class="Chemical">macrolides <class="Gene">span class="Chemical">haterumalides NA (76), NB (77), NC (78), ND (79) and NE (80) were isolated from the New Caledonian Litbistida sponges N. superstes and R. Coerulea [66]. Sphinxolides E–G (81–83) and reidispongiolide C (84) are new cytotoxic macrolides from Okinawan species of Ircinia [67]. Leucascandrolide B (85) is a 16-membered macrolide from the calcareous sponge Le. caveolata from the northeastern waters of New Caledonia [68]. The New Zealand marine sponge M. sp. contained the polyoxygenated, pyranose ring-containing, 16-membered macrolide peloruside A (86) [69], which was synthesized via a Mitsunobu-type lactonization [70].

class="Disease">Cytotoxic spongidepsin (87) has been isolated from the Vanuatu marine <class="Gene">span class="Disease">sponge Spongia sp. [71]. A new cytotoxic 20-membered macrolide, dactylolide (88), was isolated from a marine sponge of the genus Dactylospongia. This has been synthesized and the relative stereochemistry of the acyloxymethine and the absolute configuration of the whole molecule have been determined [72]. The Vanuatu marine sponge Ha. sp. was found to contain the cyclic metabolite haliclamide (89) [73].

class="Chemical">Clavosolides A–D (90–93) have been fou<class="Gene">span class="Disease">nd in sponge Myriastra clavosa [74,75]. The absolute configurations of clavosides A and B were determined by total synthesis [74,75,76]. Spirastrellolides A–G (94–100) are antimitotic macrolides isolated from the Caribbean marine sponge S. coccinea [77,78,79,80]. Spirastrellolide A exhibited selective inhibition of protein phosphatase 2A [80].

The sponge Choclass="Disease">ndrosia corticata produced two <class="Gene">span class="Chemical">oxazole-containing macrolides, neohalichondramide (101) and (19Z)-halichondramide (102), and the open ringed secohalichondramide. Neohalichondramide and (19Z)-halichondramide exhibited significant cytotoxicity and antifungal activity toward the human leukemia cell-line K562 and Candida albicans (C. albicans) [81].

Three cytotoxic class="Chemical">mycalolides, <class="Gene">span class="Chemical">30-hydroxymycalolide A (103), 32-hydroxymycalolide A (104) and 38-hydroxymycalolide B (105), have been isolated from a Japanese M. magellanica [82]. The five antiproliferative lasonolide congeners C–G (106–110) were isolated from Forcepia sponge collected in the U.S. Gulf of Mexico [83]. Exiguolide (111), isolated from the marine sponge Geodia exigua, was reported to inhibit fertilization of sea urchin (Hemicentrotus pulcherrimus) gametes but not embryogenesis [84]. The absolute configuration of exiguolide was determined by total synthesis of the enantiomer [85].

Cytotoxic class="Chemical">macrolides <class="Gene">span class="Chemical">leiodolides A (112) and B (113) were obtained from a deep-water (>200 m) Leiodermatium sponge [86,87]. Tedanolide C (114), isolated from Ircinia sp. (Papua New Guinea), was found to be potently cytotoxic, causing S-phase arrest, suggestive of protein synthesis inhibition [88]. Cytotoxic kabiramides F–I (115–118) were produced by Pachastrissa nux (P. nux) (Gulf of Thailand) [89].

An antiplasmodial class="Chemical">macrolide, <class="Gene">span class="Chemical">kabiramide L (119), was isolated from P. nux sponge [90]. Swinholide I (120) and the related hurghadolide A (121), with cytotoxicity towards human colon cancer cells, were produced by T. swinhoei (Hurghada, Egypt) [91].

class="Chemical">Oxalatrunculin B (122) was isolated from Red Sea class="Gene">sponge <class="Gene">span class="Species">Negombata corticata and showed significant antifungal and anticancer activities, suggesting it as a potential member of the bioactive latrunculin family [92]. A Lithistid sponge of the family neopeltidae contained the macrolide neopeltolide (123) with potential cytotoxic and antifungal activities. This compound was synthesized to determine its absolute configuration and the relative stereochemistry of C-13 [93]. Candidaspongiolides (124), a complex mixture of acyl esters of a macrolide related to tedanolide, was isolated from Candidaspongia sp. (Can. sp.) (Papua New Guinea) and Can. flabellata (Great Barrier Reef, Australia) [94]. Fijianolides D–I (125–130) were produced by sponge Cacospongia mycofijiensis (Cac. mycofijiensis) (Mele Bay, Vanuatu) [95]. Phorbasides A–E (131–135) are chlorocyclopropane macrolides isolated from marine sponge P. sp. [96,97].

class="Chemical">Latrunculin analogs, latrunculol A–C (136–138), <class="Gene">span class="Chemical">18-epi-latrunculol (139) and latrunculones A (140) and B (141), were obtained from Cac. mycofijiensis [98]. Salarin A (142), salarin B (143) and tulearin A (144) were obtained from repeated collections of the Madagascan sponge Fascaplysinopsis sp. (F. sp.) [99].

A further collection led to the isolation of class="Chemical">salarin C (145), which was considered to be the precursor of <class="Gene">span class="Chemical">salarins A and B [100]. Marine sponge Siliquariaspongia mirabilis contained an antitumor macrolide lactam named mirabilin (146) [101]. The nitrogenous bismacrolide tausalarin C (147) was isolated from the Madagascar sponge F. sp. and was found to inhibit proliferation of K562 leukemia cells [102]. Muironolide A (148), containing a rare hexahydro-1H-isoindolone and trichlorocarbinol ester, was isolated from marine sponge of the genus Phorbas [103].

Four variants of halichoclass="Disease">ndrin B, B-1140 (149<class="Gene">span class="Chemical">), B-1092 (150), B-1020 (151) and B-1076 (152), were extracted from the Poecilosclerid sponge Li. sp. in microgram quantities and their structures were elucidated by capillary NMR spectroscopy [104].

Cytotoxic class="Chemical">phosphate-containing <class="Gene">span class="Chemical">macrolide enigmazole A (153) and two analogs, 15-O-methylenigmazole A (154) and 13-hydroxy-15-O-methylenigmazole A (155), were extracted from the marine sponge Cinachyrella enigmatica collected in Papua New Guinea [105] and their structures were confirmed by total synthesis [106].

Seven scalarin analogs D–J (156–162) were obtained from the Madagascan F. sclass="Species">p. sponge. Scalarins D, E, H, <class="Gene">span class="Chemical">and J inhibited cell proliferation in a dose- and time-dependent manner [107]. Theonezolides A–C (163–165) were obtained from the Okinawan marine sponge T. sp. and absolute configurations were determined by combining a JBCA method, a universal NMR database, and a 13C-acetonide method [108,109].

The Iclass="Disease">ndonesian class="Gene">sponge <class="Gene">span class="Species">T. swinhoei yielded the dimeric macrolides isoswinholide B (166) and swinholide K (167) [110]. An unusual carbamate, callyspongiolide (168), with strong cytotoxicity towards human Jurkat J16 T and Ramos B lymphocytes, was isolated from marine sponge Cal. sp. [111]. Cytotoxic polyketide macrolides phormidolides B (169) and C (170) were isolated from Petrosiidae sponge with stereochemical assignment via enantioselective synthesis of the macrocyclic core [112]. Cytotoxic chondropsin-type macrolides poecillastrins E (171), F (172), and G (173) were isolated from the marine sponge Poecillastra sp. [113].

2.1.2. Microorganisms and Zooplankton

Fungi

The fungus class="Species">Periconia byssoides (Per. <class="Gene">span class="Chemical">byssoides), obtained from the sea hare Aplysia kurodai (Ap. sp.), was reported to produce the cytotoxic triols pericosides A and B, and four new macrolides, macrosphelides E–H (174–177) [114]. Macrosphelide I (178) and macrosphelides E–H from Per. byssoides isolated from Ap. kurodai were also reported elsewhere [115]. Macrosphelide E was synthesized at a high yield via a key chemoenzymatic reaction [116]. The synthesis of macrosphelides H and G has also been described [117,118]. Absolute configurations determined by spectroscopy and chemical transformation have been reported for macrosphelides L (179) and H produced by Per. byssoides from Ap. kurodai, and the cytotoxic macrosphelide M (180) [114,119,120]. Penicillum verruculosum (IMI352119) was reported to produce three macrolides with antifungal activity: BK223-A (181), BK223-B (182) and BK223-C (183) [121]. The mitosporic fungus Varicosporina ramulosa has been reported to produce (6R,11S,12S,14R)-colletodiol (184), (6R,11R,12R,14R)-colletodiol (185) and colletoketol (186) [122,123]. The 12-membered macrolides pandangolide 1 (187) and pandangolide 2 (188) were extracted from an unidentified fungus isolated from marine sponge collected in Indonesia [124].

class="Chemical">Pandangolide 3 (189), <class="Gene">span class="Chemical">macrolide dimer pandangolide 4 (190), and a new acetyl derivative of 5-hydroxymethylfuran-2-carboxylic acid were produced by the fungus Cladosporium herbarum (Cla. herbarum), associated with the sponge Callyspongia aerizusa (Cal. aerizusa) and collected in Bali [125]. The cytotoxic macrocyclic trichothecene 12,13-deoxyroridin E (191) was obtained from an extract of the marine fungus Myrothecium roridum (M. roridum) [126]. The 14-membered resorcylic macrolides aigialomycins A–E (192–196) were isolated from the mangrove fungus Aigialus parvus BCC 5311 [127]. Potential antifungal macrocyclic polyesters 15G256ɩ (197) and 15G256ѡ (198) were obtained from the marine fungus Hypoxylon oceanicum LL-15G256 [128]. Two cytotoxic macrolides, sporiolides A (199) and B (200), were produced by the fungus Cladosporium isolated from the brown alga Actinotrichia fragilis (Okinawa, Japan) [129].

An unidentified eclass="Disease">ndophytic fungus from the brown alga <class="Gene">span class="Species">Sargassum sp. (Zhanjiang Sea, China) was the source of two 12-membered ring lactones (201–202) [130]. 12-Hydroxyroridin E (203), roridin Q (204) and 2,3-deoxyroritoxin D (205) were obtained from M. roridum on submerged wood in Palau [131]. Gliocladium sp. isolated from the alga Durvillaea antarctica (Tauranga Bay, New Zealand) yielded 4-ketoclonostachydiol (206) [132].

The 14class="Chemical">-membered <class="Gene">span class="Chemical">resorcylic acid lactone derivatives 8′-hydroxyzearalanone (207) and 2′-hydroxyzearalanol (208) were isolated from the marine-derived fungus Penicillium sp. (Pen. sp.) [133]. β-resorcylic macrolide 5′-hydroxyzearalenol (209) was obtained from the culture broth of the fungus Fusarium sp. 05ABR26 [134]. The cytotoxic 14-membered macrolides aspergillide A–C (210–212) were isolated from the culture broth of the marine sponge-derived fungus Aspergillus ostianus (As. ostianus) (Pohnpei, Micronesia) [135].

The marine-derived fungus As. sp. SCSGAF 0076 was reported to produce the class="Chemical">16-membered macrolide <class="Gene">span class="Chemical">aspergillide D (213) [136]. Apralactone A (214) and enantiomers of curvularin (215–220) were isolated from Curvularia sp. (Cur. sp.) [137,138]. The macrolide curvulone A (221) was produced by Cur. sp. isolated from the marine alga Gracilaria folifera and inhibited the growth of B. subtilis, Microbotryum violaceum, Septoria tritici, and Chlorella fusca [139].

Three class="Chemical">decalactones, <class="Gene">span class="Chemical">xestodecalactones D–F (222–224), were purified from an ethyl acetate extract of Corynespora cassiicola isolated from leaf tissues of the Chinese mangrove medicinal plant Laguncularia racemose [140]. Seiricuprolide pestalotioprolides A (225) and B (226) (as the diacetate) were isolated from the fungus Pestalotiopsis spp., which is associated with mangrove twigs of Rhizophora mucronata [141]. Calcarides A–C (227–229), 15G256α (230), and 15G256β (231) were obtained from crude extracts of the fungus Calcarisporium sp. KF525 isolated from German Wadden Sea water samples [142].

Thirteen new class="Chemical">12-membered macrolides, <class="Gene">span class="Chemical">dendrodolides A–M (232–244), were obtained from the fungus Dendrodochium sp. derived from sea cucumber Holothuria nobilis Selenka in the South China Sea [143]. Dendrodolide K was obtained from a commercially available substrate by a convergent strategy, and the dendrolides F, G, I, J, and L were synthesized via a unified strategy employing ring-closing metathesis [144,145].

class="Chemical">Cochliomycin C (245) was produced by the gorgonian-derived fungus <class="Gene">span class="Species">Cochliobolus lunatus (Coc. lunatus) [146], its absolute configuration was corrected in a later study [147].

The fungus Pen. sumatrense class="Chemical">MA-92, associated with the mangrove <class="Gene">span class="Species">Lumnitzera racemose, yielded the sulfur-containing curvularin derivatives sumalarins A−C (246–248) [148]. Chemical epigenetic manipulation of the marine-derived fungus Coc. lunatus (TA26-46) with histone deacetylase inhibitors led to the elucidation of two 14-membered resorcylic acid lactones: 5-bromozeaenol (249) and 3,5-dibromozeaenol (250) [149]. Gliomasolides A–E (251–255) were obtained from a sponge-derived fungus Gliomastix sp. ZSDS1-F7-2, their structures being determined by spectroscopy and single crystal X-ray diffraction [150]. Two 13-membered macrolides (256–257) were isolated from the marine-derived fungus Pen. meleagrinum var. viridiflavum [151]. Application of published procedures for experimental design and chemometric analysis to enhance the production of curvularin-related compounds by marine-derived Penicillium sp. DRF2 led to the isolation of cyclothiocurvularins (258–260) and cyclosulfoxicurvularins (261–262) [152]. Thiocladospolide E (263) was produced by the mangrove endophytic fungus Cladosporium sp. (Cla. sp.) SCNU-F0001 and its absolute configuration was determined by X-ray diffraction [153]. Thiocladospolides F–J (264–268) were isolated from another mangrove-derived endophytic fungus species in the same Cla. genus [154]. The macrolide 6,7,9,10-tetrahydromutolide (269) was isolated from endophytic fungus Aplosporella javeedii [155]. Two trichothecene macrolides, myrothecines H and I (270–271), were obtained from the endophytic fungus Paramyrothecium roridum isolated from the medicinal plant Morinda officinalis [156].

Bacteria

The 24class="Chemical">-membered macrolide <class="Gene">span class="Chemical">maduralide (272) was isolated from a marine bacterium in the order Actinomycetales [157]. Halichomycin (273) was produced by Streptomyces hygroscopicus (S. hygroscopicus) isolated from the marine fish Halichoeres bleekeri [158]. 7-O-Succinyl macrolactin F (274) and 7-O-succinyl macrolactin A (275) were isolated from a culture of marine Bacillus sp. (B. sp.) Sc026 [159].

Cytotoxic class="Chemical">macrolide <class="Gene">span class="Chemical">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].

class="Chemical">Marinomycins A–D (283–286) were isolated from <class="Gene">span class="Species">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].

Marine class="Species">actinomycete <class="Gene">span class="Species">Salinispora arenicola yielded the three macrolide polyketides arenicolides A–C (287–289), with arenicolides A showing moderate cytotoxicity [166]. Macrolactin 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].

Two class="Chemical">36-membered macrolides, <class="Gene">span class="Chemical">bahamaolides A and B (295–296), were obtained from the culture of a marine actinomycete S. sp. isolated from a sediment sample collected at North Cat Cay in the Bahamas [170].

class="Species">B. subtilis isolated from marine sediment collected at Gageocho (Republic of Korea) was a source of three new <class="Gene">span class="Chemical">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].

Investigation of a S. sp. in sediment from Heishijiao Bay (Dalian, China) yielded 11′,12′-dehydroclass="Chemical">elaiophylin (305) <class="Gene">span class="Chemical">and 11,11′-O-dimethyl-14′-deethyl-14′-methylelaiophylin (306)—both 6-deoxyhexose-containing antibiotics—with the former exhibiting inhibition of MRSA and vancomycin-resistant Enterococci pathogens [175]. A rare 18-membered macrolide, macplocimine A (307), was produced by a marine-derived filamentous sulfur bacteria, Thioploca sp. [176]. A potent anthrax antibiotic, anthracimycin (308), was isolated from marine sediment-derived actinomycete S. sp. (Santa Barbara, California, U.S.A.) [177]. Fijiolides A (309) and B (310) were identified in marine-derived bacteria of the genus Nocardiopsis and demonstrated inhibition towards TNF-α-induced NFκB activation (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].

Cyanobacteria

Cyanobacteria Scytonema mirabile BY-8-1, S. burmanicum class="Chemical">DO-4-1, <class="Gene">span class="Chemical">and S. ocellatum DD-8-1, FF-65-1 and FF-66-3 have been reported to produce tolytoxin (315). S. burmanicum DO-4-1 also yielded scytophycin B (316), 6-hydroxyscytophycin B (317), 19-O-demethylscytophycin C (318), 6-hydroxy-7-O-methylscytophycin E (319), and scytophycin E (320) [181]. A macrolide, oscillatoriolide (321), was isolated from Japanese Oscillatoria sp. and demonstrated inhibition towards fertilized echinoderm eggs [182]. The marine cyanobacterium Lyngbya bouillonii (L. bouillonii) collected on Laing Island (Papua New Guinea) produced lyngbyaloside (322) [183] in addition to the macrolides laingolide (323), madangolide (324), and laingolide A (325) [184,185], and the glycosidic macrolide lyngbouilloside (326), for which the configuration of C-11 was later revised [186,187].

Two class="Chemical">glycosylated <class="Gene">span class="Chemical">swinholides, ankaraholides A (327) and B (328), together with swinholide A previously obtained from the marine sponge T. swinhoei [91], were isolated from cyanobacterium Geitlerinema sp. collected in Madagascar [188]. Cyanolide A (329), demonstrating significant molluscicidal activity towards the snail vector Biomphalaria glabrata, was also isolated from L. bouillonii from Papua New Guinea [189]. Biselyngbyolide A (330) was isolated from L. sp. and showed strong apoptosis-inducing activity in HeLa S3 and HL60 cells [190], while its analogs, biselyngbyolide B–D (331–333), were produced by another L. cyanobacterium sampled on Tokunoshima Island (Japan) [191]. Biselyngbyolide B exhibited inhibition and apoptosis-inducing activity in HeLa S3 and HL60 cells and increased the cytosolic Ca2+ concentration in HeLa S3 cells [191].

The Caribbean Okeania cyanobacterium VQR28MAR11-2 has been reported to produce class="Chemical">polycavernoside D (334) [192], while four cytotoxic <class="Gene">span class="Chemical">macrolides, leptolyngbyolides A–D (335–338), have been isolated from Leptolyngbya sp. collected in Okinawa [193].

Dinoflagellates

class="Chemical">Amphidinolide E (339) was isolated from the Okinawan flatworm <class="Gene">span class="Species">Amphiscolops sp. (Amphis. sp.) and exhibited cytotoxicity towards murine leukemia cells L1210 and L5178Y [194]. The absolute stereochemistry of amphidinolide E was determined by NMR spectroscopy, modified Mosher’s method and the exciton chirality method [195]. The potent cytotoxic macrolides amphidinolides F (340), G (341) and H (342) were produced by dinoflagellate Amphidinium sp. (Amphid. sp.) associated with the Okinawan flatworm Amphis. breviviridis [196,197].

class="Chemical">Amphidinolides G <class="Gene">span class="Chemical">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. [201,202,203], as were amphidinolides L (348), M (349) and N (350) [204,205,206].

The structure of class="Chemical">amphidinolide N was later revised <class="Gene">span class="Chemical">and stereochemistry assigned [207]. 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 by convergent total synthesis [209]. The 12-membered macrolide amphidinolide Q (353), 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 exhibited 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), were isolated from a culture of a symbiotic dinoflagellate Amphid. sp. from Amphis. 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].

The class="Chemical">Amphid. strain S1-36-5 yielded the highly cytotoxic 26<class="Gene">span class="Chemical">-membered caribenolide I (377) [229].

The class="Chemical">13-membered macrolide <class="Gene">span class="Chemical">amphidinolactone A (378) and a 26-membered macrolide amphidinolactone B (379) have been isolated from cultures of Amphid. sp. Amphidinolactone A was synthesized totally via a ring-closing metathesis reaction and the absolute configuration was elucidated [8,230,231]. The vasoconstrictors zooxanthellatoxins A (380) and B (381) were isolated from a symbiotic dinoflagellate Symbiodinium sp. (Y-6 strain), which was associated with Amphis. sp. [232,233]. Bioassay-guided fractionation of a butanol extract of the tropical dinoflagellate Prorocentrum maculosum Faust yielded the fast-acting toxin prorocentrolide B (382) [234]. Hoffmanniolide (383) was identified in the marine dinoflagellate P. hoffmannianum [235]. The 20-membered iriomoteolide-1a (384), -1b (385) and -1c (386) were isolated from a marine benthic dinoflagellate Amphid. sp. (strain HYA024) [236,237].

The cytotoxic class="Chemical">23-membered <class="Gene">span class="Chemical">iriomoteolide-2a (387) was also obtained from Amphid. sp. [238]. The 15-membered macrolide iriomoteolide-3a (388) containing an allyl epoxide was obtained from Amphid. sp. strain HYA024 and was potently cytotoxic to human B lymphocyte DG-75 cells and Epstein–Barr virus (EBV)-infected Raji cells [239]. Iriomoteolide-4a (389) and -5a (390) were isolated from a benthic dinoflagellate Amphid. sp. (strain HYA024) and showed moderate cytotoxicity towards human B lymphocytes DG-75 [240]. The 15- and 19-membered iriomoteolide-9a (391) and -11a (392) were cytotoxic towards human cervix adenocarcinoma HeLa and murine hepatocellular carcinoma MH134 cells [241].

class="Chemical">Iriomoteolide-10a (393) <class="Gene">span class="Chemical">and -12a (394) were isolated from a marine dinoflagellate Amphid. sp. (KCA09053 strain) with iriomoteolide-10a being cytotoxic to human cervix adenocarcinoma HeLa and murine hepatocellular carcinoma MH134 cells [242]. The 62-membered novel polyol macrolide symbiodinolide (395) was isolated from the symbiotic dinoflagellate Symbiodinium sp. (S. sp.) and showed significant voltage-dependent N-type Ca2+ channel-opening activity at 7 nM and immediately ruptured the surface tissue of the acoel flatworm Amphis. sp. at 2.5 mM [14]. The stereochemistries of C-23–C-34 were revised by stereoselective synthesis and the (17S,18R,21R) configurations were determined by synthesis [243,244]. The synthesis of the C-33–C-42 fragment elucidated (36S,40S) and (C-1′–C-25′) [243,244,245]. The dinoflagellate-derived macrolide acuminolide A (396) caused potent stimulation of actomyosin ATPase activity [246]. The 25-membered polyketide-derived macrocycle belizentrin (397) was isolated from cultures of the marine dinoflagellate Prorocentrum belizeanum [247]. Gymnodimine D (398) was extracted and purified from a culture of dinoflagellate Alexandrium ostenfeldii from the Baltic Sea [248]. Symbiodinolactone A (399) was isolated from a culture of the symbiotic marine dinoflagellate S. sp. [249].

2.1.3. Red algae

Polycavernosa tsudai (class="Species">Gracilaria edulis) contained the <class="Gene">span class="Chemical">macrolide polycavernoside A (400), which led to human illness and death in Guam [250]. The relative configuration of polycavernosolide A was assigned and the sugar substructure was synthesized [251,252]. Its structure was confirmed by total synthesis in a stereocontrolled manner [253]. Polycavernosides A2 (401), A3 (402), B (403) and B2 (404) were also obtained from Polycavernosa red algae [254].

Two analogs of class="Chemical">polycavernosolide A, <class="Gene">span class="Chemical">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 (410) and manauealide C were extracted from Hawaiian G. coronopifolia [257]. Investigation 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 antifungal properties while bromophycolides A demonstrated potent anti-HIV and moderate cytotoxic activities [258]. Bromophycolides C–I (414–420) were also isolated from extracts of C. serratus. All the bromophycolides exhibited modest antineoplastic activity towards a range of human tumor cell lines while bromophycolides F and I showed weak antifungal activity [259].

Further investigation of the class="Species">C. serratus extract yielded a series of unusual antimalarial <class="Gene">span class="Chemical">diterpene-benzoate macrolides, bromophycolides J–Q (421–428), with a range of moderate to strong antimicrobial and anticancer properties [260]. C. serratus was also a source of the diterpene-benzoate macrolides bromophycolides R–U (429–432). These demonstrated modest cytotoxicity toward selected human cancer cell lines while bromophycolide S was active (at submicromolar concentrations) against the human malaria parasite Plasmodium falciparum (Pla. falciparum) [261].

The α-pyrone class="Chemical">macrolides <class="Gene">span class="Chemical">neurymenolides A (433) and B (434) were obtained from the Fijian red alga Neurymenia fraxinifolia [262]. The brown alga Ecklonia stolonifera produced ecklonialactones C (435) and D (436) containing a 14-membered lactone moiety, and ecklonialactones E (437) and F (438), with a 16-membered moiety [263]. The absolute configurations of ecklonialactones A, B and E were determined from chiroptical data [264]. Eight oxylipins (439–446) with a macrolide scaffold and one cymathere-type oxylipin with an open ring were isolated from the brown alga Eisenia bicyclis. The absolute configurations of compounds 439–443 and 446 were determined by NMR spectroscopy with the relative stereochemistry at C-9 in 446 remaining unassigned [265]. The metamorphosis-enhancing macrodiolide luminaolide (447) was isolated from the crustose coralline alga Hydrolithon reinboldii and its absolute relative configuration was determined by NMR spectroscopy with the relationships of the two side chains to the macrolide ring remaining unassigned [266,267].

2.1.4. Cnidarians

Two avermectin congeners, avermectins B1c (448) <span class="Chemical">and B1e (449), exhibiting moderate antifouling activity were obtained from Anthrogorgia caerulea collected in the South China Sea [268].

2.1.5. Bryozoans

Large-scale isolation of class="Chemical">bryostatin 1 (450) from the marine bryozoan <class="Gene">span class="Species">Bugula neritina (L.) was carried out to provide material for clinical study [269]. Bryostatin 2 (451) has been converted to bryostatin 1 and bryostatin 12 (452) by selective protection and deprotection involving the C-26 hydroxyl group [270]. The stereochemistries of bryostatins 1 and 2 were assigned by X-ray analysis of p-bromobenzoate (453) [271], while the assignments of bryostatin 1 from 1H- and 13C-NMR were later revised [272]. Bryostatin 3 was isolated from B. neritina and reinvestigation of 2D NMR spectroscopic data revised the structure of bryostatin 3 to structure 454 [273].

Further investigation of class="Species">B. neritina led to the identification of <class="Gene">span class="Chemical">bryostatins 14 (455) and 15 (456) [274]. The structures of bryostatin 3 and 20-epi-bryostatin 3 (457) have been elucidated by NMR spectroscopy [271,273,275]. Bryostatin 3 was then synthesized in an enantioselective manner [276]. Bryostatin 10 (458) was determined to be the major cytotoxic component of B. neritina [277]. Three additional antileukemic macrolides, bryostatins 16 (459), 17 (460), and 18 (461), were isolated in trace amounts from B. neritina from the Gulf of Mexico [278]. Antineoplastic bryostatin 19 (462) was isolated from B. neritina collected from the South China Sea [279]. A further member 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].

2.1.6. Mollusks

class="Chemical">Aplysiatoxin (465) was isolated from an extract of the <class="Gene">span class="Species">sea hare Stylocheilus longicauda and synthesized [282,283]. The sea hare Aplysia kurodai Baba contained the novel and potently cytotoxic macrolides aplyronines A (466), B (467) and C (468). The absolute configuration of aplyronine A was assigned following enantioselective synthesis of its degradation products and total synthesis was also reported [284,285]. Five cytotoxic macrolides, 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 lactones named aplyolides A–E (478–482) were found in the skin of the marine mollusk Aplysia depilans, and were ichthyotoxic to the mosquito fish Gambusia affinis [290]. The stereochemistry of (-)-aplyolide A was confirmed by synthesis [291] and the absolute stereochemistries of aplyolides B–E were confirmed by total synthesis [292,293]. Pectenotoxins 4 (483) and 7 (484) were isolated from Patinopecten yessoensis scallops [294]. LC–MS analysis of shellfish extracts identified PTX-12 (485) as a pectenotoxin accumulating in Norwegian blue mussels (Mytilus edulis) and cockles (Cerastoderma edule) [295]. Dolastatin 19 (486), containing a 14-membered macrocyclic lactone linked to a 2,4-di-O-methyl-L-R-rhamnopyranoside, was found in the Gulf of California in the shell-less mollusk Dolabella auricularia [296]. The stereochemistry of (+)-dolastatin 19 was confirmed by total synthesis [297].

2.1.7. Tunicates

Two 24class="Chemical">-membered macrolide sulfates showing antineoplastic activity, <class="Gene">span class="Chemical">iejimalides C (487) and D (488), were isolated from the Okinawan tunicate Eudistoma cf. rigida [298]. Two cytotoxic macrolides, lobatamides A (489) and B (490), were reported in the tunicate Aplidium lobatum [299]. A. lobatum from shallow waters in Australia, A. sp. from deep water, and an unidentified Philippine ascidian have been reported as sources of a series of macrolides, lobatamides C–F (491–494), demonstrating cytotoxicity towards human tumor cell lines [300]. The absolute stereochemistry of lobatamide C 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 investigation of the D. sp. led to the isolation of biselides C (498), D (499) and E (500) which exhibited cytotoxicity against human cancer cells NCI-H460 and MDA-MB-231 [304]. Cytotoxic palmerolide A (501) was obtained from the Antarctic tunicate Synoicum adareanum [305] and its stereochemistry was revised and confirmed by synthesis [306,307].

class="Chemical">Glycosylated macrolides <class="Gene">span class="Chemical">mandelalides A−D (502–505) were isolated from Lissoclinum ascidian collected in Algoa Bay near Port Elizabeth and the surrounding Nelson Mandela Metropole in South Africa [308].

2.2. Bioactivities of Marine-Derived Macrolides

The biological activities of marine-derived class="Chemical">macrolides have been studied extensively. As listed in Table 1, marine <class="Gene">span class="Chemical">macrolides harbor a broad range of bioactive properties including cytotoxicity, antibacteria, antifungi, antimitotic, antiviral, and other activities, with cytotoxicity being their most significant bioactivity.

Biological activities of marine-derived <span class="Chemical">macrolides.

a In the pharmacology column, cytotoxic, antibacteria <span class="Chemical">and antifungal parts present class="Gene">species to which the compou<class="Gene">span class="Disease">nds show inhibition bioactivities. b Vascular cell adhesion molecule.

3. Conclusions and Outlook

This review presents a summary of 505 marine-derived class="Chemical">macrolides reported from 1990 to 2020 <class="Gene">span class="Chemical">and highlights their chemical and biological diversity. As shown in Figure 1, 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 (Figure 2). 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 (Table 1). Cytotoxicity is their most significant bioactivity, highlighting that marine macrolides include many potential antitumor drug leads.

For class="Chemical">macrolides with larger macrocyclic rings, such as <class="Gene">span class="Chemical">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.