marine drugs

Review Natural Polypropionates in 1999–2020: An Overview of Chemical and Biological Diversity

Zhaoming Liu, Hongxin Liu and Weimin Zhang * State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, 100 Central Xianlie Road, Yuexiu District, Guangzhou 510070, China; [email protected] (Z.L.); [email protected] (H.L.) * Correspondence: [email protected]



Received: 2 November 2020; Accepted: 16 November 2020; Published: 19 November 2020


Abstract: Natural polypropionates (PPs) are a large subgroup of polyketides with diverse structural features and bioactivities. Most of the PPs are discovered from marine organisms including mollusks, fungi and actinomycetes, while some of them are also isolated from terrestrial resources. An increasing number of studies about PPs have been carried out in the past two decades and an updated review is needed. In this current review, we summarize the chemical structures and biological activities of 164 natural PPs reported in 67 research papers from 1999 to 2020. The isolation, structural features and bioactivities of these PPs are discussed in detail. The chemical diversity, bioactive diversity, biodiversity and the relationship between chemical classes and the bioactivities are also concluded.

Keywords: polypropionate; marine organism; chemical diversity; bioactive diversity; biodiversity

1. Introduction

Natural polypropionates (PPs) are a large subgroup of polyketides constructed by C3-units. Most of the PPs are discovered from marine organisms including mollusks, fungi and actinomycetes, while some of them are also isolated from terrestrial resources. One of the main characteristics to distinguish the PPs is the regularly interspaced methyl groups in the polyketide chain or the cyclic polyketide core, which are driven directly from propionate unit or from the acetate-methionine motif. Due to their flexible biosynthetic connections, polypropionate derivatives always perform abundant structural diversities. Moreover, they also play as important building blocks in the biosynthesis of several kinks of antibiotics such as macrolides, polyether and cyclic peptides. While some of the polypropionate metabolites exert an ecological influence in the organisms, most of them have been demonstrated to exhibit various kinds of bioactivities, especially antitumor and antimicrobial effects [1]. The first propionate-derived metabolite was isolated from marine mollusk Tridachiella diomedea in 1978, which was identified as tridachiosne through X-ray diffraction by C. Ireland and D.J. Faulkner. [2] Since then, there has been an increasing number of PPs with different structural features reported from nature or by genomic engineering. However, the only review in the past reported by Michael T. Davies-Coleman and Mary J. Garson summarized 168 PPs from marine resources up to the end of 1997 [3] and there is no additional updated review in the past two decades. In the current review, we focus on the chemical structures and bioactive properties of the new PPs discovered from both marine and terrestrial systems in 1999–2020. A total of 67 research papers containing 164 new PPs (74% of which were from marine resources), which are driven from either the putative polypropionate-related biosynthesis pathway or the mixed biogenetic pathway involving propionate units, have been summarized in this review. The new compounds can be divided into three main groups according to their structure features: the first one is linear molecular (8%), the second

Mar. Drugs 2020, 18, 569; doi:10.3390/md18110569 www.mdpi.com/journal/marinedrugs Mar. Drugs 2020, 18, x 2 of 23 Mar. Drugs 2020, 18, 569 2 of 23 divided into three main groups according to their structure features: the first one is linear molecular (8%), the second one is cyclic polypropionate (76%) and the last one is macrocyclic derivatives (16%). one is cyclic polypropionate (76%) and the last one is macrocyclic derivatives (16%). Moreover, it can Moreover, it can be noticed that the cycle containing PPs is the most abundant group with the largest be noticed that the cycle containing PPs is the most abundant group with the largest proportion, proportion, which can be further distributed into five subcategories shown in the pie chart of Figure which can be further distributed into five subcategories shown in the pie chart of Figure1: carbocyclic 1: carbocyclic (10%), pyran derivatives (47%), furan derivatives (9%), pyran and furan containing (10%), pyran derivatives (47%), furan derivatives (9%), pyran and furan containing (6%) and other (6%) and other cyclic analogues (4%). We will present their isolation, structure and bioactivities in cyclic analogues (4%). We will present their isolation, structure and bioactivities in detail; meanwhile, detail; meanwhile, the chemical diversity, bioactive diversity and the biodiversity are also discussed the chemical diversity, bioactive diversity and the biodiversity are also discussed in this review. in this review.

Figure 1. 1.164 164 natural natural polypropionates polypropionates were divided were intodivided three into main threegroups; main the cyclic groups; polypropionates the cyclic (PPs)polypropionates were further (PPs classified) were intofurther five classified sub-groups; into the five characteristic sub-groups; chemicalthe characteristic classes are chemical highlighted classes in diareff erenthighlighted colors. in different colors.

2. Isolation, Structural Features and Bioactivities of Polypropionates 2.1. Linear Metabolites 2.1. Linear Metabolites The linear polypropionate derivatives are a relatively rare group discovered from nature, which The linear polypropionate derivatives are a relatively rare group discovered from nature, which are driven directly from propionate pathway or acetate-methionine pathway. From 1999 to 2020, are driven directly from propionate pathway or acetate-methionine pathway. From 1999 to 2020, 14 14 linear analogues have been isolated from marine mollusks, microorganisms, terrestrial plants and linear analogues have been isolated from marine mollusks, microorganisms, terrestrial plants and insects (Figures2 and3). insects (Figures 2 and 3). Caribbean marine sponge Discodermia dissolute collected from Grand Bahama Island yielded Caribbean marine sponge Discodermia dissolute collected from Grand Bahama Island yielded an an amide containing polypropionate 5-hydroxymethyldiscodermolate (1)[4] with 13 chiral amide containing polypropionate 5-hydroxymethyldiscodermolate (1) [4] with 13 chiral centers. The centers. The absolute configuration was determined by a comparison of the NMR data with absolute configuration was determined by a comparison of the NMR data with those of the those of the methanolysis product derived from the known polypropionate discodermolide [5]. methanolysis product derived from the known polypropionate discodermolide [5]. Compound 1 Compound 1 exhibited strong cytotoxicity against murine P388 leukemia and human lung exhibited strong cytotoxicity against murine P388 leukemia and human lung adenocarcinoma A549 adenocarcinoma A549 cell lines with the IC50 values of 65.8 and 74 nM, respectively. Exiguaone cell lines with the IC50 values of 65.8 and 74 nM, respectively. Exiguaone (2) [6] was isolated from the (2)[6] was isolated from the lipidic extract of Mediterranean cephalaspidean mollusk Haminoea lipidic extract of Mediterranean cephalaspidean mollusk Haminoea exigua while micromelones A and exigua while micromelones A and B (3 and 4)[7] were isolated from marine gastropod B (3 and 4) [7] were isolated from marine gastropod Micromelo undata. The absolute configuration of Micromelo undata. The absolute configuration of them remains unknown. The chemical them remains unknown. The chemical investigation of two species of South African mollusk investigation of two species of South African mollusk Siphonaria led to the discovery of two Siphonaria led to the discovery of two new linear PPs, (6E,8E,10S,12S)-3-hydroxy-4,6,8,10,12- new linear PPs, (6E,8E,10S,12S)-3-hydroxy-4,6,8,10,12-pentamethylpentadeca-6,8-dien-5-one (5) and pentamethylpentadeca-6,8-dien-5-one (5) and (2E,4S,6S,8S)-2,4,6,8-tetramethyl-2-undecenoic acid (6) (2E,4S,6S,8S)-2,4,6,8-tetramethyl-2-undecenoic acid (6)[8,9]. The stereochemistry of 6 was further [8,9]. The stereochemistry of 6 was further elucidated by oxidative degradation. elucidated by oxidative degradation.

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Figure 2. Chemical structures of 1–6.

Microorganisms, especially the terrestrial fungi, are the potential source of natural PPs. Six new PPs, including two linear ones, fiscpropionates C and F (7 and 8) [10], were isolated from the deep- sea-derived fungus Aspergillus fischeri, which represented the first discovery of polypropionate derivatives from the deep-sea-derived fungus. The absolute configuration at C-11 of 8 was deduced by the modified Mosher’s method. In the bioassays, 7 was detected to show strong noncompetitive inhibitory effects against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) with the IC50 value of 4.0 µM. A limestone soil-derived fungus Penicillium decumbens yielded an aliphatic acid 3,11-dihydroxy-6,8-dimethyldodecanoic acid (9) [11] which constructed a polypropionate fragment in the aliphatic chain. The bioassay-guided fractionation of the actinobacterium Saccharothrix xinjiangensis collected from Caspian Sea beach led to isolation of a N-containing polypropionate saccharonoic acid (10), which exhibited weak inhibitory activity against Mucor hiemalis and Candida albicans (IC50: 66.7 and 33.4 µg/mL) [12]. Xylarinic acids A and B (11 and 12) were antifungal PPs from the fruiting body of Xylaria polymorphaFigure [13]. 2.2. Chemical structures of 1–6..

Microorganisms, especially the terrestrial fungi, are the potential source of natural PPs. Six new PPs, including two linear ones, fiscpropionates C and F (7 and 8) [10], were isolated from the deep- sea-derived fungus Aspergillus fischeri, which represented the first discovery of polypropionate derivatives from the deep-sea-derived fungus. The absolute configuration at C-11 of 8 was deduced by the modified Mosher’s method. In the bioassays, 7 was detected to show strong noncompetitive inhibitory effects against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) with the IC50 value of 4.0 µM. A limestone soil-derived fungus Penicillium decumbens yielded an aliphatic acid 3,11-dihydroxy-6,8-dimethyldodecanoic acid (9) [11] which constructed a polypropionate fragment in the aliphatic chain. The bioassay-guided fractionation of the actinobacterium Saccharothrix xinjiangensis collected from Caspian Sea beach led to isolation of a N-containing polypropionate saccharonoic acid (10), which exhibited weak inhibitory activity against Mucor hiemalis and Candida albicans (IC50: 66.7 and 33.4 µg/mL) [12]. Xylarinic acids A and B (11 and 12) were antifungal PPs from the fruiting body of Xylaria polymorpha [13].

Figure 3. ChemicalChemical structures of 7–14.

Microorganisms, especially the terrestrial fungi, are the potential source of natural PPs. Six new PPs, including two linear ones, fiscpropionates C and F (7 and 8)[10], were isolated from the deep-sea-derived fungus Aspergillus fischeri, which represented the first discovery of polypropionate derivatives from the deep-sea-derived fungus. The absolute configuration at C-11 of 8 was deduced by the modified Mosher’s method. In the bioassays, 7 was detected to show strong noncompetitive inhibitory effects against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) with the IC50 value of 4.0 µM. A limestone soil-derived fungus Penicillium decumbens yielded an aliphatic acid 3,11-dihydroxy-6,8-dimethyldodecanoic acid (9)[11] which constructed a polypropionate fragment in the aliphatic chain. The bioassay-guided fractionation of the actinobacterium Saccharothrix xinjiangensis collected from Caspian Sea beach led to isolation of a N-containing polypropionate saccharonoic acid (10), which exhibited weak inhibitory activity against Mucor hiemalis and Candida albicans (IC50: 66.7

Figure 3. Chemical structures of 7–14.

Mar. Drugs 2020, 18, 569 4 of 23 and 33.4 µg/mL) [12]. Xylarinic acids A and B (11 and 12) were antifungal PPs from the fruiting body ofMar.Xylaria Drugs polymorpha2020, 18, x [13]. 4 of 23 Two linear metabolites were also isolated from a terrestrial insect. 4,6,8,10,16,18-hexa- and Two linear metabolites were also isolated from a terrestrial insect. 4,6,8,10,16,18-hexa- and 4,6,8,10,16-pentamethyldocosanes (13 and 14) were two major methylated hydrocarbons obtained from 4,6,8,10,16-pentamethyldocosanes (13 and 14) were two major methylated hydrocarbons obtained cane beetle species Antitrogus parvulus [14,15], and their absolute configuration was established by a from cane beetle species Antitrogus parvulus [14,15], and their absolute configuration was established series of chemical conversion, chromatographic and spectroscopic comparisons. by a series of chemical conversion, chromatographic and spectroscopic comparisons. 2.2. Cyclic Metabolites 2.2. Cyclic Metabolites 2.2.1. Carbon Homocyclic Metabolites 2.2.1. Carbon Homocyclic Metabolites PPs containing a carbon homocycle are always driven from the mixed biogenetic pathway. PPs containing a carbon homocycle are always driven from the mixed biogenetic pathway. They They usually present a five-/six-member ring or the benzene ring. The complicated ring systems such usually present a five-/six-member ring or the benzene ring. The complicated ring systems such as as spirocyclic or bridged cyclic are also discovered but quite rare in polypropionate derivatives. spirocyclic or bridged cyclic are also discovered but quite rare in polypropionate derivatives. Three pairs of enantiomers ( )-ocellatusones A–C (15–17), constructing a bicyclo[3.2.1]octane Three pairs of enantiomers (±)±-ocellatusones A–C (15–17), constructing a bicyclo[3.2.1]octane or or bicyclo[3.3.1]nonane, were discovered from a South-China-Sea-derived photosynthetic mollusk bicyclo[3.3.1]nonane, were discovered from a South-China-Sea-derived photosynthetic mollusk Placobranchus ocellatus [16]. These represent the most complex carbon homocycle containing PPs to Placobranchus ocellatus [16]. These represent the most complex carbon homocycle containing PPs to date (Figure4). The optically pure enantiomers of the racemic compounds were obtained by chiral date (Figure 4). The optically pure enantiomers of the racemic compounds were obtained by chiral HPLC resolution. Furthermore, the biomimetic semisynthesis of 15 from a known polypropionate HPLC resolution. Furthermore, the biomimetic semisynthesis of 15 from a known polypropionate tridachiahydropyrone [17] was performed through ZnCl2 catalysis, which confirmed the new and tridachiahydropyrone [17] was performed through ZnCl2 catalysis, which confirmed the new and diversity-generating rearrangements from the same precursor in the biosynthetic pathway. A mollusk diversity-generating rearrangements from the same precursor in the biosynthetic pathway. A Siphonaria capensis collected from the intertidal zone at the Bushman’s River mouth yielded a mollusk Siphonaria capensis collected from the intertidal zone at the Bushman’s River mouth yielded cyclopentanone-derived polypropionate capensinone (18) (Figure4)[9]. a cyclopentanone-derived polypropionate capensinone (18) (Figure 4) [9].

FigureFigure 4. Chemical structures of of 1515––2222..

TenTen carbon carbon homocyclic homocyclic PPsPPs werewere obtained from microorganisms including including fungi, fungi, actinomycetes actinomycetes andand myxobacteria myxobacteria (Figure (Figure4 ). 4). Porosuphenols Porosuphenols A–C A–C ( (1919––2121)) were were isolated isolated from from a a marine marine-derived-derived AspergillusAspergillus porosusporosus [[18]18],, andand asperolanasperolan (22)) waswas isolated from a a Garcinia preussii preussii endophyticendophytic fungus fungus AspergillusAspergillus japonicus [19].[19]. The The absolute absolute configuration configuration of 19 ofwas19 establishedwas established using NMR using data NMR guided data guidedconformer conformer searching searching and e andlectrostatic electrostatic circular circular dichroism dichroism (ECD (ECD)) calculations. calculations. A ACamaropsCamarops-like-like endophyticendophytic fungus fungus collected collected from from AlibertiaAlibertia macrophylla yielded three eremophilane sesquiterpene sesquiterpene derivativesderivatives xylarenonesxylarenones C–EC–E (23–25) which constructed a a polypropion polypropionateate side side chain chain (Figure (Figure 5)5 )[[20].20 ]. InIn the the bioactivity bioactivity tests,tests, onlyonly 2323 displayeddisplayed strongstrong enzyme inhibition activities activities against against subtilisin subtilisin and and 50 pepsinpepsin proteaseprotease withwith the IC 50 valuesvalues of of 0.462 0.462 and and 0. 0.288288 µM,µM, respectively. respectively. Further, Further, pacificanones pacificanones A Aand and B B(26 ( 26andand 27)27 were) were produced produced by a bymarine a marine actinomycete actinomycete SalinisporaSalinispora pacifica pacifica (Figure(Figure 5) [21],5 while)[ 21 ], whilea new a new cytotoxic cytotoxic polyketide polyketide synthase synthase–nonribosomal–nonribosomal peptide peptide synthetase synthetase (PKS (PKS-NRPS)-NRPS) hybrid hybrid polypropionate, haliamide (28) was isolated from a marine myxobacterium Haliangium ochraceum and showed cytotoxicity against HeLa-S3 cells (IC50 = 12 µM) [22].

Mar. Drugs 2020, 18, 569 5 of 23 polypropionate, haliamide (28) was isolated from a marine myxobacterium Haliangium ochraceum and showedMar. Drugs cytotoxicity 2020,, 18,, xx against HeLa-S3 cells (IC = 12 µM) [22]. 5 of 23 Mar. Drugs 2020, 18, x 50 5 of 23

Figure 5. Chemical structures of 23–28.. Figure 5. Chemical structures of 23–28. 2.2.2. Pyran-Related Metabolites 2.2.2. Pyran Pyran-Related--Related Metabolites Pyran ring is very common in PPs and nearly half (47%) of the naturally occurring PPs PyranPyran ringring is is very very common common inPPs in andPPs nearly and nearly half (47%) half of (47%) the naturally of the naturallyoccurring PPsoccurring possessing PPs possessing one or more pyran or pyran-related cycle(s). A total of 77 new PPs were concluded in this onepossessing or more one pyran or more or pyran-related pyran or pyran cycle(s).--related A cycle(s). total of A 77 total new of PPs 77 new were PPs concluded were concluded in this section in this section (Figure 6), including 37 metabolites containing a 2-pyrone ring, 34 metabolites containing 4- (Figuresection 6(Figure), including 6), including 37 metabolites 37 metabolites containing containing a 2-pyrone a 2-- ring,pyrone 34 ring, metabolites 34 metabolites containing containing 4-pyrone 4-- pyrone ring(s), 5 metabolites containing a hydrogenated pyran ring and a derivative containing an ring(s),pyrone 5ring(s), metabolites 5 metabolites containing containing a hydrogenated a hydrogenated pyran ring pyran and ring a derivative and a derivative containing containing an unusual an unusual 3-pyrone moiety (Figure 7, hyapyrones A 29 from myxobacteria H. minutum [23]). 3-pyroneunusual 3 moiety--pyrone (Figure moiety7 ,(Figure hyapyrones 7, hyapyrones A 29 from A myxobacteria 29 fromfrom myxobacteriamyxobacteriaH. minutum H. minutum[23]). [[23]).

FigureFigure 6.6. ClassificationClassification of pyran-relatedpyran-related PPs. Figure 6. Classification of pyran-related PPs.

FigureFigure 7.7. Chemical structures ofof 2929... Figure 7. Chemical structures of 29. Metabolites Containing 2-Pyrone(s) Metabolites Containing 2--Pyrone(s)(s) The marine sponge Discodermia sp. has yielded a linear polypropionate (1) together with four 2- The marine sponge Discodermia sp. has yielded a linear polypropionate (1)) togethertogether withwith fourfour 22-- pyrone-containing series 30–33 (Figure 8). All of them showed strong in vitro inhibitory activity pyrone--containing series 30–33 ((Figure 8). All of them showed strong inin vitro vitro inhibitoryinhibitory activity activity against proliferation of the P-388 cell line with the IC50 values in the range of 0.13–5.0.0 µM µM [4]. [4]. against proliferation of the P-388 cell line with the IC50 values in the range of 0.13–5.0 µM [4].

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Metabolites Containing 2-Pyrone(s) The marine sponge Discodermia sp. has yielded a linear polypropionate (1) together with four 2-pyrone-containing series 30–33 (Figure8). All of them showed strong in vitro inhibitory activity againstMar. Drugs proliferation 2020, 18, x of the P-388 cell line with the IC50 values in the range of 0.13–5.06 µofM[ 23 4]. Fusaripyrones A and B (34 and 35) were isolated from Mediterranean mollusk Haminoea fusari [24] whileFusaripyrones exiguapyrone A and (36) B was (34 isolated and 35) fromwere molluskisolated H.from exigua Mediterranean[6]. (+)-Discodermolide mollusk Haminoea (37) wasfusari obtained [24] while exiguapyrone (36) was isolated from mollusk H. exigua [6]. (+)-Discodermolide (37) was from a sponge D. dissolute previously and its diverse pharmacological activities made it to be a obtained from a sponge D. dissolute previously and its diverse pharmacological activities made it to synthetic target for chemists. The solution structure of 37 was determined via NMR techniques and be a synthetic target for chemists. The solution structure of 37 was determined via NMR techniques conformational analysis by Amos B. Smith III and his co-workers for the first time, which demonstrated and conformational analysis by Amos B. Smith III and his co-workers for the first time, which α thatdemonstrated37 occupies athat helical 37 occupies conformation a helical inconformation solvent [25 –in30 solvent]. Four [25-pyrones–30]. Four propionatesα-pyrones propionates (38–41) were produced(38–41) bywere mediterranean produced by mediterranean sacogolssan Placida sacogolssan dendritica Placida(Figure dendritica8). (Figure 8).

FigureFigure 8.8. ChemicalChemical structures structures of of 3030–41–41. .

TheThe fungi fungi are are the the main main producer producer ofof 2-pyrone-containing2-pyrone-containing PPs PPs (Figure (Figure 9).9 ).Three Three different di fferent species species of Aspergillus genus yielded five metabolites, including nipyrones A‒C (42–44) [31], versicolone A of Aspergillus genus yielded five metabolites, including nipyrones A-C (42–44)[31], versicolone A (45) [32] and neovasinin (46) [19]. The stereochemistry of the chiral centers at the side chain of 42–44 (45)[32] and neovasinin (46)[19]. The stereochemistry of the chiral centers at the side chain of 42–44 was deduced by the NOE correlations and ECD calculations while the 9R, 11R configuration of 45 was deduced by the NOE correlations and ECD calculations while the 9R, 11R configuration of 45 was established by comparing the optical rotation between natural isolates and ascosalitoxin isomers. wasThe established absolute configuration by comparing of the 45 opticalwas directly rotation confirmed between by natural X-ray crystallographic isolates and ascosalitoxin analysis. In isomers. the Thebioactivity absolute configurationtests, 44 not only of 45showedwas directly promising confirmed activity against by X-ray Staphylococcus crystallographic aureusanalysis. and Bacillus In the bioactivitysubtilis with tests, the44 MICnot onlyvalues showed of 8 and promising 16 µg/mL, activity respectively, against butStaphylococcus also displayed aureus weakand antitubercularBacillus subtilis withactivity the MIC against values M. oftuberculosis 8 and 16,µ withg/mL, an respectively, MIC value of but 64 alsoµg/mL. displayed Bioassay weak-guided antitubercular investigation activity of againstanotherM. tuberculosisplant-associated, with fungus an MIC Aspergillus value of sp. 64 µ ledg/ mL. to the Bioassay-guided isolation of a new investigation enzyme inhibitor of another plant-associatedaspopyrone A fungus(47) [33],Aspergillus which exhibitedsp. led significant to the isolation Protein Tyrosine of a new Phosphatase enzyme inhibitor 1B (PTP1B aspopyrone) and T- A cell PTP inhibitory activities with the IC50 values of 6.7 and 6.0 µM. Two new α-pyrones fupyrones A and B (48 and 49) were isolated from an endophytic fungus Fusarium sp. [34] while three 2-pyrone phomapyrones D‒G (50–52) were identified from the mixed extract of pathogen Leptosphaeria maculans. Using the incorporations of 13C-labeled acetate/malonate and deuterated methionine led to

Mar. Drugs 2020, 18, 569 7 of 23

(47)[33], which exhibited significant Protein Tyrosine Phosphatase 1B (PTP1B) and T-cell PTP inhibitory activities with the IC50 values of 6.7 and 6.0 µM. Two new α-pyrones fupyrones A and B (48 and 49) were isolated from an endophytic fungus Fusarium sp. [34] while three 2-pyrone phomapyrones D-G (50–52) were identified from the mixed extract of pathogen Leptosphaeria maculans. Using the Mar. Drugs 2020, 18, x 7 of 23 incorporations of 13C-labeled acetate/malonate and deuterated methionine led to the illustration of an acetate-methioninethe illustration of biosynthetican acetate-methionine pathway biosynthetic of phomapyrones pathway [35 of]. phomapyrones An endophytic [35].Penicillium An endophyticsp. from CatharanthusPenicillium roseus sp. yielded from Catharanthus a novel bicyclo[4.2.0]octadiene roseus yielded a novel containing bicyclo[4.2.0] polypropionateoctadiene citreoviripyrone containing A(53polypropionate)[36]. Interestingly, citreoviripyrone using the Zn(II)-type A (53) [36]. and Interestingly, NAD+-dependent using histone the Zn(II) deacetylase-type and inhibitors NAD+- in fermentationdependent couldhistone significantly deacetylase enhanceinhibitors the in fermentation production of could53 in significantly this strain. enhance A polypropionate-related the production alp geneof 53 in cluster this strain. was shownA polypropionate to be almost-related silent alp ingene wheat cluster pathogen was shownParastagonospora to be almost silent nodorum in wheat, but it couldpathogen be significantly Parastagonospora upregulated nodorum when, but reconstructed it could be significantly heterologously upregulated in Aspergillus when nidulans reconstructed. Based on theheterologously point, three new in Aspergillus 2-pyrone nidulans PPs alternapyrones. Based on the point, B-D ( 54three–56 new) were 2-pyrone obtained PPs [alternapyrones37]. The bioactivity B‒ D (54–56) were obtained [37]. The bioactivity screening indicated that 54 displayed potential screening indicated that 54 displayed potential antibacterial activity against B. subtilis, anti-parasitic antibacterial activity against B. subtilis, anti-parasitic activity against Giadia duodenalis and activity against Giadia duodenalis and cytotoxicity against murine myeloma. Chemical investigation of cytotoxicity against murine myeloma. Chemical investigation of the other two unusual fungi theStemphylium other two unusual sp. and fungiTalaromycesStemphylium sp. led tosp. the and isolationTalaromyces of infectopyronessp. led to the A isolationand B (57 ofand infectopyrones 58) [38] as A andwell B as (57 rasfoninand 58 ()[5938) (Figure] as well 10) as [39]. rasfonin 57 and (5859 )had (Figure a broad 10 )[spectrum39]. 57 andof antibacterial58 had a broad activity spectrum against of antibacterialfive terrestrial activity pathogenic against bacteria five terrestrial while rasfonin pathogenic could bacteria induce cell while death rasfonin in Ba/F3 could-V12 induce cells with cell the death in BaIC/F3-V1250 of 0.16 cells µg/mL. with the IC50 of 0.16 µg/mL.

FigureFigure 9. 9.Chemical Chemical structures of of 4242–58–58. .

SevenSeven PPs PPs were were isolated isolated from from several several antinomycetes,antinomycetes, myxobacteria myxobacteria and and slime slime molds molds (Figure (Figure 10), 10), includingincluding60 and60 and61 61from from marine-sediment-derived marine-sediment-derived Nocardiopsis tangguensis tangguensis [40],[40 salinipyrones], salinipyrones A and A and B (62 and 63) from marine-derived Salinispora pacifica [21], hyapyrones B (64) from the myxobacterium H. minutum [23] and lycogalinosides A‒B (65–66) from slime mold Lycogala epidendrum [41]. The absolute configuration of 60 and 61 was established by NOESY analysis followed by hydrolysis and

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B(62 and 63) from marine-derived Salinispora pacifica [21], hyapyrones B (64) from the myxobacterium H. minutumMar. Drugs[ 232020], and 18, x lycogalinosides A-B (65–66) from slime mold Lycogala epidendrum [41]. The8 absolute of 23 configuration of 60 and 61 was established by NOESY analysis followed by hydrolysis and Mosher’s Mosher’s method. Further, 64, 65 and 66 exhibited antibacterial activities against Gram-positive method. Further, 64, 65 and 66 exhibited antibacterial activities against Gram-positive bacteria. bacteria.

FigureFigure 10. 10.Chemical Chemical structures of of 5959––6666. .

MetabolitesMetabolites Containing Containing 4-Pyrone(s) 4-Pyrone(s) A totalA total of 34 of 4-pyrone-containing 34 4-pyrone-containing PPs werePPs were discovered discovered (Figures (Figures 11–13 11), 29–13 of), which 29 of whichwere produced were by mollusks.produced Theby mollusks. structural The features structural of 4-pyrone features PPs of are4-pyrone more diversePPs are than more those diverse of 2-pyrone than those derivatives. of 2- In general,pyrone derivatives. 2-pyrone PPs In construct general, 2- anpyroneα-pyrone PPs construct core and a anpropionate α-pyrone core chain, and while a propionate the 4-pyrone chain, PPs alwayswhile form the 4 two-pyrone or three PPs always 4-pyrone form moieties two or throughthree 4-pyrone dehydration. moieties through dehydration. TheT studyhe study of of Pacific Pacific sacoglossan sacoglossanElysia Elysia diomedeadiomedea led to to isolation isolation of of two two propionates propionates elysiapyrones elysiapyrones A andA and B (B67 (67and and68 68),), constructing constructing a bicyclo[4.2.0]octane bicyclo[4.2.0]octane core core and and a substituted a substituted 4-pyrone 4-pyrone moiety. moiety. It It waswas speculated speculated thatthat thethe bicyclo[4.2.0]octanebicyclo[4.2.0]octane core core was was formed formed through through an an enzymatic enzymatic intramolecular intramolecular [2+2]-cycloadditions [42]. A similar analogue (69) without the epoxide moieties was isolated from [2+2]-cycloadditions [42]. A similar analogue (69) without the epoxide moieties was isolated from another species of sacoglossan Placobranchus ocellatus together with its peroxy derivative (70) [43]. In another species of sacoglossan Placobranchus ocellatus together with its peroxy derivative (70)[43]. the same year, Aubry K. Miller and Dirk Trauner completed the total synthesis of 69 and 70 [44]. The In thesacoglossan same year, Elysia Aubry patagonica K. yielded Miller a and main Dirk constituent Trauner phototridachiapyrone completed the total J (71 synthesis) [45], which of is69 anand 70 [44isomer]. The of sacoglossan bicyclo[4.2.0]octaneElysia patagonica propionateyielded by constructing a main constituent an bicyclo[3.1.0]octane phototridachiapyrone core. Fifteen J muti (71)[-45], whichpyrones is an containing isomer of PPs bicyclo[4.2.0]octane 72–86, belonging to propionate onchidione by family, constructing were isolated an bicyclo[3.1.0]octane from four species of core. FifteenOnchidium muti-pyrones [46–51]. containing76–81 possess PPs a propionate72–86, belonging chain with to onchidione 4-pyrones at family, both sides. were In isolated the antitumor from four speciesassays, of Onchidium the isolated[ 46 onchidione–51]. 76– 81 derivativespossess a showed propionate moderate chain to with strong 4-pyrones inhibitory at both effects sides. against In the antitumordifferent assays, kinds of the human isolated cancer onchidione cell lines, and derivatives compound showed 83 was moderate further detected to strong to show inhibitory significant effects againstactivation different on the kinds splicing of human of the cancerXBP1 mRNA cell lines, by 217.8% and compound at 10 µg/mL.83 wasChemical further investigation detected to of showa significantsacoglossan activation mollusk on Placobranchus the splicing of ocellatus the XBP1 collected mRNA in by the 217.8% Philippines at 10 µ gled/mL. to Chemicalthe isolation investigation of four of anew sacoglossan tridachione mollusk-type metabolitesPlacobranchus tridachiapyrones ocellatus collected G‒J (87 in–90 the) as Philippines well as a mixture led to the of peroxideisolation of fourcontaining new tridachione-type tridachiahydropyrones metabolites B‒C tridachiapyrones (91 and 92) [52]. G-J For (87 compounds–90) as well 87 as–90 a, mixture only theof relative peroxide 10 containingconfiguration tridachiahydropyrones was determined by NOESY B-C (91 analysis.and 92)[ 9152 and]. For92 were compounds isomers at87 the–90 double, only thebond relative Δ but the stereochemistry at C-4, C-5, C-8 and C-9 has not been identified. The peroxide group was configuration was determined by NOESY analysis. 91 and 92 were isomers at the double bond ∆10 confirmed by EIMS fragmentation analysis. Another peroxide containing polypropionate 93 was but the stereochemistry at C-4, C-5, C-8 and C-9 has not been identified. The peroxide group was isolated from mantle extract of Placida. dendritica [53]. An unusual non-contiguous polypropionate 93 confirmedsiserrone by A EIMS(94) was fragmentation obtained from analysis. Siphonaria Another serrata and peroxide its relative containing configuration polypropionate was determinedwas isolatedby a combination from mantle of extract ROESY of andPlacida. H-H coupling dendritica constant[53]. An analysis. unusual The non-contiguous absolute configuration polypropionate could siserronenot be A identified (94) was becauseobtained 94 from wasSiphonaria unstable and serrata easyand to its be relative degraded configuration [54]. The Caribbean was determined sponge by a combinationSmenospongia of ROESY aurea yielded and H-H a coupling bis-γ-pyrone constant polypropionate analysis. The absolute smenopyrone configuration (95) [55]. could The not be

Mar. Drugs 2020, 18, 569 9 of 23

identifiedMar. Drugs because 2020, 18,94 x was unstable and easy to be degraded [54]. The Caribbean sponge Smenospongia9 of 23 aurea yielded a bis-γ-pyrone polypropionate smenopyrone (95)[55]. The stereochemistry of the pyrone stereochemistry of the pyrone ring was identified by comparing the J values with those of the known ringstereochemistry was identified of by the comparing pyrone ring the wasJ values identified with by those comparing of the knownthe J values compounds with those containing of the known similar compounds containing similar moiety, while the configuration at C-9 and13 C-10 was determined moiety, while13 the configuration at C-9 and C-10 was determined through C NMR calculations. A through 13C NMR calculations. A further ECD analysis led to the establishment of the absolute furtherthrough ECD analysisC NMR led calculations. to the establishment A further ECD of the analysis absolute led configuration to the establishment of 95. of the absolute configuration of 95.

FigureFigure 11. 11.Chemical Chemical structures of of 6767––8686. .

Figure 12. Chemical structures of 87–95. FigureFigure 12. 12.Chemical Chemical structures of of 8787––9595. .

Mar. Drugs 2020, 18, x 10 of 23

Three new simple 4-pyrone PPs, 96–98, were isolated from Aspergillus versicolor, Acremonium citrinum and Fusarium solani, respectively [32,56,57]. 98 displayed a dose-dependent neuroprotective effect against glutamate-induced cytotoxicity in HT22 murine hippocampal neuronal cells. Besides, two 4-pyrone propionates, 99 and 100, constructed a relatively long side chain, were produced by an actinomycete Streptomyces sp [58,59]. 99 dose-dependently inhibited luciferase expression in 2- deoxyglucose treated HT1080 human fibrosarcoma cells (IC50 = 7.8 nM) and it could also inhibit GRP78 protein expression and induce cell death under endoplasmic reticulum stress. 100 exhibited Mar.moderate Drugs 2020 ,cytotoxicity18, 569 against HCT-116, HepG2 and A549 cell lines with the IC50 values in the range10 of 23 of 3.0–6.0 µg/mL.

FigureFigure 13. 13.Chemical Chemical structures of of 9696––100100. .

MetabolitesThree new Containing simple 4-pyrone Hydrogenated PPs, 96 Pyran–98,(s) were isolated from Aspergillus versicolor, Acremonium citrinumTheand Fusarium deep-sea- solaniderived, respectively fungus A. [32 , fischeri56,57]. 98yieldeddisplayed two a dose-dependent tetrahydropyran-derived neuroprotective PPs effectfiscpropionates against glutamate-induced A and B (101 and cytotoxicity 102) (Figure in14). HT22 The stereochemistry murine hippocampal of side chain neuronal was deduced cells. Besides, by twothe 4-pyrone J-HMBC propionates, experiments, 99whichand was100 the, constructed first example a relativelyto use the C long-H coupling side chain, constants were to produced solve the by an actinomyceteconfiguration ofStreptomyces PPs. Both 101sp. and [58 102,59]. exhibited99 dose-dependently significant MptpB inhibited inhibition luciferase activities expression through a in 2-deoxyglucosenoncompetitive treated mechanism HT1080 with human the IC fibrosarcoma50 values of 5.1 cells and (IC 1250 µ=M,7.8 respectively. nM) and it The could quantitative also inhibit GRP78structure protein-activity expression relationship and induce (QSAR cell) analysis death suggested under endoplasmic that the terminal reticulum hydrophilic stress. 100functionalexhibited moderategroup cytotoxicityas well as an againstopposing HCT-116, hydrophobic HepG2 chain and would A549 play cell linesan important with the role IC50 invalues MptpB in inhibition the range of 3.0–6.0activitiesµg/mL. [10]. Another marine-derived fungus A. porosus produced three new PPs porosuphenols A‒ C (19–21) and a hydrogenated benzopyran derivative porosuphenol D 103 (Figure 14) [18]. Though Metabolitesa series of Containing conformation Hydrogenated analysis was adapted Pyran(s) to solve the stereochemistry of 19 and 20, the attempts to assign the absolute configuration of 21 and 103 were unsuccessful. Dolabriferols B and C (104 and The deep-sea-derived fungus A. fischeri yielded two tetrahydropyran-derived PPs fiscpropionates 105) were two propionate-related metabolites from Caribbean mollusk Dolabrifera dolabrifera collected A andfrom B Puerto (101 and Rico102 (Figure) (Figure 14) [60].14). The The absolute stereochemistry configuration of side was chain established was deduced by a combination by the J -HMBCof X- experiments,ray diffraction which and was chemical the first degradation example to studies. use the C-H coupling constants to solve the configuration of PPs. Both 101 and 102 exhibited significant MptpB inhibition activities through a noncompetitive mechanism2.2.3. Furan with-Related the IC Metabolites50 valuesof 5.1 and 12 µM, respectively. The quantitative structure-activity relationshipExcept (QSAR) for the analysisthree pairs suggested of carbon that homocyclic the terminal PPs (±) hydrophilic-15–(±)-17, the functional mollusk P. group ocellatus as wellalso as an opposingproduced hydrophobic a pair of furanone chain- wouldcontaining play analogues an important (±)-106 role [16], in M whichptpB inhibition represents activities a unique [ 10]. Anotherdimethylfuran marine-derived-3(2H)-one fungus nucleusA. porosus connectedproduced with athree mesitylene new PPs moiety porosuphenols (Figure 15). A-C An (19 – X21-ray) and a hydrogenateddiffraction was benzopyran carried out derivative to confirm porosuphenol its racemic natureD 103 (Figure by a P -141 )[space18]. group. Though 6Z a,8 seriesE-Δ8- of conformationSiphonarienfuranone analysis was (107 adapted) and 6 toE,8 solveE-Δ8- thesiphon stereochemistryarienfuranone of (10819 and) are20 two, the new attempts epimers to assign at Δ6 the absoluteproduced configuration by the mollusk of 21 andSiphonaria103 were oculus unsuccessful. [8]. In the structures Dolabriferols of 107 B and and 108 C (,104 a hemiketaland 105 )moiety were two propionate-relatedwas constructed in metabolites the 3-furanone from ring Caribbean but the stereochemistry mollusk Dolabrifera at C-2 dolabriferawas unidentifiedcollected so far from (Figure Puerto Rico15). (Figure The chemical 14)[60]. investigation The absolute of configuration the same species was mollusk established Siphonaria by a combinationcapensis led to of isolation X-ray di offf ractiona 2- andfuranone chemical-containing degradation polypropionate studies. capensifuranone (109) [9]. The all S configuration at the side chain was proposed by the same biosynthetic pathway with those of siphonarienfuranone and its Z- 2.2.3. Furan-Related Metabolites Except for the three pairs of carbon homocyclic PPs ( )-15–( )-17, the mollusk P. ocellatus ± ± also produced a pair of furanone-containing analogues ( )-106 [16], which represents a unique ± dimethylfuran-3(2H)-one nucleus connected with a mesitylene moiety (Figure 15). An X-ray diffraction was carried out to confirm its racemic nature by a P-1 space group. 6Z,8E-∆8-Siphonarienfuranone (107) and 6E,8E-∆8-siphonarienfuranone (108) are two new epimers at ∆6 produced by the mollusk Siphonaria oculus [8]. In the structures of 107 and 108, a hemiketal moiety was constructed in the 3-furanone ring but the stereochemistry at C-2 was unidentified so far (Figure 15). The chemical investigation of the same species mollusk Siphonaria capensis led to isolation of a 2-furanone-containing polypropionate capensifuranone (109)[9]. The all S configuration at the side chain was proposed Mar. Drugs 2020, 18, 569 11 of 23

Mar.Mar. DrugsDrugs 20202020,, 1188,, xx 1111 ofof 2323 by the same biosynthetic pathway with those of siphonarienfuranone and its Z-isomer, which were isomer,isomer, whichwhich werewere previouslypreviously isolatedisolated fromfrom S.S. lessonlesson andand thethe absoluteabsolute configurationconfiguration waswas establishedestablished previously isolated from S. lesson and the absolute configuration was established by ozonolysis [61,62]. byby ozonolysisozonolysis [61,62].[61,62].

FigureFigure 14.14. ChemicalChemical structures structures ofof 101101––105105..

FigureFigure 15.15. ChemicalChemical structures structures ofof 106106––115115..

SixSix complexcomplex PPs, PPs, indoxamycins indoxamycins A A–FA––FF ( (110110––115115)) constructing constructing a a new new 5/5/6 55/5/6/5/6 tricyclictricyclic system,system, werewere isolatedisolated from from from a a a marine-derived marine marine--derivedderived StreptomycesStreptomycesStreptomyces sp.spsp (Figure (Figure 15).15 15).). Compounds Compounds Compounds 110110110 andand 115115 exhibitedexhibiexhibitedted significant growth inhibition against HT-29 tumor cell line with the IC values of 0.59 and 0.31 significantsignificant growthgrowth inhibitioninhibition againstagainst HTHT--2929 tumortumor cellcell lineline withwith thethe ICIC5050 valuesvalues50 ofof 0.590.59 andand 0.310.31 µµM,M, µrespectivelyrespectivelyM, respectively [63]. [63]. [ 63 The The]. The myxobacterium myxobacterium myxobacterium HyalangiumHyalangiumHyalangium minutum minutum minutum yieldedyieldedyielded three three three 33-furanone-containing 3--furanonefuranone--containingcontaining derivativesderivatives hyafuroneshyafuroneshyafurones A1, A1,A1, A2 A2A2 and andand B BB ( 116((111616––118–118118)) (Figure) (Figure(Figure 16 16)16))[23 [23],[23],], of ofof which whichwhich the thethe absolute absoluteabsolute configuration configurationconfiguration at C-2,atat CC-- C-7,2,2, CC--7, C-97, CC-- C-18,99 CC--18,18, C-19 CC--1919 and andand C-20 CC--2020 remained remainedremained to toto be bebe determined. determined.determined. The TheThe116 116116 could couldcould slowly slowlyslowly convertconvertconvert toto 117117 whenwhen exposedexposed toto lightlight oror storestore inin methanol.methanol. The The antibacterial antibacterial assays assays indicated indicated that that only only 118118 showedshowed moderatemoderate activityactivity againstagainst NocardiaNocardia flavaflavaflava (MIC(MIC(MIC == 8.38.3 µµg/mL).gg/mL)./mL).

Mar. Drugs 2020, 18, 569 12 of 23 Mar. Drugs 2020, 18, x 12 of 23

FigureFigure 16.16. Chemical structures ofof 116116––118118..

2.2.4.2.2.4. Metabolites Containing bothboth PyranPyran andand FuranFuran TenTen PPsPPs containingcontaining bothboth pyranpyran andand furanfuran ringsrings werewere isolatedisolated fromfrom sixsix speciesspecies ofof fungifungi andand twotwo speciesspecies ofof antinomycetesantinomycetes (Figure(Figure17 17).). AsteltoxinAsteltoxin GG ((119119) was isolated from a sponge-derivedsponge-derived fungus,fungus, AspergillusAspergillus ochraceopetaliformis ochraceopetaliformis[64 [64]], and, and aurovertin aurovertin E (120 E) was (120 isolated) was isolated from the frommushroom the mushroomAlbatrellus confluensAlbatrellus[65 confluens]. The heterologous [65]. The heterologous expression expression of the alp gene of the cluster alp gene from clusterP. nodorum from P.not nodorum only produced not only theproduced 2-pyrone the PPs 2-pyrone54–56 but PPs also 54– gave56 but two also analogues, gave two121 analoguesand 122, ,121 constructing and 122, constructing a furan ring ata furan the end ring of theat the side end chain. of the121 sideand chain.122 were 121 detectedand 122 were to inhibit detected wheat to germination inhibit wheat significantly germination at 100significantlyµg/mL [37 at]. The100 remainingµg/mL [37]. four The fungal-derived remaining four metabolites, fungal-derived penicyrones metabolites, A and penicyrones B (123 and 124 A ),and deoxyverrucosidin B (123 and 124), (deoxyverrucosidin125) and (+)-neocitreoviridin (125) and (+) (126-neocitreoviridin), were all isolated (126) from, werePenicillium all isolatedsp. from [66 –Penicillium68] In the sp. bioassays, [66–68] 125 In thedose-dependently bioassays, 125 dose inhibited-dependently the expression inhibited of GRP78 the expression promoter of with GRP78 an IC promoter50 of 30 nM; with meanwhile, an IC50 of 12630 nMexhibited; meanwhile, broad-spectrum 126 exhibited antiviral broad e-ffspectrumects against antiviral influenza effects A virusagainst (IAV) influenza (IC50 =A3.6 virusµM )(IAV and) Helicobacter pylori antibacterial(IC50 = 3.6 µM) activity and againstantibacterial activity against(including Helicobacter drug-sensitive pylori (including strain G27 drug and-sensitive drug-resistant strain strainG27 and 159) drug with-resistant an MIC of strain 4 and 159) 16 µ withg/mL, an respectively. MIC of 4 and A 16 new µg/mL,p-nitrophenyl-possessed respectively. A new polypropionate p-nitrophenyl- alloaureothinpossessed polypropionate (127) with cytotoxicity alloaureothin against (127 HT1080) with cytotoxicity was obtained against from StreptomycesHT1080 was sp.obtained MM23 from [69]. AnotherStreptomycesStreptomyces sp. MM23sp. [69] MK756-CF1. Another alsoStreptomyces yielded asp. similar MK756 analogue-CF1 also arabilin yielded (128 a ).similar Arabilin analogue could competitivelyarabilin (128). block Arabilin the binding could competitively of androgen to block the ligand-binding the binding of domain androgen of AR to thein vitro ligand; moreover,-binding itdomain could inhibit of AR androgen-inducedin vitro; moreover, prostate-specific it could inhibit androgen antigen mRNA-induced expression prostate in-specific prostate antig canceren LNCaPmRNA cellsexpression [70]. in prostate cancer LNCaP cells [70]. 2.2.5. Other Heterocyclic Metabolites 2.2.5. Other Heterocyclic Metabolites A few other unusual heterocyclic PPs were also discovered from nature (Figure 18). A few other unusual heterocyclic PPs were also discovered from nature (Figure 18). Two 3- Two 3-hydroxypiperidin-2-one containing isomers at ∆6 (129 and 130) were produced by A. fischeri. hydroxypiperidin-2-one containing isomers at Δ6 (129 and 130) were produced by A. fischeri. This was This was the first example of polypropionate derivatives incorporating a 3-hydroxypiperidin-2-one via the first example of polypropionate derivatives incorporating a 3-hydroxypiperidin-2-one via an an imide linkage but the configuration of C-2’ remained unknown [10]. Like the other metabolites imide linkage but the configuration of C-2’ remained unknown [10]. Like the other metabolites from from this strain, 129 exhibited an MptpB inhibitory effects with an IC50 of 11 µM. However, 130 did this strain, 129 exhibited an MptpB inhibitory effects with an IC50 of 11 µM. However, 130 did not not show any activity at the concentration of 50 µM, suggesting that the geometry configuration show any activity at the concentration of 50 µM, suggesting that the geometry configuration changes changes will make a difference to the bioactivities. The myxobacterium H. minutum produced a series will make a difference to the bioactivities. The myxobacterium H. minutum produced a series of of heterocyclic PPs including two pyrrolidone-related derivatives hyapyrrolines A and B (131 and 132), heterocyclic PPs including two pyrrolidone-related derivatives hyapyrrolines A and B (131 and 132), which were the only members of propionates incorporating pyrrolidone to date [23]. Another two which were the only members of propionates incorporating pyrrolidone to date [23]. Another two unusual four-membered lactone derivatives 133 and 134 were discovered from feeding male striped unusual four-membered lactone derivatives 133 and 134 were discovered from feeding male striped cucumber bettles Acalymma vittatum. The absolute configuration was assigned by modified Mosher’s cucumber bettles Acalymma vittatum. The absolute configuration was assigned by modified Mosher’s method applied to the methanolysis products. An electrophysiological study indicated that 133 was method applied to the methanolysis products. An electrophysiological study indicated that 133 was possibly an aggregation pheromone for A. vittatum [71]. possibly an aggregation pheromone for A. vittatum [71].

Mar. Drugs 2020, 18, 569 13 of 23 Mar. Drugs 2020,, 18,, xx 13 of 23

Figure 17. ChemicalChemical structures structures of 119119–128..

Figure 18. ChemicalChemical structures structures of 129129–134..

2.3. Macrocyclic Metabolites The macrocyclic metabolites covered inin thisthis sectionsection areare chosenchosen toto illustrateillustrate thethe structuralstructural featuresfeatures and biological activities because their biosynthetic pathway involves propionates. Twenty-six related derivatives were concluded belonging to two families: mangromicins family from an actinomycete and jaspamide family from mollusks.

Mar. Drugs 2020, 18, 569 14 of 23

2.3. Macrocyclic Metabolites The macrocyclic metabolites covered in this section are chosen to illustrate the structural features and biological activities because their biosynthetic pathway involves propionates. Twenty-six related derivatives were concluded belonging to two families: mangromicins family from an actinomycete Mar. Drugs 2020, 18, x 14 of 23 and jaspamide family from mollusks. The mangromicin analogues possess a complicated cyclopentadecane skeleton and show The mangromicin analogues possess a complicated cyclopentadecane skeleton and show antitrypanosomal and ROS scavenging activities (Figure 19). Takuji Nakashima and his co-workers antitrypanosomal and ROS scavenging activities (Figure 19). Takuji Nakashima and his co-workers discovered nine mangromicins A-I (135–143) using a physical-chemical screening system in the discovered nine mangromicins A‒I (135–143) using a physical-chemical screening system in the actinomycete Lechevalieria aerocolonigenes K10-0216 [72–74]. Although an X-ray diffraction of 135 actinomycete Lechevalieria aerocolonigenes K10-0216 [72–74]. Although an X-ray diffraction of 135 was was carried out, the absolute configuration could not be determined by the unreliable Flack carried out, the absolute configuration could not be determined by the unreliable Flack parameter— parameter—0.1 (3). Thus, only the relative configuration of mangromicins was assigned. 135 and 136 0.1 (3). Thus, only the relative configuration of mangromicins was assigned. 135 and 136 exhibited exhibited antitrypanosomal activities against Trypanosoma brucei brucei with the IC50 values of 2.4 and antitrypanosomal activities against Trypanosoma brucei brucei with the IC50 values of 2.4 and 43.4 43.4 µg/mL. Besides, except for 136, 139 and 143, all mangromicin analogs had more potent DPPH µg/mL. Besides, except for 136, 139 and 143, all mangromicin analogs had more potent DPPH scavenging activity than α-tocopherol. scavenging activity than α-tocopherol.

Figure 19. Chemical structures of 135–143.

Jaspamide derivatives, derivatives, with with a propionate a propionate chain in chain the macro in ring, the are macro a group ring, of cyclodepsipeptides are a group of drivencyclodepsipeptide from the NRPS-PKSs driven hybridfrom the biosynthetic NRPS-PKS pathway hybrid biosynthetic (Figure 20). In pathway 1998 and (Figure 2008, Angela 20). In Zampella1998 and and2008, his Angela co-workers Zampella published and his four co papers-workers to describe published the four isolation papers and to bioactivities describe the of isolation 14 jaspamide and derivativesbioactivities jaspamidesof 14 jaspamide B-P (derivatives144–157) from jaspamide the sponges B‒P Jaspis(144–157 splendans) from .the The sponge stereochemistry Jaspis splendans was. elucidatedThe stereochemistry by comparing was the elucidated NMR data by with comparing those of the metabolites NMR data containingwith those the of same the metabolites fragments. Allcontaining the jaspamides the same isolated fragments. from J. All splendans the jaspamidesexhibited significantisolated from cytotoxicities J. splendans against exhibited different significant human cancercytotoxicities cell lines against [75–78 different]. Chemical human investigation cancer ce ofll anotherlines [75 Pacific–78]. Chemical marine sponge investigationPopestela of candelabra another ledPacific to the marine isolation sponge of another Popestela three candelabra unusual led jaspamide to the isolation analogues of pipestelidesanother three A-C unusual (158–160 jaspamide), which containanalogues a bromotyrosine pipestelides [3-amino-3-(bromo-4-hydroxyphenyl)propanoic A‒C (158–160), which contain a bromotyrosine acid] unit, [3-amino a polypropionate-3-(bromo-4- 3 withhydroxyphenyl)pro a Z configurationpanoic at ∆ , acid] and a unit, 2-hydroxyquinolinone a polypropionate unit, with respectively a Z configuration [79]. 158 atexhibited Δ3, and strong a 2- inhibitoryhydroxyquinolinone activities against unit, respectively the KB cell line[79]. with 158 exhibited the IC50 value strong of inhibitory 0.11 µM. activities against the KB cell line with the IC50 value of 0.11 µM.

Mar. Drugs 2020, 18, 569 15 of 23 Mar. Drugs 2020, 18, x 15 of 23

Figure 20. ChemicalChemical structures structures of 144–160..

3. Summary Summary Overall, except for the two PPs from unknown source source-derived-derived fungi, 121 121 of the 164 new PPs were isolated from the marine system,system, while 41 were produced by terrestrial organisms.organisms. It could be concluded that mollusks are are the main producer among the marine organisms during the last two decades, which contributedcontributed 64%64% of of the the new new marine-derived marine-derived PPs PPs (Figure (Figure 21 )21) and and nearly nearly half half (48%) (48%) of the of thetotal total natural natural PPs (Figure PPs (Figure 22). Fungi 22). Fungi (containing (containin marine-derivedg marine-derived and terrestrial) and terrestrial) provided provided the second the secondlargest number largest ofnumber the PPs of (46 the compounds PPs (46 compounds accounting accounting for 28% of total) for 28% and theseof total) fungi and belonged these fungi to 11 belongedgenera including to 11 generaAcremonium including, Albatrellus Acremonium, Aspergillus, Albatrellus, Camarops, Aspergillus, Fusarium, Camarops, Penicillium, Fusarium, Leptosphaeria, Penicillium,, LeptosphaeriaParastagonospora, Parastagonospora, Penicillium, Talaromyces, Penicilliumand, TalaromycesXylaria. The and common XylariaAspergillus. The commonand Penicillium Aspergillusare and still Penicilliumthe main producers are still the of PPs. main It producers is noticed thatof PPs. the fungiIt is noticed are the mostthat the important fungi are source the most in the important terrestrial sourcesystem in (23 the compounds terrestrial accounting system (23 for compounds 56%) compared accounting to the marinefor 56%) system comp (19ared compounds to the marine accounting system (19for onlycompounds 16%) (Figure accounting 21). Infor the only marine 16%) (Figure system, 2 the1). In actinomycetes the marine system, are also the the actinomycetes focused research are alsoproducers, the focused of which research 23 PPs producers, have been of discovered. which 23 PPs have been discovered.

Mar.Mar. Drugs Drugs 20 2020202020, 1,,8 181, 8x,, 569x 1616 of of23 2323

FigureFigure 21. 21. Sources SSourcesources of ofthe the 164 164 new new PPs PPs and and the the related related fun fungalfungalgal genes. genes.

FigureFigure 22. 22. Comparison Comparison of ofthe the biodiversity biodiversity between between marine marine-marine- and- and terrestrial terrestrial-derivedterrestrial-derived-derived PPs. PPs.PPs.

TheThe relationship relationship between between the the chemical chemical features features of of PPs PPs and and their their producers producers was was further further further analyzed. analyzed. analyzed. TheTheThe compounds compoundscompounds containing containing both both pyran pyran and and furan furan-relatedfuran-related-related moiety moiety were were counted counted in in both both the the pyran pyran pyran-- - andand furan furan-containingfuran-containing-containing categor categories.categoriesies. As. As As shown shown in in Figure Figure 23 23 and and Table Table 1,1 1, ,mollusks mollusks mollusks performed performedperformed the thethe most mostmost abundantabundant chemical chemical diversity diversity by by producing producing all all classes classesclasses of of PPs. PPs.PPs. The The culturable culturable fungi fungi can can also also produce produce differentdidifferentfferent classes classesclasses of ofof PPs PPsPPs exc exceptexceptept the thethe macrocyclic macrocyclicmacrocyclic PPs. PPs.PPs. It Itwas was noticed noticednoticed that that mollusks mollusks contributed contributed most most of of thethethe 4 - 4-pyrone-containing4pyrone-pyrone-containing-containing PPs PPsPPs (81%) (81%) while while fungi fungi are are the the most most important important source source of of 2 -2 2-pyrone-containingpyrone-pyrone-containing-containing PPsPPs (accounting (accounting(accounting for forfor 58% 58% 58% of of of the the total total isolates).isolates). isolates). TheT heThe speculatedspeculated speculated reason reason reason is is that isthat that the the the mollusks m mollusksollusks synthesize synthesize synthesize PPs PPsviaPPs viaa viadirect a a direct propionatedirect propionate propionate polymerization polymerization polymerization [80,81 ],[80,81 which[80,81], ], is which whicheasy to is is form easy easy a to 4-pyrone to form form a by a 4 - 41,5-condensation.pyrone-pyrone by by 1,5 1,5- - condensation.However,condensation. the However, PPsHowever, from fungithe the PPs arePPs from generatedfrom fungi fungi byare are an generated generated acetate-methionine by by an an acetate acetate pathway-methionine-methionine [82] and pathway pathway the 2-pyrone [82] [82] andwasand the formedthe 2 -2pyrone-pyrone by the was was esterification formed formed by by the at the theesterification esterification terminal carboxyl at at the the terminal terminal group ofcarboxyl carboxyl the C2-generated group group of of the polyketidethe C 2C-generated2-generated chain. polyketideAspolyketide far as fungal chain. chain. generaAs As far far areas as fungal concerned, fungal genera genera the are Aspergillus are concerned, concerned,and the Penicillium the Aspergillus Aspergillusare and theand predominantPenicillium Penicillium are are fungal the the predominantsourcespredominant of PPs, fungal fungal accounting sources sources for of 39% of PPs, PPs, and accounting 15% accounting of the fungi-derived for for 39% 39% and and PPs,15% 15% respectively. of of the the fungi fungi-derived-derived PPs, PPs, respectively.respectively. Table 1. The number of PPs with different chemical features from different resources.

Mollusk Fungi Actinomycetes Myxobacter-ia Insects Slime Molds linear PPs 6 5 1 - 2 - carbon homocyclic PPs 7 7 2 1 - - 2-pyrone-related PPs 13 26 4 1 - 2 4-pyrone-related PPs 29 3 4 - - - other pyran-related PPs 2 3 - 1 - - furan-related PPs 5 8 8 3 - - other heterocyclic PPs - 2 - 2 2 - macrocyclic PPs 17 - 9 - - -

Mar. Drugs 2020, 18, 569 17 of 23 Mar. Drugs 2020, 18, x 17 of 23

FigureFigure 23. 23.Relationship Relationship between between the the chemical chemical features features of PPs of PPs and and their their producers. producers. The The number number in the in the barsbars represents represents the the number number of PPs of PPs from from diff erentdifferent resources. resources.

In the bioassaysTable 1. ofThe the number new of isolated PPs with PPs, different there chemica are 69l features metabolites from different (42% of resources. total) exhibiting various activities, among which, cytotoxicity is the most significant pharmacological activity with 37 compounds exhibiting in vitroMolluskcytotoxicity Fungi against Actinomycetes different tumor Myxobacter cell lines-ia suchInsects as A549, Slime HT1080, Molds HeLa, etc. Then,linear14 PPs PPs were detected6 to show5 antimicrobial1 effects, including- antibacterial2 activities- carbon homocyclic PPs 7 7 2 1 - - for eight compounds, antifungal activities for five compounds and antiviral activity for one compound. 2-pyrone-related PPs 13 26 4 1 - 2 The antioxidative activities (eight compounds) were mainly detected in macrocyclic metabolites of 4-pyrone-related PPs 29 3 4 - - - the mangromicinother pyran-related family. PPs The other2 ten PPs3 exhibited- activities including1 enzyme- inhibition e-ff ects (six compounds),furan-related anti-parasite PPs activities5 (three8 compounds)8 and wheat antigermination3 - (one compound).- A primaryother relationship heterocyclic betweenPPs the- chemical2 classes of the- PPs and their2bioactivities 2was summarized- in Figure macrocyclic24. It could PPs be concluded17 that the- macrocyclic9 metabolites were- the most- active among- all classes of PPs since nearly all the isolated macrocyclic PPs were detected to show pharmacological activities.In Thethe bioassays pyran-related of the PPs new showed isolated the PPs, most there extensive are 69 activities, metabolites of which (42% theof total) 4-pyrone-containing exhibiting various PPsactivities, were observed among to exhibitwhich, cytotoxicity cytotoxicity specifically. is the most significant pharmacological activity with 37 compounds exhibiting in vitro cytotoxicity against different tumor cell lines such as A549, HT1080, HeLa, etc. Then, 14 PPs were detected to show antimicrobial effects, including antibacterial activities for eight compounds, antifungal activities for five compounds and antiviral activity for one compound. The antioxidative activities (eight compounds) were mainly detected in macrocyclic metabolites of the mangromicin family. The other ten PPs exhibited activities including enzyme inhibition effects (six compounds), anti-parasite activities (three compounds) and wheat antigermination (one compound). A primary relationship between the chemical classes of the PPs and their bioactivities was summarized in Figure 24. It could be concluded that the macrocyclic metabolites were the most active among all classes of PPs since nearly all the isolated macrocyclic PPs were detected to show pharmacological activities. The pyran-related PPs showed the most extensive activities, of which the 4-pyrone-containing PPs were observed to exhibit cytotoxicity specifically.

Mar. Drugs 2020, 18, 569 18 of 23 Mar. Drugs 2020, 18, x 18 of 23

Figure 24. RRelationshipelationship between the chemical classes of PPs and theirtheir bioactivities.bioactivities. 4. Conclusions and Outlook 4. Conclusions and Outlook This review presents an overview of 164 PPs published in 67 research papers from 1999 to 2020, This review presents an overview of 164 PPs published in 67 research papers from 1999 to 2020, including their isolation, chemical features and bioactivities. The marine organisms (mainly the including their isolation, chemical features and bioactivities. The marine organisms (mainly the mollusks) are the dominant source of these PPs. It is worth noting that the culturable fungi and mollusks) are the dominant source of these PPs. It is worth noting that the culturable fungi and actinomycetes (not only from marine system but also from terrestrial resources) are becoming a more actinomycetes (not only from marine system but also from terrestrial resources) are becoming a more important source for the discovering of PPs. The modern molecular biological approaches including important source for the discovering of PPs. The modern molecular biological approaches including the genomic mining and heterologous expression will promote the rapid discovery of structural novel the genomic mining and heterologous expression will promote the rapid discovery of structural and biologically active PPs from fungi. novel and biologically active PPs from fungi. The assignment of the absolute configuration, especially the chiral centers in the side chain, The assignment of the absolute configuration, especially the chiral centers in the side chain, remains a major obstacle for the structure identification of natural PPs. Nearly half of the natural PPs remains a major obstacle for the structure identification of natural PPs. Nearly half of the natural PPs were reported without identifying the stereochemistry or with establishing the relative configuration were reported without identifying the stereochemistry or with establishing the relative configuration only. In general, the configuration of the chiral centers at the cyclic core can be determined by NOE only. In general, the configuration of the chiral centers at the cyclic core can be determined by NOE correlations and the quantum chemical calculation of ECD spectra, and the Mosher’s method is an correlations and the quantum chemical calculation of ECD spectra, and the Mosher’s method is an effective approach to establish the hydroxyl-substituted chiral centers at the side chain. However, effective approach to establish the hydroxyl-substituted chiral centers at the side chain. However, the the assignment of methylated chiral centers at the side chain is the most difficult. Some methods such assignment of methylated chiral centers at the side chain is the most difficult. Some methods such as as chemical degradation, spectroscopic comparisons and semi-synthesis from the know precursors chemical degradation, spectroscopic comparisons and semi-synthesis from the know precursors have have been tried to solve the issue but are always limited by their instability or the small amount of been tried to solve the issue but are always limited by their instability or the small amount of the the compounds obtained. The X-ray diffraction of a crystal with high-quality through Cu Kα can compounds obtained. The X-ray diffraction of a crystal with high-quality through Cu Kα can give a give a direct sight of the planar and absolute configuration; nevertheless, due to the flexibility of direct sight of the planar and absolute configuration; nevertheless, due to the flexibility of the side the side chain, the high-quality crystals of most PPs are still hard to obtain. In recent years, some chain, the high-quality crystals of most PPs are still hard to obtain. In recent years, some advanced advanced methods have been applied to solve the stereochemistry of the methylated side chain such methods have been applied to solve the stereochemistry of the methylated side chain such as the as the C-H coupling constant, NMR data guided conformer searching, 13C NMR calculations, etc. C-H coupling constant, NMR data guided conformer searching, 13C NMR calculations, etc. Some Some interdisciplinary technologies, for example, the “crystal sponge” [83–85], will also provide some interdisciplinary technologies, for example, the “crystal sponge” [83–85], will also provide some efficient solutions of the stereochemistry of PPs in the future. Moreover, inspired by their diverse efficient solutions of the stereochemistry of PPs in the future. Moreover, inspired by their diverse

Mar. Drugs 2020, 18, 569 19 of 23 complex structures and stereochemistry, an increasing total synthesis or semisynthesis of PPs has been carried out by chemists around the world [86]. Although nearly half of the natural PPs have been discovered to show potential pharmacological properties, few of them were selected to be lead compounds for further development of new drugs, which may be limited by the small amounts of compounds isolated from nature and the difficulty of obtaining the synthetic substitutes. Therefore, the multi-targeted screening and deeper biological mechanisms of PPs should be put on the agenda in the future. The continuous studies toward the chemistry and biology of PPs will make an important contribution to the discovery of the lead compounds and the development of polypropionate-related drugs.

Author Contributions: Literature searching and collection, Z.L. and H.L.; writing—original draft preparation, Z.L.; writing—review and editing, Z.L. and W.Z.; funding acquisition, W.Z. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported financially by the National Natural Science Foundation of China (41906106, 31272087), Guangdong Provincial Special Fund for Marine Economic Development Project (GDNRC [2020]042), the Team Project of the Natural Science Foundation of Guangdong Province (2016A030312014), the GDAS’ Project of Science and Technology Development (2019GDASYL-0103007). Conflicts of Interest: The authors declare no conflict of interest.

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