European Journal of Medicinal Chemistry 97 (2015) 747e777

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European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Review article Benzenediol lactones: a class of fungal metabolites with diverse structural features and biological activities

* Weiyun Shen, Hongqiang Mao, Qian Huang, Jinyan Dong

Key Laboratory of Eco-environments in Three Gorges Reservoir Region (Ministry of Education), School of Life Science, Southwest University, Chongqing 400715, People's Republic of China article info abstract

Article history: Benzenediol lactones are a structurally variable family of fungal polyketide metabolites possessing a Received 29 July 2014 macrolide core structure fused into a resorcinol aromatic ring. These compounds are widespread in fungi Received in revised form mainly in the genera such as Aigialus, Cochliobolus, Curvularia, Fusarium, Humicola, Lasiodiplodia, Peni- 4 November 2014 cillium and Pochonia etc. Most of these fungal metabolites were reported to possess several interesting Accepted 26 November 2014 biological activities, such as cytotoxicities, nematicidal properties, inhibition of various kinases, receptor Available online 3 December 2014 agonists, anti-inflammatory activities, heat shock response and immune system modulatory activities etc. This review summarizes the research on the isolation, structure elucidation, and biological activities of Keywords: e Secondary metabolites the benzenediol lactones, along with some available structure activity relationships, biosynthetic fi Benzenediol lactones studies, rst syntheses, and syntheses that lead to the revision of structure or stereochemistry, published Dihydroxyphenylacetic acid lactones up to the year of 2014. More than 190 benzenediol lactones are described, and over 300 references cited. Resorcylic acid lactones © 2014 Elsevier Masson SAS. All rights reserved. Bioactivities Structureeactivity relationships

1. Introduction macrocyclic lactone ring, respectively (Fig. 1) [10,11]. To better describe these structures, there exist different numbering systems. Fungi have been proved to be a fertile and important biosource Take 14-membered RALs for example, the older system uses the of numerous secondary metabolites with a huge variety of chemical numbers 1e6 for the aromatic ring and 10e120 for the aliphatic structures and diverse bioactivities. Fungal metabolites are of macrocycle, whereas the more recent IUPAC system counts the C- considerable synthetic interest and remarkable importance as new atoms from 1 to 18 (Fig. 2). This situation, although unsatisfactory, lead compounds for medicine as well as for plant protection. did not cause major problems to date, because the number of BDLs Importantly, fungal polyketides are one of the largest and most was quite limited [12]. Considering the coherence of the previous structurally diverse classes of naturally occurring compounds, review, here we retain both systems. ranging from simple aromatic metabolites to complex macrocyclic To date, over 190 natural BDLs were found in numerous fungi lactones [1e8]. mainly belonging to the genera Aigialus, Cochliobolus, Curvularia, Among these polyketide secondary metabolites, benzenediol Fusarium, Humicola, Lasiodiplodia, Penicillium and Pochonia etc. lactone (BDL) is a growing class which is defined by a 1, 3-benze- Table 1 shows all the natural BDLs discovered including names, nediol moiety bridged by a macrocyclic lactone ring [9]. They fungal sources and references published between the end of 1953 represent a rich scaffold for structural variation, which differ and July 2014. Although these BDLs are anabolited by many particularly in the degree and positioning of oxidation and unsa- different fungal species, they are known to be produced via a pair of turation about the macrolactone ring. Meanwhile, the phenolic similar collaborating iterative polyketide synthases (iPKSs): a hydroxyl groups on the benzene ring can be methylated. The BDL highly reducing iPKS (hrPKS) with product that is further elabo- family may be split into resorcylic acid lactones (RALs) and dihy- rated by a nonreducing iPKS (nrPKS) to yield a 1, 3-benzenediol droxyphenylacetic acid lactones (DALs) based on a substituted moiety bridged by a macrolactone [11,13]. Of course, subtle differ- resorcinol fragment fused to a, b-, and b, g-positions of the ences exist between the biosynthetic pathways for different compounds. In recent years, these fungal metabolites were reported to * Corresponding author. exhibit a wide range of significant biological activities such as E-mail address: [email protected] (J. Dong). http://dx.doi.org/10.1016/j.ejmech.2014.11.067 0223-5234/© 2014 Elsevier Masson SAS. All rights reserved. 748 W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777

2. Overview of BDLs

2.1. 8-Membered benzenediol lactones (benzenediol octalactones)

To date, coryoctalactones AeE(1e5)(Table 1 and Fig. 3), isolated from Corynespora cassiicola (JCM 23.3), an endophyte of the mangrove plant Laguncularia racemosa (Combretacaeae) from the island of Hainan, China are the only members of benzenediol Fig. 1. Basic scaffold of benzenediol lactones. octalactones [27]. The relative stereochemistry of coryoctalactones were determined on the basis of one and two-dimensional NMR spectroscopy as well as by high resolution mass spectrometry. The absolute configuration of the side chain hydroxyl C in 1e3 and 5 were tentatively assigned as “R” based on biogenetic consideration in comparison with xestodecalactones DeF. Moreover, the com- parison of the optical rotation value of 3 with those of 1 and 2 as well as comparison of NMR data of C-9 and H-9 indicated that 2 and 3 share identical configuration at C-9, and 1 and 2 are epimers at C- 9. All isolated compounds were evaluated for their antimicrobial, cytotoxic, and antitrypanosomal activities, but no significant results were obtained. Fig. 2. Different numbering systems of 14-membered RALs.

2.2. 10-Membered benzenediol lactones (benzenediol decalactones) inhibition of heat shock protein 90 (Hsp90) and kinases [14],aswell as antimicrobial [9], cytotoxic [15], antineoplastic [16], and anti- To data, only ten examples of 10-membered benzenediol lac- inflammatory activities [17]. In view of their promising biological tones have been reported, from marine or terrestrial fungi, namely, activities and interesting structural characteristics, BDLs have sporostatin (6), xestodecalactones AeF(7e12), sonnerlactones (13, increasingly received a great deal of research focus. Since the 1970s, 14), relgro (15)(Table 1 and Fig. 4). Among them relgro and son- a number of synthetic studies on BDLs have been disclosed. The nerlactones belong to 10-membered RALs and the other com- general synthetic routes usually involve olefin metathesis together pounds belong to 10-membered DALs. with some classical chemical reactions (such as the Heck coupling The first natural 10-membered benzenediol lactone, sporostatin reaction, the Witting reaction, the Mitsunobu reaction, the Stille (6), was isolated from the fermentation filtrate of the fungus, coupling reaction, DielseAlder reaction etc) [18]. Sporormiella sp. M5032 in 1997 by Kinoshita et al. [28]. The struc- Some BDLs have already been mentioned in a number of certain ture of 6 was secured by an X-ray diffraction study [28], but the bioactivity reviews [19e23]. However, these authors cover only a absolute configuration was reported by its first total synthesis in fraction of all known BDLs, since their articles naturally omit the 2009 [29]. Sporostatin has been found to have an inhibitory effect 0 0 compounds with other activities not included in their reviews. In on cyclic adenosine 3 ,5-monophosphate phosphodiesterase m addition, the resorcylic acid lactones containing a cis-enone or with (cAMP-PDE) with an IC50 value of 41 g/mL. Further biological kinase inhibitory activities of this family have been frequently evaluation indicated that 6 was a specific kinase inhibitor in vitro m m reviewed by several authors [24e26]. In 2007, Winssinger and whose IC50 values were 0.1 g/mL for EGF receptor kinase, 3 g/mL Barluenga published a topical review article focused on the for ErbB-2, and 100 mg/mL or greater for other kinases, including biosynthesis, chemical synthesis, and biological activity of RALs the platelet derived growth factor (PDGF) receptor, n-src and pro- covered the literature up to 2007. Yet, it only described ten typical tein kinase. Kinetic analyses revealed that inhibition of EGF re- RALs in detail [9]. Recently, a review from Xu et al. [18] described 60 ceptor kinase and cAMP-PDE by sporostatin was noncompetitive resorcinolic macrolides concerning their isolation, bioactivities, either with substrate or with ATP [28,30]. biosyntheses, and representative chemical syntheses in recent The xestodecalactones AeC(7e9) were secondary metabolites decades. According to their literature, over 60 different resorcinolic of a fungus Penicillium cf. montanense obtained from the marine macrolides are produced by fungi. However, we found a signifi- sponge Xestospongia exigua, and the constitutions, stereostructures cantly higher number of relevant fungal metabolites up to 2014: including the relative configurations of 8 and 9 were initially Around 190 compounds are presented in this review. established using online HPLC-NMR, ESI-MS/MS, and CD spectra In this review we survey the chemical and biological literature analysis after isolating these compounds [31]. The absolute con- regarding the isolation, structure elucidation, biological activities, figurations at C-11 of 7e9 were initially reported as S; however, biosyntheses, and chemical syntheses of BDL derivatives from na- they were later revised as R until their total syntheses were ture. Additionally, those available structureeactivity relationships accomplished and reported during the period 2004e2007 [32e34]. and action mechanisms of some bioactive compounds will also be Xestodecalactone B produced 25, 12, 7 mm inhibition zones against discussed. We focus on work that has appeared in the literature up Candida albicans at 100, 50, 20 mmol, respectively [31]. It was also to July 2014. We also hope that we can provide some references for noted that xestodecalactone A has been patented for antitumor further development and utilization of this kind of natural com- activity [35]. In 2012, the chemical investigation on the ethyl ace- pounds. For ease of illustration and comparison, these natural tate extract of C. cassiicola from leaf tissues of the mangrove plant products are divided into six subclasses according to their ring sizes L. racemosa collected at Hainan Island in China, led to the isolation and structural characteristics: 8-membered BDLs, 10-membered of xestodecalactones DeF(10e12) [36]. The structures of 10e12 BDLs, 12-membered BDLs, 13-membered BDLs, 14-membered were determined by analysis of NMR and MS data. The relative BDLs and other BDLs. configuration of xestodecalactone D was obtained from a careful analysis of the coupling constants observed in the well resolved 1D 1H NMR spectrum, as well as from ROESY correlations. Their ab- solute configurations were assigned by TDDFT ECD calculations of W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777 749 their solution conformers, proving that they belong to the (11S) from the fermentation broth and mycelium of L. theobromae IFO series of xestodecalactones, opposite to the (11R) configuration of 31059 [57e59]. The relative configuration of 16 was assigned by the known xestodecalactones AeC. In this paper, the cytotoxic, single-crystal X-ray, whereas the absolute stereochemistry at C-3, antibacterial, antifungal and antitrypanosomal activity of these initially deduced to be S from chemical reduction to afford phenyl- compounds were investigated, but no positive results were 2-nonanol, was later revised to R on the basis of the synthetic obtained. studies [41,56,60e63]. The structures including absolute configu- In 2010, two new metabolites, (3R,5R)-sonnerlactone (13) and rations, of the other compounds from L. theobromae were deter- (3R,5S)-sonnerlactone (14), were isolated from the mangrove mined by means of spectroscopic analyses, mainly 1D and 2D NMR, endophytic fungus strain Zh6-B1 obtained from the bark of Son- the modified Mosher's method, and chemical derivation. Especially, neratia apetala growing in Zhuhai, Guangdong, China [37]. The the S-configuration of C-3 in compounds 18e20 deduced from the absolute configuration of 13 was determined by single-crystal X-ray structure of 16 based on the comparisons of spectral data in the analysis and spectroscopic data. While 14 was deduced by NOESY previous report [57] also needs to be revised to R. Compounds analysis and comparing circular dichroism spectroscopy with 18e24 were found be active in potato micro-tuber induction at a compound 13. Both sonnerlactones (13, 14) exhibited weak anti- concentration of 10 3e10 4 M and the activity of 21 was stronger proliferative activity against multidrug-resistant human oral floor than that of the others [57e59]. We presumed that the hydroxyl carcinoma cell lines (KV/MDR) (42.4% and 41.6%, respectively, at was essential for potato micro-tuber inducing activity, and S- 100 mM). The stereoselective synthesis of 13 and 14 has been configuration has higher activity. The biosynthetic pathways of 16 accomplished starting from L-aspartic acid [38]. The key steps and 20 in L. theobromae have been studied by Kashima with 13C- involved asymmetric allylation, AldereRickert reaction and Mit- labeled acetate tracer experiments [64,65], and the biosynthetic sunobu macrolactonization. gene clusters was first identified by Xu et al. [66]. Apart from the natural benzenediol decalactones as described In 2006, two new 12-membered resorcylic acid lactones, namely above, a novel compound, relgro (15), was mentioned incidentally 6-oxo-de-O-methyllasiodiplodin (25) and E-9-etheno-lasiodiplodin as an artificial product for the purpose of active test in 1973 [39].Up (26), together with 16, 17 and 22, were isolated from the mycelium to 2011, it was isolated and elucidated together with other 14- extracts of an unidentified endophytic fungus (No. ZZF36) obtained membered RALs from the seagrass-derived fungus Fusarium sp. from a brown alga (Sargassum sp.) collected from Zhanjiang sea PSU-ES73 [40]. Antimicrobial activity test showed that it was area, China [67]. The structure of 25 was confirmed by X-ray crys- inactive against Staphylococcus aureus ATCC25923, methicillin- tallographic analysis. In this paper, (3R)-lasiodiplodin (16), de-O- resistant S. aureus SK1 and Cryptococcus neoformans ATCC90113. methyllasiodiplodin (17) showed in vitro antimicrobial active We presumed that the structure may be related to the rearrange- against S. aureus, Bacillus subtilis, and Fusarium oxysporum. The ment from the 14-membered RALs together isolated. bioassay result implied that C-13 and C-15 hydroxyls of lasiodi- plodins probably may enhance their antibiotic activities. In 2009, 2.3. 12-Membered benzenediol lactones one new lasiodiplodin derivative, named botryosphaeriodiplodin (27) together with 16, 19 and 20, were isolated from an endophytic The number of natural 12-membered benzenediol lactones re- fungus Botryosphaeria rhodina PSU-M114, which was obtained from ported by July of 2014 is 53. This group is distributed in more than the leaves of Garcinia mangostana collected in Suratthani Province, 30 species and can be divided into three subgroups: lasiodiplodin Thailand [68]. The absolute configuration at C-3 in 27 was assumed macrolides (RAL12), curvularin macrolides (DAL12) and other 12- to analogous to that of 16, while the C-7 stereochemistry was not membered benzenediol lactones. performed as 27 was obtained in low quantity. In this paper, (3R)- lasiodiplodin (16) exhibited antibacterial activity against S. aureus 2.3.1. Lasiodiplodin macrolides (RAL12) and methicillin-resistant S. aureus with the respective MIC values of To date, 16 lasiodiplodins, 16e31 (Table 1 and Fig. 5), have been 64 and 128 mg/mL. In 2014, two further lasiodiplodins, (3R,4R)-4- produced by fungi Lasiodiplodia theobromae (syns. Botryodiplodia hydroxy-de-O-methyl-lasiodiplodin (28) and (E)-9-etheno-de-O- theobromae and Diplodia gossypina, teleomorph Botryosphaeria methyl-lasiodiplodin (29), together with 17, 23 and 25, from a rodina), Sarocladium kiliense and Syncephalastrum racemosum,as cytotoxic extract obtained from a culture of L. theobromae,an well as various plants, Euphorbia splendens [41], Arnebia euchroma endophyte from the root tissues of Mapania kurzii (Cyperaceae) [42], Euphorbia fidjian [43], Annona dioica [44], Dioclea violacea [45], from the Malaysian rain forest, were characterized on microgram Durio zibethinus [46], Pholidota yunnanensis [47], Cibotium barometz scale (capillary NMR probe) [69]. The structures including absolute [48], Osbeckia opipara [49], Ficus nervosa [50], Cyphostemma gre- configurations, of the other compounds were determined by means veana [51], Ampelopsis japonica [52], Macroptilium lathyroides [53], of spectroscopic analyses by analogy with the data for the known and Caesalpinia minax [54]. Among them, L. theobromae, the com- lasiodiplodins. The cultural extract was found to biologically active mon pathogenic fungi isolated in the tropics and subtropics on a against the P388 murine leukemia cell line (>80% growth inhibi- variety of host plants, was found to be a remarkable producer of tion) [69]. Interestingly, lasiodiplodins isolated from the plant have lasiodiplodins. Additionally, it should be noted that several authors been previously reported to have antileukemic activities [41]. assumed that lasiodiplodins may not be plant metabolites but may The crude EtOAc extract of the strain S. racemosum from soil in be from fungal epiphytes or endophytes [55]. tropical and subtropical regions was found to show cytotoxicity (3R)-Lasiodiplodin (16) and (R)-de-O-methyllasiodiplodin (17) against cholangiocarcinoma cell line KKU-M156 with an IC50 value were the first members of 12-membered resorcylic acid lactone of 18.02 mg/mL. Bioassay-guided fractionation of this fungal extract (RAL12) subclass of the benzenediol lactone (BDL) family to be led to the isolation of five lasiodiplodins, (3R,5S)-5-hydroxy-de-O- discovered and were isolated from the cultural filtrate of methyllasiodiplodin (30), (3R)-lasiodiplodin (16), de-O-methyl- L. theobromae S22L by Aldridge et al. in 1971 [56]. Later, another lasiodiplodin (17)(3R,5R)-5-hydroxy-de-O-methyllasiodiplodin seven metabolites, 5-oxo-lasiodiplodin (18), (3R,5R)-hydrox- (22) and 6-oxo-de-O-methyllasiodiplodin (25) [70]. Compound 30 ylasiodiplodin (19), (3R,5S)-hydroxylasiodiplodin (20), (3R,4S)-4- showed cytotoxicity against cholangiocarcinoma, KKU-M139, KKU- hydroxylasiodiplodin (21), (3R,5R)-5-hydroxyl-de-O-methyl- M156, and KKU-M213 cell lines with IC50 values in the range of lasiodiplodin (22), (3R,6R)-6-hydroxyl-de-O-methyllasiodiplodin 14.30e19.04 mg/mL, while 17 showed cytotoxicity against KB, BC1, (23) and (3R,6S)-6-hydroxylasiodiplodin (24) were also isolated and NCI-H187 cell lines with IC50 values of 12.67, 9.65, and 11.07 mg/ 750 W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777

Table 1 Table 1 (continued ) Benzenediol lactones (BDLs). Name (stereochemistry) (alternative name) Producing species References Name (stereochemistry) (alternative name) Producing species References Lasiodiplodia Benzenediol octalactone theobromae Coryoctalactone A (1) Corynespora [27] (3R,5S)-5-Hydroxyl-de-O- Syncephalastrum [70] cassiicola methyllasiodiplodin (30) racemosum Coryoctalactone B (2) Corynespora [27] (3S,6R)-6-Hydroxylasiodiplodin (31) Sarocladium [73] cassiicola kiliense Coryoctalactone C (3) Corynespora [27] Curvularin (32) Alternaria [77] cassiicola cinerariae Coryoctalactone D (4) Corynespora [27] Alternaria zinniae [78] cassiicola Ascochytula [79] Coryoctalactone E (5) Corynespora [27] obiones cassiicola Beauveria bassiana [80] Benzenediol decalactone Chrysosporium [84] Sporostatin (6) Sporormiella sp. [28] lobatum Xestodecalactone A (7) Penicillium cf. [31] Cochliobolus [81] montanense spicifer Xestodecalactone B (8) Penicillium cf. [31] Curvularia [83] montanense eragrostidis Xestodecalactone C (9) Penicillium cf. [31] Curvularia [82] montanense inaequalis Xestodecalactone D (10) Corynespora [36] Curvularia lunata [76] cassiicola Curvularia [83] Xestodecalactone E (11) Corynespora [36] pallescens cassiicola Drechslera [85] Xestodecalactone F (12) Corynespora [36] australiensis cassiicola Eupenicillium sp. [86] (3R,5R)-Sonnerlactone (13) Zh6-B1 [37] Helminthosporium [87] (3R,5S)-Sonnerlactone (14) Zh6-B1 [37] maydis Relgro (15) Fusarium sp. [40] Penicillium [89] 12-Membered benzenediol lactones baradicum (3R)-Lasiodiplodin (16) Lasiodiplodia [56] Penicillium gilmanii [88] theobromae Penicillium [92] Sarocladium [72] sumatrense kiliense Penicillium citreo- [91,107,119] Syncephalastrum [70] viride racemosum Ulocladium sp. [94] Unidentified [27] a, b-Dehydrocurvularin (33) (also named Alternaria [78] endophytic fungus trans-dehydrocurvularin, macrospora (R)-de-O-Methyllasiodiplodin (17) Lasiodiplodia [56] dehydrocurvularin) Alternaria [104] theobromae cucumerina Syncephalastrum [70] Alternaria [106] racemosum cinerariae Unidentified [27] Alternaria zinniae [108] endophytic fungus Alternaria tomato [105] 5-oxo-Masiodiplodin (18) Lasiodiplodia [58] Aspergillus sp. [109] theobromae Aspergillus terreus [110] (3R,5R)-Hydroxylasiodiplodin (19) Lasiodiplodia [58] Chrysosporium [84] theobromae lobatum Syncephalastrum [70] Curvularia [83] racemosum eragrostidis (3R,5S)-Hydroxylasiodiplodin (20) Lasiodiplodia [58] Curvularia lunata [76] theobromae Curvularia [83]; Sarocladium [73] pallescens kiliense Cercospora [111] (3R,4S)-4-Hydroxylasiodiplodin (21) Lasiodiplodia [58] scirpicola theobromae Drechslera [85] (3R,5R)-5-Hydroxyl-de-O- Lasiodiplodia [58] australiensis methyllasiodiplodin (22) theobromae Eupenicillium sp. [86] Unidentified [27] Helminthosporium [87] endophytic fungus maydis (3R,6R)-6-Hydroxyl-de-O- Lasiodiplodia [58] Nectria galligena [112] methyllasiodiplodin (23) theobromae Penicillium [90] (3R,6S)-6-Hydroxylasiodiplodin (24) Lasiodiplodia [59] turbatum theobromae Penicillium citreo- [107] 6-oxo-de-O-Methyllasiodiplodin (25) Unidentified [27] viride endophytic fungus Stemphylium [113] Syncephalastrum [70] radicinum racemosum 9F series marine [114] (E)-9-Etheno-lasiodiplodin (26) Unidentified [27] fungi endophytic fungus Ulocladium sp. [94] Botryosphaeriodiplodin (27) Lasiodiplodia [68] 11-Hydroxycurvularin (34) Aspergillus terreus [112] theobromae Penicillium sp. [120] (3R,4R)-4-Hydroxy-de-O- Lasiodiplodia [69] 11-a-Hydroxycurvularin (34a) Penicillium citreo- [107] methyllasiodiplodin (28) theobromae viride (E)-9-Etheno-de-O-methyllasiodiplodin (29) [69] Penicillium sp. [93] W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777 751

Table 1 (continued ) Table 1 (continued )

Name (stereochemistry) (alternative name) Producing species References Name (stereochemistry) (alternative name) Producing species References

11-b-Hydroxycurvularin (34b) Alternaria tomato [105] (69) Aigialus parvus [142] Penicillium citreo- [107] 14-Membered benzenediol lactones viride Aigialomycin A (70) Aigialus parvus [141] Penicillium sp. [93] Aigialomycin B (71) Aigialus parvus [141] 11-Methoxycurvularin (35) Aspergillus terreus [110] Paecilomyces sp. [155] Penicillium sp. [120] Cochliobolus [156] 11-a-Methoxycurvularin (35a) Penicillium citreo- [107] lunatus viride Aigialomycin C (72) Aigialus parvus [141] Penicillium sp. [93] Paecilomyces sp. [155] Curvularia oryzae [123] Aigialomycin D (73) Aigialus parvus [141] 11-b-Methoxycurvularin (35b) Penicillium citreo- [107] Fusarium sp. [154] viride Paecilomyces sp. [216] Penicillium sp. [93] Aigialomycin E (74) Aigialus parvus [141] Cis-dehydrocurvularin (36) Penicillium citreo- [91,107,119] Aigialomycin F (75) Aigialus parvus [142] viride Paecilomyces sp. [155] 12-oxo-Curvularin (37) (also named 7-oxo- Aspergillus sp. [109] Aigialomycin G (76) Aigialus parvus [142] curvularin) Penicillium citreo- [91,107,119] 10,20-Epoxyaigialomycin D (77) Hypomyces [153] viride subiculosus 11-b-Hydroxy-12-oxo-curvularin (38) (also Aspergillus sp. [109] Paecilomyces sp. [155] named 8-b-Hydroxy-7-oxo-curvularin) Penicillium citreo- [91,107,119] Deoxyaigialomycin C (78) Cochliobolus [156] viride lunatus Penicillium sp. [93] Caryospomycins A (79) Caryospora [157] 11, 12-Dihydroxycurvularin (39) Penicillium citreo- [91,107,119] callicarpa viride Caryospomycins B (80) Caryospora [157] 12-Hydroxy-10, 11-trans-dehydrocurvularin Penicillium citreo- [91,107,119] callicarpa (40) viride Caryospomycins C (81) Caryospora [157] Citreofuran (41) Penicillium citreo- [91,107,119] callicarpa viride Cochliomycin A (82) Cochliobolus [159] Penilactone (42) Penicillium sp. [124] lunatus 10,11-Epoxycurvularin (43) Penicillium sp. [124] Cochliomycin B (83) Cochliobolus [159] b,g-Dehydrocurvularin (44) Penicillium Aspergillus sp. [109] lunatus citreo-viride Cochliomycin C (84) Cochliobolus [159] E-6-Chloro-10, 11-dehydrocurvularin (45) Cochliobolus [81] lunatus spicifer Cochliomycin D (85) Cochliobolus [156] 11-O-Acetyldehydrocurvularin (46) Cercospora [111] lunatus scirpicola Cochliomycin E (86) Cochliobolus [156] Curvularin-7-O-b-D-glucopyranoside (47) Beauveria bassiana [80] 0 lunatus Curvularin-4 -O-methyl-7-O-b-D- Beauveria bassiana [80] Cochliomycin F (87) Cochliobolus [156] glucopyranoside (48) 0 lunatus 6-Hdroxycurvularin-4 -O-methyl-6-O-b-D- Beauveria bassiana [80] Hamigeromycin A (88) Hamigera avellanea [140] glucopyranoside (49) Hamigeromycin B (89) Hamigera avellanea [140] Oxacyclododecindione (50) Exserohilum [125] Hamigeromycin C (90) Hamigera avellanea [163] rostratum Hamigeromycin D (91) Hamigera avellanea [163] þ ( )-(15R)-10,11-E-Dehydrocurvularin (51) Curvularia sp. [126] Hamigeromycin E (92) Hamigera avellanea [163] þ ( )-(15R)-12-Hydroxy-10,11-E- Curvularia sp. [126] Hamigeromycin F (93) Hamigera avellanea [163] dehydrocurvularin (52) Hamigeromycin G (94) Hamigera avellanea [163] þ ( )-(15R)-13-Hydroxy-10,11-E- Curvularia sp. [126] Hypothemycin (95) Aigialus parvus [141] dehydrocurvularin (53) Coriolus versicolor [166] þ ( )-(11S,15R)-11-Hydroxycurvularin (54) Curvularia sp. [126] Hypomyces [153] þ ( )-(11R,15R)-11-Hydroxycurvularin (55) Curvularia sp. [126] subiculosis þ ( )-(15R)-12-Oxocurvularin (56) Curvularia sp. [126] Hypomyces [171,172] Curvulone A (57) Curvularia sp. [127] trichothecoides Sumalarins A (58) Penicillium [128] Phoma sp. [169] sumatrense 70,80-Dihydrohypothemycin (96) Hypomyces [172] Sumalarins B (59) Penicillium [128] trichothecoides sumatrense 50-O-Methylhypothemycin (97) Phoma sp. [169] Sumalarins C (60) Penicillium [128] L-783,277 (98) Phoma sp. [180] sumatrense L-783,290 (99) Phoma sp. [180] Trans-resorcylide (61) Drechslera phlei [131] 4-O-Demethylhypothemycin (100) Aigialus parvus [141] Penicillium sp. [129,133] Hypomyces [153] Pyrenophora teres [130] subiculosus Cis-resorcylide (62) Drechslera phlei [131] (101) Hypomyces [153] Penicillium [134] subiculosus roseopurpureum (102) Hypomyces [153] Penicillium sp. [129,133] subiculosus Pyrenophora teres [130] Monorden (103) (also named radicicol, or Chaetomium [191] (R)-7-Hydroxydihydroresorcylide (63) Drechslera phlei [131] monorden A) chiversii Penicillium sp. [133] Colletotrichum [192] Acremonium zeae [132] graminicola (S)-7-Hydroxydihydroresorcylide (64) Drechslera phlei [131] Humicola fuscoatra, [198] Penicillium sp. [133] Humicola sp. [193,194] Acremonium zeae [132] Monocillium [181,210] (R)-7-Methoxydihydroresorcylide (65) Penicillium sp. [133] nordinii (S)-7-Methoxydihydroresorcylide (66) Penicillium sp. [133] Neocosmospora sp. [215] Dihydroresorcylide (67) Acremonium zeae [132] 13-Membered benzenediol lactones (continued on next page) (68) Aigialus parvus [142] 752 W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777

Table 1 (continued ) Table 1 (continued )

Name (stereochemistry) (alternative name) Producing species References Name (stereochemistry) (alternative name) Producing species References

Neonectria [182] Pochonin A (136) Pochonia [209] radicicola chlamydosporia Neophaeosphaeria [191,195] Pochonin B (137) Humicola fuscoatra [214] quadriseptata Pochonia [209] Paecilomyces sp. [155] chlamydosporia Pochonia [219] Pochonin C (138) Humicola fuscoatra [214] chlamydosporia Pochonia [209] Penicillium luteo- [196] chlamydosporia aurantium Pochonin D (106)(also named Monorden D) [197] Pochonin E (139) Pochonia [209,222] Tetrahydromonorden (104) (also named Humicola sp. [194] chlamdosporia monorden B) Pochonin F (140) Pochonia [209,222] Monorden C (105) Humicola sp. [194] chlamdosporia Monorden D (106) (also named pochonin D) Humicola sp. [194] Pochonin G (141) Pochonia [213] Pochonia [209] chlamdosporia chlamdosporia Pochonin H (142) Pochonia [213] Monorden E (107) Humicola sp. [194] chlamdosporia Monocillin I (108) Chaetomium [191]; Pochonin I (143) Pochonia [213] chiversii chlamdosporia Colletotrichum [192] Pochonin J (144) Pochonia [213] graminicola chlamdosporia Monocillium [210,211] Pochonin K (145) Pochonia [213] nordinii chlamdosporia Paraphaeosphaeria [191,195] Pochonin L (146) Pochonia [213] quadriseptata chlamdosporia Monocillin II (109) Colletotrichum [192] Pochonin M (147) Pochonia [213] graminicola chlamdosporia Monocillium [210,211] Pochonin N (148) Fusarium sp. [154] nordinii Humicola fuscoatra [214] Neocosmospora sp. [215] Pochonia [213] Pochonia [209] chlamdosporia chlamydosporia Pochonin O (149) Pochonia [213] Monocillin III (110) Colletotrichum [192] chlamdosporia graminicola Pochonin P (150) Pochonia [213] Monocillium [210,211] chlamdosporia nordinii LL-Z1640-1 (151) (also named L-783,279) Lederle Culture [228] Pochonia [209] 21640 chlamydosporia Cochliobolus [159] Monocillin IV (111) Monocillium [210,211] lunatus nordinii Drechslera [231] Neocosmospora sp. [215] portulacae Humicola fuscoatra [203] Filamentous [15] Penicillium sp. [202] fungus Monocillin V (112) (also named Monocillium [210,211] (MSX63935) tetrahydromonocillin I) nordinii Paecilomyces sp. [155] Nordinone (113) Monocillium [211] Sterile fungus [232] nordinii (MF6280&6293) Nordinonediol (114) Monocillium [211] LL-Z1640-2 (152) (also named C292, 5Z-7- Lederle Culture [228] nordinii oxo-zeaenol or L-783,278) 21640 Monocillin II glycoside (115) Pochonia [209] Cochliobolus [159,230] chlamydosporia lunatus Monorden analogue-1 (116) Humicola fuscoatra [198] Filamentous [15,230] Pochonia [213] fungus chlamdosporia (MSX63935) Radicicol B (117) Humicola fuscoatra [214] Sterile fungus [232] Radicicol C (118) Humicola fuscoatra [214] (MF6280&6293) Radicicol D (119) Humicola fuscoatra [214] LL-Z1640-3 (153) Lederle Culture [228] Neocosmosin A (120) Neocosmospora sp. [215] 21640 Neocosmosin B (121) Neocosmospora sp. [215] LL-Z1640-4 (154) Lederle Culture [228] Neocosmosin C (122) Neocosmospora sp. [215] 21640 Paecilomycin A (123) Paecilomyces sp. [216] Zeaenol (155) Cochliobolus [229] Paecilomycin B (124) Paecilomyces sp. [216] lunatus Paecilomycin C (125) Paecilomyces sp. [216] Drechslera [231] Paecilomycin D (126) Paecilomyces sp. [216] portulacae Paecilomycin E (127) Paecilomyces sp. [216] Filamentous [15] Paecilomycin F (128) Cochliobolus [156] fungus lunatus (MSX63935) Paecilomyces sp. [216] Paecilomyces sp. [155] Paecilomycin G (129) Paecilomyces sp. [155] (5E)-7-oxo-Zeaenol (156) (also named (70E)- Cochliobolus [156,230] Paecilomycin H (130) Paecilomyces sp. [155] 60-oxozeaenol) lunatus Paecilomycin I (131) Paecilomyces sp. [155] Drechslera [231] Paecilomycin J (132) Paecilomyces sp. [218] portulacae Paecilomycin K (133) Paecilomyces sp. [218] Filamentous [15] Paecilomycin L (134) Paecilomyces sp. [218] fungus Paecilomycin M (135) Paecilomyces sp. [218] (MSX63935) W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777 753

Table 1 (continued ) mL, respectively. In addition, compound 16 showed cytotoxicity Name (stereochemistry) (alternative name) Producing species References against KB, BC1 and NCI-H187 cell lines with IC50 values of 20.77, 25.89, and 20.89 mg/mL, respectively. The first stereo selective total 5,6-Dihydo-5-methoxy-7-oxo-zeaenol (157) Cochliobolus [230] fi lunatus synthesis of 30 and 22 was nished by Yadav et al. in 2010 [71]. 15-O-Desmethyl-(5Z)-7-oxozeaenol (158) Filamentous [15] In 2013, Yuan et al. reported the isolation and structure eluci- fungus dation of (3S,6R)-6-hydroxylasiodiplodin (31), (3R)-lasiodiplodin (MSX63935) (16), and (3R,5S)-5-hydroxylasiodiplodin (20) from an endophytic Zearalenone (ZEA, ZEN) (159) Fusarium sp. [239,274,276] fungus S. kiliense grown in rice medium isolated from the gut of Paecilomyces sp. [217] SC0924 healthy Apriona germari (Hope) collected from the campus of 13-Formyl-zearalenone (5- Fusarium [274] Jiangsu Normal University, Jiangsu Province, China [72]. The formylzearalenone) (160) graminearum structure of 31 was elucidated by a combination of spectroscopic 0 5, 6-Dehydro-zearalenone (7 - Fusarium [274] data interpretation, single-crystal X-ray diffraction analysis, and dehydrozearalenone) (161) graminearum fi fi Cochliobolus [40] modi ed Mosher's method. The absolute con guration at C-6 was lunatus determined by a modified Mosher's method, based on the analysis Paecilomyces sp. [217] of differences in proton chemical shifts between the (R), (þ) -and 5-Hydroxy-zearalenone (162) Fusarium [268,269] (S), ()-a-methoxy-a-(trifluoromethyl) phenylacetyl (MTPA) esters graminearum 0 of 31. The absolute configuration at C-3 was deduced from the 5-Hydroxy-zearalenone (8 - Fusarium [274]; fi hydroxyzearalenone, F-5-3) (162a) graminearum relative con guration of C-3 with C-6 by the X-ray diffraction Streptomyces [283] analysis. The result indicated S configuration for C-3 in lasiodiplo- rimosus din analogues also exist in nature. Penicillium sp. [297] (3R)-Lasiodiplodin (16) and (R)-de-O-methyllasiodiplodin (17) 5-Epi-hydroxy-zearalenone (80-Epi- Fusarium [274] hydroxy-zearalenon, F-5-4) (162b) graminearum are the most widely studied metabolites in the lasiodiplodin series. 5-Hydroxy-zearalenol (60 80- Fusarium [272] (3R)-Lasiodiplodin (16), isolated from plant C. greveana, was found Dihydroxyzearalene) (163) graminearum to be active with IC50 ¼ 0.045 mg/mL against the A2783 ovarian 0 10-Hydroxy-zearalenone (3 - Fusarium [273] cancer cell line [51].In2007,16 was revealed to be phytotoxic by Hydroxyzearalenones) (164) graminearum blocking the electron transport chain in thylakoids at multiple 10-a-Hydroxy-zearalenone (164a) 10-b-Hydroxy-zearalenone (164b) targets that were different from those of current herbicides [73]. Zearalenol (ZOL) (165) Fusarium sp. [270,271,274] De-O-methyllasiodiplodin (17) obtained in the roots of A. euchroma a-Zearalenol (165a) (a traditional Chinese medicine), was found to be responsible, at b-Zearalenol (165b) least in part, for the pharmacological properties of the plant ex- Zearalanone (166) Fusarium sp. [274] tracts as the result of its efficient inhibition of prostaglandin a-Zearalanol (also named zeranol) (167a) Fusarium sp. [274] b-Zearalanol (also named taleranol) (167b) biosynthesis [55,63].In2010,17 was reported to be a potent in- Cis-zearalenone (168) Fusarium sp. [274] hibitor of pancreatic lipase (PL) (IC50 ¼ 4.73 mmol/L), an enzyme Cis-a-zearalenol (169a) Fusarium sp. [274] that plays a key role in the efficient digestion of triglycerides and Cis-b-zearalenol (169b) that was a target for treating obesity [74].In2011,17 was found to 14, 16-Dimethoxyzearalenone (2,4- Cunninghamella [283] dimethoxyzearalenone) (170) bainieri be a novel, natural, non-steroidal mineralocorticoid receptor (MR) 16-Methoxyzearalenone (2- Cunninghamella [283] antagonist (IC50 ¼ 8.93 mmol/L) and an efficient therapeutic target methoxyzearalenone) (171) bainieri for the treatment of hypertension and other cardiovascular diseases Zearalenone-14-b-D-glucopyranoside (172) Mucor bainieri; [284,287 [75]. In this paper, the authors assumed that the acetylation at Rhizopus sp. e289] phenolic hydroxyl groups in analogs of 17 can increase the antag- Thamnidium elegans onistic effect against MR and the ring size of the lactone was also Zearalenone-14-sulfate (ZEN-4-sulfate) Fusarium [285] very crucial for its activity [75]. It should be noted that this is the (173) graminearum first macrolide compound found to behave as MR antagonist to 0 5 -Hydroxyzearalenol (174) Fusarium sp. [40,285] date, different from the other nonsteroidal MR antagonists. 80-Hydroxyzearalanone (175) Penicillium sp. [297] 20-Hydroxyzearalanol (176) Penicillium sp. [297] Zearalenone-11, 12-oxide (177) Fusarium [298] 2.3.2. Curvularin macrolides (DAL12) graminearum This group including 30 compounds, 32e60 (Table 1 and Fig. 6), Zearalenone-11, 12-dihydrodiol (178) Fusarium [298] is a subclass of DALs with a 12-membered ring system. These graminearum compounds almost apparently stem from varied oxidation levels at 10-oxo-Zearalenone (10-keto-ZEA) (179) Fusarium [298] graminearum the C-11 and C-12 position. They are produced by some fungal 50-Hydroxyzearalenone (180) Fusarium sp. [40] species mainly from different ascomycete species including Alter- 0 0 Trans-7 ,8-dehydrozearalenol (181) Paecilomyces sp. [217] naria, Aspergillus, Curvularia, and Penicillium spp. Radicicol A (182) (also named 89-250904- Cochliobolus [230] Curvularin (32), the best known member of the curvularin F1) lunatus Hamigera avellanea [140] family, was originally isolated as an antifungal agent from the Ro 09-2210 (183) Curvularia sp. [303] culture filtrate of a species of Curvularia by Musgrave in 1956 [76] Queenslandon (184) Chrysosporium [304] and later reisolated from a number of phytopathogenic fungal queenslandicum genera such as Alternaria [77,78], Ascochytula [79], Beauveria [80], Cryptosporiopsin A (185) Cryptosporiopsis [306] Cochliobolus [81], Curvularia [82,83], Chrysosporium [84], Drechslera sp. Y5-02-B (186) Unknown [307] [85], Eupenicillium [86], Helminthosporium [87], Penicillium Y5-02-C (187) Unknown [307] [88e93], Ulocladium [94] etc and from the root extract of Patrinia Apralactone A (188) Curvularia sp. [126] scabra plant [92,95]. The structure of 32 was established by spec- Menisporopsin A (189) Menisporopsis [308] troscopic, X-ray and synthetic studies [96e102] and it was usually theobromae synthesized based on the AldereRickert strategy [99,101]. Another well known curvularin-type compound, a, b-dehydrocurvularin (trans-dehydrocurvularin) (33), which features a trans double bond 754 W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777

Fig. 3. The structures of 8-membered benzenediol lactones (benzenediol octalactones).

Fig. 4. The structures of 10-membered benzenediol lactones (benzenediol decalactones).

Fig. 5. The structures of lasiodiplodin macrolides (RAL12). W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777 755

Fig. 6. The structures of curvularin macrolides (DAL12). in C-10eC-11 usually co-occurs with curvularin in fungi and revealed collaborating hrPKS-nrPKS pairs whose efficient [78,83e85,90,93,103e110]. Besides, it was also independently heterologous expression in Saccharomyces cerevisiae provided a found from Cercospora scirpicola [111], Nectria galligena [112], convenient access to the DAL12 scaffolds [13]. Stemphylium radicinum [113] and several 9F series marine fungi Both curvularin (32) and a, b-dehydrocurvularin (33), have [114]. Early biosynthetic studies supported that a, b-dehy- shown non-specific phytotoxic activity e.g. against Zinnia elegans drocurvularin was a polyketide product, which was excreted from and Cirsium arvense [105,106,116], selective antimicrobial activity the cells and reduced to curvularin by extracelullar enzymes e.g. against B. subtilis, S. aureus, and Escherichia coli [83,110], inhi- [106,115]. Recently, Molnar's group predicted the biosynthesis of 33 bition of TGF-b signaling activities (IC50 ¼ 34.2 and 1.7 mM, 756 W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777

Fig. 7. The structures of novel 12-membered resorcylides. respectively) [116], cytotoxic activities against different human [110,120]. They acted as inhibitors in blocking the cell division [81] tumor cell lines like A549 (IC50 ¼ 13.91 ± 0.15 and 2.10 ± 0.33 mM, by specifically disordering the microtubule centers [101] and respectively), HeLa (IC50 ¼ 25.64 ± 0.37 and 21.01 ± 0.19 mM, inducing barrel-shaped spindles [90], and inhibited Hsp90 [16],a respectively), MDA-MB-231 (IC50 ¼ 1.3 ± 0.37 and 9.34 ± 0.38 mM, promising target for anticancer drug discovery (Janin 2005). The respectively) and MCF-7 (IC50 ¼ 21.89 ± 0.19 and 11.19 ± 0.31 mM, ability likely originated from the conformation of their macrocyclic respectively) [84]. Additionally, 32 has been revealed to reduce the ring, which mimiced the M-helicity of the colchicin skeleton, a expression of the proinflammatory enzyme iNOS in a stereochemical feature known to be important for tubulin binding glucocorticoid-resistant model of rheumatoid arthritis by inhibit- of these agents [81,100]. Compounds, 34, 37 and 38, had nemati- ing the JAK/Stat signaling pathway [95,117,118]. It also exhibited cidal activities against Pratylenchus penetrans of 35%, 80% and 23% 80% acetylcholinesterase (AChE) inhibitory activity [84], and had at a respective concentration of 300 mg/L [109,122]. Moreover, 11- the antioxidant activity of Helminthosporium maydis FBF at a high a-methoxycurvularin (35a) was independently identified from the concentration [87]. While compound 33 showed good superoxide crude extract of Curvularia oryzae MTCC 2605 by silica gel column anion scavenging activity with an EC50 value of 16.71 mg/mL [84] chromatography in 2009 [123]. In this paper, it showed strong and it was also active against COLO 205 with an IC50 of 7.9 mM antibacterial activities against gram-positive bacteria e.g. S. aureus, [84]. Taking together, the IC50 values of 33 were almost always one Bacillus sphericus with a mean MIC value of 100 mg/mL and gram- order of magnitude higher than those of 32 against the corre- negative bacteria e.g. Pseudomonas aeruginosa, Pseudomonas oleo- sponding test cell lines except for MDA-MB-231 cell line. However, vorans with inhibition zones between 12 and 16 mm, as well as the presence of a double bond is the only structural difference moderate antifungal activity. Against Spodoptera litura 4th instar between two compounds (as one counterpart), which might be one larvae LD50 was determined to be 205.59 mg/mL [123]. of the important structural property essential for effective inter- Recently, the chemical investigation of the endophytic fungus action in the bioactive profiles. Penicillium sp. obtained from stem tissues of Limonium tubiflorum Ten new members of the curvularin family, which include 11-a- (from L. tubiflorum growing in Egypt) resulted in the isolation of hydroxycurvularin (34a), 11-b-hydroxycurvularin (34b), 11-a- two new curvularins, named penilactone (42) and 10,11- methoxycurvularin (35a), 11-b-methoxycurvularin (35b), cis- epoxycurvularin (43), along with four known curvularin-type me- dehydrocurvularin (36), 12-oxo-curvularin (37), 11-b-hydroxy-12- tabolites (33, 35a, 35b, 36) [124]. Penilactone (42) is characterized oxo-curvularin (38), 11,12-dihydroxycurvularin (39), 12-hydroxy- by a 4-chromanone ring system formed by connecting the 10,11-trans-dehydrocurvularin (40) and citreofuran (41) together oxygenated aromatic carbon C-7 and CH-11. It was noteworthy that with two known 32 and 33, were isolated from the mycelium of the 42 incorporated a 4-chromanone ring system was rather rare hybrid strain ME 005 derived from Penicillium citreoviride 4692 and among macrolides. The configuration of 42 and 43 at C-15 was 6200, upon fermentation on rice [91,107,119]. Their structures were assumed by comparison the of measured [a]D values with those of established by spectroscopic data. It is worth mentioning that cit- similarly curvularin-type metabolites [124]. In this paper, com- reofuran (41) is a structurally unique octaketide derivative pounds (35a and 35b) showed pronounced antitrypanosomal ac- belonging to the curvularin family containing a furan ring. tivities with MIC values of 4.96 and 9.68 mM, respectively. Furthermore, these authors still pointed that the abosolute Compounds (35a, 35b, 36) selectively inhibited the growth of hu- configuration of the biologically active compound previously iso- man T cell leukemia cells (Jurkat) (IC50 ¼ 3.9, 2.3, and 5.5 mM, lated from Alternaria tomato in 1976 was b-hydroxycurvularin (34b) respectively), and human histiocytic lymphoma cells (U937) [105]. Later, 11-hydroxycurvularin (34) and 11-methoxycurvularin (IC50 ¼ 1.8, 4.6, 2.5, and 7.6 mM, respectively), and reduced TNFa- (35) (the mixtures of 11a- and 11b-epimers) were also reported induced NF-kB activation as expressed by their IC50 values of 4.7, as metabolites of several fungi such as Aspergillus cervinus [110] and 10.1, 5.6, and 1.6 mM, respectively [124]. We presume that the Penicillium sp. [120].(Trichonaceae) isolated from the rhizosphere presence of a free methoxy group at C-11 is essential for anti- of Anicasanthus thurberi and Fallugia paradoxa, respectively. The trypanosomal activity, whereas trans isomer is more active than cis author assumed 34 and 35 was probably produced by a Michael- one. type addition of H2O and MeOH to the enone system of 33 during Other well known curvularin analogues included b, g-dehy- the processing of these microorganisms, respectively [110].In2007, drocurvularin (44) isolated from the culture filtrate and mycelial the first total synthesis of 35a and 35b was reported by Liang et al., mats of Aspergillus sp. [109], E-6-chloro-10, 11-dehydrocurvularin in which the spectral data of originally proposed structure for 11- (45) from Cochliobolus spicifer [81],11-O-acetyldehydrocurvularin methoxycurvularin were pointed to 35a [121]. The curvularin de- (46) from C. scirpicola [111]. 44 showed nematicidal activities rivatives 32e41 were discovered to have considerable cytotoxicities against P. penetrans of 35% and 87% at a respective concentration of toward a panel of human cancer cell lines (NCI-H460, MCF-7, SF- 300 and 1000 mg/L [109]. In 2005, three new curvularin-derived 268, MIA. Pa Ca-2), with IC50 values ranging from 0.90 to 13.30 mM products were obtained during the course of biotransformation of W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777 757

Fig. 8. The structures of 13-membered benzenediol lactones.

Scheme 1. Possible mechanisms for the production of 13-Membered benzenediol lactones. curvularin (32) with Beauveria bassiana ATCC 7159. They were dehydrocurvularin (53), (þ)-(15R)-13-hydroxy-10,11-E-dehy- identified as curvularin-7-O-b-D-glucopyranoside (47), curvularin- drocurvularin (54), and C-11 stereocenter epimers of (þ)-(15R)- 11- 40-O-methyl-7-O-b-D-glucopyranoside (48), 6-hydroxycurvularin- hydroxycurvularin (55 and 56), were obtained together with a 14- 40-O-methyl-7-O-b-D-glucopyranoside (49) which resulted from membered macrolide. The planar structures of 51e56 were hydroxylation, glucosidation, and methylglucosidation of the sub- confirmed by interpretation of extensive 1D and 2D NMR experi- strate, respectively [80]. In 2008, a new curvularin analogue, oxa- ments (HMBC, HSQC and COSY). Based on their optical rotation and cyclododecindione (50), was isolated from the fermentations of the CD spectra, the configuration at C-15 of newly isolated metabolites fungal strain Exserohilum rostratum IBWF99121, as a potent inhib- 51e56 was assigned as R, which was different from the known itor of IL-4 signaling by inhibiting the binding of the activated Stat6 curvularin-type compounds as described above. The newly iden- transcription factors to the DNA binding site without affecting tified metabolites 51 and 53e55 were found to exhibit structure- tyrosine phosphorylation [125]. The structure of 50 was deter- dependent cytotoxic properties. Especially, 51 displayed strong mined by a combination of spectroscopic techniques. Unfortu- cytotoxicity, about 24-fold more cytotoxic potency than its 13- nately, neither the relative nor the absolute configuration could be hydroxy derivative 53, against nine tested human cancer cell lines determined from the existing data. Later, in a screening for fungal (BXF 1218L (bladder cancer), BXF T24 (bladder cancer), CNXF SF268 compounds with a cell-based reporter assay, 32, 33 and 50 were (glioblastoma), LXFA 289L (lung adenocarcinoma), MAXF 401NL found to suppresse the TGF-b inducible activation of a Smad 2/3 (mammary cancer), MEXF 462NL (melanoma), MEXF 514L (mela- dependent transcriptional reporter in HepG2 cells in a dose- noma), OVXF 899L (ovarian cancer), and PRXF PC3M (prostate dependent manner without displaying cytotoxic effects. Among cancer)) in a concentration-dependent manner (IC50 ¼ 1.25 mM), them, 50 was the most highly potent inhibition with IC50 values of suggesting that the stereochemistry at C-15 chiral center of the 190e217 nM [117]. We assume that free methyl groups may curvularin-type macrolides is not crucial for their cytotoxic activity. enhance the activity. In contrast, variations of the oxidation levels around the macrocycle During the chemical investigation of the cytotoxic extract of the seem to influence the cytotoxic activity of the (þ)-(15R)-curvularin- marine-derived fungus Curvularia sp. (strain no. 768), isolated from type metabolites [126]. Curvulone A (57), another novel (15R)- the red alga Acanthophora spicifera, six novel curvularin-type curvularin-type metabolites has been isolated from a Curvularia sp. macrolides, (þ)-(15R)-10,11-E-dehydrocurvularin (51), (þ)-(15R)- associated with a marine red alga Gracilaria folifera, with two 12-oxocurvularin (52), (þ)-(15R)-12-hydroxy-10,11-E- known 15R series compounds (51 and 54). Structurally, 57 features 758 W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777

Fig. 9. The structures of aigialomycins. a unique benzofuranone ring linked to 12-membered macro- 10 mM, while 32 was inactive. The data implied that the structural lactone, which can be formed by an intramolecular oxa-Michael feature of sulfur substitution at C-11 or a double bond at C-10 addition of the phenolic hydroxyl group to the a, b-unsaturated significantly increased the cytotoxic activities of the curvularin ketone moiety. The relative configurations of two chiral centers analogues [128]. were determined as 10S*, 15R* by X-ray diffraction analysis, and the fi absolute con guration of 57 was accomplished independently by 2.3.3. Novel 12-membered resorcylides the solid state TD-DFT ECD method and by measuring the anom- To date, 7 12-membered benzenediol lactones including trans- alous dispersion effect. The metabolites (51, 54 and 57) had pro- resorcylide (61), cis-resorcylide (62), dihydroresorcylide (67), 7- nounced antibacterial activities against the Bacillus. megaterium, hydorxyresorcylide enantiomers (63 and 64), and their methyl antifungal activities against Microbotryum violaceum and Septoria esters (65 and 66)(Table 1 and Fig. 7), have been included in this tritici, and were antialgal against Chlorella fusca. Particularly, 57 type. They are produced by fungi Penicillium spp. [129], Pyrenophora showed the strong activity against the Gram positive bacterium teres [130], Drechslera phlei [131] and Acremonium (Sarocladium) Bacillus strain 6540 inhibiting 92% of the bacterial growth [127]. zeae [132]. Structurally, they are related to both curvularinds and fi More recently, in order to nd new bioactive secondary me- lasiodiplodins, but possess a modified carbon skeleton [129]. The tabolites from marine-derived fungi, three rare curvularin de- skeleton of these compounds contains one more ketone carbonyl e e rivatives, sumalarins A C(58 60), along with three known than lasiodiplodin's. Meanwhile, the ketone carbonyl in these metabolites (32, 33 and 47), were identified in the cytotoxic extract compounds is linked to the isolated benzylic CH2 corresponding to of Penicillium sumatrense MA-92, a fungus obtained from the C-10 rather than directly to the aromatic ring in curvularins. e rhizosphere of the mangrove Lumnitzera racemosa. 58 60 were the Trans-(61) and cis-resorcylide (62)werefirst isolated as new fi rst examples of curvularin derivatives possessing sulfur substi- plant growth inhibitors from an unidentified species of Penicillium tution. Their structures were established by a detailed interpreta- by Oyama et al. in 1978 [133]. Later, they were reisolated from tion of NMR and MS data, including determining the crystal X-ray another fungus Penicillium SC2193 along with 7- structure of 58. The authors assumed that 60 was likely produced hydorxyresorcylide enantiomers (63 and 64), and their methyl via Michael addition of the cysteine metabolite 3-mercaptolactate esters (65 and 66) [129]. In 1996, 62 has been isolated from Peni- to the double bond of dehydrocurvularin and thus was reminis- cillium roseopurpureum [134]. Besides the genus Penicillium, trans- fi cent of glutathione detoxi cation of Michael acceptors in (61) and cis-resorcylide (62) also was found in P. teres, the cause of mammalian metabolism. Compounds 58 and 59 can be derived net-type net blotch of barley [130], and D. phlei, a pathogenic fi fi from 60 by esteri cation or esteri cation and acylation, respec- fungus on timothy grass, along with 63 and 64 [131]. The structures tively. The bioassay results showed that the sulfur-containing cur- of 61e66 were determined using a combination of spectroscopic e vularin derivatives 58 60 exhibited cytotoxic activities against techniques with emphasis on NMR spectroscopy. The spectral data seven tested tumor cell lines (Du145, HeLa, Huh 7, MCF-7, NCI- indicated that 61 and 62 possess a rather unique structural mark: H460, SGC-7901, and SW1990) with IC50 values ranging from 3.8 to the cis isomer (62) is characterized by a strong H-bond between the W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777 759

Fig. 10. The structures of caryospomycins.

Fig. 11. The structures of cochliomycins. phenol hydroxyl and the lactone carbonyl, while trans isomer (61) lines, anti-microbial activity against Pyricularia oryzae, and was an lacks that feature [133]. The S-configuration at C-3 of resorcylides inhibitor of 15-hydroxyprostaglandin dehydrogenase, whereas 62 was originally assigned on the basis of the chemical degradation of does not inhibit that enzyme [138]. Cis-R-()-resorcylide (62) cis-resorcylide [133], and this was later confirmed by total synthesis specifically inhibits blood coagulation factor XIIIa and may be ad- [135]. In 2008, a new metabolite, dihydroresorcylide (67), was also vantageous to enhance fibrinolysis and resolve blood clots revealed to have wide spread occurrence in A. zeae (105 of 154 [134,139]. Apparently, the configuration of double bond has a isolates), a protective endophytic fungus of maize, along with the strong impact on bioactivities. two diastereomers of 7-hydroresorcylide (64 and 64) [132]. The fi con guration of a methyl group in 67 had been originally deter- 2.4. 13-Membered benzenediol lactones mined to be the S configuration; however, the optical rotation sign ½ 25:0þ of naturally isolated 67 { a D 15.0 (c 0.33, MeOH)} was opposite Natural occurring 13-membered 1, 3-dihydroxybenzene mac- ½ 24:0 e to that of the synthetic 67 {[ a D ] 40.0 (c 0.8, MeOH)}, indicating rolides are very rare. Only two compounds without definite names fi that the con guration of naturally isolated 67 most likely needs to were reported as the derivatives of 14-Membered RALs so far. The further revised [136]. authors thinked that these two 13-membered macrolides (68, 69) Resorcylides were phytotoxic as demonstrated in leaf puncture (Table 1 and Fig. 8) isolated from the marine mangrove fungus wound assays and inhibited seedling root elongation Aigialus parvus BCC 5311 were possibly produced from air oxidation e [130 133,137]. 61 caused necrosis on corn and crabgrass (Digitaria of aigialomycin A and hypothemycin, respectively. Possible mech- m m sanguinalis) at 0.06 g per leaf. At 2 g/leaf, timothy (Phleum pra- anism for the production of 68 is proposed in Scheme 1. Rear- fl tense), wild poinsettia, and sun ower (Helianthus annuus) were rangement from a 14-membered to 13-membered macrolides m also very sensitive to 61, while 62 was inactive at 1 g per leaf. could be explained by carbon migration of hemiacetal [140]. Other saturated resorcylide (63e66) fell midway between the two and retained activity at 0.5 mg per leaf. Compound 61 was a plant growth inhibitor and was >10 times more effective than 62 at 2.5. 14-Membered benzenediol lactones inhibiting seedling root elongation [133]. Additionally, trans- resorcylide (61) exhibited cytotoxicity against a panel of tumor cell 14-Membered benzenediol lactones constituted the largest group of BDLs including more than 100 substances, the majority of 760 W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777

Fig. 12. The structures of hamigeromycins.

which belonged to RALs family. These included aigialomycins, (IC50:6mM for CDK1/5, 21 mM for CDK2, and 14 mM for GSK) caryospomycins, cochliomycins, hamigeromycins, hypothemycins, although it did't belong to those resorcylic macrolides containing a monocillins, monordens, neocosmosins, paecilomycins, pochonins, cis-enone moiety, which are well known as one of the more zeaenols and zearalenones etc, which were mainly obtained from promising groups of natural products that have recently emerged fungal species of genera Aigialus, Caryospora, Cochliobolus, Hami- as new lead structures for kinase inhibition. The result suggested gera, Hypomyces, Monocillium, Humicola, Neocosmospora, Paecilo- that different RAL scaffolds might inhibit different kinases via myces, Pochonia, Drechslera and Fusarium etc. In addition, only three various mechanisms. Consequently, 73 has attracted considerable natural 14-membered benzenediol lactones resembled the DALs. interest from the synthetic community, resulting in eight total syntheses [143,145e151]. In addition, 73 has recently been shown 2.5.1. Aigialomycins to bind to Hsp90, but does not function as an indiscriminate ATP Compounds of this type include 9 RALs, 70e78 (Table 1 and antagonist [152]. Fig. 9). They were mainly reported as the secondary metabolites of The compounds of this class have been found from other fungi. 0 0 fi the genus Aigialus. 1 ,2-Epoxyaigialomycin D (77)was rst isolated from Hypomyces In the course of screening for novel bioactive compounds from subiculosus in 2006 with other hypothemycin analogues [153]. The microbial sources, five resorcylic macrolides, aigialomycins AeE structure was established by analysis of NMR and MS data, and the fi (70e74), were isolated from the mangrove fungus, A. parvus BCC relative con gurations were assigned by NMR analyses (1H, 13C, 5311, along with previously reported hypothemycin (95) (see in HSQC, HMBC, and TOCSY) and performing X-ray crystallographic Fig. 13)in2002[141]. The structures and absolute configuration of analysis. The analysis revealed that the structure of 77 was very 70e74 were elucidated by chemical conversions, detailed analysis similar to that of 73, which just bore an epoxide functionality be- 0 0 fi of the NMR spectroscopic and mass data in conjunction with X-ray tween C-1 and C-2 instead of the trans-ole nic bond [153]. data obtained on hypothemycin [141]. Several years later, another Aigialomycin D (73), isolated from the cultures of Fusarium sp. LN- six new nonaketide metabolites including aigialomycin F and G (75 10, an endophytic fungus originated from the leaves of Melia aze- fi and 76), which can be looked as distinct aigialomycin derivatives, darach in 2011, was revealed to have signi cant toxicity toward m were isolated from the same marine mangrove fungus by the same brine shrimp larvae (76.7% at a concentration of 10 g/mL) [154].In e group [142]. The stereochemistry of 75 and 76 was addressed by 2012, compounds 71 73, 75 and 77, obtained from the mycelial conversion to acetonide derivatives. The result that the same solid culture of Paecilomyces sp. SC0924, were found to have weak compound could be prepared by hydrogenation of 75 and reduction activities against Peronophythora litchii in an assessment of anti- of 76 with NaBH revealed that 75 and 76 possessed the same fungal activity by the well plate diffusion method [155]. Recently, 4 fi relative stereochemistry. On the basis of these experimental data deoxy-aigialomycin C (78)was rst reported as a natural product and by biogenetic correlation to 71, the absolute configurations of isolated from the sea anemone-derived fungus Cochliobolus lunatus. fi fi 75 and 76 were deduced to be 10R, 20S, 40S, 50S, 60 S, 100S and 10R, 20S, Its relative and absolute con gurations were con rmed using NOE 40S, 50S, 100S, respectively. Compounds (70e75) displayed weak experiments of its acetonide derivative and the CD exciton chirality activity against Plasmodium falciparum K1, cytotoxicities against method with its pdimethylaminobenzoyl derivative. It exhibited two cancer cells (KB, BC-1) and Vero cells (African green monkey potent antifouling activity at nontoxic concentrations with the EC50 m kidney fibroblast), of which aigialomycin D (73) was the most value of 22.5 g/mL [156]. Previously, 78 was obtained as a new aigialomycin analogue along with epi-Aigialomycin D through the potent (IC50 were 6.6, 3.0, 18 and 1.8 mg/mL, respectively) [141]. Additionally, 73 also exhibited kinase inhibitory activities [143,144] syntheses studies of aigialomycin D [152]. W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777 761

Fig. 13. The structures of hypothemycins.

Fig. 14. The structures of monordens and monocillins. 762 W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777

Fig. 15. The structures of neocosmosins.

2.5.2. Caryospomycins Structureeactivity relationships suggested that the enone and Three compounds of this type, 7981 (Table 1 and Fig. 10), acetonide functionalities and hydroxy configurations may have possessed a rare structure in which a 1,2-dimethoxy-4- obvious influence on antifouling activity. Additionally, only 82 was hydroxybenzene ring fused into the 14-membered macrolides. In found to have moderate antibacterial activity against S. aureus with 2007, our group reported the isolation of caryospomycins AeC an inhibition zone of 11 mm in diameter at a concentration of 50 mg/ (79e81), as a result of the investigation of the metabolites with mL [156]. Very recently, cochliomycin A was firstly synthesized by activities against plant parasite nematodes from the fresh-water Nanda's group from L-(t)-tartaric acid in 6.5% overall yields fungus Caryospora callicarpa YMF1.01026, which was initially iso- employing Keck allylation [160] and then was stereoselectively lated from a submerged woody substrate collected from a fresh- synthesized based on chiron approach by Wang et al. [161]. water habitat in Yunnan Province, China. The chemical structures of Cochliomycin B (83) and zeaenol (155) have been synthesized from 7981 were determined through NMR spectroscopic analysis. The natural chiral template i-arabinose in overall yield of 4.8%, by Takai spectra data combined with 2D NMR experiments indicated 80 was olefination, Suzuki coupling, alkoxide-mediated transesterification, a deacetonided derivative of 79, and 81 was an analogue of 80 but and RCM macrocyclization as the crucial steps [162]. with a different oxidation state at C-60. In this report, these com- pounds were demonstrated to be active in an in vitro microtiter 2.5.4. Hamigeromycins plate assay and exhibited moderate killing activity against the This group of 7 compounds 8894 (Table 1 and Fig. 12) features nematode Bursaphelenchus xylophilus with the LC50 values of 103.1, a 1, 2-dimethoxy-4-hydroxybenzene ring and a 14-member 105.8, and 105.1 ppm, at 36 h, respectively [157]. macrocyclic lactone ring, which includes a 10-20 trans double bond, a ketone and one or two hydroxys. These compounds were all 2.5.3. Cochliomycins isolated from Hamigera avellanea. fi The compounds of this class, 8287 (Table 1 and Fig. 11), were Hamigeromycins A (88) and B (89) were rst isolated from the only obtained from fungus C. lunatus. soil fungus H. avellanea BCC 17816 together with radicicol (103) Cochliomycins AeB(82e83), two with a rare natural acetonide [140]. In a subsequent study, the same team got hamigeromycins e e group, and cochliomycin C (84), one with a 5-chloro-substituted C G(90 94) by altering a liquid fermentation medium (PYGM). lactone, were isolated from the culture broth of C. lunatus, a fungus The structures and the stereochemistry of these compounds were obtained from the gorgonian Dichotella gemmacea collected in the deduced by analyses of the NMR spectroscopic and mass spec- South China Sea [158]. Their structures were elucidated by exten- trometry data in combination with chemical means. It should be sive spectroscopic analysis including 1D NOE and 2D NOESY ex- noted that 88, 90, 91 and 92 were stereoisomers differing from each other in the absolute configurations of the 40,50-diol moiety; while periments and chemical conversions. The only difference between 0 0 cochliomycin A and B was the position of acetonide group. The 93 and 94 were unusual 5 -keto-analogs, and they were 6 -epimers absolute configurations of 82 and 83 were further confirmed after to each other. Besides, 89 were characterized by containing an treatment of zeaenol (155) with 2, 2-dimethoxypropane in the oxygen bridge [163]. In a cytotoxicity assay, all compounds were presence of p-toluenesulfonic acid (PTSA) resulted in a mixture of inactive against cancer cell lines (KB, MCF-7, and NCI-H187) at a cochliomycin A and B. However, cochliomycin C initially published concentration of 50 mg/mL, whilst compounds 88 and 90 showed structure 84a, was later revised to 84, which was assigned as 40S, weak growth inhibition against Vero cells (African green monkey fi 50R, 60S, 100S, by the same authors [159]. Interestingly, a trans- kidney broblasts) with IC50 values of 42 and 13 mg/mL, respec- tively. All compounds were inactive in an antimalarial activity assay etherification reaction that compound 83 in a solution of CDCl3 slowly can be rearranged to give 82 at room temperature indicated against P. falciparum K1 at 10 mg/mL [163]. Recently, several syn- cochliomycin A can arise from cochliomycin B via a trans- thestic pathways of 89 were accomplished [164,165]. etherification reaction in which the ether migrated from O-40 to O- 60 [158]. Recently, the reinvestigation of the secondary metabolites 2.5.5. Hypothemycins from the sea anemone-derived fungus C. lunatus (collected from Compounds in this type are some of the highly oxygenated Weizhou coral reef in the South China Sea) led to the isolation of analogues in the group of 14-membered resorcylic acid lactones. three new 14-membered resorcylic acid lactones, cochliomycins There are 8 compounds, 95102, within this type (Table 1 and DF(85e87), and eight known analogues. Detailed analysis of the Fig. 13), mainly isolated from genus Hypomyces and Phoma. 1D and 2D NMR spectra established the same planar structures for As the best known compounds in this type, hypothemycin (95) 85e87. Their absolute configurations were established by the CD was originally isolated from Hypomyces trichothecoides along with exciton chirality method and TDDFT ECD calculations. The result 70,80-dihydrohypothemycin (96), and later reisolated from the indicated that these compounds were diastereomers differing from fungal fermentations of A. parvus [141], Coriolus Versicolor [166], each other by the absolute configurations of the 40,50-diol chiral Hypomyces subiculosis [153] and Phoma sp. [167]. The absolute centers [156]. In antifouling assays, compound 82, 85 and 87 configuration of 95 had been tentatively determined many times by exhibited potent antifouling activities against the larval settlement different methods, which included X-ray analysis using anomalous of the barnacle Balanus amphitrite at nontoxic concentrations, with dispersion of oxygen atoms [166], X-ray analysis of an aigialomycin EC50 values of 1.2, 17.3 and 6.67 mg/mL, respectively. C4-bromobenzoyl derivative chemically correlated to W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777 763

Fig. 16. The structures of paecilomycins. hypothemycin [141], single crystal X-ray analysis in combination especially the plasma membrane, mitochondria, and vacuoles, with the new solid-state CD/TDDFT methodology [167], and ste- reduced decay and suppressed peel browning of postharvest litchi reospecific total synthesis of 95 [168e170].Both95 and 96 were fruit inoculated with P. litchii [179]. active against the protozoan, Tetrahymena furgasoni and the plant Several other hypothemycin analogues were found in fungi as pathogenic fungi Ustilago maydis and Botrytis allii [171,172].In well. 50-O-Methylhypothemycin (97) was isolated from a Phoma sp. addition, hypothemycin 95 also exhibited strong antimalarial ac- with 95. The structure of 97 was elucidated by means of spectro- tivity in vitro (IC50 ¼ 2.2 mg/mL) [141] and could identify therapeutic scopic data analysis [167]. In 1999, L-783,277 (98) and its trans- targets in Trypanosoma brucei [173]. Additionally, detailed enzy- isomer, L-783,290 (99) were both obtained from a Phoma sp. matic and biochemical studies revealed that 95 inhibited a variety (ATCC 74403) which was isolated from fruitbody of Helvella ace- of kinases including MEK1/2 (Kd ¼ 17 nM and 38 nM), b-type tabulum [180]. 98 found by researchers at Merck was reported to be platelet-derived growth factor receptor (PDGFRb)(Kd ¼ 900 nM), a potent and irreversible inhibitor of MEK1 with an IC50 at 4 nM, FMS-like tyrosine kinase-3 (FLT-3) (Kd ¼ 90 nM), vascular endo- weakly inhibit Lck, and has no activity on Raf, PKA, and PKC to a thelial growth factor receptor 1 (VEGFR1) (Kd ¼ 70 nM) and limited degree. Detailed analysis revealed the inhibition was ATP- (VEGFR2) (Kd ¼ 10 nM) at low nanomolar levels, and including competitive associated with the formation of a covalent adduct extracellular-signal-regulated kinase (ERK) (Kd ¼ 8.4 mM) at low between the enzyme and the inhibitor. The latter compound (99) micromolar levels [141,166,174,175]. It also exhibited potent anti- showed dramatically reduced inhibitory effect on MEK compared to tumor efficacy [176e178]. In 2013, Xu et al. [179] made an inves- 98 (IC50 ¼ 300 nM). Three hypothemycin analogues (100e102) tigation on the antifungal activity of hypothemycin against P. litchii were isolated from the fungal strains H. subiculosus DSM 11931 and in vitro and in vivo. They found that 95 inhibited spore germination DSM 11932. The structures of these compounds were elucidated by of P. litchii with the inhibition rate of 90% at 0.39 mg/mL, of 100% at spectroscopic methods, in combined with chemical conversion of 0.78 mg/mL, caused the ultrastructural modifications of P. litchii, the C-4 hydroxyl group of 100 to an O-methyl group and X-ray 764 W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777

Fig. 17. The structures of pochonins.

Fig. 18. The structures of zeaenols. crystallographic analysis on a single crystal of 101. One of the an- members, (103e119)(Table 1 and Fig. 14), were always isolated alogues, 4-O-demethylhypothemycin (100) exhibited potent and together from Humicola sp. Among them, monordens are struc- selective cytotoxic activities against cell lines (COL829, HT29 and turally characterized by a chlorine substitution on the aromatic SKOV3 with IC50 values of 0.038, 0.10 and 1.8 mM, respectively) with ring. Monocillins were first isolated from Monocillium nordinii a BRAF mutation [153]. except compound monocillin II glycoside (115). The first 14-membered resorcylic lactone, monorden (103), (also 2.5.6. Monordens and monocillins known as monorden A or radicicol), was originally isolated as a This subgroup of 14-membered benzenediol lactones with 20 potent tranquilizer from Monosporium bonorden in a soil sample W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777 765

Fig. 19. The structures of zearalenone and its structurally related compounds.

Fig. 20. The structures of other 14-membered resorcinylic acid lactones. 766 W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777

Fig. 21. The structures of 14-membered dihydroxyphenylacetic acid lactones. collected in the Belgian Congo in 1953 [181]. After ten years, the (108e112)werefirst isolated as co-metabolites of monorden (103) same molecule was independently obtained from the culture from the fungus M. nordinii, a destructive mycoparasite of pine filtrate of Neonectria radicicolas (anam. Cylindrocarpon destructans) stem rusts in North America in 1980. Among them, only monorden (syn. Cylindrocarpon radicicola) and was named radicicol [182]. (103) and monocillin I (108) were detected to have significant With the establishment of its three chiral centers by X-ray crystal antifungal activities (MICs ¼ 10e25 mg/mL) against structure in 1987, it was figured out that the initial structure pro- Pythium debaryanum and weak activities against Rhizoctonia solani posed for monorden was incorrect, thus leading to the common (MICs ¼ 100e200 mg/mL) [210]. Seven years later, these metabo- acceptance of radicicol as the name of this molecule [183,184].In lites were re-isolated with two new structurally related com- 1992, Lett and Lampilas reported the first total synthesis of radi- pounds, namely nordinone (113) and nordinonediol (114), from the cicol, which confirmed its absolute configurations in three stereo- same fungi [211]. The structures of 108e112 were all identified centers [185e187]. The biosyntheses of radicicol in Chaetomium based on 1H and 13C NMR techniques and mass spectra while that of chiversii and Pochonia chlamydosporia have been studied 113 was confirmed by its direct conversion into radicicol [184,211]. [188e190]. Later, radicicol has been found to widely distribute in Structurally, monocillins V, III, II and IV (112, 110, 109 and 111) diverse fungal species, including C. chiversii [191], Colletotrichum corresponded to 13-unchlorinated monordens B, C, D and E graminicola [192], Humicola sp. FO-4910 & FO-2942 [193,194], (104e107), respectively. In recent decades, the monocillins were Neophaeosphaeria quadriseptata [191,195], Paecilomyces sp. SC0924 usually encountered from diverse fungal species. Monocillin II and [155], P. chlamydosporia var. catenulatum (syn. Diheterospora chla- III (109, 110) and a monocillin II glycoside (115) were isolated from mydosporias; Verticillium chlamydosporium) [196], Penicillium luteo- P. chlamydosporia var. catenulate [209]. Monocillins I (108)was aurantium [197] etc. It was also found to have antifungal activities separately isolated from N. quadriseptata (Basionym: Para- against Neurospora sitophila, Giberella zeae [197] and Aspergillus phaeosphaeria quadriseptata) occurring in the rhizosphere of the flavus (MIC > 28 mg/mL) [198], antimalarial activity (with in vivo Christmas cactus Opuntia leptocaulis, and C. chiversii endophytic on efficacy) [193], the inhibition of various signal transduction prod- Mormon tea Ephedra fasciculate [191,195]. Monocillin IV (111)was ucts such as p60v-src, p60c-src and p53/56lyn [199e201], inhibi- reported from Humicola fuscoatra [198] and Penicillium sp. [202] tion of HIV-1 Tat transactivation (IC50 ¼ 0.027 mM) [202], inhibition together with 103. 111 displayed antimicrobial activity against the of human breast cancer [203] and inhibition in vitro of heat shock A. flavus (MIC ¼ 56 mg/mL) and inhibitory activity on HIV-1 Tat protein 90 (Hsp90) (IC50 ¼ 20 nM) [204e206]. Of them, the inhi- transactivation (IC50 ¼ 5 mM) [202]. Both monocillin I and II (108, bition of Hsp90 attracted much attention of many researchers. 109) exhibited selective cytotoxicities against the human cancer Further study indicated 103 inhibited the ATPase activity of Hsp90 cell lines MCF-7 and NCI-H460 (IC50 ¼ 0.98 and 0.62 mM, respec- via competitive binding to the N-terminal ADP/ATP binding pocket tively), SF-268, and MIA Pa Ca-2, MDAMB-231 [195,203]. In 2009, with nanomolar affinity [205]. However, due to the highly sensitive 108e110 were reported as bioactive secondary metabolites from functionalities of 103, including a Michael acceptor and an epoxide, C. graminicola (Holomorph: Glomerella graminicola), which dis- both of which were readily metabolized, it was inactive to Hsp90 played significant antifungal activities against A. flavus and in vivo [14,207]. F. verticillioides in conventional paper disc assay [192]. In the same Monorden B (tetrahydromonorden) (104) was originally re- year, 108e111 were found from P. chlamydosporia TF-0480, and the ported as a synthetic compound but later was shown to be sec- former three (108e110) and 103 showed WNT-5A expression ondary metabolites of the fungus Humicola sp. FO-2942, which was inhibitory activities with the IC50 values of 1.93, 7.36,17.62 and 0.19, originally discovered as a producing fungus of amidepsines, in- respectively [213]. It was also noteworthy that monocillin I was hibitors of diacylglycerol acyltransferase (DGAT), by UV spectrum- well-known for its potent inhibitory activity against Hsp90 as guided purification [194]. Along with 104, monoden and three radicicol (103) did [191]. Moreover, monocillin I (108) displayed new analogues, monordens C to E (105e107) were also isolated in vitro activity against the stalk- and ear-rot pathogen Stenocarpella from the same fungus [194]. Based on spectroscopic evidence maydis [192]. As expected, the biosyntheses of monocillin I (108) mainly by NMR analysis, the structures of compounds (105e107) and monocillin II (109) have been proven to use a similar pathway were elucidated. The result showed that 105 was 50,60-dihy- although there are structural variations that have been attributed to dromonorden A, that 106 and 104 lacked the epoxide moiety of 105 different oxidation and reduction patterns during the hrPKS step and 103, instead by transenone [194,208]. All monordens and putative post-PKS enzymatic modifications (e.g. epoxidation (103e107) caused the cell cycle arrest at G1 and G2/M phases in and halogenation) [13,189]. Tichkowsky and Lett reported the total Jurkat cells at a higher concentration of 30 mM. But among them, synthesis of 108 and 103 via MiyauraeSuzuki couplings in 2002 only monordens A and E (113, 117) showed antifungal activities [212]. against Aspergillus niger with IC50 values of 12 and 70 mM, respec- A new monorden analog, monorden analogue-1 (116), along tively [194]. Furthermore, monordens D (106) was found to inhibit with two known monorden (103) and monocillin IV (111), was Herpes Simplex Virus (HSV) and be antiparasitic against parasitic isolated from H. fuscoatra NRRL 22980. In this paper, the authors protozoan Eimeria tenella [209]. only established the planar structure of 116 after analysis of 1H Monocillins were closely related to monorden in the aspects of NMR, 13C NMR, 2D-NMR, and mass spectral data [198]. In 2009, biogenetic derivation, structure and bioactivity. Monocillins I ~ V Shinonaga and co-works reported the reisolation of 116 from W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777 767

highly oxygenated analogues possessing epoxy, hydroxyl, and other oxygen-containing groups on the macrolide ring. During the investigation on the secondary metabolites of Pae- cilomyces sp. SC0924, Xu et al. reported the isolation and identifi- cation of 13 new benzenediol lactones, named paecilomycins AeM (123e135), together with several known RALs (71e73, 77, 109, 159, 161, 181) from the mycelial solid culture of this fungus, successively [216e218]. Their structures (123e135) were elucidated by exten- sive NMR analysis and chemical correlations in conjunction with X- ray analysis of paecilomycins A and J. Furthermore, the absolute configurations of paecilomycins JeM(132e135) were assigned by Time-Dependent Density-Functional Theory (TDDFT) calculations of their electronic circular dichroism (CD) spectra after their isolation. Paecilomycins E (127) and F (128) were reversedly assigned in the original isolation report then revised [219] while 135, initially assigned structure 135a, was also revised to 135 Fig. 22. The structures of novel benzenediol lactones. [217,220]. Among them, paecilomycin C and D (125 and 126) having a dihydroisobenzofuranone ring and a polyhydroxylated linear C- P. chlamydosporia var. chlamydosporia and its WNT-5A expression 10 side chain, which were believed to be biogenetically derived inhibitory activities. Here, the relative stereochemistry of 116 was from common macrocyclic RALs through intramolecular SN2-type elucidated to be 3a-methyl and 5a-hydroxyl based on 1He1H nucleophilic substitution, were unusual for RALs [142]. It was also very rare in natural RALs that 124 contained an oxygen bridge be- coupling constants and NOESY data [213]. 0 0 e tween C-1 and C-5 to form a pyran ring and 132e135 each con- More recently, three new radicicol analogues, radicicols B D 0 0 (117e119), with four known compounds radicicol and pochonins B, tained an ether linkage between C-2 and C-5 to form a C, and N, were obtained from a marine-derived fungus H. fuscoatra tetrahydrofuran (THF) ring. In the assay against the P. falciparum, (UCSC strain no. 108111A) via a bioassay-guided isolation process paecilomycin E (127) displayed antiplasmodial activity against [214]. The extract of this species was shown to reactivate latent P. falciparum line 3D7 with IC50 value of 20.0 nM, while paecilo- HIV-1 expression in an in vitro model of central memory CD4þ T mycin A, B, F (123, 124, 128) showed moderate activities with IC50 m cells. In this report, the structures of 117e119 were determined on values of 0.78, 3.8, 1.1 M, respectively. Additionally, 127 and 128 the basis of the molecular formulas and NMR properties of the showed moderate activities against P. falciparum line Dd2 with IC50 m known compounds. The C-2 stereochemistry of 117e119 was all values of 8.8, 1.7 M, respectively. Paecilomycin M (135) exhibited proposed to be analogous to that of radicicol (103). However, the weak antifungal activity against P. litchii [155,179,218]. In 2012, the relative configurations of the secondary alcohols of 118 and 119 stereoselective total synthesis of 128 and the asymmetric total were not assigned by NOESY correlation spectroscopy, due to the synthesis of 127 were achieved by Srihari [221] and Nanda group flexible skeleton lacking a, b, g, d-unsaturated ketone functional- [160], respectively. More recently, paecilomycin F (128) was iden- fi ities. Compounds 103 and 117 exhibited moderate activities in the ti ed from a sea anemone-derived fungus C. lunatus [156]. How- ever, no activity was reported in this paper. memory T cell model of HIV-1 latency (EC50 ¼ 9.1 and 24.9 mM, respectively), while 118 and 119 were inactive, indicating that the epoxide functionality is not required for activation of HIV-1. 2.5.9. Pochonins e Moreover, it was also noted that the active compounds (103, 117) These RALs include 16 pochonins, 136 150 (Table 1 and Fig. 17) all contain a Michael acceptor functionality, something the inactive and 106 (Fig. 14) which were obtained from P. chlamydosporia var. compounds 118 and 119 do not possess. catenulata strains P0297 and TF-0480 by two different research groups. The entire family of pochonins shared a common structural motif of a 14-membered macrocyclic resorcylic acid lactone core, 2.5.7. Neocosmosins which was analogous to radicicol (103) except for pochonins F and J In 2013, bioassay-guided fractionation of a fungus Neo- (140 and 144) chlorinated at C-5 of the aromatic ring [209,213]. cosmospora sp. (UM-031509) led to the isolation of three new Differed from the other pochonins,140 and 144 demonstrated more resorcylic acid lactones, named neocosmosins A (120), B (121), and semblances to the aigialomycin and hypothemycin families of C(122), (Fig. 15) along with three known RALs (103, 109 and 111). natural products, partly, due to the lack of C-13 chlorination The structures of new compounds were established on the basis of [141,171]. Interestingly, many pochonins were found to inhibit extensive 1D and 2D-NMR spectroscopic analysis, and mass spec- Hsp90, which may be due to the same pharmacophore as radicicol. trometric (ESIMS) data in conjunction with X-ray data obtained on Pochonins AeF(136e138, 106, 139e140) were isolated from the 111. In the binding assays in vitro, neocosmosins C showed good strain P. chlamydosporia var. catenulata P0297 [209] while pocho- fi binding af nity for the human opioid receptors, which selectively nins EeP(139e150) were obtained from P. chlamydosporia var. fi inhibited 54.9% of the speci c binding of [3H]-enkephalin to CHO- chlamydosporia TF-0480 [213,222]. Their structures were eluci- K1 cell membranes expressing human d-opioid receptors at the m m dated by means of a combination of 1D and 2D spectroscopic concentration of 10 M (IC50 value of 14.82 M). Meanwhile, known techniques. The stereochemistry of the C-70 chlorine in pochonin C fi compounds 103 and 109 also showed potent binding af nities at (138) had not been firmly established until confirmation by total the m-opioid receptor (63.5% and 84.9%, respectively). The authors syntheses [168,223,224]. While the stereochemistry of the C-60 fi declared that this was the rst report on resorcylic acid lactone hydroxyl group in pochonin E and F (139, 140)wasfirst assigned as fi derivatives with strong af nities for human opioid receptors [215]. S-stereochemistry by Shinonaga's group [222], but later revised R by comparison between the reported proton NMR data of the 2.5.8. Paecilomycins natural products and the synthetic compounds [225].Anefficient This group of 13 RALs, 123e135 (Table 1 and Fig. 16), are marked synthesis of ent-pochonin J has been achieved by Martinez-Solorio as the secondary metabolites of Paecilomyces sp. They are usually et al., but does not match the spectroscopic data of pochonin J (144) 768 W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777 as initially reported. Further attempts at the structural verification related to zearalenone, a well-known estrogen hormones. Here, the of pochonin J are ongoing [226]. Interestingly, we find pochonin D information about the double bond in 154 was not given. In the has the same chemical structure as monorden D (106). In the HSV1 same year, Japanese scientists Yuki et al. reported the isolation and (Herpes Simplex Virus 1) replication assay, all the pochonins with structure elucidation of a new metabolite zeaenol (155) from Cur- epoxide moieties or allyl alcohol moieties (e.g., 136, 137, 139, 140) vularia lunata grown on potato and (or) Czapek-Dox medium dur- exhibited bioactivities in the low mM range. Pochonin D (106) ing the chemical studies on aversion-antagonism [229]. In this which contains a double bond instead of the epoxide ring, showed paper zeaenol was not only confirmed to have the same planar only cytostatic effects. The authors presumed that the chlorine structure to 154 but also the authors further revealed that the substituent was probably not essential for the antiviral activity stereochemistry of the double bond at C-70-C-80 was trans-config- because monocillin (110) without halogenation also showed uration while the C-6 hydroxyl had a-configuration orientation. inhibitory activity against HSV1 in the nM range. The antiparasitic Later, some researchers held the opinion that 154 and 155 were the activities of 136e140 and 106 were tested against Neospora cani- same compound [230]. In 1992, a paper published the fact that LL- num and E. tenella. The result indicated that all the test compounds Z1640-1 (151) and zeanol (the same structure as that of 155) was not susceptible to N. caninum, but the partly hydrogenated cooccured in Drechslera, inhibited plant growth [231]. Additionally, pochonins containing an epoxide function showed moderate ac- we found that compounds L-783,278 and L-783,279 reported from tivities against E. tenella. Among these, pochonin A (136) exhibited strains (MF6280, MF6293) during the course of screening for potent the best selectivity toward the parasite. In searching for an inhibitor inhibitors of MEK kinase were 152 and 151, respectively, by of WNT-5A expression, radicicol (103) showed the strongest WNT- comparing their physical and spectroscopic data [232]. Recently, 5A inhibitory activity of the tested samples, however, it also total syntheses of 155 were accomplished by Jana and Nanda [160], showed relatively high cytotoxicity. The inhibitory activities of 141, Gao et al. [162] and Dakas et al. [233], respectively. 145 and 149 were 10-fold weaker than that of 103 while pochonins In 1999, the capacity of several zearalenone derivatives (152, 142e144, 147e148 and 150 were practically inactive. However, 155, 156 and 157) to inhibit lipopolysaccharide (LPS)-induced compared with 103, compound 141 and 149 showed no cytotoxicity cytokine production in phorbol 12-myristate-13-acetate (PMA)- at concentrations above 100 mM. The data implied that the 4,5- treated cultured myelomonocytic cells (U937) was revealed. They epoxide or 4,5-E-olefin moieties present in 145 and 149,or139 exhibited IC50 values of 6 nM, 10 mM, 500 nM and 5 mM, respec- and 140, respectively, may be necessary for radicicol-type com- tively [230]. They were obtained from a 50 L fermentation of pounds designed to inhibit WNT-5A expression, but the chlorine Xenova fungus 20,416, C. lunatu and named 5Z-7-oxo-zeaenol atom at C-13 may decrease the toxicity against dermal papilla cells. (152), zeaenol (155), 7-oxo-zeaenol (156) as well as 5, 6-dihydro-5- Besides the species P. chlamydosporia, recently, pochonin N methoxy-7-oxo-zeaenol (157), respectively. The first total synthesis (148) was found in the cultures of Fusarium sp. LN-10, an endo- of 152 was published by Tatsuta et al. [168] in 2001 followed by the phytic fungus originated from the leaves of M. azedarach, and dis- Lett et al. [169,170]. Structurally, we found that 5Z-7-oxo-zeaenol played significant growth inhibitory activity against the brine had the same structure as 152. Later, 152 was found to be an ATP- shrimp Artemia salina at a concentration of 10 mg/mL, with mor- competitive potent and selective inhibitors of TAK1 tality rate of 82.8% [154]. Pochonins BeCandN(137e138, 148)were (IC50 ¼ 8.1 nmol/L) and ERK2 (IC50 ¼ 8.0 nmol/L) [17,234]. Since also identified from the extract of H. fuscoatra (UCSC strain no. then, interest in these molecules was renewed. Many 152 analogs 108111A) with 103. Among them, 137 and 138 showed moderate were surveyed their inhibitory activities against a variety of kinases activities in the memory T cell model of HIV-1 latency [214]. and their SARs were presented [25]. With regard to the macrocyclic Many pochonins have already been determined the inhibitory ring of these molecules, the cis-enone was essential for the activ- activities of Hsp90 by severeal authors because they are structurally ities and modification on the enone moiety or adjacent position related to radicicol [14,225]. The result found only pochonin A, D, E (C4) may improve metabolic stability by summarizing the SAR of and F (136, 106, 139, 140) were active to Hsp90. Of pochonins tested, RALs' inhibitory activity on kinases established so far. It was also the best strong compound pochonin D had an affinity for Hsp90 noted that the diol moiety at C8eC9 contributed to the bioactivity, (IC50 ¼ 80 nM), which was 4-fold less than radicicol (IC50 ¼ 20 nM). although the C9eOH was more important than the C8eOH. The epoxide derivative, 136 was also found to be a good inhibitor of Moreover, in the case of the resorcylic ring: addition of N or O- 0 0 Hsp90 (IC50 ¼ 90 nM) whereas the 7 ,8-diol analog was inactive functional group at C13 or C13eC14 fused bicyclic heterocycle can [19]. The data suggested that neither an epoxide ring nor the enhance both potency and PK properties [25]. dienone was critical for Hsp90 binding. The study on action Two new compounds, 15-O-desmethyl-(5Z)-7-oxozeaenol (158) mechanism indicated these compounds had very different confor- and 7-epi-zeaenol, along with four known RALs (151, 152, 155, 156) mations in solution which could rationalize their different biolog- were found in filamentous fungal extract of the Mycosynthetix li- ical activities. Interestingly, Moulin E. and his team have brary (MSX 63935; related to Phoma sp.) [15]. Noticeably, the exemplified how macrocycle functionalization could not only direct author described 7-epi-zeaenol not a natural product which was kinase selectivity, but also selectivity between target classes produced by reduction of (5E)-7-oxozeaenol (156) with sodium [143,227]. borohydride. In a series of assays, 152 was the most potent repre- sentative of this class of compounds in both cytotoxicity assays 2.5.10. Zeaenols against cancer cell lines (MCF-7, H460, SF268, HT-29, MDA-MB- Natural resorcylic lactones of fungal origin from the zeaneols 435) and the NF-kB assay [15]. group, 151e158,(Table 1 and Fig. 18) are mainly spread in Drechslera In the recent studies, LL-Z1640-1 (151), LL-Z1640-2 (152), portulacae, C. lunatus, and other unidentified fungus. They exhibit a zeaenol (155), (5E)-7-oxo-Zeaenol (156), have also been found in wide range of biological properties which include estrogenic, the culture broth of C. lunatus (obtained from the gorgonian antifungal, phytotoxic and anti-inflammatory activity. D. gemmacea) [156]. All the four compounds showed potent anti- LL-Z1640-1 to 4 (151e154)werefirst isolated from an uniden- fouling activity against the larval settlement of barnacle tified fungus (Lederle Culture 21640) in 1978 [228]. In this paper, B. amphitrite (EC50 values of 5.3, 1.82, 1.2, 18.1 mg/mL, respectively). the authors found these compounds no particularly interesting 151 showed moderate cytotoxicities against A549 and HepG2 tu- activities. They emphasized that these compounds were devoid of mor cell lines with IC50 values of 44.5 and 98.6 mM, respectively, anabolic and estrogen-like activity even if they were structurally while LL-Z1640-2 showed cytotoxicity against HCT-116 with an IC50 W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777 769 value of 3.24 mM. Among these compounds, only 152 exhibited aliphatic ring may have a pronounced effect on the estrogenic ac- promising antifungal activity against Pestalotia calabae tivity [271,279]. a-Zearalanol (167a), also named zeranol, was used ® (MIC ¼ 0.39 mM) and excellent agricultural fungicidal activities as a growth promoter in livestock under the product name Ralgro against Plasmopara viticola and Phytophthora infestans on the [280] because of its high estrogenic activity. In 2003, a study has whole-plant assay [156,158,159]. Additionally, it was also noted that demonstrated that the catechol metabolites of the 167a had a DNA- 151 found in Paecilomyces sp. showed weak activity against P. litchii damaging potential [244]. Recent investigation indicated that 159, [155]. 167a and 167b can interfere with various enzymes involved in steroid metabolism [281,282]. 2.5.11. Zearalenone and its structurally related compounds A series of important papers on zearalenone (159) trans- The compounds (159e181)(Table 1 and Fig. 19) of this group formation by fungi and actinomycetes have been published were usually reported as the metabolites of zearalenone in fungi, [283,288,289]. Two new transformation products, 2, 4- plants and mammalian systems, as well as the pharmacokinetics. dimethoxyzearalenone (168) and 2-methoxyzearalenone (171), These compounds shared the same carbon backbone close spatial were obtained from 159 by the cultures of the fungus Cunning- similarity to 17-estradiol [235]. A few review papers have been hamella bainieri. They were found not bind to rat estrogen receptor, given on the occurrence, structures and pharmacokinetics of a part indicating a loss of oestrogenicity [283]. A considerable amount of of this group [236e238] before. Here we summarize and update the 159 was found to be present as zearalenone-14-b-D-glucopyrano- information to date. side (172) [284] or zearalenone -14-O-sulfate (173)inFusarium Compound 159 described as 6-(10-hydroxy-6-oxotrans-1- cultures [285,286]. In 1988, Engelhardt et al. found that 159 can be undecenyl)-ß- resorcyclic acid lactone, was first isolated from the transformed to 172 by maize cell suspension cultures [284]. 172 can mycelium of the fungus Gibberella zeae (Syn. Fusarium graminea- also be produced from 159 by several fungi and actinomycetes such rum) growing as a mould on corn by Stob et al. in 1962 [239], and its as Rhizopus sp. [288], Mucor bainieri, and Thamnidium elegans etc. chemical structure disclosed by Urry et al., who also coined the [289]. Taking together, there were two sites for glycosylation pre- name zearalenone (ZEA, ZEN, 159), by combining elements of its sent in 159, but conjugation in position 14 was strongly favored predominant occurrence (‘zea’ for maize) with characteristic compared to position 16 [290]. structural features (‘RAL’ for the resorcylic acid lactone structure, Zearalenone-14-sulfate (formerly known as zearalenone-4- ‘en’ for the olefinic double bond, and ‘one’ for the keto group) [240]. sulfate) (173)wasfirst isolated by Plasencia and Mirocha from Zearalenone has attracted much attention since it was found. So far, rice inoculated with F. graminearum [285]. El-Sharkawy et al. re- it has been shown to have estrogenicity [241], teratogenicity [242], ported the conversion of zearalenone into 173 by many microor- mutagenicity [243], genotoxicity [244e246], cytotoxicity [245], ganisms [291] and Berthiller et al. identified zearalenone-14-sulfate immunotoxicity [247e250] and hepatonephrotoxicity [251,252], as phase II metabolite of zearalenone in the model plant Arabidopsis and to be an enhancer of lipid peroxidation [253] and a cattle- thaliana [292]. The conjugate most likely retained biological prop- growth stimulant [254,255] etc. Additionally, it was noted that erties of the mycotoxin, since the sulfate moiety was easily cleaved zearalenone is also one of the most worldwide distributed myco- under acidic conditions and in rats [291]. Therefore, 173 was toxins [256]. The major mycotoxicity of 159 was attributed to its included in analytical methods for the determination of free and estrogenic effects on genital organs [257] and on reproductive masked mycotoxins during the last years [293e295]. performance [258,259]. The toxicity to the reproductive system Recent decades, some new natural zearalenone derivatives were resulted in uterine enlargement, alterations to the reproductive identificated. In 2008, 50-hydroxyzearalenol (174) was isolated from tract, reduced litter size, increased embryolethal resorption, the culture broth of a marine-derived fungus Fusarium sp. 05ABR26 decreased fertility and changes in progesterone and estradiol with three known compounds (159, 162a and 165). The structure serum levels in animals [260e264]. Zearalenone (159) is the only and relative stereochemistry of 174 were elucidated on the basis of member of this family of which the biosynthesis has been geneti- spectroscopic data and single-crystal X-ray diffraction data. Of the cally characterized, with two reports detailing the identification of antifungal and antimitotic activities tested, compound 159 dis- the biosynthetic gene cluster from G. zeae [265,266]. For zear- played potent inhibitory activity against Pyricularia oryzae with a alenone, more than ten synthetic strategies have been designed MIC value of 6.25 mg/mL, while compound 162a was much less after its first total synthesis was published in 1967 [267]. active; however, 174 and 165 showed no obvious activity [296].In Following the isolation of zearalenone, Bolliger and Tamm re- the same year, two new derivatives, 80-hydroxyzearalanone (175) ported the identification of four zearalenone-related fungal me- and 20-hydroxyzearalanol (176), were isolated from the marine- tabolites in F. graminearum cultures, i.e. 13-formyl-zearalenone derived fungus Penicillium sp. along with four known zearalanone (160), 5, 6-dehydro-zearalenone (161), and the two stereoisomers derivatives. The structures were elucidated by spectroscopic of 5-hydroxy-zearalenone (162a, 162b)in1972[268]. The forma- methods [297]. In 2010, a culture of F. graminearum has been tion of 5-hydroxy-zearalenone (162) was later confirmed by several reinvestigated using LC-DAD-MS and, in part, NMR spectroscopy. In groups [269e271], and further metabolites were disclosed, i.e. 5- addition to confirming most of the previously reported zearalenone hydroxy-zearalenol (163) [272], the epimers of 10-hydroxy-zear- metabolites (162a, 162b, 164a, 164b), several novel compounds alenone (164a, 164b) [273]. were identified. Three of the metabolites were shown to have the In 1985, several closely related compounds were detected in structures of zearalenone-11, 12-oxide (177), zearalenone-11, 12- fungal incubations, i.e. zearalenone (159), a-zearalenol (165a), b- dihydrodiol (178) and 10-keto-zearalenone (179) [298]. As a novel zearalenol (165b), zearalanone (166), a-zearalanol (also named compound, 50-hydroxyzearalenone (180) and six known ß-resor- zeranol) (167a), ß-zearalanol (also named taleranol) (167b), cis- cylic macrolides (15, 159, 161, 162, 165b and 174) were isolated from zearalenone (168), as well as the epimers of cis-zearalanol (169a, the seagrass-derived fungus Fusarium sp. PSU-ES73 in 2011. Their 169b) [274]. Early studies on the metabolism of zearalenone have structures were established by analysis of spectral data. Among also disclosed the formation of reductive metabolites, in particular them only the known compound zearalenone (159) displayed weak stereoisomers of zearalenol (165a, 165b) [246,275e278]. Among antibacterial against S. aureus (MIC ¼ 400 mM) and antifungal ac- them, a-Zearalenol (167a) exhibited an even higher estrogenic ac- tivities against C. neoformans (MIC ¼ 50.26 mM) [40].In2010,trans- tivity than b-zearalanol (taleranol) (167b) and zearalenone (159) 70,80-dehydrozearalenol (181), along with zearalenones (159, 161), suggesting that the orientation of the hydroxyl group at the were isolated from the mycelial solid culture of Paecilomyces sp. 770 W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777

SC0924. Their structures were established by spectroscopic structures of 185 were elucidated on the basis of spectroscopic methods and chemical means [217]. analysis and comparison of its spectrometric data with that of Structureeactivity relationships for human estrogenic activity ponchonin D. It was noteworthy that resorcylic acid monomethyl in zearalenone mycotoxins have been reported. The 60 functional ethers with a non-chelated OH group as in 185 were very rare. group had the largest effect on estrogenicity. In both the zear- Cryptosporiopsin A exhibited motility inhibitory and lytic activities alenone series (trans double bond at 10,20) and the zearalanone against zoospores of the grapevine downy mildew pathogen series (saturated double bond at 10,20) the order of estrogenicity for P. viticola (10 mg/mL), inhibitory activity against mycelial growth of 0 6 substituents was a-OH > NH2 ]O z b-OH > b-OAc. Mean- two other peronosporomycete phytopathogens, Pythium ultimum, while, increased flexibility in the macrocyclic lactone ring would be Aphanomyces cochlioides and a basidiomycetous fungus R. solani, expected to favor tighter binding of a zearalenone analog to the and displayed cytotoxic activity to brine shrimp larvae [306]. estrogen receptor. Because saturation of the 10,20 double bond increased flexibility of the macrolide ring, the order of estrogenicity 2.5.13. 14-membered dihydroxyphenylacetic acid lactones for 10,20 double bond was dihydro > trans > cis. This order of ac- So far only three compounds, 186e188 (Table 1 and Fig. 21), tivity was observed for 60-ketone derivatives, however, not belong to 14-membered DALs. Two naturally derived 14-membered observed in the present study for derivatives with other 60-func- macrolactones, y5-02-B and y5-02-C (186, 187), have appeared in a tional groups (a-OH, b-OH, b-OAc), in which case saturating the 10, Japanese patent as lead structure concerning the inhibition of 20 trans double bond resulted in a 5- to 8-fold reduction in estro- neuropeptide Y receptor for anti-obesity programs [307], however genicity. In addition, resorcinol OH groups contributed little to the the more detailed information could not be obtained. In 2008, the binding of zearalenones to the human estrogen receptor. Placing a chemical investigation of the cytotoxic extract of the marine- hydroxyl group near the macrolide ring methyl group enhanced derived fungus Curvularia sp. (strain no. 768), isolated from the receptor binding, even though the hydroxyl was one carbon further red alga A. spicifera, yielded the novel macrolide apralactone A away than in 17b-estradiol [235]. (188). The structure was elucidated by interpretation of its spec- troscopic data (1D and 2D NMR, CD, MS, UV and IR). The compound 2.5.12. Other 14-membered resorcinylic acid lactones was evaluated for the cytotoxic activity towards a panel of up to 36 Apart from the types as described above, there are some special human tumor cells and showed concentration-dependent cyto- 14-membered RALs, 182e185 (Table 1 and Fig. 20). toxicities with a mean IC50 value of 9.87 mM [126]. Radicicol A (87-250904-F1) (182) belongs to the subset of RALs bearing a cis-enone. 182 was first reported as a kinase inhibitor by 2.6. Novel benzenediol lactones researchers from Sandoz who identified this fungal metabolite during a screen for IL1ß inhibition [299]. The authors found that Menisporopsin A (189)(Table 1 and Fig. 22), a novel BDL, was 182 accelerated the specific mRNA sequences including IL1ß' s and isolated from a cell extract of the seed fungus Menisporopsis theo- inhibited tyrosine [230,299e301]. As a natural product, radicicol A bromae. The structure of 189 was elucidated on the basis of spec- was also isolated from C. lunatus [230] and H. avellanea [140].In troscopic analysis and chemical transformations, with the absolute 2005, Marzinzik and co-workers accomplished the first synthesis of configuration established by application of the modified Mosher's 182 [302]. Later, concise syntheses and total syntheses of 182 were method and by using chiral HPLC. Menisporopsin A possessed an also reported by Dakas et al. [301] and Hofmann et al. [24], unprecedented residue, 2, 4-dihydroxy-6-(2, 4-dihydroxy-n-pen- respectively. In 1998, using high throughput screening of microbial tyl) benzoic acid. This compound exhibited antimalarial activity broths (Curvularia sp.), Williams et al. identified Ro 09-2210 (183) with an IC50 value of 4.0 mg/mL, and antimycobacterial activity with as a selective inhibitor of MAP kinase kinase 1 (MEK1) with an IC50 a MIC value of 50 mg/mL [308]. at 59 nM. Interestingly, Ro 09-2210 was a highly selective MEK1 inhibitor although it only showed marginal inhibition on other ki- 3. Conclusions nases such as PKC, PhK, PKA, ZAP-70, and Lck [303]. Queenslandon (184) characterized by a dihydroxyacetone sub- The review summarized in the above sections illustrates the unit and a highly oxidized benzoic acid, was isolated from the strain isolation, structural determination, biogenetic studies, biological Chrysosporium queenslandicum IFM51121, which was isolated from evaluation, and synthesis of eight-, ten-, twelve-, thirteen-, a soil sample collected in Egypt, and deposited in the collection of fourteen-membered BDL compounds. These natural products have Research Center for Pathogenic Fungi and Microbial Toxicoses, attracted much attention from biologists and chemists because Chiba University, Japan. The structure, initially elucidated 184a on they were isolated from a variety of fungi and possessed fascinating the basis of optical spectroscopy(IR), electrospray (ESI-MS) and molecular architectures and attractive biological activities. To date, high-resolution electron impact mass spectrometry (HREI-MS), one about 190 BDLs with broad-spectrum bioactivities have been and two dimensional NMR spectroscopy (1H, 13C, DEPT, COSY, identified from the fungi. The members of BDL family are still HMQC, HMBC, NOESY and TOCSY) [304], was later revised to 184 on expanding and the wide-range bioactivities of BDLs are still the basis of the synthetic studies [305]. It showed distinct activity explored extensively. For this kind of compounds, general biosyn- against fungi including Aspergillus nidulans IFM 5369, Aspergillus thetic pathways have been defined; however, significant pathway alternata IFM 41348, Paecilomyces variotii IFM 40913, Penicillium branching for individuals is still needed to explore. From a chemical chrysogenum IFM 40614, A. flavus IFM 41934, Aspergillus fumigatus synthesis perspective, while several elegant approaches to impor- IFM 41088, Aspergillus terreus IFM 40851, and A. niger IFM 5368, but tant BDLs have been reported, synthesizing such compounds not against bacteria such as Micrococcus luteus IFM2066 and through concise and modular routes which can be used to extend B. subtilis PCI 219 [305]. the diversity of this family remains challenging. From a therapeutic In 2012, in the course of screening for environmentally benign perspective, these fungal lactones may serve as promising lead secondary metabolites regulating the motility and viability of structures for the development of new therapeutics for the treat- zoospores of P. viticola, cryptosporiopsin A (185) together with ment of cancer progression and metastasis as well as chronic hydroxypropan-20,30-diol orsellinate, pentapeptide were isolated fibrotic diseases. However, the preclinical development of some from the culture of Cryptosporiopsis sp., an endophytic fungus from promising results from in vitro studies was hindered due to poor leaves and branches of Zanthoxylum leprieurii (Rutaceae) [306]. The stability in blood plasma and liver microsomes, which need an W. Shen et al. / European Journal of Medicinal Chemistry 97 (2015) 747e777 771 extensive medicinal chemistry effort to improve its pharmacoki- DGAT Diacylglycerol acyltransferase netic properties. Meanwhile, demand for BDLs in medicinal lead UV Ultraviolet spectroscopy identification and in understanding mechanism of activities will HSV Herpes simplex virus lead to continuing the research in this field. THF tetrahydrofuran SAR Structure activity relationship Acknowledgments TNF-a Tumor necrosis factor-alpha ZEA Zearalenone This work was financially supported by the National Natural ZEN Zearalenone Science Foundation of China (20762015, 31270091) and the Sci- ZAL Zearalanol entific Research Foundation of Southwest University to Dr. Jinyan IL Interleukin Dong (swu109046). RNA Ribonucleic Acid

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