Literature DB >> 35628759

Stachybotrys chartarum-A Hidden Treasure: Secondary Metabolites, Bioactivities, and Biotechnological Relevance.

Sabrin R M Ibrahim1,2, Hani Choudhry3,4, Amer H Asseri3,4, Mahmoud A Elfaky4,5, Shaimaa G A Mohamed6, Gamal A Mohamed5.   

Abstract

Fungi are renowned as a fountainhead of bio-metabolites that could be employed for producing novel therapeutic agents, as well as enzymes with wide biotechnological and industrial applications. Stachybotrys chartarum (black mold) (Stachybotriaceae) is a toxigenic fungus that is commonly found in damp environments. This fungus has the capacity to produce various classes of bio-metabolites with unrivaled structural features, including cyclosporins, cochlioquinones, atranones, trichothecenes, dolabellanes, phenylspirodrimanes, xanthones, and isoindoline and chromene derivatives. Moreover, it is a source of various enzymes that could have variable biotechnological and industrial relevance. The current review highlights the formerly published data on S. chartarum, including its metabolites and their bioactivities, as well as industrial and biotechnological relevance dated from 1973 to the beginning of 2022. In this work, 215 metabolites have been listed and 138 references have been cited.

Entities:  

Keywords:  Stachybotriaceae; Stachybotrys chartarum; bioactivity; biotechnology; fungi; metabolites; phenylspirodrimanes

Year:  2022        PMID： 35628759      PMCID： PMC9144806          DOI： 10.3390/jof8050504

Source DB:  PubMed          Journal:  J Fungi (Basel)        ISSN： 2309-608X


1. Introduction

Fungi are found predominantly in all environments and have substantial roles in preserving eco-balance, diversity, and sustainability [1,2,3]. They have demonstrated a wide array of industrial and biotechnological potentials [1,4,5,6]. Additionally, they are an important source of metabolites with unique chemical skeletons that have the potential for discovering drugs of clinical relevance [7,8,9,10,11,12]. This was evident by many reported fungi-derived drugs that are in use, for example camptothecin, cyclosporine, paclitaxel, torreyanic acid, compactin, vincristine, lovastatin, and cytarabine [13,14,15]. Additionally, they are a pool of new scaffolds, which can be further modified to achieve the needed action [16]. Many of these metabolites can be obtained in considerable amounts and at a feasible cost through fermentation utilizing genetically modified or wild type fungi [15]. Regardless of the remarkable advancement in discovering drugs that provide treatment for most ailments, epidemics, and infections, novel drugs are requested to counter the reported resistance of some diseases and infections to the existing drugs [17,18,19]. Despite the biodiversity of the fungi kingdom, only a limited number of fungi have been explored for their capacity to produce bioactive metabolites. Stachybotryschartarum (black mold) (Stachybotriaceae, S. atra or S. alternans) is a toxigenic fungus that is widely present in the indoor air of buildings or homes which have water damage or sustained flooding from roofs, broken pipes, floor or wall leaks, and condensation. S. chartarum a hydrophilic fungus, needing wet conditions for maintaining and initiating its growth. It is also found on gypsum, cellulose-based ceiling tiles, fiberglass, wallpaper, paper products, natural fiber carpets, insulated pipes paper covering, wood and wood paneling, and organic debris, as well as soil, grains, and litter [20,21]. S. chartarum is one of the most common pathogenic indoor fungi that is capable of producing mycotoxins, having life-threatening health impacts [21]. Several reports stated that the exposure to this fungus or its mycotoxins through contaminated indoor air and construction material causes severe fungi-mediated sick building illnesses and even human death [20,21,22]. The common symptoms of this illness are fatigue, chest tightness, mucosal irritation, and headache [20]. It can also cause respiratory disorders that range from cough and congestion to more dangerous syndromes including bronchiectasis, alveolitis, and pulmonary fibrosis [23]. It was also found that exposure to this fungus has been related to infants’ pulmonary hemorrhage outbreaks [24]. Further, the exposure to S. chartarum in damp environments exceeds the threshold of sensitization in susceptible people [25]. This fungus causes stachybotryotoxicosis in horses and other animals [26]. The fungus’ biosynthesized macrocyclic trichothecenes are considered one of the most powerful inhibitors for protein synthesis. Additionally, it produces biometabolites (e.g. atranones and spirodrimanes), protein factors (e.g. stachylysin and hemolysin), immunosuppressive agents, and proteinases (e.g. serine proteases) that are attributed to pulmonary destruction, hemosiderosis, and hemorrhage [27,28,29]. Most of the reported studies on S. chartarum highlighted its pathogenic influences on humans and animals [21,30,31,32]. Surveying the literature revealed no review article that shed light on the positive impact of this important fungus. Therefore, this work reviewed the published studies on this fungus, particularly its metabolites and their bioactivities. In addition, the reported research on S. chartarum, including biotechnological and industrial applications, as well as nanoparticles’ preparation, have been reviewed. The reported studies from 1973 to the beginning of 2022 are cited. For the reported metabolites, molecular weights and formulae, classes, places, hosts, and bioactivities were recorded, and their structures were also illustrated. Further, the pathways for biosynthesis of the main metabolites were discussed. The aim of this work is to draw the attention of chemists, biologists, and phytochemistry and fungi-interested researchers to these interesting metabolite producing fungus. Additionally, it highlights the possible utilization of these metabolites as drug leads that could change the research direction regarding this fungus. The data for this work were gathered via computer searches in various databases (Web of Knowledge, PubMed, and SCOPUS), scientific websites (Science Direct and Google Scholar), and publishers (Wiley Online Library, Taylor & Francis, JACS, Springer, Bentham, and Thieme).

2. S. chartarum Enzymes and Their Possible Applications

Fungi possess diverse digestive-enzyme batteries. They can utilize agro-industrial wastes by yielding diverse enzyme types, such as xylanases, cellulases, amylases, laccases, and pectinases. These enzymes play a substantial ecological role in lignin-cellulosic materials’ decomposition and can be utilized in various biotechnological applications. In this work, the reported research on S. chartarum enzymes and their possible biotechnological and industrial applications have been discussed. Polythene wastes are adversely affecting the environment due to strong reluctance towards degradation [33]. Biodegradation is one of the favorable solutions for conquering this problem [34]. S. chartarum was found to possess degradation potential for biodegradable and low-density polythene [34]. Andersen et al. also reported that the indoor strain of S. chartarum had no or little xylanolytic and cellulolytic potentials in the AZCL (Azurine-cross-linked) assay [35]. On the contrary, it exhibited amylolytic and cellulolytic potential [36,37] and had a lignocellulose complex-degrading enzymes system [28]. Kordula et al. purified and characterized stachyrase A (chymotrypsin-like serine protease) from S. chartarum that had wide substrate specificity and hydrolyzed various physiologically potential proteins, protease inhibitors, and collagen in the lung [38].

2.1. Laccases

Enzymes’ oxidizing phenols have diversified applications in various industries, including paper and wood pulp delignification, textile (dye and stain bleaching), and biosensors. Laccases are phenol oxidases that can oxidize several aromatic compounds [4,39,40]. Fungal laccases have a crucial role in developing the fruiting body, as well as in lignin degradation [41]. Some laccases are produced upon exposure to phenolic substances. Mander et al. purified a laccase enzyme from S. chartarum and its gene was separated and expressed in Trichoderma reesei, Aspergillus niger, and A. nidulans. This enzyme oxidized the artificial substrate ABTS (2,2-azino-di-(3-ethylbenzthiazolinsulfonate) [42]. Further, Janssen et al. stated that the insertion of the peptide sequences IERSAPATAPPP, YGYLPSR, SLLNATK, KASAPAL, and CKASAPALC inserted in the C-terminal of S. chartarum laccase by recombinant DNA tools resulted in laccase- peptide fusions that selectively targeted carotenoid stains and displayed enhanced bleaching potential on stained fabrics [43]. This suggested that the modification of certain enzymes could improve their activity, suggesting a new area of research in this fungus.

2.2. Mannanases

Mannans are constituents of hemicellulose that are found in plants, some algae, microorganisms, and tremella [44]. They include gluco-, galacto-, and galactogluco-mannanase well as linear mannan [45]. They have diverse applications, for example KG (konjac glucomannan) and LBG (locust bean gum, galactomannan) are commonly utilized for chronic diseases and obesity prevention and viscosity-boosting food additives, respectively [46,47]. Mannans’ degradation is accomplished by various GHs (glycoside hydrolases) such as β-mannanase, β-mannosidase, β-glucosidase, acetyl-mannan-esterase, and α-galactosidase producing manno-oligosaccharides [48]. The later were utilized as prebiotics that enhance immune responses and modulate gut microbiota [49]. Yang et al. identified two β-mannanase genes (s331 and s16942) from S. chartarum that were expressed in Aspergillus niger with high protein titers and activities [50].

2.3. β-Glucanases

β-Glucans comprise glucose polymers heterogeneous group, including lichenan (β-1,4-1,3-glucan), cellulose (β-1,4-glucan), β-1,3(4)-glucan, and laminarin (β-1,3-glucan). Their hydrolysis is catalyzed by various kinds of β-glucanases, such as lichenases, cellulases, laminarinases, and β-1,3(4)-glucanases [51]. Lichenases are produced by various microorganisms, including fungi and bacteria, and have remarkable applications in detergent, food, feed, brewing, and wine industries as well as biodiesel and bioethanol production [51]. The expression of the gene Cel12A isolated from rotting cellulose rag-associated-S. chartarum by Picart et al. was triggered by rice straw than 0.1% glucose or 1% lactose [52,53]. The resulting enzyme Cel12A (GH12 family) had a lichenase potential. It also exhibited high potential towards barley mixed glucans and lichenan and low effectiveness on cellulose. Hence, Cel12A could have potential applications in various industries [53]. r-ScEG12, a recombinant glucanase gene from S. chartarum, belonging to GH12 (glycosyl hydrolase family12), was purified and expressed in Pichia pastoris [54]. It was found that Mn2+ and Cu2+ (%inhibition 50.97 and 71.64%, respectively) prohibited its activity, while Ca2+ and Na+ enhanced the activity. This proved the capacity of S. chartarum to secrete endoglucanases that could be beneficial for industrial use [54]. Xylanase is the principal enzyme accountable for hemicellulose hydrolysis. The xya6205a gene obtained from S. chartarum was expressed in A. niger. The obtained xylanase had optimum potential at 5.8 pH and 50℃ temperature and maintained 83% activity after 18 h in the alkaline buffer [55].

2.4. Fucoidanases and Alginate Lyases

Alginate and fucoidan are polysaccharides found in brown seaweed that have wide potential applications because of their diversified bioactivities. Alginate lyases are polysaccharide lyases that hydrolyze alginate by cleaving the glycosidic bond to produce oligo-alginates, which have a substantial role in feed, food, nutraceutical, biofuel, and pharmaceutical industries [56]. In addition, they possess film-formation, emulsifying, gelling, and plant-growth promoting capacities [57]. Fucoidan showed antioxidant, anticoagulant, antiviral, anticancer, anti-inflammatory, and immunomodulatory capacities [56,58]. In spite of these beneficial bioactivities, fucoidan molecules possess structural variation, high molecular weight, and viscous nature that limit their therapeutic and pharmaceutical applications, however, low molecular-weight fucoidan-derived oligosaccharides have a wide potential for applications [59]. Fucoidanases are accountable for fucoidan hydrolysis to fucooligosaccharides and are a substantial tool for fucoidan structural characterization [59]. It is noteworthy that S. chartarum was found to have fucoidanase and alginate lyases producing potential [60]

3. Secondary Metabolites from S. chartarum

Reported data displayed that S. chartarum is rich with various types of metabolites with diverse structural characteristics, including phenylspirodrimanes, trichothecenes, isoindoline derivatives, atranones, dolabellane diterpenoids, xanthones, chromenes, cochlioquinones, and cyclosporins. Here, they are classified according to their chemical classes. Furthermore, it was detected that some reported compounds having the same molecular formulae and chemical structures were given different nomenclature (e.g., stachartin A/stachybotrysin (13), arthproliferin E/stachybotrin E (31), stachybotrysin/stachybotramide (32)). Besides, some metabolites with different structures had the same names. Some formerly reported metabolites were also separated recently as new ones, e.g., atranone Q (180) and stachatranone C (187), reported in 2019 by Yang et al. [61] and isolated as new metabolites in 2020 by Qin et al. [62], which may be due to improper literature search. Herein, the separated metabolites from S. chartarum and their bioactivities, as well as their biosynthesis and structure/activity relation, have been highlighted.

3.1. Phenylspirodrimanes

Phenylspirodrimanes are an uncommon class of meroterpenoids (terpenylphenol) reported from Stachybotrys genus. Structurally, they are featured by the fusion of spirocyclic drimane with a phenyl moiety via spirofuran ring. They are created from farnesyl-diphosphate and orsellinic acid via ilicicolin B intermediate [63]. Their dimers are derivatives with various structural scaffolds that are produced from two monomers’ dimerization through C-C or C-N linkage with or without an alkyl chain. These metabolites are designated as the most dominant and characteristic kind of mycotoxins in this genus [64]. Various phenylspirodrimanes have been purified and characterized from S. chartarum utilizing diverse chromatographic and spectral tools (Table 1). Their bioactivities were assessed using different bioassays that were discussed in this work.
Table 1

List of compounds isolated from Stachybotrys chartarum.

Compound NameMol. Wt.Mol. FormulaHost (Part, Family)PlaceRef.
Stachybotrydial (1)386C23H30O5Cultured-[65]
K-76 (2)402C23H30O6Cultured-[65]
Mer-NF5003E (3)388C23H32O5Xestospongia testudinaris (Sponge, Petrosiidae)Xisha Island, China[66]
--Cultured-[67]
Stachybotrysin B (4)430C25H34O6Cultured-[67]
Mer-NF5003B (5)404C23H32O6Xestospongia testudinaris (Sponge, Petrosiidae)Xisha Island, China[66]
Stachybotrysin C (6)446C25H34O7Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[68]
--Himerometra magnipinna (Crinoids, Himerometridae)-[67]
Stachybonoid D (7)488C27H36O8Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[68]
Stachyboside A (8)550C29H42O10Xestospongia testudinaris (Sponge, Petrosiidae)Xisha Island, China[66]
Stachyboside B (9)566C29H42O11Xestospongia testudinaris (Sponge, Petrosiidae)Xisha Island, China[66]
Stachybotrysin D (10)468C23H32O8SCultured-[67]
Stachybotrysin E (11)428C25H32O6Cultured-[67]
F1839-I (12)372C23H32O4Xestospongia testudinaris (Sponge, Petrosiidae)Xisha Island, China[66]
Stachybotrysin A (13)414C25H34O5Cultured-[67]
Stachartin A = Stachybotrysin (14) 428C26H36O5Cultured-[67]
--Soil sample Datun tin mine tailings area, Yunnan, China[69]
Stachybochartin G (15)388C23H32O5Pinellia ternata (rhizomes, Araceae)Nanjing, Jiangsu, China[70]
Stachybotrysin F (16)428C26H36O5Cultured-[67]
Stachybotrysin G (17)428C26H36O5Cultured-[67]
Stachybotrysin H (18)444C26H36O6Cultured-[71]
Stachybotrysin I (19)444C26H36O6Cultured-[71]
Stachybotrylactone = Stachybotrolide (20) 386C23H30O5Cultured-[65]
--MudEast Dongting Lake, Hunan, China[72]
--Sinularia sp. (Soft coral, Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
--Soil sample Datun tin mine tailings area, Yunnan, China[69]
--Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[68]
Stachybotrylactone acetate (21)428C25H32O6Cultured-[65,67]
--MudEast Dongting Lake, Hunan, China[72]
Stachybotrane A (22)386C23H30O5MudEast Dongting Lake, Hunan, China[72]
--Pinellia ternata (rhizomes, Araceae)Nanjing, Jiangsu, China[70]
Stachybotrane B (23)428C25H32O6MudEast Dongting Lake, Hunan, China[72]
--Pinellia ternata (rhizomes, Araceae)Nanjing, Jiangsu, China[70]
2α-Hydroxystachybotrylactone (24)402C23H30O6Cultured-[65]
--MudEast Dongting Lake, Hunan, China[72]
Stachybochartin E (25) 444C25H32O7Pinellia ternata (rhizomes, Araceae)Nanjing, Jiangsu, China[70]
--MudEast Dongting Lake, Hunan, China[72]
2α-Acetoxystachybotrylactone acetate (26)486C27H34O8Cultured-[65]
Stachybotrane C (27)402C23H30O6MudEast Dongting Lake, Hunan, China[72]
Stachybotryslactone B = Stachartin B (28)386C23H30O5Cultured-[67]
--Soil sample Datun tin mine tailings area, Yunnan, China[69]
--Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[68]
Stachybotrylactam (29)385C23H31NO4Cultured-[65]
--Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
--Soil sample Datun tin mine tailings area, Yunnan, China[69]
--Cultured-[71]
--Pinellia ternata (rhizomes, Araceae)Nanjing, Jiangsu, China[70]
Stachybotrylactam acetate (30)427C25H33NO5Cultured-[65]
--Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
--Sinularia sp. (Soft coralm Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
Arthproliferin E = Stachybotrin E (31)399C24H33NO4Sinularia sp. ( Soft coral, Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
--Cultured-[71]
Stachybotrin = Stachybotramide (32)429C25H35NO5Sinularia sp. (Soft coral, Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
--Pinellia ternata (rhizomes, Araceae)Nanjing, Jiangsu, China[70]
--Cultured-[65,75]
--Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
--MudEast Dongting Lake, Hunan, China[72]
Stachybochartin F (33)471C27H37NO6Pinellia ternata (rhizomes, Araceae)Nanjing, Jiangsu, China[70]
Stachybotrin D (34)441C26H35NO5Xestospongia testudinaris (Sponge, Petrosiidae)Xisha Island, China[66]
Stachybotrysam E (35)471C27H37NO6Cultured-[76]
K-76-1 (36)515C28H37NO8SoilHimalaya, India[77]
--Xestospongia testudinaris (Sponge, Petrosiidae)Xisha Island, China[66]
K-76-2 (37)487C27H37NO7SoilHimalaya, India[77]
Stachybotrin E (38)529C29H39NO8Xestospongia testudinaris (Sponge, Petrosiidae)Xisha Island, China[66]
Stachybotrin F (39)529C29H39NO8Xestospongia testudinaris (Sponge, Petrosiidae)Xisha Island, China[66]
Chartarlactam A (40)399C23H29NO5Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
--Soil sample Datun tin mine tailings area, Yunnan, China[69]
Chartarlactam B (41)485C28H39NO6Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
Chartarlactam C (42)401C23H31NO5Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
Chartarlactam D (43)563C30H45NO9Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
Chartarlactam E (44)383C23H29NO4Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
--Sinularia sp. (Soft coral, Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
Stachartin C (45)499C29H41NO6Soil sample Datun tin mine tailings area, Yunnan, China[69]
Stachartin D (46)513C30H43NO6Soil sample Datun tin mine tailings area, Yunnan, China[69]
Stachybonoid E (47)457C26H35NO6Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[68]
--Soil sample Datun tin mine tailings area, Yunnan, China[78]
Stachybonoid F (48)485C28H39NO6Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[68]
--Soil sample Datun tin mine tailings area, Yunnan, China[78]
Stachartin E (49)547C33H41NO6Soil sample Datun tin mine tailings area, Yunnan, China[69]
N-(2-Benzenepropanoic acid) stachybotrylactam (50)533C32H39NO6Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
F1839-A (51)401C23H31NO5Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
--Sinularia sp. (Soft coral, Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
Chartarlactam I (52)401C23H31NO5Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
Chartarlactam J (53)401C23H31NO5Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
Chartarlactam K (54)443C25H33NO6Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
Chartarlactam M (55)385 C23H31NO4Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
Chartarlactam P (56)401C23H31NO5Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
F1839-E (57)445C25H35NO6Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
--MudEast Dongting Lake, Hunan, China[72]
--MudEast Dongting Lake, Hunan, China[72]
Stachybotrane D (58)445C25H35NO6MudEast Dongting Lake, Hunan, China[72]
K-76-3 (59)487C27H37NO7SoilHimalaya, India[77]
K-76-4 (60)501C28H39NO7SoilHimalaya, India[77]
K-76-5 (61)515C29H41NO7SoilHimalaya, India[77]
K-76-6 (62)515C29H41NO7SoilHimalaya, India[77]
K-76-7 (63)549C32H39NO7SoilHimalaya, India[77]
2α-Acetoxystachybotrylactam acetate (64)485C27H35NO7Cultured-[65]
--Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
--Sinularia sp. (Soft coral, Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
Chartarlactam F (65)385C23H31NO4Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
--Sinularia sp. (Soft coral, Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
Chartarlactam G (66)385C23H31NO4Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
Chartarlactam H (67)429C25H35NO5Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
Chartarlactam N (68)429C25H35NO5Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
Chartarlactam O (69)385C23H31NO4Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
Stachartin F (70)485C28H39NO6Soil sample Datun tin mine tailings area, Yunnan, China[78]
F1839-D (71)401C23H31NO5Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
Chartarlactam L (72)766C46H58N2O8Niphates recondita (Sponge, Niphatidae)Coral reef near Weizhou Island, Beibuwan Bay, Guangxi, China[74]
Bistachybotrysin A (73)774C46H62O10Cultured-[79]
Bistachybotrysin B (74)816C48H64O11Cultured-[79]
Bistachybotrysin C (75)790C46H62O11Cultured-[79]
Bistachybotrysin D (76) 772C47H64O9Cultured-[80]
Bistachybotrysin E (77)772C47H64O9Cultured-[80]
Bistachybotrysin F (78)800C48H64O10Cultured-[81]
Bistachybotrysin G (79)774C46H62O10Cultured-[81]
Bistachybotrysin H (80)816C48H64O11Cultured-[81]
Bistachybotrysin I (81)788C47H64O10Cultured-[81]
Bistachybotrysin J (82)816C49H66O11Cultured-[81]
Bistachybotrysin K (83) 758C46H62O9Cultured-[82]
Bistachybotrysin L (84)772C47H64O9Cultured-[83]
Bistachybotrysin M (85)772C47H64O9Cultured-[83]
Bistachybotrysin N (86)772C47H64O9Cultured-[83]
Bistachybotrysin O (87)772C47H64O9Cultured-[83]
Bistachybotrysin P (88)814C49H66O10Cultured-[83]
Bistachybotrysin Q (89)814C49H66O10Cultured-[83]
Bistachybotrysin R (90)854C52H70O10Cultured-[83]
Bistachybotrysin S (91)854C52H70O10Cultured-[83]
Bistachybotrysin T (92)798C49H66O9Cultured-[83]
Bistachybotrysin U (93)756C46H60O9Cultured-[83]
Bistachybotrysin V (94)758C46H62O9Cultured-[83]
Bistachybotrysin W (95)832C48H64O12Cultured-[84]
Bistachybotrysin X (96)832C48H64O12Cultured-[84]
Bistachybotrysin Y (97)874C50H67O13Cultured-[84]
Chartarolide A (98)772C44H49O10ClNiphates sp. (Sponge, Niphatidae)Near coral reef, Beibuwan Bay, GuangXi, China[85]
Chartarolide B (99)772C44H49O10ClNiphates sp. (Sponge, Niphatidae)Near coral reef, Beibuwan Bay, GuangXi, China[85]
Chartarolide C (100)771C44H50NO9ClNiphates sp. (Sponge, Niphatidae)Near coral reef, Beibuwan Bay, GuangXi, China[85]
Chartarlactam Q (101)753C46H59NO8Cultured-[86]
Chartarlactam R (102)797C48H63NO9Cultured-[86]
Chartarlactam S (103)771C46H61NO9Cultured-[86]
Chartarlactam T (104)855C50H65NO11Cultured-[86]
Stachybochartin A (105) 774C46H62O10Pinellia ternata (Rhizomes, Araceae)Nanjing, Jiangsu, China[70]
Stachybochartin B (106)844C50H68O11Pinellia ternata (Rhizomes, Araceae)Nanjing, Jiangsu, China[70]
Stachybochartin C (107)772C47H64O9Pinellia ternata (Rhizomes, Araceae)Nanjing, Jiangsu, China[70]
Stachybochartin D (108)858C50H66O12Pinellia ternata (Rhizomes, Araceae)Nanjing, Jiangsu, China[70]
Stachyin B (109)755C46H61NO8Cultured-[86]
Stachartone A (110)758C46H62O9Soil sample Datun tin mine tailings area, Yunnan, China[87]
Stachartarin A (111)758C46H62O9Soil sample Datun tin mine tailings area, Yunnan, China[88]
Stachartarin B (112)772C47H64O9Soil sample Datun tin mine tailings area, Yunnan, China[89]
Stachybocin E (113)824C50H68N2O8Xestospongia testudinaris (Sponge, Petrosiidae)Xisha Island, China[66]
Stachybocin F (114)838C51H70N2O8Xestospongia testudinaris (Sponge, Petrosiidae)Xisha Island, China[66]
12,13-Epoxytrichothec-9-ene (115)234C15H22O2Cultured-[90,91]
2,4,12-Trihydroxyapotrichothecene (116)268C15H24O4Niphates recondita (Sponge, Niphatidae)Inner coral reef, Beibuwan Bay, Guangxi, China[92]
Chartarene A (117)398C21H34O7Niphates recondita (Sponge, Niphatidae)Inner coral reef, Beibuwan Bay, Guangxi, China[92]
Chartarene B (118)282C16H26O4Niphates recondita (Sponge, Niphatidae)Inner coral reef, Beibuwan Bay, Guangxi, China[92]
Chartarene C (119)264C16H24O3Niphates recondita (Sponge, Niphatidae)Inner coral reef, Beibuwan Bay, Guangxi, China[92]
Trichodermol (120)250C15H22O3Air and surface samplesHomes enrolled in a case-control study of pulmonary hemosiderosis in infants, Cleveland, Ohio, USA[93]
Verrucarol (121) 266C15H22O4Cultured-[65,91,94]
--Straw Hungarian village of Jaszapati from a field case of mycotoxicosis in horses [95]
Trichodermin (122)292C17H24O4Air and surface samplesHomes enrolled in a case-control study of pulmonary hemosiderosis in infants, Cleveland, Ohio, USA[93]
Isotrichoverrol B (123)420C23H32O7Niphates recondita (Sponge, Niphatidae)Inner coral reef, Beibuwan Bay, Guangxi, China[92]
Verrol (124)362C21H30O5Air and surface samplesHomes enrolled in a case-control study of pulmonary hemosiderosis in infants, Cleveland, Ohio, USA[93]
--Niphates recondita (Sponge, Niphatidae)Inner coral reef, Beibuwan Bay, Guangxi, China[92]
Trichoverrol (125)434C24H34O7Cultured-[65]
Trichoverrol A (126)434C24H34O7Dead animalsVarious parts of Hungary and Czechoslovakia [96]
--Egyptian paddy grainsEgypt[97]
Trichoverrol B (127)434C24H34O7Dead animalsVarious parts of Hungary and Czechoslovakia [96]
Trichodermadienediol B (128)404C23H32O6Niphates recondita (Sponge, Niphatidae)Inner coral reef, Beibuwan Bay, Guangxi, China[92]
Roridin L-2 (129)544C30H40O9Cultured-[65,94,98]
--Air and surface samplesHomes enrolled in a case-control study of pulmonary hemosiderosis in infants, Cleveland, Ohio, USA[93]
--Niphates recondita (Sponge, Niphatidae)Inner coral reef, Beibuwan Bay, Guangxi, China[92]
Chartarene D (130)512C29H36O8Niphates recondita (Sponge, Niphatidae)Inner coral reef, Beibuwan Bay, Guangxi, China[92]
Verrucarin J (131)484C27H32O8Cultured-[91]
--Straw Hungarian village of Jaszapati from a field case of mycotoxicosis in horses [95]
--Dead animalsVarious parts of Hungary and Czechoslovakia [96,99]
--Egyptian paddy grainsEgypt[97]
Roridin A (132)532C29H40O9Cultured-[91]
Roridin D (133)530C29H38O9Cultured-[91]
Roridin E (134)514C29H38O8Cultured-[65,91,94]
--Straw Hungarian village of Jaszapati from a field case of mycotoxicosis in horses [95]
--Dead animalsVarious parts of Hungary and Czechoslovakia [96,99]
--Egyptian paddy grainsEgypt[97]
--Niphates recondita (Sponge, Niphatidae)Inner coral reef, Beibuwan Bay, Guangxi, China[92]
Isororidin E (135)514C29H38O8Cultured-[65]
Epiroridin E (136)514C29H38O8Cultured-[65]
Epiisororidin E (137)514C29H38O8Cultured-[65]
Roridin H (138)512C29H36O8Cultured-[91]
Muconomycin B (139)484C27H32O8Niphates recondita (Sponge, Niphatidae)Inner coral reef, Beibuwan Bay, Guangxi, China[92]
Satratoxin F (140)542C29H34O10Cultured-[90]
--Straw Hungarian village of Jaszapati from a field case of mycotoxicosis in horses [95,100]
--Dead animalsVarious parts of Hungary and Czechoslovakia [96]
--Egyptian paddy grainsEgypt[97]
--Air and surface samplesHomes enrolled in a case-control study of pulmonary hemosiderosis in infants, Cleveland, Ohio, USA[93]
--Sinularia sp. (Soft coral, Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
Isosatratoxin F (141)542C29H34O10Air and surface samplesHomes enrolled in a case-control study of pulmonary hemosiderosis in infants, Cleveland, Ohio, USA[93]
Satratoxin G (142)544C29H36O10Cultured-[65,90,98]
--Straw Hungarian village of Jaszapati from a field case of mycotoxicosis in horses [95,100]
--Dead animalsVarious parts of Hungary and Czechoslovakia [96,99]
--Egyptian paddy grainsEgypt[97]
--Bedding Straw of a Sheep Flock with Fatal StachybotryotoxicosisHungaria[101]
---Finland[102]
--Air and surface samplesHomes enrolled in a case-control study of pulmonary hemosiderosis in infants, Cleveland, Ohio, USA[93]
--Indoor Air from a Water-Damaged buildingSartorius, Goettingen, Germany[103]
--Niphates recondita (Sponge, Niphatidae)Inner coral reef, Beibuwan Bay, Guangxi, China[92]
Isosatratoxin G (143)544C29H36O10Air and surface samplesHomes enrolled in a case-control study of pulmonary hemosiderosis in infants, Cleveland, Ohio, USA[93]
Satratoxin H (144)528C29H36O9Cultured-[65,75,91]
--Straw Hungarian village of Jaszapati from a field case of mycotoxicosis in horses [75,95]
--Dead animalsVarious parts of Hungary and Czechoslovakia [96,99]
--Egyptian paddy grainsEgypt[97]
---Finland [102]
--Bedding Straw of a Sheep Flock with Fatal StachybotryotoxicosisHungaria[101]
--Indoor Air from a Water-Damaged buildingSartorius, Goettingen, Germany[103]
--Sinularia sp. (Soft coral, Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
--Niphates recondita (Sponge, Niphatidae)Inner coral reef, Beibuwan Bay, Guangxi, China[92]
Satratoxin H diacetate (145)612C33H40O11Cultured-[91]
Mytoxin A (146)544C29H36O10Niphates recondita (Sponge, Niphatidae)Inner coral reef, Beibuwan Bay, Guangxi, China[92]
Chartarutine A (147)403C23H33NO5Niphates sp. (Sponge, Niphatidae)Near coral reef, Beibuwan Bay, GuangXi, China[104]
Chartarutine B (148)369C23H31NO3Niphates sp. (Sponge, Niphatidae)Near coral reef, Beibuwan Bay, GuangXi, China[104]
--Cultured-[76]
Chartarutine C (149)449C23H31NO6SNiphates sp. (Sponge, Niphatidae)Near coral reef, Beibuwan Bay, GuangXi, China[104]
Chartarutine D (150)448C23H32N2O5SNiphates sp. (Sponge, Niphatidae)Near coral reef, Beibuwan Bay, GuangXi, China[104]
Chartarutine E (151)401C23H31NO5Niphates sp. (Sponge, Niphatidae)Near coral reef, Beibuwan Bay, GuangXi, China[104]
Chartarutine F (152)401C23H31NO5Niphates sp. (Sponge, Niphatidae)Near coral reef, Beibuwan Bay, GuangXi, China[104]
Chartarutine G (153)367C23H29NO3Niphates sp. (Sponge, Niphatidae)Near coral reef, Beibuwan Bay, GuangXi, China[104]
Chartarutine H (154)367C23H29NO3Niphates sp. (Sponge, Niphatidae)Near coral reef, Beibuwan Bay, GuangXi, China[104]
Stachybotrin G (155)503C27H39N2O5SXestospongia testudinaris (Sponge, Petrosiidae)Xisha Island, China[105]
Stachybotrysam A (156)413C25H35NO4Cultured-[76]
Stachybotrysam B (157)493C25H35NO7SCultured-[76]
Stachybotrysam C (158)535C27H37NO8SCultured-[76]
Stachybotrysam D (159)611C29H41NO11SCultured-[76]
Atranone A (160)416C24H32O6Cultured-[75,106]
Methylatranone A (161) 430C25H34O6Cultured-[107]
--Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve inGuangdong, China[108]
Atranone B (162)446C25H34O7Cultured-[62,75,106]
--Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[108]
Methylatranone B (163)460C26H36O7Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[108]
22-Epimer-methylatranone B (164)460C26H36O7Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[108]
Atranone C (165)416C24H32O6Cultured-[75,106]
Methylatranone C (166)430C25H34O6Cultured-[107]
Atranone D (167)386C24H34O4Cultured-[106]
Atranone E (168)386C24H34O4Cultured-[106]
Atranone F (169)432C24H32O7Cultured-[106]
Atranone G (170)462C25H34O8Cultured-[106]
Atranone H (171)432C24H32O7Cultured-[107]
Atranone I (172)432C24H32O7Cultured-[107]
Atranone J (173)404C23H32O6Cultured-[107]
Atranone K (174)448C24H32O8Cultured-[107]
Atranone L (175)478C26H38O8Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[108]
Atranone M (176)476C26H36O8Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[108]
Atranone N (177)462C26H38O7Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[108]
Atranone O (178)480C25H36O9Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[108]
Atranone P (179)404C23H32O6Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[108]
Atranone Q (180)390C23H34O5Sarcophyton subviride (Coral, Alcyoniidae)Xisha Island, South China Sea, China[61]
--Cultured-[62]
Atranone R (181)450C25H38O7Sarcophyton subviride (Coral, Alcyoniidae)Xisha Island, South China Sea, China[61]
Atranone S (182)402C24H34O5Sarcophyton subviride (Coral, Alcyoniidae)Xisha Island, South China Sea, China[61]
Atranone T (183)432C24H32O7Cultured-[62]
Atranone U (184)446C25H34O7Cultured-[62]
Stachatranone A (185)318C20H30O3Sarcophyton subviride (Coral, Alcyoniidae)Xisha Island, South China Sea, China[61]
Stachatranone B (186)334C20H30O4Sarcophyton subviride (Coral, Alcyoniidae)Xisha Island, South China Sea, China[61]
Stachatranone C (187)334C20H30O4Sarcophyton subviride (Coral, Alcyoniidae)Xisha Island, South China Sea, China[61]
--Cultured-[62]
6α-Hydroxydolabella-3E,7E,12-trien-14-one (189)302C20H30O2Cultured-[106]
(1S*,3R*,4R*,6S*,11S*)-3,4-Epoxy-6-hydroxydolabella-7E,12-dien-14-one (188)318C20H30O3Cultured-[106]
(1R,6R,11R)-6-Hydroxydolabella-3E,7E, 12-trien-14-one (190)302C20H30O2Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[108]
Arthproliferin B (191)360C22H32O4Sinularia sp. (Soft coral, Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
Arthproliferin C (192)388C23H32O5Sinularia sp. (Soft coral, Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
Stachybotrychromene A (193)354C23H30O3Cultured-[64]
Stachybotrychromene B (194)412C25H32O5Cultured-[64]
Stachybotrychromene C (195)368C23H28O4Cultured-[64]
Stachybonoid A (196)460C26H36O7Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[68]
Stachybonoid B (197)446C25H34O7Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[68]
Stachybonoid C (198)388C23H32O5Himerometra magnipinna (Crinoids, Himerometridae)Zhanjiang Mangrove National Nature Reserve, Guangdong, China[68]
Epi-cochlioquinone A (199)532C30H44O8Cultured-[109]
11-O-Methyl-epicochlioquinone A (200) 546C31H46O8Cultured-[109]
Arthproliferin D (201)358C20H22O6Sinularia sp. (Soft coral, Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
Pestaxanthone (202)358C20H22O6Sinularia sp. (Soft coral, Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
Prenxanthone (203)340C20H20O5Sinularia sp. (Soft coral, Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
Staprexanthone A (204)394C24H26O5Root of an unidentified mangrove plantFujian, China[110]
Staprexanthone B (205)392C25H28O4Root of an unidentified mangrove plantFujian, China[110]
Staprexanthone C (206)392C25H28O4Root of an unidentified mangrove plantFujian, China[110]
Staprexanthone D (207)392C25H28O4Root of an unidentified mangrove plantFujian, China[110]
Staprexanthone E (208)392C25H28O4Root of an unidentified mangrove plantFujian, China[110]
Cyclosporin A (209)1202C62H111N11O12SoilHahajima Island Tokyo, Japan[111]
FR901459 A (210)1218C62H111N11O13SoilHahajima Island Tokyo, Japan[111]
Arthproliferin A (211)407C25H29NO4Sinularia sp. (Soft coral, Alcyoniidae)Yongxing Island, South Chian Sea, China[73]
5-[(2-Methoxyphenoxy)methyl]-1,3-oxazolidin-2-one (212)223C11H13NO4Black moldUzbekistan[112]
Cyclopentanone oxime (213)99C5H9NOBlack moldUzbekistan[113]
BR-011 (214)372C23H32O4Niphates sp. (Sponge, Niphatidae)Near coral reef, Beibuwan Bay, GuangXi, China[104]
β-Sitosterol (215)414C29H50OBlack moldUzbekistan[112]
Various illnesses are featured by unregulated and persistent angiogenesis [77,114]. The agents that inhibit angiogenesis have a substantial role in various diseases such as metastasis, cancer, hemangioma, arthritis, and ocular diseases [114]. Angiogenesis is a complicated multicellular process in which specified receptors and their ligands have a considerable role. It was reported that Tie2 receptor (tyrosine kinase receptor) and its ligands have an important function in angiogenesis [77,115]. Compounds 4, 6, 10, 11, 13, 16, and 17 are new phenylspirodrimane derivatives that were isolated by Zhao et al. along with 3, 12, 14, 21, and 28 from S. chartarum CGMCC-3.5365 by using SiO2, RP, and HPLC. Their structures and configurations were established by spectral analyses, as well as X-ray, ECD (electronic circular dichroism), calculated ECD, and optical rotation. Stachybotrysin D (10) is an alcoholic O-sulfating derivative, whereas stachybotrysins F and G (16 and 17) have isobenzo-tetrahydrofuran moiety with a C-8’-attached acetonyl group. Their antiviral potential versus HIV-1 virus and influenza A virus (IAV) was estimated. Compounds 4, 11, 13, and 17 displayed weak anti-HIV capacity (IC50 range 18.1–35.7 μM) compared to efavirenz (IC50 4.0 nM), however 11, 13, 14, 16, 17, and 21 possessed inhibitory effectiveness versus IAV (IC50 range 12.4–45.6 μM) relative to ribavirion (IC50 2.0 nM). In the cytotoxicity MTT assay, 12, 13, and 17 revealed weak potential versus HepG2 cell (IC50 18.4, 24.7, and 24.6 μM, respectively) in comparison to paclitaxel (IC50 6.3 nM), besides, 12 was weakly active versus BGC823 and NCI-H460 cell lines (IC50s 21.9 and 15.8 μM, respectively) [67]. These metabolites are terpenoid-polyketide hybrids that were proposed to be originated from ilicicolin B, which was established to be biosynthesized from farnesyldiphosphate and orsellinic acid (Scheme 1).
Scheme 1

Biosynthetic pathways of compounds 3, 4, 6, 10–13, 21, and 28 from ilicicolin B [67].

On the other side, 14, 16, and 17 featured an additional C3 chain bound to the phenolic unit, revealing their origin from a non-orsellinic acid precursor (Scheme 2). It was suggested that they had a polyketone precursor (1a) derived from an acetyl-CoA (starter) and 5 malonyl-CoA (extenders). The polyketone farnesylation, oxidation, and decarboxylation yield 1b. The latter undergoes several enzymatic cyclization to afford 14 and subsequent oxidation and non-stereoselective cyclization to form 16 and 17 [67].
Scheme 2

Biosynthetic pathway of 14, 16, and 17 [67].

Further, new phenylspirodrimanes; stachybotrysins H and I (18 and 19) and stachybotrin E (31) along with stachybotrylactam (29) were separated from S. chartarum CGMCC-3.5365 mycelia and filtrate EtOAc extract by SiO2 CC and HPLC that were established by NMR and ECD analyses, as well as optical rotation [71]. They have 2R/3S/5S/8R/9R/10S/8’R, 2R/3S/5S/8R/9R/10S/8’S, and 3R/5S/8R/9R/10S configurations, respectively. Kv1.3 (voltage-gated K channel) controls both non-excitable and excitable cell membrane potential and has a remarkable contribution in Ca2+ signaling regulation [116]. It has been signaled as a pronounced target for remedial intervention, particularly for multiple sclerosis, type 1 diabetes, psoriasis, and autoimmune disorders [116]. Compounds 18 and 19 possessed Kv1.3 inhibitory effectiveness (IC50 13.4 and 10.9 μM, respectively) compared to clofazamine (IC50 2.01 μM) and PAP-1 (5-(4-phenoxybutoxy)psoralen, IC50 0.17 μM) in the Kv1.3 FLIPR (fluorometric imaging plate reader) thallium flux assay using CHO-Kv1.3 stable cell line [71]. Seven novel K-76 (2) derivatives, K-76-1 (36), K-76-2 (37), K-76-3 (59), K-76-4 (60), K-76-5 (61), K-76-6 (62), and k-76-7 (63), were purified from ethyl-methyl-ketone extract by flash SiO2 CC and HPLC and elucidated by NMR and MS spectroscopic tools (Figure 1). They are drimane sesquiterpenoids having phenylspirodrimane moiety linked with an α,β-unsaturated γ-lactam ring. They differed in the hydroxylation at C-2 and the nature of the N-linked substituent of the γ-lactam ring [77]. These metabolites were assessed for their potency to prohibit the ATP 33P incorporation into the Tie2 intracellular tyrosine kinase portion in the auto-phosphorylation reaction. All metabolites notably prohibited Tie2 kinase receptor (IC50s ranging from 0.025 to 0.146 mM), where 60 was the most powerful one (IC50 0.025 mM) [77].
Figure 1

Structures of phenylspirodrimane derivatives (1–12) reported from S. chartarum.

From the wetland strain, new phenylspirodrimanes, stachybotranes A–D (22, 23, 27, and 58) and formerly reported 20, 21, 24, 25, and 32, were purified by RP-18 and Sephadex CC and HPLC and assigned via spectroscopic, X-ray, and CD analyses. Compounds 22/23 and 27/58 had 3R,5S,8S,9R,10S and 2R,3S,5S,8S,9R,10S configurations, respectively (Figure 2). Compounds 21, 22, and 23 were moderately cytotoxic (IC50 ranging from 9.23 to 31.22 μM) versus A-549, SMMC-7721, MCF-7, SW-480, and HL-60 in the MTT assay compared to cisplatin (IC50 1.25–17.63 μM). The structure/activity relation demonstrated that the lactone groups had a positive influence on cytotoxicity compared with the lactam ring [72].
Figure 2

Structures of phenylspirodrimane derivatives (13–26) reported from S. chartarum.

The new phenylspirodrimanes; stachybonoids D–F (7, 47, and 48), in addition to stachybotrysin C (6), stachybotrylactone (20), and stachartin B (28), were separated using HPLC and SiO2 and Sephadex LH-20 CC and characterized based on spectral, X-ray, and ECD. These metabolites shared the same 2S,3S,8S,10S-configurations. Their inhibition capacity versus LPS-boosted NO production in RAW264.7 cells was estimated in the Griess assay. It was found that 6, 20, and 48 displayed moderate inhibition of NO production (IC50 27.2, 17.9, and 52.5 μM, respectively) compared to indomethacin (IC50 37.5 μM), while 7, 47, and 28 were inactive [68]. Zhang et al. assumed that these metabolites are generated from the addition reaction of farnesyl diphosphate and orsellinic acid to produce an intermediate ilicicolin B (Scheme 3). After that, the epoxidation of the prenyl group terminal olefinic bond takes place and the aromatic OH group reacts with C2 of the prenyl group. This is followed by a series of reactions, including cyclization, addition, oxidation, and acetylation, to produce 6, 7, 20, 28, 47, and 48 [68].
Scheme 3

Biosynthetic pathway of 6, 7, 20, 28, 47, and 48 [68].

From Xestospongia testudinaris-associated S. chartarum, the new derivatives, stachybosides A (8) and B (9), stachybotrins D-F (34, 38, and 39), and stachybocins E (113) and F (114), along with 3, 5, 12, 36, and 51, were separated (Figure 3) and elucidated using spectroscopic tools and their configuration was estimated based on alpha D, modified Mosher‘s and Marfey‘s methods, and chemical hydrolysis. Compound 34 was like 36, except the side chain on the N-atom was replaced by an acetonyl group and had 3R/5S/8R/9R/10S configuration, whilst 38 and 39 are methylated derivatives 36 having the same alpha D but differing in the position of the methyl group. Besides, 113 and 114 are dimers that were structurally like 34 except for the replacement of the acetonyl moiety at nitrogen with two and three methylenes, respectively.
Figure 3

Structures of phenylspirodrimane derivatives (27–38) reported from S. chartarum.

On the other side, 8 and 9 have glycosylated hydroxymethyl moiety instead of the hydroxymethyl group in 3, whereas 9, a 2-OH congener of 8, has 2R/3S/5S/8R/9R/0S configuration. Compound 34 prohibited HIV-1 replication towards 5 NNRTI-resistant and wild-type HIV-1 strains by targeting reverse transcriptase (EC50 6.2–23.8 μM) compared to nevirapine (EC50 0.023–51.9 μM) in the luciferase assay system [66] (Table 2).
Table 2

List of biological activities of compounds isolated from Stachybotrys chartarum.

Compound NameBiological ActivityAssay, Organism, or Cell LineBiological ResultsPositive ControlRef.
Stachybotrysin B (4)Anti-HIV-1 virusLuciferase/VSV-G19.2 μM (IC50)Efavirenz 4.0 nM (IC50)[67]
Stachybotrysin C (6)Antiinflammtory Griess assay/RAW264.7 cells/ LPS-induced NO production inhibition27.2 μM (IC50)Indomethacin 37.5 μM (IC50)[68]
Stachybotrysin E (11)Anti-HIV-1 virusLuciferase/VSV-G20.5 μM (IC50)Efavirenz 4.0 nM (IC50)[67]
Anti-influenza A virusLuciferase/VSV-G45.6 μM (IC50)Ribavirion 2.0 nM (IC50)[67]
CytotoxicityMTT/HepG236.2 μM (IC50)Paclitaxel 6.3 nM (IC50)[67]
F1839-I (12)Anti-HIV-1 virusLuciferase/VSV-G15.6 μM (IC50)Efavirenz 4.0 nM (IC50)[67]
CytotoxicityMTT/NCI-H46015.8 μM (IC50)Paclitaxel 1.0 nM (IC50)[67]
MTT/BGC82321.9 μM (IC50)Paclitaxel 0.8 nM (IC50)[67]
MTT/Baoy41.5 μM (IC50)Paclitaxel 0.4 nM (IC50)[67]
MTT/HepG218.4 μM (IC50)Paclitaxel 6.3 nM (IC50)[67]
Stachybotrysin A (13)Anti-HIV-1 virusLuciferase/VSV-G19.6 μM (IC50)Efavirenz 4.0 nM (IC50)[67]
Anti-influenza A virusLuciferase/VSV-G12.4 μM (IC50)Ribavirion 2.0 nM (IC50)[67]
MTT/Baoy29.8 μM (IC50)Paclitaxel 0.4 nM (IC50)[67]
MTT/HepG224.7 μM (IC50)Paclitaxel 6.3 nM (IC50)[67]
Stachartin A = Stachybotrysin (14)Anti-influenza A virusLuciferase/VSV-G18.7 μM (IC50)Ribavirion 2.0 nM (IC50)[67]
CytotoxicityMTT/HepG234.0 μM (IC50)Paclitaxel 6.3 nM (IC50)[67]
Stachybochartin G (15)CytotoxicityMTT/MDA-MB2315.6 μM (IC50)-Cisplatin 11.3 μM (IC50)-Doxorubicin 1.0 μM (IC50)[70]
MTT/U2-OS4.5 μM (IC50)-Cisplatin 5.9 μM (IC50)-Doxorubicin 1.2 μM (IC50)[70]
Stachybotrysin F (16)Anti-HIV-1 virusLuciferase/VSV-G35.7 μM (IC50)Efavirenz 4.0 nM (IC50)[67]
Anti-influenza A virusLuciferase/VSV-G14.6 μM (IC50)Ribavirion 2.0 nM (IC50)[67]
CytotoxicityMTT/HCT11648.5 μM (IC50)Paclitaxel 1.0 nM (IC50)[67]
MTT/NCI-H46041.2 μM (IC50)Paclitaxel 1.0 nM (IC50)[67]
MTT/BGC82341.7 μM (IC50)Paclitaxel 0.8 nM (IC50)[67]
MTT/Baoy30.6 μM (IC50)Paclitaxel 0.4 nM (IC50)[67]
MTT/HepG228.4 μM (IC50)Paclitaxel 6.3 nM (IC50)[67]
Stachybotrysin G (17)Anti-HIV-1 virusLuciferase/VSV-G18.1 μM (IC50)Efavirenz 4.0 nM (IC50)[67]
Anti-influenza A virusLuciferase/VSV-G23.4 μM (IC50)Ribavirion 2.0 nM (IC50)[67]
CytotoxicityMTT/HCT11644.6 μM (IC50)Paclitaxel 1.0 nM (IC50)[67]
MTT/NCI-H46026.9 μM (IC50)Paclitaxel 1.0 nM (IC50)[67]
MTT/BGC82331.6 μM (IC50)Paclitaxel 0.8 nM (IC50)[67]
MTT/Baoy56.9 μM (IC50)Paclitaxel 0.4 nM (IC50)[67]
MTT/HepG224.6 μM (IC50)Paclitaxel 6.3 nM (IC50)[67]
Stachybotrysin H (18)Potassium channel inhibitionKv1.3 FLIPR thallium flux /CHO-Kv1.313.4 μM (IC50)-Clofazamine 2.01 μM (IC50)-PAP-1 0.17 μM (IC50)[71]
Stachybotrysin I (19)Potassium channel inhibitionKv1.3 FLIPR thallium flux /CHO-Kv1.310.9 μM (IC50)-Clofazamine 2.01 μM (IC50)-PAP-1 0.17 μM (IC50)[71]
Stachybotrylactone = Stachybotrolide (20)Antiinflammtory Griess assay/RAW264.7 cells/ LPS-induced NO production inhibition17.9 μM (IC50)Indomethacin 37.5 μM (IC50)[68]
Stachybotrylactone acetate (21)CytotoxicityMTT/HL-6011.44 μM (IC50)Cisplatin 1.25 μM (IC50)[72]
MTT/SMMC-772123.31 μM (IC50)Cisplatin 7.77 μM (IC50)[72]
MTT/A-54922.84 μM (IC50)Cisplatin 6.12 μM (IC50)[72]
MTT/MCF-718.20 μM (IC50)Cisplatin 17.63 μM (IC50)[72]
MTT/SW48017.38 μM (IC50)Cisplatin 14.58 μM (IC50)[72]
Anti-influenza A virusLuciferase/VSV-G18.9 μM (IC50)Ribavirion 2.0 nM (IC50)[67]
Stachybotrane A (22)CytotoxicityMTT/HL-609.23 μM (IC50)Cisplatin 1.25 μM (IC50)[72]
MTT/SMMC-772119.67 μM (IC50)Cisplatin 7.77 μM (IC50)[72]
MTT/A-54931.22 μM (IC50)Cisplatin 6.12 μM (IC50)[72]
MTT/MCF-718.74 μM (IC50)Cisplatin 17.63 μM (IC50)[72]
Stachybotrane B (23)CytotoxicityMTT/HL-6015.08 μM (IC50)Cisplatin 1.25 μM (IC50)[72]
MTT/SMMC-772124.90 μM (IC50)Cisplatin 7.77 μM (IC50)[72]
MTT/MCF-729.34 μM (IC50)Cisplatin 17.63 μM (IC50)[72]
MTT/SW48031.03 μM (IC50)Cisplatin 14.58 μM (IC50)[72]
K-76-1 (36)Tyrosine kinase inhibitionRadiometry/33P>0.2 mM (IC50)-[77]
K-76-2 (37)Tyrosine kinase inhibitionRadiometry/33P>0.031 mM (IC50)-[77]
Stachybonoid F (48)Antiinflammtory Griess assay/RAW264.7 cells/ LPS-induced NO production inhibition52.5 μM (IC50)Indomethacin 37.5 μM (IC50)[68]
Stachybochartin G (51)CytotoxicityMTT/MDA-MB2314.5 μM (IC50)-Cisplatin 11.3 μM (IC50)-Doxorubicin 1.0 μM (IC50)[70]
MTT/U2-OS5.6 μM (IC50)-Cisplatin 5.9 μM (IC50)-Doxorubicin 1.2 μM (IC50)[70]
K-76-3 (59)Tyrosine kinase inhibitionRadiometry/33P>0.4 mM (IC50)-[77]
K-76-4 (60)Tyrosine kinase inhibitionRadiometry/33P>0.025 mM (IC50)-[77]
K-76-5 (61)Tyrosine kinase inhibitionRadiometry/33P>0.097 mM (IC50)-[77]
K-76-6 (62)Tyrosine kinase inhibitionRadiometry/33P>0.146 mM (IC50)-[77]
K-76-7 (63)Tyrosine kinase inhibitionRadiometry/33P>0.046 mM (IC50)-[77]
Bistachybotrysin A (73)CytotoxicityMTT/HCT1166.7 μM (IC50)Paclitaxel 0.0038 μM (IC50)[79]
MTT/NCI-H4607.5 μM (IC50)Paclitaxel 0.0004 μM (IC50)[79]
MTT/BGC82314.2 μM (IC50)Paclitaxel 0.002 μM (IC50)[79]
MTT/Daoy2.8 μM (IC50)Paclitaxel 0.0002 μM (IC50)[79]
MTT/HepG211.9 μM (IC50)Paclitaxel 0.0102 μM (IC50)[79]
Bistachybotrysin B (74)CytotoxicityMTT/HCT11618.0 μM (IC50)Paclitaxel 0.0038 μM (IC50)[79]
MTT/NCI-H4605.5 μM (IC50)Paclitaxel 0.0004 μM (IC50)[79]
MTT/BGC8236.6 μM (IC50)Paclitaxel 0.002 μM (IC50)[79]
MTT/Daoy4.2 μM (IC50)Paclitaxel 0.0002 μM (IC50)[79]
MTT/HepG219.3 μM (IC50)Paclitaxel 0.0102 μM (IC50)[79]
Bistachybotrysin C (75)CytotoxicityMTT/HCT11619.1 μM (IC50)Paclitaxel 0.0038 μM (IC50)[79]
MTT/NCI-H46012.3 μM (IC50)Paclitaxel 0.0004 μM (IC50)[79]
MTT/BGC82319.2 μM (IC50)Paclitaxel 0.002 μM (IC50)[79]
MTT/Daoy14.6 μM (IC50)Paclitaxel 0.0002 μM (IC50)[79]
MTT/HepG219.3 μM (IC50)Paclitaxel 0.0102 μM (IC50)[79]
Bistachybotrysin D (76)CytotoxicityMTT/HCT1166.8 μM (IC50)Paclitaxel 0.00381 μM (IC50)[80]
MTT/NCI-H46014.7 μM (IC50)Paclitaxel 0.000384 μM (IC50)[80]
MTT/BGC82311.4 μM (IC50)Paclitaxel 0.00197 μM (IC50)[80]
MTT/Daoy11.6 μM (IC50)Paclitaxel 0.000187 μM (IC50)[80]
MTT/HepG27.5 μM (IC50)Paclitaxel 0.0102 μM (IC50)[80]
Antiinflammtory LPS/BV2/NO production inhibition61.1% at 10.0 μMCurcumin 67.6% at 10.0 μM[80]
Bistachybotrysin E (77)CytotoxicityMTT/HCT1168.9 μM (IC50)Paclitaxel 0.00381 μM (IC50)[80]
MTT/NCI-H46019.0 μM (IC50)Paclitaxel 0.000384 μM (IC50)[80]
MTT/BGC8236.7 μM (IC50)Paclitaxel 0.00197 μM (IC50)[80]
MTT/Daoy59.0 μM (IC50)Paclitaxel 0.000187 μM (IC50)[80]
MTT/HepG212.4 μM (IC50)Paclitaxel 0.0102 μM (IC50)[80]
Bistachybotrysin F (78)CytotoxicityMTT/HCT11622.8 μM (IC50)Taxol 0.00381 μM (IC50)[81]
MTT/NCI-H46022.5 μM (IC50)Taxol 0.000384 μM (IC50)[81]
MTT/BGC82318.3 μM (IC50)Taxol 0.00197 μM (IC50)[81]
MTT/Daoy61.8 μM (IC50)Taxol 0.000187 μM (IC50)[81]
MTT/HepG218.3 μM (IC50)Taxol 0.0102 μM (IC50)[81]
Bistachybotrysin G (79)CytotoxicityMTT/HepG222.7 μM (IC50)Taxol 0.0102 μM (IC50)[81]
Bistachybotrysin H (80)CytotoxicityMTT/HCT11620.7 μM (IC50)Taxol 0.00381 μM (IC50)[81]
MTT/NCI-H46010.6 μM (IC50)Taxol 0.000384 μM (IC50)[81]
MTT/BGC82321.1 μM (IC50)Taxol 0.00197 μM (IC50)[81]
MTT/Daoy20.7 μM (IC50)Taxol 0.000187 μM (IC50)[81]
MTT/HepG218.4 μM (IC50)Taxol 0.0102 μM (IC50)[81]
Bistachybotrysin I (81)CytotoxicityMTT/HCT1169.1 μM (IC50)Taxol 0.00381 μM (IC50)[81]
MTT/NCI-H46019.9 μM (IC50)Taxol 0.000384 μM (IC50)[81]
MTT/BGC82317.2 μM (IC50)Taxol 0.00197 μM (IC50)[81]
MTT/Daoy18.4 μM (IC50)Taxol 0.000187 μM (IC50)[81]
MTT/HepG221.4 μM (IC50)Taxol 0.0102 μM (IC50)[81]
Bistachybotrysin J (82)CytotoxicityMTT/HCT11615.8 μM (IC50)Taxol 0.00381 μM (IC50)[81]
MTT/NCI-H46020.4 μM (IC50)Taxol 0.000384 μM (IC50)[81]
MTT/BGC82316.9 μM (IC50)Taxol 0.00197 μM (IC50)[81]
MTT/Daoy25.4 μM (IC50)Taxol 0.000187 μM (IC50)[81]
MTT/HepG212.2 μM (IC50)Taxol 0.0102 μM (IC50)[81]
Bistachybotrysin K (83)CytotoxicityMTT/HCT1163.4 μM (IC50)Paclitaxel 0.0038 μM (IC50)[82]
MTT/NCI-H4604.7 μM (IC50)Paclitaxel 0.0004 μM (IC50)[82]
MTT/BGC8233.3 μM (IC50)Paclitaxel 0.0002 μM (IC50)[82]
MTT/Daoy1.1 μM (IC50)Paclitaxel 0.0002 μM (IC50)[82]
MTT/HepG24.3 μM (IC50)Paclitaxel 0.0102 μM (IC50)[82]
Bistachybotrysin L (84)NeuroprotectiveMTT/SK-N-SH0.15 % at 10.0 μM, ↑ cell viabilityResveratrol 16.1% at 10.0 μM, ↑ cell viability [83]
CytotoxicityMTT/HCT11610.6 μM (IC50)Paclitaxel 0.038 μM (IC50)[83]
MTT/NCI-H46013.5 μM (IC50)Paclitaxel 0.004 μM (IC50)[83]
MTT/BGC82322.3 μM (IC50)Paclitaxel 0.002 μM (IC50)[83]
MTT/HepG218.9 μM (IC50)Paclitaxel 0.0102 μM (IC50)[83]
Antiinflammtory LPS/BV2/NO production inhibition5.31% at 10.0 μMCurcumin 67.6% at 10.0 μM[83]
Bistachybotrysin M (85)NeuroprotectiveMTT/SK-N-SH17.4 % at 10.0 μM, ↑ cell viabilityResveratrol 16.1% at 10.0 μM, ↑ cell viability [83]
CytotoxicityMTT/HCT1162.5 μM (IC50)Paclitaxel 0.0038 μM (IC50)[83]
MTT/NCI-H4603.5 μM (IC50)Paclitaxel 0.0004 μM (IC50)[83]
MTT/BGC8231.8 μM (IC50)Paclitaxel 0.002 μM (IC50)[83]
MTT/Daoy2.4 μM (IC50)Paclitaxel 0.0002 μM (IC50)[83]
MTT/HepG22.2 μM (IC50)Paclitaxel 0.0102 μM (IC50)[83]
Antiinflammtory LPS/BV2/NO production inhibition26.3% at 10.0 μMCurcumin 67.6% at 10.0 μM[83]
Bistachybotrysin N (86)NeuroprotectiveMTT/SK-N-SH17.6 % at 10.0 μM, ↑ cell viabilityResveratrol 16.1% at 10.0 μM, ↑ cell viability [83]
CytotoxicityMTT/HCT11664.5 μM (IC50)Paclitaxel 0.0038 μM (IC50)[83]
MTT/NCI-H4608.3 μM (IC50)Paclitaxel 0.0004 μM (IC50)[83]
MTT/BGC82312.5 μM (IC50)Paclitaxel 0.002 μM (IC50)[83]
MTT/Daoy61.4 μM (IC50)Paclitaxel 0.0002 μM (IC50)[83]
MTT/HepG256.1 μM (IC50)Paclitaxel 0.0102 μM (IC50)[83]
Bistachybotrysin O (87)NeuroprotectiveMTT/SK-N-SH8.4 % at 10.0 μM, ↑ cell viabilityResveratrol 16.1% at 10.0 μM, ↑ cell viability [83]
CytotoxicityMTT/HCT11618.8 μM (IC50)Paclitaxel 0.0038 μM (IC50)[83]
MTT/NCI-H46011.5 μM (IC50)Paclitaxel 0.0004 μM (IC50)[83]
MTT/BGC82320.5 μM (IC50)Paclitaxel 0.002 μM (IC50)[83]
MTT/Daoy10.7 μM (IC50)Paclitaxel 0.0002 μM (IC50)[83]
MTT/HepG220.1 μM (IC50)Paclitaxel 0.0102 μM (IC50)[83]
Bistachybotrysin P (88)Antiinflammtory LPS/BV2/NO production inhibition12.9% at 10.0 μMCurcumin 67.6% at 10.0 μM[83]
Bistachybotrysin Q (89)Antiinflammtory LPS/BV2/NO production inhibition10.1% at 10.0 μMCurcumin 67.6% at 10.0 μM[83]
CytotoxicityMTT/HCT11618.5 μM (IC50)Paclitaxel 0.038 μM (IC50)[83]
MTT/NCI-H4608.8 μM (IC50)Paclitaxel 0.004 μM (IC50)[83]
MTT/BGC82355.4 μM (IC50)Paclitaxel 0.002 μM (IC50)[83]
MTT/Daoy17.3 μM (IC50)Paclitaxel 0.0002 μM (IC50)[83]
MTT/HepG214.1 μM (IC50)Paclitaxel 0.0102 μM (IC50)[83]
Bistachybotrysin R (90)CytotoxicityMTT/HCT1168.8 μM (IC50)Paclitaxel 0.0038 μM (IC50)[83]
MTT/NCI-H4608.2 μM (IC50)Paclitaxel 0.0004 μM (IC50)[83]
MTT/BGC82317.8 μM (IC50)Paclitaxel 0.002 μM (IC50)[83]
MTT/Daoy13.1 μM (IC50)Paclitaxel 0.0002 μM (IC50)[83]
MTT/HepG29.4 μM (IC50)Paclitaxel 0.0102 μM (IC50)[83]
Bistachybotrysin S (91)NeuroprotectiveMTT/SK-N-SH6.5 % at 10.0 μM, ↑ cell viabilityResveratrol 16.1% at 10.0 μM, ↑ cell viability [83]
CytotoxicityMTT/HCT1168.0 μM (IC50)Paclitaxel 0.0038 μM (IC50)[83]
MTT/NCI-H46011.7 μM (IC50)Paclitaxel 0.0004 μM (IC50)[83]
MTT/BGC8238.7 μM (IC50)Paclitaxel 0.002 μM (IC50)[83]
MTT/Daoy11.8 μM (IC50)Paclitaxel 0.0002 μM (IC50)[83]
MTT/HepG26.0 μM (IC50)Paclitaxel 0.0102 μM (IC50)[83]
Antiinflammtory LPS/BV2/NO production inhibition54.2 % at 10.0 μMCurcumin 67.6% at 10.0 μM[83]
Bistachybotrysin T (92)NeuroprotectiveMTT/SK-N-SH17.4 % at 10.0 μM, ↑ cell viabilityResveratrol 16.1% at 10.0 μM, ↑ cell viability [83]
Bistachybotrysin U (93)NeuroprotectiveMTT/SK-N-SH9.3 % at 10.0 μM, ↑ cell viabilityResveratrol 16.1% at 10.0 μM, ↑ cell viability [83]
CytotoxicityMTT/HCT1169.7 μM (IC50)Paclitaxel 0.038 μM (IC50)[83]
MTT/NCI-H46010.1 μM (IC50)Paclitaxel 0.004 μM (IC50)[83]
MTT/BGC8239.8 μM (IC50)Paclitaxel 0.002 μM (IC50)[83]
MTT/Daoy8.1 μM (IC50)Paclitaxel 0.0002 μM (IC50)[83]
MTT/HepG29.4 μM (IC50)Paclitaxel 0.0102 μM (IC50)[83]
Bistachybotrysin V (94)CytotoxicityMTT/HCT11615.0 μM (IC50)Paclitaxel 0.0038 μM (IC50)[83]
MTT/NCI-H46010.9 μM (IC50)Paclitaxel 0.0004 μM (IC50)[83]
MTT/BGC82323.9 μM (IC50)Paclitaxel 0.002 μM (IC50)[83]
MTT/Daoy27.7 μM (IC50)Paclitaxel 0.0002 μM (IC50)[83]
MTT/HepG212.9 μM (IC50)Paclitaxel 0.0102 μM (IC50)[83]
Bistachybotrysin W (95)CytotoxicityMTT/HCT11612.1 μM (IC50)Paclitaxel 0.0038 μM (IC50)[84]
MTT/NCI-H46011.5 μM (IC50)Paclitaxel 0.0004 μM (IC50)[84]
MTT/BGC82313.2 μM (IC50)Paclitaxel 0.002 μM (IC50)[84]
MTT/Daoy8.8 μM (IC50)Paclitaxel 0.0002 μM (IC50)[84]
MTT/HepG27.0 μM (IC50)Paclitaxel 0.0102 μM (IC50)[84]
Bistachybotrysin X (96)CytotoxicityMTT/HCT11622.6 μM (IC50)Paclitaxel 0.0038 μM (IC50)[84]
MTT/NCI-H46010.8 μM (IC50)Paclitaxel 0.0004 μM (IC50)[84]
MTT/BGC82315.1 μM (IC50)Paclitaxel 0.002 μM (IC50)[84]
MTT/Daoy21.5 μM (IC50)Paclitaxel 0.0002 μM (IC50)[84]
MTT/HepG211.5 μM (IC50)Paclitaxel 0.0102 μM (IC50)[84]
Bistachybotrysin Y (97)CytotoxicityMTT/HCT1165.9 μM (IC50)Paclitaxel 0.0038 μM (IC50)[84]
MTT/NCI-H46013.0 μM (IC50)Paclitaxel 0.0004 μM (IC50)[84]
MTT/BGC82314.1 μM (IC50)Paclitaxel 0.002 μM (IC50)[84]
MTT/Daoy6.4 μM (IC50)Paclitaxel 0.0002 μM (IC50)[84]
MTT/HepG29.8 μM (IC50)Paclitaxel 0.0102 μM (IC50)[84]
Chartarolide A (98)CytotoxicityMTT/HCT-1161.9 μM (IC50)Taxol 0.03 μM (IC50)[85]
MTT/HepG21.8 μM (IC50)Taxol 0.02 μM (IC50)[85]
MTT/BGC-8231.3 μM (IC50)Taxol 0.001 μM (IC50)[85]
MTT/NCI-H16505.5 μM (IC50)Taxol 0.07 μM (IC50)[85]
MTT/A27801.5 μM (IC50)Taxol 0.03 μM (IC50)[85]
MTT/MCF-71.4 μM (IC50)Taxol 0.09 μM (IC50)[85]
Tumor-related kinases inhibitionSpectrophotometric/FGFR32.6 μM (IC50)Satratoxin H ˂0.5 μM (IC50)[85]
Spectrophotometric/IGF1R6.8 μM (IC50)Satratoxin H ˂0.5 μM (IC50)[85]
Spectrophotometric/PDGFRb9.1 μM (IC50)Satratoxin H ˂0.5 μM (IC50)[85]
Spectrophotometric/TRKB8.0 μM (IC50)Satratoxin H ˂0.5 μM (IC50)[85]
Chartarolide B (99)CytotoxicityMTT/HCT-1162.3 μM (IC50)Taxol 0.03 μM (IC50)[85]
MTT/HepG22.8 μM (IC50)Taxol 0.02 μM (IC50)[85]
MTT/BGC-8231.6 μM (IC50)Taxol 0.001 μM (IC50)[85]
MTT/NCI-H16504.8 μM (IC50)Taxol 0.07 μM (IC50)[85]
MTT/A27803.2 μM (IC50)Taxol 0.03 μM (IC50)[85]
MTT/MCF-73.8 μM (IC50)Taxol 0.09 μM (IC50)[85]
Tumor-related kinases inhibitionSpectrophotometric/FGFR34.9 μM (IC50)Satratoxin H ˂0.5 μM (IC50)[85]
Spectrophotometric/IGF1R8.4 μM (IC50)Satratoxin H ˂0.5 μM (IC50)[85]
Spectrophotometric/PDGFRb20.3 μM (IC50)Satratoxin H ˂0.5 μM (IC50)[85]
Spectrophotometric/TRKB11.3 μM (IC50)Satratoxin H ˂0.5 μM (IC50)[85]
Chartarolide C (100)CytotoxicityMTT/HCT-1167.8 μM (IC50)Taxol 0.03 μM (IC50)[85]
MTT/HepG28.9 μM (IC50)Taxol 0.02 μM (IC50)[85]
MTT/BGC-8235.4 μM (IC50)Taxol 0.001 μM (IC50)[85]
MTT/NCI-H165011.3 μM (IC50)Taxol 0.07 μM (IC50)[85]
MTT/A278012.5 μM (IC50)Taxol 0.03 μM (IC50)[85]
MTT/MCF-78.7 μM (IC50)Taxol 0.09 μM (IC50)[85]
Tumor-related kinases inhibitionSpectrophotometric/FGFR321.4 μM (IC50)Satratoxin H ˂0.5 μM (IC50)[85]
Spectrophotometric/TRKB18.8 μM (IC50)Satratoxin H ˂0.5 μM (IC50)[85]
Chartarlactam Q (101)AntibacterialBroth microdilution/S. aureus ATCC 292138.0 μg/mL (MIC)Chloramphenicol 1.0 μg/mL (MIC)[86]
Chartarlactam R (102)AntibacterialBroth microdilution/S. aureus ATCC 2921316.0 μg/mL (MIC)Chloramphenicol 1.0 μg/mL (MIC)[86]
Chartarlactam S (103)AntibacterialBroth microdilution/S. aureus ATCC 292134.0 μg/mL (MIC)Chloramphenicol 1.0 μg/mL (MIC)[86]
Stachybochartin A (105)CytotoxicityMTT/MDA-MB23121.7 μM (IC50)-Cisplatin 11.3 μM (IC50)-Doxorubicin 1.0 μM (IC50)[70]
MTT/U2-OS19.8 μM (IC50)-Cisplatin 5.9 μM (IC50)-Doxorubicin 1.2 μM (IC50)[70]
Stachybochartin B (106)CytotoxicityMTT/MDA-MB23117.6 μM (IC50)-Cisplatin 11.3 μM (IC50)-Doxorubicin 1.0 μM (IC50)[70]
MTT/U2-OS11.2 μM (IC50)-Cisplatin 5.9 μM (IC50)-Doxorubicin 1.2 μM (IC50)[70]
Stachybochartin C (107)CytotoxicityMTT/MDA-MB23111.6 μM (IC50)-Cisplatin 11.3 μM (IC50)-Doxorubicin 1.0 μM (IC50)[70]
MTT/U2-OS14.5 μM (IC50)-Cisplatin 5.9 μM (IC50)-Doxorubicin 1.2 μM (IC50)[70]
Stachybochartin D (108)CytotoxicityMTT/MDA-MB23110.4 μM (IC50)-Cisplatin 11.3 μM (IC50)-Doxorubicin 1.0 μM (IC50)[70]
MTT/U2-OS9.2 μM (IC50)-Cisplatin 5.9 μM (IC50)-Doxorubicin 1.2 μM (IC50)[70]
Stachyin B (109)AntibacterialBroth microdilution/S. aureus ATCC 292134.0 μg/mL (MIC)Chloramphenicol 1.0 μg/mL (MIC)[86]
2,4,12-Trihydroxyapotrichothecene (116)CytotoxicityMTT/HCT-1160.87 μM (IC50)Taxol 0.03 μM (IC50)[92]
MTT/HepG20.69 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/BGC-8230.65 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/NCI-H16500.84 μM (IC50)Taxol 0.04 μM (IC50)[92]
MTT/A27800.69 μM (IC50)Taxol 0.01 μM (IC50)[92]
Tumor-related kinases inhibitionSpectrophotometric/FGFR30.5 μM (IC50)-[92]
Spectrophotometric/IGF1R1.0 μM (IC50)-[92]
Spectrophotometric/PDGFRb2.1 μM (IC50)-[92]
Spectrophotometric/TRKB1.0 μM (IC50)-[92]
Spectrophotometric/WT2.2 μM (IC50)-[92]
Chartarene A (117) CytotoxicityMTT/HCT-1163.39 μM (IC50)Taxol 0.03 μM (IC50)[92]
MTT/HepG23.95 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/BGC-8232.87 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/A27802.38 μM (IC50)Taxol 0.01 μM (IC50)[92]
Chartarene B (118) CytotoxicityMTT/HCT-1165.58 μM (IC50)Taxol 0.03 μM (IC50)[92]
Tumor-related kinases inhibitionSpectrophotometric/FGFR32.4 μM (IC50)-[92]
Spectrophotometric/IGF1R6.9 μM (IC50)-[92]
Spectrophotometric/PDGFRb10.4 μM (IC50)-[92]
Spectrophotometric/TRKB7.0 μM (IC50)-[92]
Spectrophotometric/WT12.9 μM (IC50)-[92]
Chartarene C (119) CytotoxicityMTT/HCT-1160.74 μM (IC50)Taxol 0.03 μM (IC50)[92]
MTT/HepG22.09 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/NCI-H16502.58 μM (IC50)Taxol 0.04 μM (IC50)[92]
MTT/A27802.07 μM (IC50)Taxol 0.01 μM (IC50)[92]
Tumor-related kinases inhibitionSpectrophotometric/FGFR31.1 μM (IC50)-[92]
Spectrophotometric/IGF1R3.0 μM (IC50)-[92]
Spectrophotometric/PDGFRb5.3 μM (IC50)-[92]
Spectrophotometric/TRKB2.7 μM (IC50)-[92]
Spectrophotometric/WT6.3 μM (IC50)-[92]
Trichodermol (120)CytotoxicityMTT/HCT-1167.22 μM (IC50)Taxol 0.03 μM (IC50)[92]
MTT/HepG23.69 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/BGC-8232.55 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/NCI-H16502.68 μM (IC50)Taxol 0.04 μM (IC50)[92]
MTT/A27802.68 μM (IC50)Taxol 0.01 μM (IC50)[92]
Tumor-related kinases inhibitionSpectrophotometric/FGFR30.9 μM (IC50)-[92]
Spectrophotometric/IGF1R0.8 μM (IC50)-[92]
Spectrophotometric/PDGFRb3.1 μM (IC50)-[92]
Spectrophotometric/TRKB1.8 μM (IC50)-[92]
Spectrophotometric/WT3.0 μM (IC50)-[92]
Isotrichoverrol B (123)CytotoxicityMTT/HCT-1163.48 μM (IC50)Taxol 0.03 μM (IC50)[92]
MTT/HepG22.62 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/BGC-8232.64 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/NCI-H16502.36 μM (IC50)Taxol 0.04 μM (IC50)[92]
MTT/A27802.12 μM (IC50)Taxol 0.01 μM (IC50)[92]
Tumor-related kinases inhibitionSpectrophotometric/FGFR324.0 μM (IC50)-[92]
Verrol (124)CytotoxicityMTT/HCT-1162.77 μM (IC50)Taxol 0.03 μM (IC50)[92]
MTT/HepG21.45 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/BGC-8232.33 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/NCI-H16502.68 μM (IC50)Taxol 0.04 μM (IC50)[92]
MTT/A27802.00 μM (IC50)Taxol 0.01 μM (IC50)[92]
Tumor-related kinases inhibitionSpectrophotometric/FGFR30.1 μM (IC50)-[92]
Spectrophotometric/IGF1R0.2 μM (IC50)-[92]
Spectrophotometric/PDGFRb0.7 μM (IC50)-[92]
Spectrophotometric/TRKB0.4 μM (IC50)-[92]
Spectrophotometric/WT0.9 μM (IC50)-[92]
Trichodermadienediol B (128)CytotoxicityMTT/HCT-1161.65 μM (IC50)Taxol 0.03 μM (IC50)[92]
MTT/HepG20.86 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/BGC-8230.81 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/NCI-H16501.31 μM (IC50)Taxol 0.04 μM (IC50)[92]
MTT/A27800.68 μM (IC50)Taxol 0.01 μM (IC50)[92]
Tumor-related kinases inhibitionSpectrophotometric/FGFR30.5 μM (IC50)-[92]
Spectrophotometric/IGF1R0.7 μM (IC50)-[92]
Spectrophotometric/PDGFRb1.9 μM (IC50)-[92]
Spectrophotometric/TRKB1.0 μM (IC50)-[92]
Spectrophotometric/WT1.9 μM (IC50)-[92]
Roridin L-2 (129)CytotoxicityMTT/HCT-1161.73 μM (IC50)Taxol 0.03 μM (IC50)[92]
MTT/HepG21.20 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/BGC-8231.81 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/NCI-H16502.36 μM (IC50)Taxol 0.04 μM (IC50)[92]
MTT/A27801.61 μM (IC50)Taxol 0.01 μM (IC50)[92]
Tumor-related kinases inhibitionSpectrophotometric/FGFR30.4 μM (IC50)-[92]
Spectrophotometric/IGF1R0.5 μM (IC50)-[92]
Spectrophotometric/PDGFRb2.3 μM (IC50)-[92]
Spectrophotometric/TRKB1.9 μM (IC50)-[92]
Spectrophotometric/WT1.7 μM (IC50)-[92]
Chartarene D (130) CytotoxicityMTT/HCT-1161.48 μM (IC50)Taxol 0.03 μM (IC50)[92]
MTT/HepG20.90 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/BGC-8230.68 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/NCI-H16502.23 μM (IC50)Taxol 0.04 μM (IC50)[92]
MTT/A27800.69 μM (IC50)Taxol 0.01 μM (IC50)[92]
Tumor-related kinases inhibitionSpectrophotometric/FGFR30.1 μM (IC50)-[92]
Spectrophotometric/IGF1R0.1 μM (IC50)-[92]
Spectrophotometric/PDGFRb0.8 μM (IC50)-[92]
Spectrophotometric/TRKB0.7 μM (IC50)-[92]
Spectrophotometric/WT0.7 μM (IC50)-[92]
Roridin E (134)CytotoxicityMTT/HCT-116˂0.01 μM (IC50)Taxol 0.03 μM (IC50)[92]
MTT/HepG2˂0.01 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/BGC-823˂0.01 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/NCI-H1650˂0.01 μM (IC50)Taxol 0.04 μM (IC50)[92]
MTT/A2780˂0.01 μM (IC50)Taxol 0.01 μM (IC50)[92]
Tumor-related kinases inhibitionSpectrophotometric/FGFR30.4 μM (IC50)-[92]
Spectrophotometric/IGF1R0.4 μM (IC50)-[92]
Spectrophotometric/PDGFRb1.4 μM (IC50)-[92]
Spectrophotometric/TRKB1.0 μM (IC50)-[92]
Spectrophotometric/WT2.1 μM (IC50)-[92]
Muconomycin B (139)CytotoxicityMTT/HCT-1161.32 μM (IC50)Taxol 0.03 μM (IC50)[92]
MTT/HepG20.81 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/BGC-8230.84 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/NCI-H16500.86 μM (IC50)Taxol 0.04 μM (IC50)[92]
MTT/A27800.68 μM (IC50)Taxol 0.01 μM (IC50)[92]
Tumor-related kinases inhibitionSpectrophotometric/FGFR30.3 μM (IC50)-[92]
Spectrophotometric/IGF1R0.4 μM (IC50)-[92]
Spectrophotometric/PDGFRb1.2 μM (IC50)-[92]
Spectrophotometric/TRKB0.7 μM (IC50)-[92]
Spectrophotometric/WT1.5 μM (IC50)-[92]
Satratoxin F (140)Antibacterial Serial dilution/Methicillin-resistant S. aureus ATCC 2921339.0 μg/mL (MIC)Ampicillin 10.0 μg/mL (MIC)[73]
Satratoxin G (142)CytotoxicityMTT/HCT-116˂0.01 μM (IC50)Taxol 0.03 μM (IC50)[92]
MTT/HepG2˂0.01 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/BGC-823˂0.01 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/NCI-H1650˂0.01 μM (IC50)Taxol 0.04 μM (IC50)[92]
MTT/A2780˂0.01 μM (IC50)Taxol 0.01 μM (IC50)[92]
Tumor-related kinases inhibitionSpectrophotometric/FGFR30.1 μM (IC50)-[92]
Spectrophotometric/IGF1R0.1 μM (IC50)-[92]
Spectrophotometric/PDGFRb0.5 μM (IC50)-[92]
Spectrophotometric/TRKB0.2 μM (IC50)-[92]
Spectrophotometric/WT0.9 μM (IC50)-[92]
Satratoxin H (144)CytotoxicityMTT/HCT-116˂0.01 μM (IC50)Taxol 0.03 μM (IC50)[92]
MTT/HepG2˂0.01 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/BGC-823˂0.01 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/NCI-H1650˂0.01 μM (IC50)Taxol 0.04 μM (IC50)[92]
MTT/A2780˂0.01 μM (IC50)Taxol 0.01 μM (IC50)[92]
Tumor-related kinases inhibitionSpectrophotometric/FGFR3˂0.1 μM (IC50)-[92]
Spectrophotometric/IGF1R˂0.1 μM (IC50)-[92]
Spectrophotometric/PDGFRb˂0.1 μM (IC50)-[92]
Spectrophotometric/TRKB˂0.1 μM (IC50)-[92]
Spectrophotometric/WT0.1 μM (IC50)-[92]
Mytoxin A (146)CytotoxicityMTT/HCT-116˂0.01 μM (IC50)Taxol 0.03 μM (IC50)[92]
MTT/HepG2˂0.01 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/BGC-823˂0.01 μM (IC50)Taxol 0.01 μM (IC50)[92]
MTT/NCI-H1650˂0.01 μM (IC50)Taxol 0.04 μM (IC50)[92]
MTT/A2780˂0.01 μM (IC50)Taxol 0.01 μM (IC50)[92]
Tumor-related kinases inhibitionSpectrophotometric/FGFR3˂0.1 μM (IC50)-[92]
Spectrophotometric/IGF1R˂0.1 μM (IC50)-[92]
Spectrophotometric/PDGFRb˂0.1 μM (IC50)-[92]
Spectrophotometric/TRKB˂0.1 μM (IC50)-[92]
Spectrophotometric/WT˂0.1 μM (IC50)-[92]
Chartarutine A (147)Anti-HIV virusLuciferase/VSV-G74.00 μM (IC50)Efavirenz 0.65 μM (IC50)[104]
Chartarutine B (148)Anti-HIV virusLuciferase/VSV-G4.90 μM (IC50)Efavirenz 0.65 μM (IC50)[104]
Chartarutine C (149)Anti-HIV virusLuciferase/VSV-G24.00 μM (IC50)Efavirenz 0.65 μM (IC50)[104]
Chartarutine D (150)Anti-HIV virusLuciferase/VSV-G51.76 μM (IC50)Efavirenz 0.65 μM (IC50)[104]
Chartarutine E (151)Anti-HIV virusLuciferase/VSV-G40.70 μM (IC50)Efavirenz 0.65 μM (IC50)[104]
Chartarutine F (152)Anti-HIV virusLuciferase/VSV-G18.63 μM (IC50)Efavirenz 0.65 μM (IC50)[104]
Chartarutine G (153)Anti-HIV virusLuciferase/VSV-G5.57 μM (IC50)Efavirenz 0.65 μM (IC50)[104]
Chartarutine H (154)Anti-HIVLuciferase/VSV-G5.58 μM (IC50)Efavirenz 0.65 μM (IC50)[104]
Stachybotrysam A (156)Anti-HIV virusLuciferase/293T cells9.3 μM (IC50)Efavirenz 2.0 nM (IC50)[76]
Stachybotrysam B (157)Anti-HIV virusLuciferase/293T cells1.0 μM (IC50)Efavirenz 2.0 nM (IC50)[76]
Stachybotrysam C (158)Anti-HIV virusLuciferase/293T cells9.6 μM (IC50)Efavirenz 2.0 nM (IC50)[76]
Atranone Q (180)CytotoxicityMTT/MG-638.6 μM (IC50)5-FU 10.4 μM (IC50)[62]
AntimicrobialBroth microdilution/S. aureus ATCC 4330032.0 μg/mL (MIC)Vancomycin 0.5 μg/mL(MIC) [61]
Broth microdilution/E. faecalis ATCC 2921216.0 μg/mL (MIC)Vancomycin 0.5 μg/mL(MIC) [61]
Broth microdilution/C. albicans ATCC 102318.0 μg/mL (MIC)Fluconazole 1.0 μg/mL(MIC)[61]
Stachatranone B (186)AntimicrobialBroth microdilution/A. baumannii ATCC 1960616.0 μg/mL (MIC)Ceftriaxone 8 μg/mL(MIC)[61]
Stachybotrychromene A (193)CytotoxicityAlamar Blue assay/HepG2 73.7 μM (IC50)-[64]
Stachybotrychromene B (194)CytotoxicityAlamar Blue assay/HepG2 28.2 μM (IC50)-[64]
Epi-cochlioquinone A (199)Human chemokine antagonistCCR-54.0 μM (IC50)-[109]
11-O-Methyl-epi-cochlioquinone A (200)Human chemokine antagonistCCR-57.0 μM (IC50)-[109]
Cyclosporin A (209)ImmunosuppressantLymphocyte murine inhibition/MLR9.9 ng/mL (IC50)-[111]
Mitogen suppression/ConA21.9 ng/mL (IC50)-[111]
Skin grafting, TGF-β1/ radioimmunoprecipitation19.0 day (Median serivial time)/100 mg/kg orallyVehicle treated group (Olive oil)[111]
FR901459 A (210)ImmunosuppressantLymphocyte murine inhibition/MLR26.8 ng/mL (IC50)-[111]
Mitogen suppression/ConA50.1 ng/mL (IC50)-[111]
Skin grafting, TGF-β1/ radioimmunoprecipitation10.0 day (Median serivial time)/100 mg/kg orallyVehicle treated group (Olive oil)[111]
Arthproliferin A (211)Antibacterial Serial dilution/Methicillin-resistant S. aureus ATCC 2921378.0 μg/mL (MIC)Ampicillin 10.0 μg/mL (MIC) [73]
BR-011 (214)Anti-HIV virusLuciferase/VSV-G17.90 μM (IC50)Efavirenz 0.65 μM (IC50)[104]
Yang et al. (2021) purified and characterized undescribed phenylspirodrimane derivatives, stachybotrolide (20), stachybotrylactam acetate (30), arthproliferin E (31), and formerly reported 32, 44, 51, 64, and 65 from Sinularia sp.-associated S. chartarum SCSIO4-1201 EtOAc extract (Figure 4). These metabolites were evaluated for their antimicrobial activity versus A. baumannii ATCC-19606, K. pneumonia ATCC-13883, E. coli ATCC-25922, A. hydrophila ATCC-7966, S. aureus ATCC-29213, and E. faecalis ATCC-29212 in the serial dilution technique using 96-well microtiter plates and for cytotoxicity against MDA-MB-231, C4-2B, MGC803, MDA-MB-468, and A549 cell lines in the CCK-4 assay. Compounds 30 and 31 showed weak inhibitory activity (MICs 325 and 125 µg/mL, respectively) towards methicillin-resistant S. aureus ATCC-29213 compared to ampicillin (MIC 10.0 µg/mL) and weak cytotoxic activity versus MDA-MB-231, C4-2B, MGC803, MDA-MB-468, and A549 [73].
Figure 4

Structures of phenylspirodrimane derivatives (39–48) reported from S. chartarum.

Chemical investigation of the solid culture of the S. chartarum isolated from Niphates recondita using SiO2 and ODS gel CC and HPLC resulted in the separation of sixteen new phenylspirodrimanes, chartarlactams A–P (40–44, 52–56, 65–69, and 72) along with 29, 30, 32, 50, 51, 57, 64, and 71 (Figure 5). Their structures and configuration were verified using spectral tools and single-crystal X-ray diffraction, respectively. This represented the first report of 8β-CH3 analogs, and 72 had a new framework that was formed by 40 dimerization.
Figure 5

Structures of phenylspirodrimane derivatives (49–58) reported from S. chartarum.

The antihyperlipidemic effects of 29, 30, 40–44, 50–57, 65, 67, 69, 71, and 72 (Figure 6) in HepG2 cells were estimated utilizing a cell-based lipid accumulation assay. The results revealed that 43, 44, 50, 54, 65, 68, 69, and 72 (Conc. 10 μM) possessed significant lipid-lowering potential in HepG2 cells. Besides, 44, 50, 54, 65, and 69 displayed remarkable prohibition of intracellular TG (triglyceride) levels, whereas 43, 44, 50, 65, 68, and 72 dramatically lessened TC (total cholesterol). The structure–activity relation revealed that the 8α-CH3 analogs with alkyl N-substituted (e.g., 30, 32, 41, and 67) had weak potential, except 50, that has a benzene-propanoic acid substituent. In addition, the C-8‘ γ-lactam carbonyl as in 65 and 69 boosted the inhibitory potential compared with 29 and 55, which have C-7‘carbonyl. Compound 43, with a C-2‘glucosyl moiety, possessed only inhibition on TC, whereas 54 selectively prohibited TG. The analogs with 2,3-diol had no activity, whereas C-3 acetoxy analogs (e.g., 54) had a selective inhibitory effect [74].
Figure 6

Structures of phenylspirodrimane derivatives (59–66) reported from S. chartarum.

Zhao et al. reported the separation of three dimers: bistachybotrysins A–C (73–75) from S. chartarum CGMCC-3.5365 mycelia EtOAc extract by SiO2 CC and HPLC that were assigned based on spectroscopic and ECD analyses. These metabolites are phenylspirodrimane dimers having [6,6,7,6]-tetracyclic scaffold with 6/7 oxygen heterocycle linkage and a central 2,10-dioxabicyclo[4.3.1]decan-7-ol core fused with two phenyl moieties (Figure 7).
Figure 7

Structures of dimeric phenylspirodrimane derivatives (67–74) reported from S. chartarum.

Their in vitro cytotoxic potential versus HCT-116 (colorectal carcinoma), NCI-H460 (lung carcinoma, BGC823 (gastric carcinoma), Daoy (medulloblastoma), and HepG2 (liver carcinoma) in the MTT assay was assessed. Compound 73 revealed powerful inhibitory capacity versus Daoy, HCT-116, and NCI-H460 (IC50S 2.8, 6.7, and 7.5 μM, respectively), whereas 74 had potent activity versus Daoy, NCI-H460, and BGC823 (IC50S 4.2, 5.5, and 6.6 μM, respectively). On the other side, 75 demonstrated weak cytotoxic effectiveness versus all cell lines. It was observed that 73 was more potent versus Daoy and HCT-116 than 74, while 74 possessed better influence versus BGC823 and NCI-H460 than 73, indicating that different substituents at C-3 might influence the selectivity towards tumor cell lines and substituent at 2’-OH might lessen the activity (Figure 8).
Figure 8

Structures of dimeric phenylspirodrimane derivatives (75–78) reported from S. chartarum.

Further investigation is worth pursuing for 73 and 74 as new promising antitumor lead compounds [79]. They were postulated to be originated from farnesyl-diphosphate and orsellinic acid that give phenylspirodrimane monomer (Scheme 4). Then, a pinacol coupling reaction among the two CHO groups of 3 and 2 gives a vicinal-diol intermediate I. After that, one OH group of the 22,23‘-diol moiety fuses further with the other CHO of 2 to produce II with a six-membered oxygen heterocyclic ring through acetalization intermolecularly. Subsequently, the dehydration of the mer-NF5003E (3) CH2OH and hemiacetal OH groups yields 73 through 6/7 oxygen heterocyclic linkage. Further, 74 is resulted from bistachybotrysin A by selective acetylation, whereas 75 is generated from 5 and 2 through pinacol-coupling reaction, intermolecular acetalization, and dehydration [79].
Scheme 4

Biosynthetic pathway of bistachybotrysins A–C (73–75) [79].

Bistachybotrysins D (76) and E (77), stereoisomeric phenylspirodrimane dimers, have a central [6,5,6]-tricyclic carbon skeleton involving a cyclopentanone ring. Their structures were verified by extensive spectral analysis, and their configurations were established by ECD. Compound 76 demonstrated [6,5,6]-tricyclic carbon scaffold that dimerized through 3-(hydroxymethyl)cyclopentanone core C-C connected to one phenyl ring and fused to the other. Compound 77 has the same structure as 76 with 23S/23’S instead of 23R/23′R in 76. These metabolites (IC50 ranged from 6.7 to 11.6 μM) had pronounced cytotoxic potential versus Daoy, HCT116, BGC823, and HepG2 cell lines. Besides, 76 possessed neural anti-inflammatory potential by prohibiting NO production in BV2 cells induced by LPS compared to curcumin (inhibitory rate 61.1 and 67.6%, respectively, at Conc. 10 μM) [80]. The monomers are biosynthesized from FPP (farnesyldiphosphate) and orsellinic acid by reduction, prenylation, and cyclization. Further, hydroxylation and oxidation form 3 and 1 that undergo a pinacol coupling reaction between the two aldehydic groups to produce I (vicinal diol intermediate) that is dehydrated by H-22 and OH-23′ to yield II. Subsequently, the non-stereoselective aldol reaction of II gives a stereoisomer pair, and further O-methylation affords 76 and 77 (Scheme 5) [80].
Scheme 5

Biosynthetic pathway of bistachybotrysins D (76) and E (77) [80].

Based on HPLC-UV/MS guided analyses, five new dimers, bistachybotrysins F–J (78–82), having cyclopentanone ring linkage were purified and characterized using SiO2CC/HPLC and NMR/HRMS/ECD, respectively [81]. Compound 78 displayed the same structural features as 77 and 111. Besides, 78, 80, and 82 had 23R/23’R configuration, whereas 79 and 81 possessed 23S/23’S configuration (Figure 9).
Figure 9

Structures of dimeric phenylspirodrimane derivatives (79–84) reported from S. chartarum.

Feng et al. postulated that bistachybotrysins F–J (78–82) are generated from 1 and 3. They undergo a pinacol coupling reaction among the two CHO to yield a vicinal diol intermediate, subsequently, 110 and 111 are formed through dehydration and non-stereoselective aldol reaction. After that, the regioselective hydroxylation (C-2 or C-2’) affords 78–80 and/or acetylation (OH-3’ or OH-3). Further, 79 and 80 O-methylation produces 81 and 82, respectively (Scheme 6) [81]. Additionally, these metabolites were evaluated for cytotoxic potential versus HCT116, NCI-H460, BGC823, Daoy, and HepG2. It was found that 78 and 80–82 were moderately active (IC50 9.1–22.8 μM) versus HepG2, NCI-H460, BGC823, and HCT116 [81].
Scheme 6

Biosynthetic pathway of bistachybotrysins F–J (78–82) [81].

Bistachybotrysin K (83) is a new phenylspirodrimane dimer with a central 6/7 oxygen heterocyclic core. It displayed potent cytotoxic capacity versus NCI-H460, HCT116, Daoy, BGC823, and HepG2 (IC50 ranged from 1.1 to 4.7 mM) in the MTT assay, revealing its potential as lead for promising anti-tumor [82]. Using SiO2 CC and RP-HPLC, novel dimeric phenylspirodrimanes, bistachybotrysins L–V (84–94), were separated from the mycelia broth and extracts. Their structures and configurations were secured utilizing spectroscopic, X-ray, and ECD analyses (Figure 10).
Figure 10

Structures of dimeric phenylspirodrimane derivatives (85–89) reported from S. chartarum.

Compounds 84 and 85 are stereoisomeric dimers possessing an unusual [5,6]-spiroketal aromatic skeleton with a 2-methoxy-1,6-dioxaspiro[4,5]decane central core fused with 2 phenyl moieties. On the other side, 86–92 possess two linked-furan rings, whereas 93 and 94 featured a rare lactone/furan unit and one furan ring linkages, respectively (Figure 11). It is noteworthy that 91 and 92 selectively inhibited the proliferation of NCI-H460, HCT116, Daoy, BGC823, and HepG2 cell lines (IC50 ranged from 1.8 to 11.8 μM) in the MTT assay.
Figure 11

Structures of dimeric phenylspirodrimane derivatives (90–95) reported from S. chartarum.

Furthermore, 85, 86, and 92 (Conc. 10 μM) revealed potent neuroprotection potential versus glutamate-caused toxicity in SK-N-SH cells through raising cell viability (17.4, 17.6, and 17.4%, respectively), comparable to resveratrol (16.1% at Conc. 10 μM). Additionally, 91 possessed anti-inflammatory potential by repressing LPS-produced NO production in BV2 cells (inhibition rate 54.2% at Conc. 10 μM) relative to curcumin (67.6%) at the same concentration [83]. Liu et al. reported the separation of new phenylspirodrimane dimers, bistachybotrysins W–Y (95–97), having 6/7 oxygen heterocyclic unit using SiO2 and Sephadex CC and HPLC that were characterized through spectroscopic and ECD analyses (Figure 12). Compounds 95 and 97 demonstrated selective cytotoxic potential versus HepG2, Daoy, and HCT116 cell lines (IC50 5.9–12.1 μM) [84].
Figure 12

Structures of dimeric phenylspirodrimane derivatives (96–99) reported from S. chartarum.

Novel phenylspirodrimanes chartarolides A–C (98–100) were purified from S. chartarum isolated from Niphates recondite by SiO2 andRP-18 CC and RP-HPLC and assigned relying on spectroscopic analyses, optical rotation, and TDDFT-ECD calculation. Compounds 98 and 99 possess mollicelin J and phenylspirodrimane linked via dioxabicyclononane core formation. These metabolites exerted notable prohibition versus HCT-116, BGC-823, HepG2, A2780, NCIH1650, and MCF7 (IC50 ranged from 1.4 to 12.5 µM) in the MTT assay. Compound 99 (IC50 1.6–3.8 µM) had weaker potential than 98 (IC50 1.3–1.9 µM) versus HCT- 116, BGC-823, HepG2, A2780, and MCF7, revealing the direct influence of the dioxabicyclononane moiety‘s configuration on the activity. Additionally, they possessed inhibitory effectiveness versus tumor-linked kinases, FGFR3, IGF1R, PDGFRb, and TrKB (IC50s 2.6–21.4 µM), compared to satratoxin H (144) (IC50 ˂0.5 µM) [85]. In 2020, Liu et al. purified new dimeric derivatives, chartarlactams Q–T (101–104), in addition to 109 from the broth of a sponge-derived S. chartarum WGC-25 C-6 using SiO2 and ODS CC and HPLC (Figure 13). Their structures and configurations were specified by various spectral tools, along with ECD, optical rotation, and Mosher’s method. These metabolites have two N–C linked phenylspirodrimane units without an alkyl chain.
Figure 13

Structures of dimeric phenylspirodrimane derivatives (100–104) reported from S. chartarum.

Compounds 101–103 and 109 possessed inhibitory potential versus S. aureus (MIC 8, 16, 4, and 4 μg/mL, respectively), compared with chloramphenicol (MIC 1.0 μg/mL). Additionally, their anti-ZIKV virus capacity was assessed on ZIKV (African-lineage MR766 strain) infected A549 cells. It was found that 104 significantly prohibited NS5 and E protein expression (conc. 10 μM), whereas 101–103 and 109 were inactive. Envelope (E) protein in ZIKV virus has a remarkable role in membrane fusion and binding to target the host cells receptors, whereas NS5 protein a ZIKV genome encoding non-structural proteins that serves as template for the (+)ssRNA genomic RNA synthesis and viral polyprotein synthesis. Hence, this metabolite prohibited ZIKV virus by multi-targets to block RNA replication and viral entrance [86]. Biosynthetically, they are generated from 3 that undergoes nucleophilic cyclization to give I (hemiacetal intermediate). The latter reacts by dehydroxylation with various monomers (chartarlactam E (44), stachybotrylactam acetate (30), F1839-A (51), F1839-A diacetate, and stachybotrylactam (29), respectively) to produce 101–104 and 109 (Scheme 7).
Scheme 7

Biosynthetic pathway of chartarlactams Q–T (101–104) and stachyin B (109) [86,88].

S. chartarum-associated with Pinellia ternata biosynthesized undescribed phenylspirodrimane derivatives, stachybochartins A (105), B (106), C (107), D (108), E (25), F (33), and G (51), that were separated using SiO2 CC and RP-HPLC (Figure 14).
Figure 14

Structures of dimeric phenylspirodrimane derivatives (105–110) reported from S. chartarum.

Their assignments and configurations were accomplished through spectroscopic analysis as well as modified Mosher’s and ECD-calculations/ECD-exciton chirality methods. Compounds 105–108 are uncommon C–C coupled dimeric derivatives, where the monomeric units are C7’-C7’’’- (e.g., 105 and 106) and C5’’’-C8‘‘-coupled (e.g., 107 and 108). On the other side, stachybochartin G (51) possessed a seco-bisabosqual framework with 3’S/6’R/7’S configuration. Further, their cytotoxic potential was assessed versus MDA-MB-231, MCF-7, and U-2OS cell lines in the MTT assay. It was found that 51 and 105–108 had cytotoxic potential versus U-2OS and MDA-MB-231 (IC50s 4.5–21.7 µM). Besides, 51 and 107 demonstrated powerful anti-proliferation and anti-apoptosis effectiveness versus U-2OS cells, while all metabolites had no influence (IC50 >50 µM) versus MCF-7 cells [70]. These data may provide evidence for further research into the anticancer activities of these compounds. A new phenylspirodrimane dimer, stachartarin A (111), was separated from tin mine tailings associated S. chartarum culture and elucidated by means of spectroscopic methods (Figure 15).
Figure 15

Structures of dimeric phenylspirodrimane derivatives (111–114) reported from S. chartarum.

It differed from stachartin B (28) by the absence of a lactone group in 28 and the existence of an oxymethylene and ketone carbonyl in 111. Compound 111 had (IC50 >40 μM) no remarkable effectiveness versus MCF-7, HL-60, SMMC-7721, SW480, and A-549 cells in the MTT assay [88]. Ding et al. proposed that 111 is biosynthesized from two phenylspirodrimane derivative units through a reduction–oxidation reaction by C-C bond linkage among C-7′/C-8‴ and C-8′/C8‴, respectively, as illustrated in Scheme 8 [88].
Scheme 8

Biosynthetic pathway of stachartarin A (111) [88].

3.2. Trichothecenes

Trichothecenes are sesquiterpenoid-related mycotoxins commonly produced by fungi. They possess a marked cytotoxic potential versus eukaryotic organisms through the prohibition of DNA and protein synthesis as well as mitochondrial electron transport system [92]. They have common structural features: 12,13-epoxide moiety, 9,10-double bond, and various ring oxygenation patterns [117]. Structurally, they involve three main groups: trichothecenes type A, having hydrogen, hydroxyl, or isovaleryl functionalities at C-8; trichothecenes type B, having a C-8 carbonyl group; and macrocyclic trichothecenes, having a cyclic di or tri-ester ring binding C-4 to C-15 [118,119]. Macrocyclic trichothecenes are the most powerful toxic group [120]. Bio-guided separation of the EtOAc fraction of Niphates recondite-associated S. chartarum using SiO2 and RP-18 CC and HPLC afforded four new trichothecene-related sesquiterpenes, chartarenes A–D (117–119 and 130), and eleven known analogs, 116, 120, 123, 124, 128, 129, 134, 139, 142, 144, and 146, that were verified based on spectroscopic and X-ray analyses in addition to chemical methods [92] (Figure 16 and Figure 17).
Figure 16

Structures of trichothecenes (115–127) reported from S. chartarum.

Figure 17

Structures of trichothecenes (128–138) reported from S. chartarum.

They were tested versus a panel of human cancer cell lines (e.g., HCT-116, HepG2, BGC-823, NCI-H1655, and A2780) in the MTT method. It is noteworthy that they had selective inhibitory influences versus all cell lines with 134, 142, 144, and 146 (IC50 < 10 nM) having potent effectiveness (Figure 18). The structure–activity relation study demonstrated that this effect is related to the scaffolds and substitution pattern.
Figure 18

Structures of trichothecenes (139–146) reported from S. chartarum.

The apotrichothecene-related analogs, 117 with a C-12 sugar and without C-4 and C-2 hydroxy group (IC50 2.38–3.95 µM) or 118 with a C-2 methoxy group, had a weaker influence than that of the 2,4,12-trihydroxy analog, 116 (IC50 0.65–0.87 µM). On the other side, trichodermol-type analogs, having a macrocyclic ring alongside a tetrahydropyran ring (e.g., 142, 144, and 146), possessed remarkable potential; however, those without a tetrahydropyran-attached macrocyclic moiety (130 and 139) exhibited less cytotoxicity. Compounds 123, 124, 128, and 129 with a C-14 or C-4 linear moiety had reduced effects compared with 146. Additionally, their antitumor mechanism was investigated versus tumor growth-related tyrosine kinases (e.g., FGFR3 (fibroblast growth factor receptor 3), IGF1R (insulin-like growth factor 1 receptor), PDGFRb (β-type platelet-derived growth factor receptor), and TRKB (tropomyosin receptor kinase B)). They were found to exert powerful inhibitory action, except for 117 and 123, having a weak activity (IC50 > 20 μM). FGF signaling has a role in various disorders such as cancer, involving anti-apoptosis, proliferation, angiogenesis, drug resistance, and invasion. Therefore, targeting FGFR is a promising topic in the clinical oncology field [92]. Satratoxin G (142) and its biosynthetic precursor 129 were isolated from the culture acetonitrile extract using Michel–Miller SiO2 CC and HPLC and characterized by ESI-CID (electrospray/ionization/collision-induced/dissociation). Compound 142 had a C-4 to C-15-linked cyclic ester ring, however, 129 possessed a C-4 extended carbon chain and no C-15-substituent. Satratoxin G was found to cause apoptosis of the nose and brain OSN (nasal-olfactory sensory neurons) of mice upon intranasal exposure [121]. Additionally, it induced apoptosis in PC-12 (neuronal cell model) through marked upregulation of p53, BAX, and PKR [122]. In 2009, Islam et al. compared the neurotoxic potential of both metabolites in vivo and in vitro. The study revealed that 142 (conc. 10 to 25 ng/mL) caused PC-12 cells apoptotic death, while 129 (Conc. up to 1000 ng/mL) had no effect using Alamar blue, flow cytometry, and agarose DNA fragmentation assays. Similarly, 142 (dose 100 mg/kg/body weight, intra-nasal) produced remarkable OSN apoptosis and olfactory epithelium atrophy, whereas 129 showed no influence at the same dose. These results suggested that 129 had a weak potential to adversely affect health in comparison to 142 [98]. Satratoxin F (140) and satratoxin H (144) were separated by Yang et al. using RP-18 and HPLC CC. Compound 140 displayed moderate inhibitory activity against methicillin-resistant S. aureus ATCC-29213 (MIC 39 µg/mL) [73]. Besides, 140 (IC50s < 39 nM) displayed strong cytotoxic potential versus MDA-MB-231, C4-2B, MGC803, MDA-MB-468, and A549 cell lines in the CCK-4 assay [73].

3.3. Isoindoline derivatives

Mai et al. isolated 155 using SiO2 and C18 ODS CC of the mycelia EtOAc extract S. chartarum MXH-X73-associated with Xestospongia testudinaris that was characterized by HRESIMS, NMR, and X-ray. This metabolite is a cyclized iminoisoindoline, having farnesylated decahydropyrrolo[1,2-a][1,3]diazocine moiety (Figure 19).
Figure 19

Structures of isoindoline derivatives (147–155) reported from S. chartarum.

It had no cytotoxic (versus P388, A-549, HL-60, BEL-7402, and Hela cells), antiviral (versus HIV and H1N1), and antibacterial (versus M. phlei, S. aureus, Colibacillus sp., and Blastomyces albicans) potential [105]. Ma et al. proposed that 155 is generated through both mevalonate and polyketide pathways, with subsequent modifications, including amidation, cyclizing, and sulfation (Scheme 9).
Scheme 9

Biosynthetic pathway of stachybotrin G (155) [105].

Li et al. purified eight new derivatives: chartarutines A–H (147–154) from the mycelia EtOAc extract of Niphates sp.-associated S. chartarum using SiO2 and RP-18 CC and HPLC that were elucidated by spectroscopic tools, along with Mosher method and CD analysis. Compound 148 is 1’,11’-dehydroxy-10’,11’-ene derivative of 147, whereas 150 featured an isoindolinimine unit instead of an isoindolamine unit in 149. Besides, 151/153 and 152/154 had pyrano-isoindolinone rings linked to C5-C-3’ and C-3-C-3‘, respectively. Compounds 147–154 revealed anti-HIV potential (IC50s 4.90–74.00 μM), whereas 148, 153, and 154 had the potent effectiveness (IC50 4.90–5.58 μM) in the luciferase assay with lower cell cytotoxicity (CC) than efavirenz (CC50 40 μM), suggesting their further investigation as lower cytotoxic anti-HIV candidates. The structure-activity relation indicated that the variation in side chain directly influenced the inhibitory potential. The analogs having triene (153, 154) or diene (148) side-chain had more enhanced potential than vicinal diol analogs (147, 151, and 152), whereas the variation in scaffold (e.g., 148, 153, and 154) had no influence on the activity. Replacing 3-OH by sulfate (e.g., 149 and 150) reduced the activity [104]. Stachybotrysams A–D (156–159), new farnesylated isoindolinone derivatives, and new cyclized-farnesyl, stachybotrysam E (35), along with 148 were separated using SiO2 CC and HPLC (Figure 20) and elucidated based on spectral data analysis and optical rotation. Compounds 156–158 featured prenylated isoindolinone core with N-linked side chain with (e.g., 157 and 158) or without (e.g., 156) C-4 sulphate moiety, whereas 159 has N/C-6″ linked glucose moiety. On the other side, 35 has a cyclized farnesyl moiety as chartarlactam N (68), except having N-linked butyric acid unit instead of the ethyl alcohol moiety. In the HIV-inhibition luciferase assay, 156–158 demonstrated promising inhibitory potential against HIV-1 virus (IC50 9.3, 1.0, and 9.6 μM, respectively) compared to efavirenz (IC50 2.0 nM) using 293T cells. It was reported that the farnesyl chain cyclization reducing the effectiveness and the N-attached side chain, as well as sulphate moiety existence, could influence the activity [76].
Figure 20

Structures of isoindoline derivatives (156–159) reported from S. chartarum.

3.4. Atranones and Dolabellane Diterpenoids

Atranones are an uncommon type of C-alkylated dolabellanes that are featured by a 5/11-fused bicyclic carbon skeleton. They comprise three groups: C22, C23, and C24 atranones. Li et al. separated seven new atranones, 164, 175–179, and 190 in addition to formerly reported analogs 161–163, from soybean and rice culture media CHCl3 fraction of S. chartarum using Sephadex LH-20 and SiO2 CC and HPLC (Figure 21).
Figure 21

Structures of atranones (160–171) reported from S. chartarum.

Their structures were established by spectral and X-ray analyses, as well as ECD (electronic circular dichroism) calculations and optical rotation. DRG (Dorsal root ganglia) neuron is commonly utilized for assessing the growth capacity of neurons and drugs’ therapeutic potential in peripheral nerve regeneration [108]. For successful peripheral nerve regeneration, the first step is the axonal regrowth from injured neurons. The axonal regeneration potential of 162 was estimated using primary DRG neurons. Compound 162 boosted neurite outgrowth from adult dorsal root ganglia neurons remarkably without influencing cell survival (conc. 1 μg/mL) Besides, 161–164, 175, 176, 178, and 179 (Figure 22) had no cytotoxic potential versus MDA-MB-435 in the MTT [108].
Figure 22

Structures of atranones (172–180) reported from S. chartarum.

In 2019, Yang et al. purified new atranones Q-S (180–182) and new dolabellane diterpenoids: stachatranone A–C (185–187) from the EtOAc extract of a marine-derived S. chartarum by SiO2 CC and RP-HPLC that were characterized by extensive spectral and X-ray analyses. Structurally, 186 and 187 possess 1,14-seco-dolabellane diterpenoid skeleton, whereas 180 featured C23 atranone having propan-2-one moiety connected via C-C bond to a dolabellane diterpenoid and 181 is C24 atranone with a 2-methyltetrahydrofuran-3-carboxylate unit linked at C5–C6 to dolabellane diterpenoid. Compound 186 had antimicrobial potential versus E. faecalis and A. baumannii (MIC 32 and 16 μg/mL, respectively), whereas 180 possessed noticeable inhibition versus MRSA, C. albicans, and E. faecalis (MICs 32, 8, and 16 μg/mL, respectively). Treatment of C. albicans with 180 (8 μg/mL) induced obvious agglutination in cytoplasm and thinning, deformity, wrinkling, and irregularity of the cell wall, whereas at 16 μg/mL it resulted in the appearance of cytoplasmic vacuoles, deformation of the cell membrane and wall, and complete or partial leakage of the cell contents in TEM (transmission electron microscopy). This revealed that 180 had a destructive potential on C. albicans cell wall and cell membrane [61] (Figure 23).
Figure 23

Structures of atranones (181–184) and dolabellanes (185–190) reported from S. chartarum.

Two new atranones, T (183) and U (184), and three formerly reported analogs, 162, 180, and 187, were purified from the broth and mycelia EtOAc extract of S. chartarum by SiO2 CC and RP-HPLC. They were structurally verified by spectroscopic and calculated ECD analyses. Compound 183 is atranone C (165) C-13-hydroxy analog with 1S/6R/7R/13R/21S/22R configuration, however, 184 is a C22 methoxylated derivative of 183. It was proposed that these metabolites are biosynthesized starting with GGPP (geranylgeranyl pyrophosphate), as shown in Scheme 10. The cytotoxic evaluation versus MG-63 (human osteosarcoma cells) revealed that 180 (IC50 8.6 μM) possessed promising cytotoxic capacity than 5-FU (5-fluorouracil, IC50 10.4 μM) in the MTT. Further, 180 efficiently promoted MG-63 apoptosis, accompanied with G0/G1 cell cycle arrest. Thus, this compound could be further developed to a promising antitumor agent [62].
Scheme 10

Biosynthetic pathway of atranones T and U (183 and 184) [62].

3.5. Chromenes

Three novel meroterpenoids having a chromene moiety were joined with an isoprenoid chain; stachybotrychromenes A–C (193–195) were separated using SiO2 and RP-HPLC UV. Their cytotoxic potential was assessed versus HepG2 in the Alamar Blue assay. Compound 194 (IC50 28.2 μM) had a more potent reduction in the cell survival than 193 (IC50 73.7 μM), however, 195 was inactive [64]. It is noteworthy that 195 was assumed to be generated via the intermediates 193 and 194 (Figure 24).
Figure 24

Structures of chromene derivatives (191–198) reported from S. chartarum.

The new chromene metabolites, stachybonoids A–C (196–198), were purified using HPLC and SiO2 and Sephadex LH-20 CC and characterized based on spectral, ECD, and X-ray analyses as well as Mosher’s method [68]. They were assessed for anti-dengue virus potential in luciferase assay using 293T cells. Compound 196 lessened the prM dengue virus protein expression. It is noteworthy that 196 inhibited the replication of dengue virus, whereas 197 increased the formation of dengue protein, when the only difference between their structures was whether 17-OH was methylated or not. It was proposed that they are generated from the addition reaction of farnesyl diphosphate and orsellinic acid to produce an intermediate ilicicolin B (Scheme 11) [68]). After that, the ilicicolin B prenyl group terminal olefinic bond is epoxidized to produce an intermediate. Subsequently, the linkage of the aromatic OH group to C-3 of the prenyl group occurs through electrophilic addition forms 196–198 [68].
Scheme 11

Biosynthetic pathway of stachybonoids A–C (196–198) [68].

Sinularia sp.-associated S. chartarum SCSIO4-1201 EtOAc extract yielded undescribed polyketide derivatives, arthproliferins B and C (191 and 192), that were separated using RP18 CC and HPLC. They were characterized through X-ray, spectroscopic, and ECD analyses. Compound 191 was 9R-configured and possessed structural similarity to daurichromenic acid previously reported from Rhododendron dauricum [123], except that the C16-C-17 double bond was dehydroxylated, whereas 192 was like 191 but it had an aldehydic group at C-2 and 9S configuration. Compounds 192 had no cytotoxic and antimicrobial potential [73].

3.6. Cochlioquinones

Cochlioquinones are a class of phytotoxic metabolites that have been firstly purified from the plant pathogenic fungi belonging to Cochliobolus genus [124]. They are meroterpenoids having quinone/or quinol moiety and displayed various bioactivities [125]. Chemokines, small signaling proteins, are secreted by various cells such as innate lymphocytes, stem, B, T, myeloid, dendritic, and stromal cells that are involved in diverse biological processes (e.g. leukocyte migration, chemotaxis, and inflammation) [126]. They are substantial for destructive or protective immune and inflammatory operations, as well as for the immune system development and homeostasis [126]. Moreover, they are linked with various illnesses such as viral infections, cancer, and autoimmune and inflammatory diseases [127]. The chemokine-induced pathway activation needs the selective chemokines binding to their target cell surface receptors. Chemokines and their receptors are found to be substantial targets by different antagonists for treating a variety of illnesses [128]. The quinoid derivatives, 11-O-methyl-epi-cochlioquinone A (200) and epi-cochlioquinone A (199), were purified from hexane fraction utilizing Rp-HPLC. Compound 200 was an 11-O-methyl derivative of 199. Their C-11 α-configuration was deduced based on J9α-11 (9 Hz). These metabolites effectively competed with MIP-1α (macrophage inflammatory protein-1) for binding to human CCR5 (chemokine C-C motif-receptor 5) (IC50 7.0 and 4.0 μM, respectively) [109].

3.7. Xanthones

A new xanthone arthproliferin D (201) and formerly reported pestaxanthone (202) and prenxanthone (203) were biosynthesized by Sinularia sp.-associated S. chartarum SCSIO4-1201. Compound 201 was like 202 but differs in the position of CH3 groups at C-4 and C-12 and its 16R-configuration was established by the CD spectrum (Figure 25). However, 202 possessed weak effectiveness (MIC 125 µg/mL) towards methicillin-resistant S. aureus ATCC-29213, compared to ampicillin (MIC 10.0 µg/mL). All had no cytotoxic capacity versus MDA-MB-231, C4-2B, MGC803, MDA-MB-468, and A549 cell lines in the CCK-4 assay [73].
Figure 25

Structures of cochlioquinones (199 and 200) and xanthones (201–208) reported from S. chartarum.

Gan et al. reported the separation of new prenylxanthones, staprexanthones A–E (204–208) using SiO2 CC and RP-HPLC from the mycelia EtOAc extract of the mangrove-harbored S. chartarum HDN16-358. Their structures were secured by NMR and ECD analyses. Compound 204 features a C-8-linked 4,5-dimethyl-1,3-dioxolane moiety with 13R,14R-configuration, whereas 205–208 are rare mono-oxygenated prenylated xanthones. Compounds 204, 205, and 208 remarkably increased the number of β-cells in the zebrafish model in vivo. Further, 205 and 208 boosted the mass expansion of β-cells by increasing the existing β-cells proliferation via promoting cell-cycle progression at the G1/S phase, where 205 (Conc. 25 μM) was the most active stimulator with a 10% increased existing cell proliferation/day. This indicated the potential of these metabolites as drug leads for anti-diabetes agents through stimulating regeneration of β-cells [110].

3.8. Cyclosporins

Cyclosporins as immune-suppressant agents were established to be efficient not only in suppressing the transplanted-organ rejection but also in treating various autoimmune disorders that do not respond to current therapy [129]. FR901459 (210), a novel immunosuppressant, had been purified along with cyclosporin A (CsA, 209) from S. chartarum No.19392 fermentation by Diaion HP-20, activated carbon, and SiO2 CC. It gave positive results with I2 ceric SO4, KMnO4, and Dragendorff‘s reagents and negative ninhydrin (Figure 26). Its structure varied from other cyclosporins in having Leu at position 5 instead of Val relied on various spectral tools [111]. FR901459 possessed lymphocyte proliferation inhibitory effectiveness (IC50 26.8 ng/mL) that was one-third the effectiveness of CsA (IC50 9.9 ng/mL). It repressed IL-2 production as well as the ConA-produced mitogenic responses (IC50 50.1 ng/mL) compared to CsA (IC50 21.9 ng/mL). FR901459 (doses 100 and 320 mg/kg, oral) and CsA (doses 32 and 100 mg/kg, oral) prolonged skin allograft survival in rats. Therefore, it had one-third of the CsA potency in the in vitro and in vivo immune-suppression assays [111].
Figure 26

Structures of cyclosporins (209 and 210), nitrogenous compounds (211–213), phenolic (214), and sterol (215) reported from S. chartarum.

3.9. Other metabolites

Arthproliferin A (211) is an undescribed polyketide derivative separated from Sinularia sp.-associated S. chartarum SCSIO4-1201. It was found to be like coleophomone B formerly reported from Coleophoma sp. [130], except it has C-1 oxymethylene instead of ketone group. Compounds 211 demonstrated moderate influence (MIC 78 µg/mL) versus methicillin-resistant S. aureus [73]. Korpi et al. reported that TSGC (thermal desorption-gas chromatography) and HPLC analyses of air samples of S. chartarum obtained from incubation chambers revealed the existence of 1-hexanol, 2-methy-1-propanol, formaldehyde, 3-octanone, 3-methy-1-butanol, acrolein, 1-octanol, 3-methylanisole, and geosmin [131]. In addition, trichodiene, a volatile sesquiterpene that is structurally related to trichothecene mycotoxins, was specified by GCMS in the S. chartarum headspace [132]. Further, MVOCs (microbial volatile organic compounds) of three S. chartarum strains obtained from water damaged homes by GCMS analysis included alcohols (e.g., 2-ethyl-1-hexanol, 2-butanol, 2-methyl-3-buten-2-ol, 2-methyl-1-butanol, 3-methyl-3-buten-1-ol, 2-ethyl-1-hexanol, and 2-propanol), ketones (e.g., 2-butanone, 2,2-dimethyl-3-pentanone, cyclopentanone, 3-cyclohepten-1-one, and 2-(1-cyclopent-1-enyl-1-methylethyl) cyclopentanone, and terpenes (e.g., α-farnesene, 7-dimethyl-1,3,6-octatriene, β-himachalene, β-cedrene, β-pinene, β-myrcene, β-bisabolene, terpinolene, and limonene) [133].

4. Extract Bioactivities and Nanoparticles

S. chartarum spores MeOH extract had cytotoxic effectiveness, prohibited proliferation, and induced cell death towards MH-S (murine alveolar macrophage cell line) through induction of DNA damage and p53 activation [134]. FIP-sch3, a FIP (fungal immunomodulatory protein), was identified from S. chartarum and expressed in E. coli. rFIP-shc3 (recombinant FIP-sch3) exhibited a potent anti-tumor potential versus MCF-7, H520, A549, HeLa, and HepG2 but had no effect in 293 (normal human embryonic kidney) cells. It significantly inhibited cell migration and proliferation via the induced apoptosis in A549 cells [135]. Li et al. stated that the solid rice culture EtOAc extract of S. chartarum, harboring Niphates recondite sponge, displayed noticeable cytotoxic capacity (IC50 <10 mg/mL) versus a panel of tumor cell lines (e.g., BGC-823, HCT-116 NCI-H1650, A2780, and HepG2) [92]. The fermentation broth EtOAc extract of the fungal species isolated from Himerometra magnipinna revealed moderate anti-inflammation capacity (IC50 36 µM) by suppressing LPS-produced NO production in RAW264.7 cells [108]. Recently, nanotechnology has become one of the emerging research areas for developing a variety of nanomaterials [1,3]. It is considered an economical alternative for physical and chemical methods for nanoparticles’ (NPs) synthesis. The ordinary methods for NPs’ synthesis are non-eco-friendly, costly, and toxic, which necessitates the need for clean, reliable, safe, and eco-friendly methods [136]. The microorganism’s utilization in the NPs’ synthesis emerges as an exciting and eco-friendly approach. Different kinds of NPs have been synthesized using various fungal species [2,3,5,39]. Fungi are advantageous over bacteria in NPs’ preparation because of easy handling, simple nutrient requirement, great wall-binding potential, and metal intracellular uptake capacities [137]. Mohamed synthesized S. chartarum silver NPs (AgNPs) using AgNO3 that possessed more potent potential versus bacteria than fungi [138].

5. Conclusions

Fungi represent huge reservoirs of structural varied secondary metabolites and biotechnologically useful enzymes. S. chartarum is a toxigenic fungus species that is separated from water-damaged buildings as well as plants, soil, and marine sponges and is known to have life-threatening health impacts on humans and animals. From this fungus, 215 metabolites with diverse and unique structural features have been separated from the period 1973 through 2022 (Figure 27), including phenylspirodrimanes (112 compounds), trichothecenes (32 compounds), atranones (28 compounds), and isoindoline derivatives (13 compounds) as major metabolites (Figure 28).
Figure 27

Number of metabolites per year reported from S. chartarum.

Figure 28

Different classes of metabolites reported from S. chartarum. PSD: Phenylspirodrimanes: TCT: Trichothecenes; IIDs: Isoindoline derivatives; ATs: Atranones; DLDs: Dolabellane diterpenoids; XTs: Xanthones; CHs: Chromenes; CCQ: Cochlioquinones; CS: Cyclosporins; OT: Others.

These metabolites have been evaluated for various bioactivities such as cytotoxicity, anti-HIV virus, anti-inflammatory, antimicrobial, potassium channel inhibition, tyrosine kinase, and tumor-related kinase inhibitory, neuroprotective, anti-influenza A virus, human chemokine antagonist, and immunosuppressant characteristics (Figure 29). The unique scaffold of trichothecenes sesquiterpenoids may be considered one of the characteristics of this fungus. Additionally, some trichothecenes and atranones could be promising leads for the development of antitumor agents.
Figure 29

Biological activities of reported metabolites and the number of articles.

Stachybonoid A (196) exhibited anti-dengue potential; therefore, it could be a promising metabolite for developing dengue virus inhibitory agents. Staprexanthones B (205) and E (205) markedly stimulated the regeneration of β-cells; hence, they have the potential as drug leads for anti-diabetes agents. It is noteworthy that the structural variation among these metabolites directly influences their bioactivities. It is noteworthy that this fungus possesses potential and multiple enzymatic systems that might contribute to the diversity of its metabolites. Nevertheless, the enzymes and genes accountable for these unique metabolites’ biosynthesis are a fruitful area of future research. Further, this fungus has an amazing capacity to produce diverse enzymes that could be beneficial for biotechnological and industrial applications. In addition, they could represent an eco-friendly biodegradation tool that can exchange dangerous wastes into advantageous products. It was found that certain enzymes modification could boost their activity, revealing a new area of future research in this fungus’ enzymes. There is an only one report on the synthesis of NPs using this fungus. Thus, further studies to synthesize various types of NPs from S. chartarum and possible applications of these synthesized NPs can be carried out. An obvious theme that could be garnered from this work is that, although there is remarkable progress towards the characterization of S. chartarum metabolites, we think that there remain many hidden metabolites that need to be discovered. Moreover, further biological evaluations of the reported metabolites and their biosynthetic pathway studies are required. Additionally, the limited in vivo and mechanistic studies of these metabolites necessitate the research focus in this direction. Many of the reported metabolites either are not tested or possessed no observed effectiveness in some of the evaluated activities, therefore, an in silico screening for the potential bioactivities, as well as their derivatization, should clearly be the goal of future research. Finally, we believe that the therapeutic potential and chemical diversity of this fungus’ metabolites, with more in-depth research, will provide medicinal chemists and biologists with a more promising sustainable treasure-trove for drug discovery.
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Journal:  J Asian Nat Prod Res       Date:  2019-11-18       Impact factor: 1.569

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Journal:  Curr Med Chem       Date:  2020       Impact factor: 4.530

Review 4.  Chemistry and toxicology of molds isolated from water-damaged buildings.

Authors:  Bruce B Jarvis
Journal:  Adv Exp Med Biol       Date:  2002       Impact factor: 2.622

5.  Synthesis and antibacterial activity of silver nanoparticles against gram-positive and gram-negative bacteria.

Authors:  Maribel Guzman; Jean Dille; Stéphane Godet
Journal:  Nanomedicine       Date:  2011-06-02       Impact factor: 5.307

Review 6.  Indoor mold, toxigenic fungi, and Stachybotrys chartarum: infectious disease perspective.

Authors:  D M Kuhn; M A Ghannoum
Journal:  Clin Microbiol Rev       Date:  2003-01       Impact factor: 26.132

7.  Stachybotrys toxins. 1.

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