Bioactivities and Future Perspectives of Chaetoglobosins

Chaetoglobosins belonging to cytochalasan alkaloids represent a large class of fungal secondary metabolites. To date, around 100 chaetoglobosins and their analogues have been isolated and identified over the years from a variety of fungi, mainly from the fungus Chaetomium globosum. Studies have found that chaetoglobosins possess a broad range of biological activities, including antitumor, antifungal, phytotoxic, fibrinolytic, antibacterial, nematicidal, anti-inflammatory, and anti-HIV activities. This review will comprehensively summarize the biological activities and mechanisms of action of nature-derived chaetoglobosins.


Antitumor Activity
Cancer is the second leading cause of death throughout the world and is responsible for an estimated 9.6 million deaths in 2018. Studies have shown that lots of chaetoglobosins have potent antitumor activity in many types of tumor cell lines, such as HL60, A549, SMMC7721, and MCF-7 cell lines.
ere are three noteworthy characteristics of antitumor activity of chaetoglobosins: (1) chaetoglobosins had broadspectrum antitumor activity. Compound 1 inhibited L929, KB3.1, PC-3, and HUVEC cell lines with the IC 50       Furthermore, the structure-activity analysis showed that the cytotoxicity was closely related with the epoxide ring at C-6-C-7 or a double bond at C-6 [12]. (3) Some of chaetoglobosins had differential actions on distinct subtype cell lines of the same tumor. e study by ohinung et al. showed that compound 13 inhibited the growth of cholangiocarcinoma KKU-100 cell (IC 50 � 29.85 μmol/L), but had no inhibitory activity against the cholangiocarcinoma KKU-OCA17 cell line [2]. However, there are obvious disadvantages that are lack of animal experiments and the thorough study about structure-activity relationship. erefore, further studies are needed to confirm the structure-activity relationship in order to better structural modification of lead compounds and obtain more effective drugs.

Evidence-Based Complementary and Alternative Medicine
Currently, except for compound 15, antitumor mechanisms of action of other chaetoglobosins were not reported. Studies have indicated that various mechanisms are involved in the antitumor activities of compound 15 (Figure 2). Ali and colleagues found that compound 15 supressed Rasinduced malignant phenotype due to its dual inhibitory effect on both Akt and JNK signaling pathways. Furthermore, Akt's two activation sites, T308 and S473, are known to be affected by treatment [54,55]. Further study demonstrated that pretreatment with compound 15 decreased the phosphorylation at mTORC2 S2481, which phosphorylates Akt S473, comparable to Torin1, a known mTOR specific inhibitor. erefore, it might be an mTOR inhibitor [33]. Moreover, administration of compound 15 to astroglial cell line can prevent and reverse the inhibition of lindane and dieldrin to gap junction-mediated communication, by stabilizing and reappearing the connexin 43 P2 phosphoform and activating the Akt/GSK-3β pathway [35][36][37].
us, we can infer that the mTOR/Akt/GSK-3β   Evidence-Based Complementary and Alternative Medicine signaling pathway may play an important role in the antitumor action of compound 15. Besides, Li et al. demonstrated that compound 15 showed a more potent cytotoxic to cisplatin-resistant ovarian cancer OVCAR-3 and A2780/ CP70 cell lines than normal ovarian IOSE-364 cell line, by enhancing the p53-dependent caspase-8 activation extrinsic apoptosis pathway and inducing G2 cell cycle arrest via cyclin B1 by increasing p53 expression and p38 phosphorylation. However, it is needed to note that compound 15 did not have effects on phospho-JNK and total JNK in inhibition of growth of OVCAR-3 and A2780/CP70 cells, which was different from mechanism of action in Rastransformed epithelial and human carcinoma cells through inhibition of the JNK signaling pathway [34,55]. We inferred that its antitumor mechanisms of action might be tumor type-dependent, which need to get the experiment certification further. In addition, compound 15 can effectively inhibit angiogenesis through downregulation of VEGF-binding HIF-1 [38].

Phytotoxic Activity
Chaetoglobosin exhibited significant inhibitory activity against many plant pathogenic fungi, indicating they might have a potential application value in agriculture. However, there are some literatures reported several chaetoglobosins showed phytotoxic activities. e study by Li et al. found that compounds 1, 9, 10, 12, 25 and 26 isolated from metabolites of Stenocarpella maydis showed remarkedly the growth inhibition of radish (Raphanus sativus) seedlings with inhibitory rates of >60% at a concentration of 50 ppm. e configurations of C-17 and C-21 in compounds 25 and 26 are closely related with phytotoxicity potency [12]. In addition, compounds 1, 6 and 18 had also been reported inhibited the hypocotyl and root of Alfalfa seedings [27]. erefore, the potential applications of chaetoglobosins in agriculture require comprehensive evaluation.

Antibacterial Effect
With antibacterial resistance becoming more and more serious, the search for new antibacterial agents is also urgent. Studies revealed that chaetoglobosins exhibited significant antibacterial activity against agricultural germs. Zhu et al. demonstrated that compound 17 is isolated from the solid culture of the mangrove endophytic fungus.Penicillium chrysogenum V11, possessed significantly antibacterial against Colletotrichum gloeosporioides with the IC 50 value of 6.13 μmol/L [49]. Except for inhibition against agricultural germs, it also showed the effective on clinical pathogenic bacteria. Hu and his colleague found that compound 57 showed antibacterial activity against Klebsiella pneumoniae (MIC � 4.0 μg/mL) and ESBL-producing Escherichia coli ATCC 35218 (MIC � 16.0 μg/mL), wherein the inhibitory against Klebsiella pneumoniae was stronger than that of the clinically used antibiotic meropenem (MIC � 8 μg/mL), [27].
us, these studies further indicated that they may have a great potential application value in agriculture and clinical aspects.

Immunomodulatory Property
Dendritic cells (DCs), the most potent antigen-presenting cells, possess both immune sentinels and initiators of T-cell response. It is the major target in the modulation of excessive immune responses. Hua et al. confirmed that compound 10 inhibited the CpG-induced DCs maturation and function and suppressed TLR9 expression of CpG-induced DCs through many signaling pathways. In addition, It also inhibited CpG-induced activation of MAPKs (p38 and JNK, but not ERK) and the nuclear translocation of NF-κB and STAT1 ( Figure 3) [29]. erefore, compound 10 may have a great potential application in controlling DCs-associated autoimmune and/or inflammatory diseases.

Other Activities
In addition to the effects described above, studies showed that chaetoglobosins have some other activities, including fibrinolytic, anticoagulant, nematicidal, anti-HIV, and antiinflammatory activities. Compound 1 was reported to inhibit J2 penetration and induce the production of urokinase in endothelial cells, associating with the elevation of fibrinolytic activity [7,29]. Compound 36 showed antiacetylcholinesterase activity and weak anticoagulant activity with PT at 16.8 s [10]. Mori et al. also found compounds 1 and 51 showed antiamebic activities in the cysteine-deprived medium, in comparable to in the cysteine-containing medium [24]. In addition, compounds 66, 67, 68, 71, and 72 showed significant anti-HIV activities, with EC 50 values ranging from 0.11 to 0.55 μmol/L and selectivity index values ranging from 12.33 to 75.42 [11]. Compound 12 could inhibit NF-κB and negatively regulated ERK1/2, p38, and Evidence-Based Complementary and Alternative Medicine JNK1/2 phosphorylations to exert anti-inflammatory property [30]. erefore, chaetoglobosins have a great application prospect.

Conclusion
Microbial metabolites are important sources of discovery for drug lead compounds. e researchers extracted around 100 chaetoglobosins from the fungi's secondary metabolites and found that they possessed a broad range of biological activities, such as antitumor, antifungal, phytotoxic, and anti-HIV activities. erefore, they attract reseachers to further study about antitumor and antimicrobial activities for better clinical application. However, it is needed to note that they have a dual role in agriculture, which is not only against plant-pathogenic fungi but also phytotoxic activities.
us, the potential applications of chaetoglobosins in agriculture require comprehensive evaluation.
However, there are still some shortcomings in existing researches. Firstly, the research on chaetoglobosins remained in vitro, lack of in vivo animal experiments. Secondly, only a few chaetoglobosins have been elucidated about action mechanisms, but action mechanisms of most chaetoglobosins remained unclear. irdly, there was little research on the structure-activity relationship.
In conclusion, it is necessary to further evaluate their bioactivities in vivo experiments, their action mechanisms, and structure-activity relationship, thereby better and more comprehensive development and utilization of chaetoglobosins.