Abstract
In the last decade the prevalence of diabetes has escalated globally and it is estimated that the number of diabetic people will increase to 642 million by 2040. Although numerous classes of pharmaceutical drugs are available to treat Type ll diabetes, they manifest certain side effects. PTP1B has attracted significant interest as an important therapeutic agent and has been validated to target diabetes and obesity. Fungi, in general, produce secondary metabolites with some amazing chemical and structural diversity and are recognized to be a valuable source for therapeutic molecules. In this review, the focus is on describing the PTP1B effects and their potential as anti-diabetic agents for the various metabolites isolated from fungi.
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Introduction
Hyperglycemia is the hallmark of diabetes mellitus. Despite serious efforts to address this issue, the incidence of diabetes mellitus (type-2 diabetes mellitus) and the deaths attributed due to diabetes are rapidly increasing on an international scale. Insulin is an important hormone that performs multiple functions, primarily to maintain normal glucose index within the human body (Hussain et al. 2019; Shrestha et al. 2019). Protein tyrosine phosphatase (PTP) 1B is involved in the down-regulation of insulin and leptin signaling and thus is an emerging therapeutic target for the management of diabetes and obesity (Krishnan et al. 2018).
Both protein tyrosine phosphatases (PTPs) as well as its kinases (PTKs) are signaling enzymes which play vital roles in crucial cellular pathways such as metabolic regulation, mitosis, apoptosis and cell proliferation by controlling phosphorylation of proteins. PTKs actually catalyze the phosphorylation process of tyrosine residues of proteins whereas PTPs hydrolyze the tyrosine phosphate to consequently reverse this action (Shi et al. 2019). PTP1B is a member of the non-receptor PTP family and is widely expressed in the cytoplasmic face of the endoplasmic reticulum. PTP1B mediates the dephosphorylation process that leads to inactivation of insulin and leptin signaling pathways. In connection with insulin signaling, PTP1B results in dephosphorylation of the active insulin receptor (IR) and its downstream targets of the substrate of the insulin receptor while in the case of leptin signaling, it antagonizes Janus kinase (Jak2) activity, which is directly downstream from the leptin receptor. PTP1B negatively regulates signaling pathways of both insulin and leptin and consequently is involved in glucose and lipid homeostasis. In a high fat animal diet model, ablation of the PTPN1 gene that encodes PTP1B resulted in increased insulin sensitivity and resistance to obesity (Shi et al. 2019).
PTP1B has attracted significant interest with an enormous therapeutic potential and is a validated target against diabetes and obesity. PTP1B is also associated with dendritic cell-based cancer immunotherapy since it is involved in the progression of various types of cancers (Xu et al. 2019). Since PTPs exhibit a high degree of structure similarity in their active sites, selectivity and high affinity for PTP1B are major challenges in the development of PTP1B inhibitors as drugs (Zhang et al. 2007a). During the past two decades, various efforts have been made to discover potential PTP1B inhibitors with broad structural diversity where it was found that most of the inhibitors incorporated phosphotyrosine (pTyr) mimetics in order to develop the essential binding ability at the PTP1B catalytic site. In addition, novel PTP1B inhibitors can overcome these limitations if they were able to target alternative binding sites other than the catalytic site of PTP1B (Tang et al. 2018).
Natural products are an important source in lead compounds for the fight against cancer, bacterial, malaria, fungal infections, autoimmune disorders, and cardiovascular diseases (Bills and Gloer 2016; Newman and Cragg 2016). Additional numerous natural product derived agricultural chemicals have been reported (Bills and Gloer 2016; Asolkar et al. 2013; Rimando and Duke 2006). Fungi are capable to generate interesting and novel secondary metabolites with fascinating chemical diversity from simple starting materials viz., sugars, organic acids, terpenes, amino acids, pyrimidines, and purines (González-Medina et al. 2017). Fungi are in particular, abundant sources of lead compounds and have spectacularly contributed for the beneficiation of human and animal health. The best known examples are penicillins, Cephalosporin C, cephalosporins, pleuromutilin, griseofulvin, echinocandin B, enfumafungin, lovastatin, cyclosporin A, myriocin, ergotamine, ergocryptine, mizoribine, and gibberellic acid (Bills and Gloer 2016).
A literature survey revealed that numerous natural products have been reported to possess PTP1B inhibitory effects. Moreover several reviews dealing with PTP1B inhibitor drug development, have been published. However, the majority of them centered on synthetic PTP1B inhibitors (Zhang et al. 2007b; Combs 2010; Nichols et al. 2006; Taylor and Hill 2004; Taylor 2003; Lee and Wang 2007; Mohler et al. 2009; Thareja et al. 2012). In addition Zhao et al. (2018) published a review on natural products which showed PTP1B inhibition (Zhao et al. 2018) and earlier, Wang et al. (2015) published a review about natural and semisynthetic PTP1B inhibitors covering the literature from 2009 to 2014. Additionally, Jiang et al. (2012) reviewed the natural PTP1B inhibitors from 2002 to 2011 while two reviews have been published on PTP1B inhibitory effects of marine natural products (Ezzat et al. 2018; Zhou et al. 2017). The current literature review aims to give an overview on PTP1B inhibitory effects of secondary metabolites derived from various fungi.
We have used various databases as an integral part of our literature search methodology available from the scientific literature (Science Finder, Springer, Science direct, PubMed, Scopus, and Google Scholar) in order to collect and collate all available literature reports. In addition, our search utilized keywords such as: “protein tyrosine phosphatase 1B” or “PTP1B” (alone or in combination), “fungus” or “ fungi” with an additional keyword “protein tyrosine phosphatase 1B” or “PTP1B” among others.
Alkaloids
Indole and indole diketopiperazine alkaloids
Indole-terpenoids, penerpenes A (1) and B (2) along with paxilline (3) (Fig. 1) and emindole SB (4), were reported from the fungus Penicillium sp. and their structures were established via spectroscopic and ECD analysis. Among these compounds, emindole SB (4: IC50: 0.7 µM) was the most potent PTP1B inhibitor followed by compounds 1 (IC50: 1.7 µM) and 2 (IC50: 2.4 µM). On the other hand, paxilline (3) was moderately active with IC50: 10.6 µM (Kong et al. 2019) (Table 1). Paxilline (3) was first isolated from P. paxilli (Cole et al. 1974) and showed various biological effects (Knaus et al. 1994; Zhou and Lingle 2014; McLeay et al. 1999). Emindole SB (4) was previously reported from the fungi Emericella striata (Nozawa et al. 1988), Albophoma yamanshiensis (Huang et al. 1995), Aspergillus oryzae (Qiao et al. 2010).
Fructigenine A (5) (Fig. 2) is a unique indole alkaloid which features a reverse-prenyl moiety was originally isolated from various strains of Penicillium spp. (Arai et al. 1989; Sohn et al. 2013), and exhibited PTP1B effects with IC50: 10.7 µM (Sohn et al. 2013). The diketopiperazine alkaloid, echinulin (6) was reported from the fungus Eurotium sp. (Sohn et al. 2013) along with several Aspergillus spp. (Bräse et al. 2009; Liang et al. 2018) and is reported to possess moderate PTP1B inhibition with IC50: 29.4 µM (Sohn et al. 2013).
Structures of alkaloids 1–6
Two indole diketopiperazine dimers, SF5280-451 (7) and SF5280-415 (8) (Fig. 2) were isolated from Aspergillus sp. and demonstrated PTP1B activity with IC50: 12.9 and 14.2 µM, respectively (Cho et al. 2018). The SAR study for these compounds showed that an exchange of the benzyl group (compound 7) or the iso butyl group (compound 8) does not effect the activity to any great extent. Indole-terpenoids, penerpenes E (9: IC50: 14 µM), F (10: IC50: 27 µM) and H (11: IC50: 23 µM) were reported from the fungus Penicillium sp. and possesses activity towards PTP1B. Moreover compound 9 possesses a core with an unusual 6/5/5/6/6/5/5 heptacyclic framework (Zhou et al. 2019). 7-Hydroxypaxilline-13-ene (12) was also isolated from Penicillium sp. (Zhou et al. 2019; Ariantari et al. 2019) and this paxilline analog illustrated PTP1B effects with IC50: 13 µM (Zhou et al. 2019).
Amauromine (13) was initially reported from the fungus Amauroascus sp. (Takase et al. 1984, 1985) and the subsequent synthesis of this compound, due to its unusual chemical structure, was later achieved to unambiguously confirm the assigned structure (Mueller and Stark 2016; Takase et al. 1986). Amauromine (13) was recently reported from the fungus Malbranchea circinate and demonstrated PTP1B effects with IC50: 15.3 µM (Rangel-Grimaldo et al. 2020). Malbrancheamide (14) was isolated from the fungi Penicillium sp., Aspergillus sp. and Malbranchea aurantiaca (Martinez-Luis et al. 2006; Figueroa et al. 2008; Miller et al. 2008; Rangel-Grimaldo et al. 2020) and possesses significant PTP1B effects with IC50: 14.5 µM (Rangel-Grimaldo et al. 2020).
Structures of alkaloids 7–14
Quinoline and quinazolinone alkaloids
Marinamide (15) (Fig. 3) was produced by the fungus Aspergillus sp. and this compound inhibited PTPlB with an IC50: 23.3 µg/mL. In 2006, Feng and Lin isolated marinamide (15) and proposed the structure 16 for marinamide which turned out to be incorrect (Feng & Lin 2006). In 2010, She, Lin and co-workers reported on the isolation of marinamide from Penicillium sp. (Shao et al. 2010). A year later, Koenig and coworkers determined the correct structure for marinamide via X-ray spectroscopy (Elsebai et al. 2011) to be 15 which was further confirmed via total synthesis (Naveen et al. 2017). Additionally, viridicatol, a quinoline alkaloid (17) also demonstrated PTP1B inhibition with IC50: 64 µM (Sohn et al. 2013) which compound was isolated from the fungi Penicillium sp (Birkinshaw et al. 1963) and Eurotium sp. (Sohn et al. 2013).
Quinazolinone alkaloids have been reported from various fungi and demonstrated to possess a wide range of biological effects (Kshirsagar 2015). Quite recently, the two quinazolinone alkaloids, 18 and 19 (Fig. 3) were isolated from the fungus Malbranchea circinate and demonstrated PTP1B activity with IC50: 17.3 and 106.2 µM, respectively. Interesting, compound 18 was six fold more potent than 19 which would suggest that the C-15 hydroxyl group plays a crucial role in the activity (Rangel-Grimaldo et al. 2020). Notably, compounds 18 and 19 featured a quinazolinone core linked to an aromatic part (ring C) via the imine carbon and this type of framework is also present in sclerotigenin (Witt and Bergman 2002), circumdatin F (Rahbæk and Breinholt 1999), asperlicins (Tseng et al. 2010), and benzo-malvins (Clevenger et al. 2018; Jang et al. 2012).
Structures of alkaloids 15–19
Miscellaneous alkaloids
Terreusinone A (20) was produced by the fungus Cordyceps gracilioides and PTP1B has an inhibition of 12.5 µg/mL (Wei et al. 2015). Cyclopenol (21) is a benzodiazepine alkaloid which was reported from various Aspergillus sp. (Zhuravleva et al. 2016) and Penicillium sp. (Sohn et al. 2013; Bräse et al. 2009), and illustrated activity towards PTP1B with an IC50: 30 µM (Sohn et al. 2013). The pyridone alkaloid, fumosorinone (22) (Fig. 4) is an amorphous solid produced by the fungus Isaria fumosorosea and this alkaloid demonstrated significant PTP1B effects with an IC50: 14.0 µM. Furthermore, a kinetic study revealed that compound 22 is a noncompetitive inhibitor (Liu et al. 2015a, b).
Fumosorinone (22) furthermore demonstrated a significant similarity with the 2-pyridones viz., tenellin (Eley et al. 2007), aspyridone A (Xu et al. 2010), and desmethylbassianin (Heneghan et al. 2011). These compounds could conceivably share similar biosynthetic pathways (Liu et al. 2015a, b). In another study, Liu et al. reported that compound 22 reduces PTP1B expression, increases the insulin-provoked glucose uptake, and also decreases blood glucose and lipid levels in mice (Liu et al. 2015a, b). Moreover, fumosorinone (22) is also active towards other PTPs (Chen et al. 2015a, b). The fungus Isaria fumosorosea produces fumosorinone A (23), which inhibits the activity of PTP1B with IC50: 3.24 µM (Zhang et al. 2017). This report revealed that compound 23 is more potent than compound 22 and 4-times more potent than sodium orthovanadate (IC50 = 11.3 µM). Quite recently, Schobert and his group reported the total synthesis of fumosorinone A (23) (Bruckner et al. 2018).
Structures of alkaloids 20–23
Depsides
KS-506a (24) and KS-506m (25) (Fig. 5) were isolated from Micromucor ramannianus and evaluated for their PTP1B inhibition. Interestingly, compound 24 possesses potent PTP1B inhibition with an IC50: 4.9 µM and Ki: 2.7 µM (Table 1) while metabolite 25 proved to be moderately active IC50: 69.9 µM (Oh et al. 2004). Notably, compounds 24 and 25 were previously isolated from Mortierella vinacea (Kuroda 1988). In another report the fungus Cosmospora sp. was described to produce the glycosylated depside, aquastatin A (26) and this compound was shown to possess potent PTP1B effects with an IC50: 0.19 µM (Seo et al. 2009). In addition, compound 26 was converted into its methyl ester 27 whose PTP1B activity proved to unfortunately be less than (IC50: 17 µM). This indicated that the carboxylic acid moiety plays a crucial role in the inhibition mechanism (Zhang et al. 2008a; Na et al. 2006). Compound 26 after being subjected to enzymatic hydrolysis, produced compound 28 and this latter metabolite inhibited PTP1B with IC50: 0.22 µM). Further hydrolysis of 26 with NaOH produced product 29 which inhibited PTP1B with an IC50: 0.59 µM (Seo et al. 2009). This study suggest that the additional aromatic ring present in compound 26 has a very minor influence on PTP1B effects.
Structures of depsides 24–29
Trivaric acid (30) (Fig. 6) was initially reported to be isolated from lichen (Culberson et al. 1999) but later also from the fungus F10Z1082 (Sun et al. 2017a, b). Trivaric acid (30) illustrated very potent effects towards PTP1B with an IC50: 0.17 µM. Moreover, compound 30 possesses an insulin sensitizing activity in diabetic and normal mice (Sun et al. 2017a, b). In another study trivaric acid (30) inhibited PTP1B very strongly with an IC50: 173 nM. An in vivo study of this depside demonstrated that it increased insulin stimulation and glucose consumption. In addition compound 30 decreases glucose levels and boosts insulin resistance (Sun et al. 2017a, b). Similarly, nordivaricatic acid (31) and the divarinyl divarate (32) were reported as lichen metabolites (Zheng et al. 2012) and later isolated from the fungus F10Z1082 (Sun et al. 2017a, b). Depsides 31 and 32 strongly inhibited PTP1B with IC50: 0.51 and 0.72 µM respectively (Sun et al. 2017a, b). An SAR study of compounds 31 and 32 demonstrated that the carboxylic acid plays only a minor role in PTP1B effects.
Structures of depsides 30–32
Xanthones and anthraquinones
Bis-tetrahydroxanthones, asperdichrome (33) and secalonic acid F (34) (Fig. 7) were obtained from the fungus Aspergillus sp. Metabolites 33 (IC50: 6.0 µM) and 34 (IC50: 9.6 µM) demonstrated significant activity towards PTP1B (Yamazaki et al. 2016). Secalonic acid F (34) was previously reported from Aspergillus sp. (Andersen et al. 1977) and the lichen Diploicia canescens (Millot et al. 2009). Secalonic acid F (34) was recently isolated from Aspergillus sp. and illustrated PTP1B effects with IC50: 5.9 µM (Rotinsulu et al. 2017). 4-Isoprenylravenelin (35) was produced by the fungus Malbranchea circinate and illustrated activity towards PTP1B with an IC50: 13.9 µM (Rangel-Grimaldo et al. 2020). Anthraquinone glycosides 36–39 were produced by the fungus Malbranchea circinate and these metabolites possess a D-ribofuranosyl group. Moreover, all these compounds demonstrated PTP1B effects with IC50 values ranging from 25.5 to 92.5 µM. Metabolites 37 (IC50: 27.9 µM) and 39 (IC50: 25.5 µM) illustrated better effects than compounds 36 and 38 (Rangel-Grimaldo et al. 2020). 6-O-Methylalaternin (40) was produced by the fungi Stemphylium globuliferum (Debbab et al. 2009) and Alternaria sp. (Qi 2019) and were shown to possess potent PTP1B effects with IC50: 0.62 µM (Qi 2019).
Structures of xanthones and anthraquinones 33–40
Azaphilones
Pinophilin C (41) (Fig. 8) was produced by the fungus Cordyceps sp. (Wei et al. 2015; Isaka et al. 2001) and illustrated PTP1B inhibition with 6.8 µg/mL (Wei et al. 2015) (Table 2). Deflectins C1-C3 (42–44), D1-D2 (45,46), E (47), 1a-1c (48–50), 2a (51), and 2b (52) were reported to be isolated from the fungus Aspergillus deflectus. Azaphilones 42–52 possess a wide spread of activity towards PTP1B with IC50: 2.1–40.4 µM. Among these metabolites, compounds 50 and 52 were the most potent with IC50: 2.1 and 2.6 µM. An SAR study showed that the presence of the γ-lactone ring with the double bonds at C-8/C-12, the length of the aliphatic side chain and the presence of a C-2’ methyl on the side chain all play a positive role in the PTP1B activity (Huo et al. 2020). Compounds 48–52 were previously isolated from Aspergillus deflectus (Musso et al. 2010; Anke et al. 1981; Gao et al. 2013).
Structures of azapholines 41–52
Cerebrosides
Glycosphingolipids (cerebrosides) were first reported by the German physician J. L. W. Thudichum in the second half of the nineteenth century (Thudichum 1884). The structure of the actual cerebroside isolated by J. L. W. Thudichum was determined by Carter (Carter et al. 1965). Cerebrosides are crucial and important constituents in a wide range of organs and tissues in biological systems. Cerebrosides mainly comprise two parts viz., a sugar part (red part) and a ceramide nucleus while the latter in turn comprises of a long-chain „sphingoid base“ (blue part) and an amide-linked long-chain fatty acid (green part).
A large number of cerebrosides have been reported from plants and fungi and have been shown to possess a diverse range of biological activities (Tan and Chen 2003). Cordycerebroside B (53) (Fig. 9) was isolated from the fungus Cordyceps militaris and inhibited PTP1B with an IC50: 4.68 µM. This activity was higher than the standard ursolic acid (IC50: 5.15 µM) (Sun et al. 2019). Furthermore, cerebroside 54 was isolated from the fungi, Cordyceps militaris (Sun et al. 2019), Schizophyllum commune (Kawai and Ikeda 1983) and Cortinarius tenuipes (Tan et al. 2003), and inhibited PTP1B with an IC50: 16.9 µM (Sun et al. 2019). Cordycerebroside A (55) was obtained from the fungus Cordyceps militaris (Sun et al. 2019; Chiu et al. 2016) and was shown to possess activity towards PTP1B with an IC50: 10.4 µM (Sun et al. 2019) (Table 2). On the other hand, soya-cerebroside I (56) was initially reported as a plant metabolite (Kim et al. 2001) but quite recently this compound was isolated from the fungus Cordyceps militaris (Sun et al. 2019) and reported to show PTP1B inhibition with an IC50: 18.9 µM.
Structures of cerebrosides 53–56
Triterpenes and steroids
Russula lepida is included in the subdivision of higher fungi viz., Basidiomycotina. (Clericuzio et al. 2012) after a phytochemical investigation of fruiting bodies of R. lepida led to the isolation of seco-cucurbitane triterpenes 57 and 58 (Maarisit et al. 2017) (Fig. 10). Notably, compound 57 demonstrated potent PTP1B effects with an IC50: 0.4 µM which is higher than the standard oleanolic acid (IC50: 1.1 µM) (Table 2). Moreover, metabolite 58 was moderately active with an IC50: 20.4 µM (Maarisit et al. 2017). An SAR study showed that the CH2OH group (present in compound 57) causes a larger effect than the carboxylic acid group (present in compound 58). A C25 sterol bearing the C-5/C-8 peroxide group, phomasterol A (59) was produced by the fungus Phoma sp. and illustrated activity towards PTP1Bc with an IC50 : 25 µM (Chen et al. 2015a, b).
Structures of triterpenes and steroids 57–59
Sesquiterpenes
The sesquiterpenes, clitocybulols C (60: IC50: 36.0 µM), G (61: IC50: 49.5 µM), and L (62: IC50: 38.1 µM) (Fig. 11) were reported from the fungus Pleurotus cystidiosus and illustrated activity towards PTP1B (Tao et al. 2016a, b). The SAR study of compounds 60–62 revealed that the CH2OAc and CH2OH groups enhance the PTP1B effects and activity was decreased when these groups was replaced by a methyl group (compound 61). Ylangene-type sesquiterpenes, postinins A (63) and B (64) were isolated from the fungus Postia sp. Metabolite 63 illustrated significant effects towards PTP1B with IC50: 1.6 µg/mL while compound 64 was less effective with IC50: 6.2 µg/mL (Fan et al. 2014). Bisabolene sesquiterpenes, pleurotins A (65) and E (66) were isolated from the fungus Pleurotus citrinopileatus and both compounds exhibited PTP1B inhibition with IC50: 32.1 and 30.5 µM respectively (Tao et al. 2016a, b) (Table 2).
Structures of sesquiterpenes 60–66
Isocoumarin-based metabolites
Two isocoumarin analogs, phelligridins H (67: IC50: 3.1 µM) and I (68: IC50: 3.0 µM) (Fig. 12) were isolated from the fungus Phellinus igniarius and both possess good PTP1B activity (Wang et al. 2007). Cladosporamide A (69) was isolated from the fungus Cladosporium sp. and illustrated moderate activity towards PTP1B with IC50: 48 µM (Rotinsulu et al. 2018). Asperentin B (70) was produced by the fungus Aspergillus sydowii (Wiese et al. 2017) and its structure was noted to be quite close to that of asperentin (Scott et al. 1971). Asperentin B (70) illustrated significant PTP1B effects with an IC50: 2.0 µM (Table 2) and these effects were six fold higher than the standard suramin (IC50: 11.8 µM). In addition, compound 70 was only weakly active towards Propionibacterim acnes and demonstrated no effects towards Xanthomonas campestris, Septoria tritici, Candida albicans, Staphylococcus lentus, HT29 and HepG2 cancer cells (Wiese et al. 2017).
Structures of isocoumarin-based metabolites 67–70
Meroterpenoids
Meroterpenoids are a class of secondary metabolites originating from a biosynthetic pathway between a hybrid polyketide or non-polyketide and terpenoid (Peng and Qiu 2018; Geris and Simpson 2009; Matsuda and Abe 2016). Merosesquiterpenes, verruculide A (71), chrodrimanins A (72) and H (73) (Fig. 13) were reported from the fungus Penicillium verruculosum. Compounds 71 (IC50: 8.4 µM) and 72 (IC50: 8.5 µM) inhibited PTP1B almost to the same level. Notably, metabolite 73 was less effective with IC50: 14.9 µM (Yamazaki et al. 2015). In another report the meroterpenoid, preaustinoid A6 (74) was reported from the fungus Penicillium sp. and inhibited PTP1B with an IC50: 17.6 µM. In addition, a kinetic study revealed that compound 74 is a noncompetitive inhibitor having a Ki: 17.0 µM (Park et al. 2019). It is also noted that preaustinoid A3 (75) is produced by various fungal species of Penicillium sp. (Park et al. 2019; Fill et al. 2007) and possesses PTP1B activity with IC50: 58.4 µM (Park et al. 2019).
Chrodrimanins O (76), R (77), S (78) and compound 79 are all produced by the fungus Penicillium sp. Metabolite 76 contains the unusual trichlorinated pattern bearing an uncommon dichloromethine moiety. Furthermore, metabolites 76–79 illustrated PTP1B activity with IC50 ranging from 39.6 to 71.6 µM. However, these compounds were not active towards HepG2, A549, and Hela cancer cells (Kong et al. 2017). Meroterpenoid, furanoaustinol (80) is produced by the fungus Penicillium sp. and this metabolite weakly inhibited PTP1B IC50: 77.2 µ M (Park et al. 2018).
Structures of meroterpenoids 71–80
Biphenyl ethers
The fungus Phoma sp. produces the biphenyl ether, 1-methoxy-3,5′-dimethyl-2,3′-oxybiphenyl-5,1′,2′-triol (81) and in an anti-PTP1B assay, 81 (IC50: 13.0 µM) (Fig. 14; Table 3) displayed significant activity towards PTP1B (Sumilat et al. 2017a, b). Cyperine (82) initially reported as a herbicide isolated from Alternaria sp. (Singh and Pandey 2019) as well from the plant (Cyperus rotundus) (Sharma and Rani 2016). In 2017, cyperine (82) was reported to be isolated from the fungus Phoma sp. and illustrated PTP1B activity with an IC50: 17.0 µM (Sumilat et al. 2017a, b). In comparison with the activity of oleanolic acid (positive control; IC50 = 1.3 µM), compounds 81 and 82 appear to be good candidates for further studies. A mode of action evaluation based on Huh-7 cells, demonstrated that only compound 82 exhibited 26% growth inhibition (Sumilat et al. 2017a, b).
Structures of biphenyl ethers 81 and 82
Palmarumycins and naphthopyranones
Palmarumycins have been isolated from various fungi and reported to possess interesting biological activities (Macías-Rubalcava et al. 2008; Schlingmann et al. 1996; Dong et al. 2008; Martinez-Luis et al. 2008; Seephonkai et al. 2002; Chu et al. 1994, 1995; Singh et al. 1994; Sakemi et al. 1995; Wipf et al. 2001; Powis et al. 2006). Guignardin C (83) was obtained from the fungus Guignardia sp. and inhibited PTP1B with an IC50: 25.7 µM. In addition, compounds 83 possesses antimicrobial activity towards Staphylococcus aureus (Ai et al. 2014). The naphtho-γ-pyrone, rubrofusarin B (84) (Fig. 15) is produced by various fungi viz., Aspergillus sp. (Huang et al. 2010, 2011; Sakurai et al. 2002; Zhang et al. 2008a; Song et al. 2004; Xiao et al. 2014; Zhan et al. 2007; Kim et al. 2020), Alternaria sp. (Shaaban et al. 2012), and Cladosporium herbarum (Ye et al. 2005). This compound inhibited PTP1B with IC50: 6.5 µM (Kim et al. 2020) (Table 3).
Additionally TMC-256A1 (85) was obtained from various Aspergillus sp. (Zhang et al. 2008b; Zahn et al. 2007; Huang et al. 2007; Sakurai et al. 2002; Kim et al. 2020) and illustrated PTP1B effects with IC50: 5.1 µM (Kim et al. 2020). The SAR study of compounds 84 and 85 revealed that the methyl group in compound 84 does not alter the PTP1B effects. Interestingly, aurasperone F (86) (Shaaban et al. 2012; Bouras et al. 2005, 2007; Kim et al. 2020) and fonsecin (87) (Shaaban et al. 2012; Zhang et al. 2008a; Ehrlich et al. 1984; Bouras et al. 2005; Zhan et al. 2007; Sakurai et al. 2002; Kim et al. 2020) are both quite active and strongly inhibited PTP1B with IC50: 7.9 and 3.3 µM respectively (Kim et al. 2020). Notably, the effects of fonsecin (87) was higher than the standard ursolic acid (IC50: 4.3 µM (Kim et al. 2020).
Structures of palmarumycins and naphthopyraones 83–87
Polyketides
The polyketides, penostatins A (88), B (89), C (90) and J (91) (Fig. 16) produced by the fungus Isaria tenuipes were tested for their biological activity. It was found that compounds 88–91 possess significant effects towards PTP1B with IC50 values ranging from 0.37 to 43.6 µM. Among these compounds, penostatin B (89) was the most potent inhibitor with an IC50: 0.37 µM followed by penostatin A (88: IC50: 12.5 µM) (Chen et al. 2014). The SAR study of compounds 88 and 89 revealed that the stereochemistry of the hydroxyl group plays an important role in the PTP1B effects. Polyketides, trichoketides A (92) and B (93) are produced by the fungus Trichoderma sp. together with a few C-8 epimers. Octaketides 92 and 93 possess PTP1B effects with IC50: 53.1 and 65.1 µM, respectively (Yamazaki et al. 2015). Similarly, trichodermaketones C (94) and D (95) are produced by various Trichoderma sp. (Song et al. 2010; Mukhopadhyay et al. 1996; Yamazaki et al. 2015a) and these compounds also inhibited PTP1B with IC50: 68.0 and 55.9 µM (Table 3), respectively (Yamazaki et al. 2015a).
Structures of polyketides 88–95
The fungus Aspergillus sp. produces the polyketides, (±)-tylopilusin D (96) and funalenone (97) (Fig. 17). Both compounds possess PTP1B activity with IC50 values of 8.1 and 6.1 µM, respectively (Kim et al. 2020). Botcinin A (98) and B (99) are produced by the fungus Botryotinia sp. In a PTP1B evaluation study, metabolite 99 illustrated significant inhibition with an IC50: 53.6 µM, while metabolite 98 was only a weak inhibitor (IC50 = 340.7 µM) (Table 3). An SAR study of compounds 98 and 99 demonstrated that the length of the alkyl chain plays a crucial role of PTP1B effects. The authors observed that botcinins A (98) and B (99) were unstable in MeOH and slowly transformed into botcinin D (100) and botcinin G (101) respectively. The metabolite 101 was two-fold less active (IC50 = 96.2 µM) than compound 99. Similarly, 100 was also less active (IC50 = 461.2 µM) than its natural precursor 98 (Kim et al. 2012).
Structures of polyketides 96–101
Ascochitine (102) (Fig. 18) was reported to be isolated from various fungal species of Ascochyta sp. (Seibert et al. 2006; Kim et al. 2016; Bertini et al. 1956; Oku and Nakanishi 1963; Venkatasubbaiah and Chilton 1992) and found to possess PTP1B activity with an IC50: 38.5 µM (Seibert et al. 2006). The polyketides, tanzawaic acids A (103) and B (104) were isolated from Penicillium sp. (Quang et al. 2014; Shin et al. 2016) and demonstrated activity towards PTP1B with IC50 values of 8.2 µM and 30 µM respectively (Quang et al. 2014). The fungus Phoma sp. produces (10’S)-verruculide B (105) which was shown to possess PTP1B effects with an IC50: 13.7 µM. Moreover, this compound was also active towards SHP1 and TCPTP (Gubiani et al. 2017).
Penicillium sp. produced the pyrone-derived metabolite, penstyrylpyrone (106) which demonstrated good PTP1B inhibitory effects with an IC50: 5.28 µM (Lee et al. 2013). The chaetocyclinone derivative, anhydrofulvic acid (107) was produced initially by Penicillium sp. (Lösgen et al. 2007) and possesses antimicrobial effects towards Candida sp. (Fujita et al. 1999). The latter compound 107 was also reported from various Penicillium sp. Yamauchi et al. (1984) synthesized this compound to confirm its assigned structure. Lee et al. (2013) reported that anhydrofulvic acid (107) possesses inhibitory effects towards PTP1B with an IC50: 1.90 µM and this compound was more potent than the standard ursolic acid (IC50: 3.1 µM).
Structures of polyketides 102–107
Cryptosporioptide A (108) (Fig. 19) was produced by the fungi Cordyceps gracilioides (Wei et al. 2015) and Cryptosporiopsis sp. (Tousif et al. 2014). This compound illustrated reasonable PTP1B inhibition with an IC50: 7.3 µg/mL (Wei et al. 2015). The polyketide, neglectine A (109), was reported from the fungus Pestalotiopsis neglecta and illustrated PTP1B inhibitory effects with an IC50: 6.7 µg/mL (Gao et al. 2019) (Table 4).
Structures of polyketides 108 and 109
Micellaneous
Butanolide A (110) (Fig. 20) was reported from the fungus Penicillium sp. and illustrated moderate inhibitory effects towards PTP1B with an IC50: 27.4 µM (Zhou et al. 2018). Betulactone B (111) was reported from the fungus Lenzites betulinus and demonstrates PTP1B inhibitory effects with an IC50: 21.5 µg/mL (Wen et al. 2017). Talarodride (112) was produced by the fungus Talaromyces purpurogenus and inhibited PTP1B by 76% (Zhao et al. 2019).
Structures of compounds 110–112
Monodictyphenone (113) (Fig. 21) was produced by the fungus Penicillium albobiverticillium and was shown to possess moderate PTP1B inhibitory effects with an IC50: 36 µM (Sumilat et al. 2017a, b). Flavoglaucin (114) was isolated from Eurotium sp. (Gao et al. 2011; Sohn et al. 2013) and showed PTP1B inhibition with an IC50: 13.4 µM (Sohn et al. 2013). Prenylflavanone, (2S)-7,4’-dihydroxy-5-methoxy-8-(γ,γ-dimethylallyl)-flavanone (115) was initially isolated as a plant metabolite (Kang et al. 2000) and later from the fungus Cladosporium sp. and illustrated moderate inhibitory effects towards PTP1B with IC50: 11 µM (Table 4) (Rotinsulu et al. 2018).
Structures of compounds 113–115
The fungus Isaria fumosorosea produces the most intriguing peptide, beauvericin (116) (Fig. 22), which exhibited very low inhibitory activity with an IC50 value (0.59 µM) against PTP1B. Interestingly, this compound’s inhibitory effects was 22-times more potent than sodium orthovanadate (IC50 = 11.3 µM) which is used as reference compound (Zhang et al. 2017). In another investigation, the fungus Aspergillus sp. afforded the very interesting cyclic peptide, malformin A1 (117) which inhibited PTP1B with an IC50: 5.2 µM (Kim et al. 2020).
A mixture of arugosin N (118) and its 1,6,10-trihydroxy-8-methyl-2-(3-methyl-2-butenyl)dibenz[b,e]oxepin-11(6H)-one (119) were produced by the fungi Malbranchea circinate (Rangel-Grimaldo et al. 2020) and Talaromyces flavus (Sun et al. 2016). The epimeric mixture of compounds 118 and 119 has been reported to possess PTP1B inhibitory effects with an IC50: 30.3 µM (Rangel-Grimaldo et al. 2020) (Table 3). Divaric acid (120) and 2,4-dihydroxy-6-[(3E,5E)-nona-3,5-dien-1-yl] benzoic acid (121) were produced by the fungus F10Z1082 and these compounds possess PTP1B inhibitory effects with IC50: 1.58 and 4.27 µM respectively. The PTP1B activity of metabolite 120 was 2.7-fold more potent than that of metabolite 121, indicating that that the length and double bonds of the carbon side chain on C-6 of the aromatic ring might be crucial for activity (Sun et al. 2017a, b).
Structures of compounds 116–121
Conclusion and future perspective
Fungal metabolites play a vitally important and sustainable role in initiating drug development. In this context, the last two decades have been observed as a most fruitful period in isolating low molecular weight antidiabetic compounds from fungi. The fascinating research on PTP1B inhibitors that has been accomplished based on fungal metabolites cannot be underestimated. Moreover some of these fungal metabolites possess PTP1B effects with IC50: < 1 µM and notably the depside analog trivaric acid (30) inhibited PTP1B very strongly with an IC50: 173 nM. These active fungal metabolites furnish new chemical entities for developing novel candidates for the treatment of diabetes and obesity. Notably, further synthetic and biological studies on these chemical templates are necessary in order to obtain intriguing SAR information. Furthermore, the mode of actions of these compounds have not yet been fully investigated and future research should focus on establishing the mechanism of action of these active compounds.
It has been reported that an insufficient number of lead compounds have reached clinical trials. A benzothiophene derivative (Liu 2003) and ertiprotafib (Xue et al. 2019) have failed in the Phase II clinical trial because of their unsatisfactory side effects. Some reports showed that two more PTP1B inhibitors viz., SI-1436 (Lantz et al. 2010) and JTT-551 (Ito et al. 2014) have reached clinical trials. The major issues which are associated with PTP1B drug development is their cell permeability, bioavailability coupled with their poor selectivity. Although some of these fungal metabolites illustrated significant PTP1B effects, very few semi-synthetic secondary metabolites have been synthesized for PTP1B activity employing natural product scaffolds. Furthermore, computational studies illustrated that natural products cover larger areas of chemical space than synthetic compounds. In addition, natural products comprise higher numbers of stereogenic centers along with greater diversity in heteroatomic rings. Moreover, natural products have inspired synthetic protocols which can therefor access lead compounds with better potency, selectivity, lipophilicity and bioavailability.
Another strategy for the establishment of PTP1B inhibitors is that these can be used in combination therapy by utilizing PTP1B inhibitors for treatment regarding diabetes/obesity protocols. These combined treatment strategies could have a synergistic effect and may be more effective than either treatment alone. Literature revealed that a PTP1B inhibitor is used with anti-ErbB2 antibodies to treat breast cancer (Julien et al. 2007). In another study, Delibegovic et al. (2009) proposed that the combined treatment of PPARγ agonist and PTP1B inhibition could be more effective for diabetes and obesity. In view of the outstanding value of PTP1B drug targeting, only a few screening methods are available for testing for PTP1B inhibition viz., fluorescence method, colorimetric method employing p-nitrophenyl phosphate (PNPP) as substrate and scintillation proximity assay (SPA). However, those technologies could lead to false positive results in some cases which could create more difficulties in PTP1B drug discovery. Therefore, further high-throughput methods are essential in order to screen lead PTP1B inhibitors more efficiently and accurately. The information provided in this literature review may help to achieve the goal of establishing therapeutic drugs for diabetes and obesity with more efficacy.
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The author H. Hussain is thankful to the Alexander von Humboldt Foundation for its generous support in providing the research opportunity in Germany which facilitated the writing of this review.
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This research work is dedicated to Prof. Dr. M. Iqbal Choudhary on his 60th birthday.
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Nazir, M., Saleem, M., Ali, I. et al. Fungal metabolites as anti-diabetic agents: emphasis on PTP1B inhibitors. Phytochem Rev 20, 119–143 (2021). https://doi.org/10.1007/s11101-020-09701-9
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DOI: https://doi.org/10.1007/s11101-020-09701-9