*3.6. α-Glucosidase Inhibitory Activity*

Diabetes is considered as one of the biggest current health crises. Controlling carbohydrate digestibility by inhibiting starch digestive enzyme (i.e., α-amylase and α-glucosidase) activities is an efficient strategy to control postprandial hyperglycemia [43]. Some sorbicillinoids have been screened for their α–glucosidase inhibitory activity (Table S9).

Six sorbicillinoids, including 5-hydroxy-dihydrodemethylsorbicillin (**15**), bisorbicillpyrone A (**41**), dihydrodemethylsorbicillin (**79**), tetrahydrotrichodimerol (**88**), tetrahydrobisvertinolone (**89**), and 10,11-dihydrobisvertinolone (**90**), exhibited α-glucosidase inhibitory activity, with IC<sup>50</sup> values ranging from 115.8 to 208.5 µM. Among these, 5 hydroxy-dihydrodemethylsorbicillin (**15**) showed the strongest inhibitory activity against α-glucosidase with an IC<sup>50</sup> value of 36.0 µM, stronger than that of acarbose [10].

2 0 ,30 -dihydrosorbicillin (**2**), which was isolated from the fungus *Aspergillus* sp. HNWSW-20 from Chinese agarwood (*Aquilaria sinensis*), showed α-glucosidase inhibitory activity [44].

#### *3.7. Other Biological Activities*

Other biological activities of the sorbicillinoids recently revealed from fungi mainly include antiallergic, antioxidant, neuroprotective and neuritogenic, antihuman-immunodeficiency-virus (HIV), and antimicroalgal activities, as well as inhibitory activities against acetylcholinesterase (AChE) and protein tyrosine phosphatase 1B (Table S10).

Bisorbicillinol (**82**) is a bisorbicillinoid previously isolated from a few fungi such as *Trichoderma* sp. USF-2690 [45], *Trichoderma* sp. f-13 [31], and *Penicillium notatum* [34]. Bisorbicillinol (**82**) from *Trichoderma* sp. USF2690 was found to be an inhibitor of βhexosaminidase release and tumor necrosis factor (TNF)-α, and 9nterleukin (IL)-4 secretion from rat basophilic leukemia (RBL-2H3) cells, with IC<sup>50</sup> values of 2.8, 2.9, and 2.8 µM, respectively. The results showed that the inhibitory mechanism of β-hexosaminidase release and TNF-α secretion involve inhibition of Lyn, a tyrosine kinase. This indicated that bisorbicillinol (**82**) should be a candidate antiallergic agent [46].

Scipyrone K (**14**), isolated from the fungus *Phialocephala* sp. FL30r obtained from a deep seawater sample, exhibited weak radical scavenging activity against 2,2-diphenyl-1 picrylhydrazyl (DPPH) with an IC<sup>50</sup> value of 27.9 µM [15].

Sorbicillin (**1**) was proven to have neuroprotective and neuritogenic activity on PC-12 Adh cells of the 6-hydroxydopamine-induced Parkinson's disease cell model at 1 and 10 µg/mL. The water fraction of halotolerant *Penicillium flavigenum* isolated from Salt Lake in Konya, Turkey, also showed similar activity. The water extract was revealed to contain sorbicillin-like active metabolites by LC-MS compared to a sorbicillin (**1**) standard [47]. Sorbicillin (**1**) and 20 ,30 -dihydrosorbicillin (**2**) showed acetylcholinesterase inhibitory activities with inhibition rates of 15.47% and 1.78%, respectively, at a concentration of 50 µg/mL [44].

At a concentration of 40 µM, both 20 ,30 -dihydrosorbicillin (**2**) and sohirnone A (**78**) exhibited moderate inhibitory activity of protein tyrosine phosphatase 1B (PTP1B) with inhibitory ratios of 10.58% and 8.47%, respectively, to show their antidiabetic potential [48].

Sorrentanone (**84**) showed a significant inhibitory effect of HIV-1 virus with an IC<sup>50</sup> value of 4.7 µM, so is worthy of further investigation as a lead anti-HIV compound [38].

Glucagon-like peptide-1 (GLP-1), a gut incretin hormone that stimulates insulin and inhibits glucagon secretion on pancreatic β-cells and α-cells, is considered a target protein related to diabetes. Eukaryotic elongation factor-2 kinase (eEF2K) is a potential therapeutic target for cancer. Both 13-hydroxy-dihydrotrichodermolide (**55**) and 10,11,27,28 tetrahydrotrisorbicillinone C (**60**) displayed high affinities to target proteins GLP-1R and eEF2K with K<sup>d</sup> values of 0.0285 and 0.0162 µM for GLP-1R, and 0.118 and 0.0746 µM for eEF2K, respectively. These findings indicate that 13-hydroxy-dihydrotrichodermolide (**55**) and 10,11,27,28-tetrahydrotrisorbicillinone C (**60**) are promising new drug candidates for diabetes and cancer treatment [26].

Both tetrahydrobisvertinolone (**89**) and tetrahydrotrichodimer ether (**91**) exhibited weak acetylcholinesterase (AChE) inhibitory activity with 51.1% and 55.1% inhibitions at a concentration of 50 µg/mL, respectively [10].

Trichoreesin A (**32**) showed antimicroalgal activity against the marine algae *Chattonella marina*, *Heterosigma akashiwo*, and *Prorocentrum donghaiense* with IC<sup>50</sup> values of 13, 29, and 2.8 µg/mL, respectively [18].

#### **4. Conclusions**

From 2016 to 2021, 69 new sorbicillinoids were isolated from fungi. Mainly belonging to the monomeric and dimeric sorbicillinoids, some sorbicillinoids have special structures such as ustilobisorbicillinol A (**56**) [19], and sorbicillasins A (**70**) and B (**71**) [15], increasing their diversity. The majority of sorbicillinoids were reported from the fungi genera of *Acremonium*, *Penicillium*, *Trichoderma*, and *Ustilaginoidea*. This provides a basis for fungal chemotaxonomy, which should be further studied in detail. It is worth mentioning that 21 sorbicillinoids were firstly isolated from the rice false smut pathogen *Ustilaginoidea virens* [14,19], which can produce many types of bioactive secondary metabolites [49–58]. Some sorbicillinoids exhibited cytotoxic (Table S4), antibacterial (Table S5), antifungal (Table S6), anti-inflammatory (Table S7), phytotoxic (Table S8), and α-glucosidase-inhibitory (Table S9) and PTP1B-inhibitory activities (Table S10). They may be utilized as pigments and food colorants as well. Due to the limitation of activity screening models by each research group, many sorbicillinoids need to be further screened for their biological activities. Furthermore, the comparative investigations on the biological activities of sorbicillinoids and other classes of compounds along with their action mechanisms need to be further conducted [59–61]. In recent years, more and more new members of sorbicillinoids have been revealed from plant endophytic, marine-derived, extremophilic, phytopathogenic, and soil-derived fungi. All these sorbicillinoids may be rich resources of biologically active substances with significant pharmaceutical, food colorant, and agricultural value [2].

Fungal sorbicillinoids were studied extensively from 2016 to 2021. Apart from the discovery of new sorbicillinoids and clarification of their biological activities and action mechanisms, other related studies include biosynthetic gene clusters [6], biosynthetic pathways and their related enzymes [5,24,62–65], relevant regulatory mechanisms [7,25,66–68], biochemical engineering to increase the production of sorbicillinoids [59], chemoenzymatic synthesis [69], development of chemical synthesis methods [70], and applications of sorbicillinoids in the agriculture, pharmaceutical, and food industries [37,60,61]. Among them, the most promising is clarification of the Diels–Alder reactions during the biosynthesis of sorbicillinoids. Through co-expression of *sorA*, *sorB*, *sorC*, and *sorD* from *Trichoderma reesei* QM6a, the biosynthetic pathway to epoxysorbicillinol and dimeric sorbicillinoids resembling Diels–Alder-like and Michael-addition-like products was reconstituted in *Aspergillus oryzae* NSAR1 [24].

**Supplementary Materials:** The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jof8010062/s1, Table S1: Occurrence of the monomeric sorbicillinoids (**5**–**38**) in fungi; Table S2: Occurrence of the bisorbicillinoids (**39**–**59**) in fungi; Table S3: Occurrence of the hybrid sorbicillinoids (**61**–**73**) in fungi; Table S4: Cytotoxic activity of the screened sorbicillinoids in fungi; Table S5: Antibacterial activity of the sorbicillinoids screened from fungi; Table S6: Antifungal activity of the sorbicillinoids screened from fungi; Table S7: Anti-inflammatory activity of the sorbicillinoids screened from fungi; Table S8: Phytotoxic activity of the sorbicillinoids screened from fungi; Table S9: α-Glucosidase inhibitory activity of the sorbicillinoids screened from fungi; Table S10: Other biological activities of the sorbicillinoids screened from fungi.

**Author Contributions:** Conceptualization, L.Z.; writing—original draft preparation, X.H., X.Z., M.X., Z.Z., H.Z., D.X. and L.Z.; writing—review and editing, D.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the National Natural Science Foundation of China (32072373), and the National Key R&D Program of China (2017YFC1600905).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
