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The chemical structures and biological activities of indole diterpenoids

  • Jingwen Niu 1 ,  
  • Jianzhao Qi 1,2 ,  
  • Pengchao Wang 1 ,  
  • Chengwei Liu 1 ,  
  • Jin-ming Gao 2
    •     
Received date: 14 October 2022; Accepted: 8 December 2022; Published online: 3 January 2023

Abstract

Indole diterpenoids (IDTs) are an essential class of structurally diverse fungal secondary metabolites, that generally appear to be restricted to a limited number of fungi, such as Penicillium, Aspergillus, Claviceps, and Epichloe species, etc. These compounds share a typical core structure consisting of a cyclic diterpene skeleton of geranylgeranyl diphosphate (GGPP) and an indole ring moiety derived from indole-3-glycerol phosphate (IGP). 3-geranylgeranylindole (3-GGI) is the common precursor of all IDTs. On this basis, it is modified by cyclization, oxidation, and prenylation to generate a large class of compounds with complex structures. These compounds exhibit antibacterial, anti-insect, and ion channel inhibitory activities. We summarized 204 compounds of IDTs discovered from various fungi over the past 50 years, these compounds were reclassified, and their biological activities were summarized. This review will help to understand the structural diversity of IDTs and provide help for their physiological activities.

Graphical Abstract

Keywords

Indole diterpenoids    Structural classification    Physiological activity    Fungus    
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1 Introduction

IDTs are a structurally diverse class of fungal secondary metabolites, all sharing a common core structure consisting of indole, and a diterpene carbon backbone derived from four mevalonate-derived isoprene units [1]. The molecular complexity of these compounds is achieved by adding more isoprene units to the core structure and by various modifications such as oxidation, cyclization, and halogenation. IDTs are ubiquitous in the natural environment, and moldy food produced by Penicillium sp. is a common source of these compounds. For example, the fungus P. tularense found in tomatoes has metabolites such as janthitrems, paspalinine, paxilline, etc. [2]. P. crustosum, which produces the shivering mycotoxin penitrems, is a common food-borne fungus that can cause the spoilage of many foods [3].

Most of the IDTs are potent tremor mammalian mycotoxins [4], that also exhibit excellent biological activities, including cytotoxic, antibacterial, antiviral, and protein tyrosine phosphatase inhibitory activities [5]. To date, some IDT compounds have been used for drug discovery. For example, as BK channel blockers, IDTs have been shown to reduce intraocular pressure and have been used to treat glaucoma [6]. The H1N1 virus is an invasive strain of influenza virus that can cause death in humans, and many IDTs have also shown significant activity against the H1N1 virus, especially emndole SB [7]. In agricultural settings, there has been a general trend toward using tremor-free IDTs as pesticides, such as 20, 25-dihydroxyaflavinine [8].

According to previous reports, 3-GGI is a common precursor compound of all IDTs. The origin of the indole ring in its structure was clarified in 1983, when Jesus et al. studied the biosynthesis of penitrem A, the results of isotope labeling experiments showed that the indole part was derived from the IGP precursor of tryptophan[9]. In 2013, Tagami et al. analyzed a pentenyltransfer PaxC in paxilline biosynthetic gene cluster, and proved that indole ring derived from IGP through in vitro enzyme activity experiment [10]. Next, on this basis, IDT can be further divided into two types, namely the paspaline type with a large proportion and a small part of the non-paspaline type. There are some reviews related to IDTs have been presented. For example, the synthesis and activity of paspaline-type compounds [11, 12], the structural diversity and biological activity [5], biosynthesis of IDTs are described [13-15]. However, considering that these reviews do not classify these two types of compounds uniformly, and exclude the cover of the latest IDT compounds in recent years. So here, we renamed the IDT skeleton rings A, B, C, D, E, and F, and 77 non-paspaline skeleton and 127 paspaline skeleton IDTs were uniformly reclassified and summarized according to their structures and oxidative modifications. This review will contribute to the scientific community's comprehensive and compact understanding of the complex and diverse IDTs.

2 Non-paspaline skeleton type

2.1 Nodulisporic acid series

A significant feature of this series is a caproic acid attached to the E ring, which contains 31 kinds of IDT compounds (Fig. 1 and Table 1). Nodulisporic acid A (NsA A, 1) was discovered in Hypoxylon pulicicidum in 1992, and was first reported as a potent insecticide in 1997 [16]. It exhibits optimal activity with an LD90 (lethal dose 90%) of 1.5 μM in the flea assay and an IC50 (half maximal inhibitory concentration) of 0.00027 μM in the binding assay [17]. In 1999, Otto D et al. found the compounds nodulisporic acid A1 (NsA A1, 2) and nodulisporic acid A2 (NsA A2, 3) from Nodulisporium spp., the LD50 (lethal dose 50%) of 2 to green flies was 0.3–1 μg/mL, like compound 1. In the mosquito larvae assay, compound 2 was the strongest with an LD90 of 200 ng/mL [18], while 3 was slightly less active, with an LD50 of 0.6–1.5 μg/mL [19]. From Nodulisporium spp., nodulisporic acid B (NsA B, 4), nodulisporic acid B1 (NsA B1, 5), nodulisporic acid B2 (NsA B2, 6), dehydro-NsA B (7), dehydro-NsA C (8) and derivative-compound 9–12 were found in 2002, in which 4 was 100 fold less active on fleas than 1. 5 is slightly more active than 6. It was also found that while the methyl ester derivative of 11 was tenfold less active than the corresponding acid 1, the activity of 5 and its methyl ester 10 was similar. 10 might be slightly more potent than 4. However, compounds 5, 6, and 12 were inactive at 100 ppm (parts per million) [20]. In 2003, nodulisporic acid C (NsA C, 13), nodulisporic acid C1 (NsA C1, 14), nodulisporic acid C2 (NsA C2, 15) were found. 13 showed good activity against fleas, which was 10 times lower than 1, and the LD90 was 10 μg/ml; but compounds 14 and 15 had no activity in the flea test. The activity of compound 13 was significantly lower in mosquito larvae and fly maggot larvae assays (LD90 = 10, 000 ng/mL) [21]. In 2004, nodulisporic acid D (NsA D, 16), D1 (NsA D1, 17), D2 (NsA D2, 18), D3 (NsA D3, 19), E (NsA E, 20), F (NsA F, 21), A4 (NsA A4, 22) and compound 23–29 were successively discovered in the mutant strain Nodulisporium spp. In the flea assay test, compounds 16, 20, and 21 were 62, 12, and 30 fold less active than 1, respectively. Nodulisporic acid containing a dienoic acid chain showed better activity in its series. For example, 1 is more active than 2 and 3. However, in the NsA D series, the biological activity of 18 is significantly better than that of 16 and 17. No biological activity was detected for compounds 23–29, andΔ23 or 24-nodulisporic acids (27, 28, 29) were less active than corresponding nodulisporic acids of the same class [18]. In 2022, Zhang YH et al. isolated two specific compounds, oxalerpene A and B (30 and 31), from Penicillium oxalicum. 30 is the first IDT derivative with a 4-hydroxy-5, 5-dimethylhydrofuran-3-one in the five-membered side chain. 31 has a unique 6/5/6/6/6/6/6/5/5/5 ring system. Oxalerpene A and B have antiviral activity against H1N1 and respiratory syncytial virus (RSV) with IC50 values from 2.8 to 9.4 µM [22].

Fig. 1

Chemical structures of nodulisporic acid series

Table 1

Name, bioactivities and source of nodulisporic acid series

Number Compound name Biological activity Species origin References
1 Nodulisporic acid A Insecticidal activity H. pulicicidum [16]
2 Nodulisporic acid A1 Insecticidal activity Nodulisporium spp. [19]
3 Nodulisporic acid A2 Insecticidal activity Nodulisporium spp. [19]
4 Nodulisporic acid B Insecticidal activity Nodulisporium spp. [20]
5 Nodulisporic acid B1 Insecticidal activity Nodulisporium spp. [20]
6 Nodulisporic acid B2 Insecticidal activity Nodulisporium spp. [20]
7 Dehydro-NsA B Nodulisporium spp. [17]
8 Dehydro-NsA C Nodulisporium spp. [17]
9 Methyl esters-NsA B Insecticidal activity Nodulisporium spp. [20]
10 Methyl esters-NsA A Insecticidal activity Nodulisporium spp. [20]
11 Methyl esters-dehydro-NsA B Less active Nodulisporium spp. [20]
12 Oxidized-NsA B Insecticidal activity Nodulisporium spp. [20]
13 Nodulisporic acid C Flea agent Nodulisporium spp. [21]
14 Nodulisporic acid C1 Nodulisporium spp. [21]
15 Nodulisporic acid C2 Nodulisporium spp. [21]
16 Nodulisporic acid D Flea agent Nodulisporium spp. [18]
17 Nodulisporic acid D1 Flea agent Nodulisporium spp. [18]
18 Nodulisporic acid D2 Flea agent Nodulisporium spp. [18]
19 Nodulisporic acid D3 Nodulisporium spp. [18]
20 Nodulisporic acid E Insecticidal activity Nodulisporium spp. [18]
21 Nodulisporic acid F Flea agent Nodulisporium spp. [18]
22 Nodulisporic acid A4 Insecticidal activity Nodulisporium spp. [18]
23 Methyl esters-NsA D Nodulisporium spp. [18]
24 Methyl esters-NsA D1 Nodulisporium spp. [18]
25 Methyl esters-NsA D2 Nodulisporium spp. [18]
26 Methyl esters-NsA E Nodulisporium spp. [18]
27 Δ23-NsA A4 Less active Nodulisporium spp. [18]
28 Δ23-NsA C4 Less active Nodulisporium spp. [18]
29 Δ24-NsA D Nodulisporium spp. [18]
30 Oxalierpene A Antiviral P.oxalicum [22]
31 Oxalierpene B Antiviral P.oxalicum [22]

2.2 Emindole SB series

The emindole SB series is different from the Nodulisporic acid series in that there is no caproic acid on the E ring (Fig. 2 and Table 2). In 1966, the compound emindole SB (32) was isolated from Claviceps paspali, which was cytotoxic to cancer cell lines, and also showed antibacterial activity against Staphylococcus aureus ATCC 6538 and Bacillus subtilis ATCC 6633 [23-25]. In 2010, asporyzin C (33) was isolated from Aspergillus oryzae, and the antibacterial activity against E. coli as well as the antifungal activity against plant pathogens Colletotrichum lagenarium and Fusarium oxysporium were assayed. 33 exhibited intense activity against E. coli with an inhibitory diameter of 8.3 mm [25]. In 2020, the natural product penerpene J (34) was found in the fungus Penicillium sp. KFD28. This compound has inhibitory activity against both PTP1B (protein tyrosine phosphatase 1B) and TCPTP (protein tyrosine phosphatase), with IC50 values of 9.5 μM and 14.7 μM, respectively [26]. In 2021, Chaiyosang B et al. isolated three novel IDTs aculeatupenes A-C (35–37) from the mycelium of Aspergillus aculeatus KKU-CT2. Compounds 35 and 36 showed weak cytotoxicity against HelaS3, KB, HepG2, MCF-7, and A549 cancer cell lines with IC50 values of 11.12–67.81 μM. 37 showed weak cytotoxicity against the HelaS3 cell line with an IC50 value of 17.48 μM, but no cytotoxicity against the vero cell line. Moreover, it was also found to exhibit weak antifungal activity against Bacillus cereus [27].

Fig. 2

Chemical structures of emindole SB series

Table 2

Name, bioactivities and source of emindole SB series

Number Compound name Biological activity Species origin References
32 Emindole SB Anti-cancer, antibacterial C. paspali [24]
33 Asporyzin C Antibacterial A. oryzae [25]
34 Penerpene J Anti-cancer Penicillium sp.KFD28 [26]
35 Aculeatupene A Anti-cancer A. aculeatus KKU-CT2 [27]
36 Aculeatupene B Anti-cancer A. aculeatus KKU-CT2 [27]
37 Aculeatupene C Anti-cancer A. aculeatus KKU-CT2 [27]

2.3 Emindole DA series

The common feature of this series of compounds is that they contain a 6/6-membered ring linked to a methylene group at the 3-position of the indole ring (Fig. 3 and Table 3). In 1988, the X-ray molecular structures of emindole DA (38) and DB (39) from Emericella desertorum were reported, both of which are tremor toxic to mammals [28, 29]. In 1989, nominine (40) was isolated as the leading organic soluble component of the sclerotium of the fungus Aspergillus nomius NRRL 13, 137, which showed potent activity against the widespread crop pest Heliothis zea. When added to the standard test diet at 100 ppm dry weight, it resulted in 40% mortality and 97% weight loss relative to controls [30]. In 1992, compounds radarin A–D (41–44) were isolated from the fungus Aspergillus sulphureus. When added to a standard test diet of the corn worm Helicoverpa zea at 100 ppm, 41 reduced body weight gain by 52.7% relative to the control after 1 week. 43 also showed some activity at the same concentration, resulting in a 17.1% reduction in body weight gain. While 42 and 44 were inactive. Further biological evaluations were then performed to show that 41 was active against human lung cancer A549, breast cancer MCF7, and colon adenocarcinoma HT-29 cells with ED50 values of 2.5, 5.5, and 1.9 µg/mL, respectively. 42 was active in all three cell lines with ED50 (median effective dose) values of 2.0, 2.0, and 0.7 µg/mL, respectively [31]. In 1992, emeniveol (45) was isolated from Emericella nivea, and when the concentration was 100 mg/L, it could inhibit the germination of pine pollen and the growth of camellia pollen by about 35.5% [32]. In 2006, three IDTs were isolated from the mycelium of Emericella purpurea, namely emindoles PA (46), PB (47), and PC (48), among which 47 has strong anti-cancer activity [33]. Later, it found that its precursor compound preemindole PA (49) [13]. Liu L et al. isolated the compound penicindopene A (50) from Penicillium sp. YPCMAC1 in 2019, that showed moderate cytotoxicity to A549 and HeLa cell lines, with IC50 values of 15.2 and 20.5 µM, respectively [34]. In 2021, the compound penerpenes M (51) was discovered from the fungus Penicillium sp. KFD28. However, no antibacterial activity was found [35].

Fig. 3

Chemical structures of emindole DA series

Table 3

Name, bioactivities and source of emindole DA series

Number Compound name Biological activity Species origin References
38 Emindole DA Tremor toxin E. desertorum [28]
39 Emindole DB Tremor toxin E. desertorum [28]
40 Nominine Insect resistance A. nomius [30]
41 Radarin A Insect resistance A. sulphureus [31]
42 Radarin B Insect resistance A. sulphureus [31]
43 Radarin C Insect resistance A. sulphureus [31]
44 Radarin D Insect resistance A. sulphureus [31]
45 Emeniveol Pollen growth inhibitor E. nivea [32]
46 Emindole PA E. purpurea [33]
47 Emindole PB Anti-cancer E. purpurea [33]
48 Emindole PC E. purpurea [33]
49 Preemindole PA [13]
50 Penicindopene A cytotoxicity Penicillium sp. [34]
51 Penerpenes M Penicillium sp. [35]

2.4 Aflavinine series

This series difference from the emindole DA series is that the 3-position of the indole ring is directly connected with the 6/6-membered ring (Fig. 4 and Table 4). In 1988, aflavinine (52) and its natural derivative products 20, 25-dihydroxyaflavinine (53), 14-hydroxyflavinine (54), 24, 25-dihydro-10, 11-dihydro-20-hydroxyflavinine (55) and 10, 11-dihydro-11, 12-dihydro-20-hydroxyflavinine (56) were isolated from the fungus Aspergillus flavus, and these metabolites were selectively distributed to the sclerotia, It also showed antifeedant activity to fungus eating insects that usually encounter sclerotia in nature [8]. Compound 52 was non-toxic and non-tremor to 1-day-old chickens at 300 mg/kg. Compounds 54–56 were inactive against C. hemipterus at 100 ppm, but showed significant feeding deterrence when tested at the levels found in the sclerotia (400–1100 ppm). Compounds 53 and 54–56 also showed mild activity against Bacillus subtilis in a standard disk assay of 100 mg/disk, but were not toxic to brine shrimp at 250 mg/ml [36]. In 2019, Han X et al. isolated a new IDT cladosporine A (57) from the extract of the fungal strain Cladosporium sp. JNU17DTH12-9-01, which was the first report of the existence of IDT in Cladosporium spp. The MIC(minimum inhibitory concentration) of this compound to Staphylococcus aureus 209P and Candida albicans FIM 709 was 4 μg/mL and 16 μg/mL, respectively [37].

Fig. 4

Chemical structures of aflavinine series

Table 4

Name, bioactivities and source of aflavinine series

Number Compound name Biological activity Species origin References
52 Aflavinine Insect resistance A. tubingensis [36]
53 20, 25-Dihydroxyaflavinine Insect resistance A. flavus [8]
54 14-Hydroxyaflavinine Insect resistance A. flavus [8]
55 24, 25-Dehydro-10, 11-dihydro-20-hydroxyaflavinine Insect resistance A. flavus [8]
56 10, ll-Dihydro-ll, 12-dehydro-20-hydroxyaflavinine Insect resistance A. flavus [8]
57 Cladosporine A Antibacterial Cladosporium sp. [37]

2.5 Tubingensin A series

The structure of this series is characterized by the presence of a benzene ring attached to the indole ring B (Fig. 5 and Table 5). In 1989, tubingensin A (58) and its structural isomer tubingensin B (59) were isolated from the fungus Aspergillus tubingensis by Gloer JB and colleagues, and 58 was found to be resistant to the general crop pest Heliothis zea, and exhibit showed in vitro antiviral activity against herpesvirus type I [38], while 59 showed mild activity against the crop pest H. zea, resulting in a 10% mortality rate when added to a standard diet at 125 ppm. The compound also showed almost identical activity to 58 in assays against herpes simplex virus type I with an IC50 of 9 μg/mL, but was more cytotoxic to HeLa cells (IC50 4 μg/mL) [39]. In 1990, the compound aflavazole (60) was isolated from Aspergillus flavus. When added at 100 ppm to the standard test diet, 60 showed significant feeding-rejecting activity against the fungus-eating beetle Carpophilus hemipterus and was second only to dihydroxyaflavinine in activity against C. hemipterus among the IDT mycorrhizal metabolites of A. flavus [40]. When added to diets at concentrations found in A. flavus sclerotia (200–600 ppm), almost complete feeding deterrence was observed [40, 41]. In 2019, Miles CO and his colleagues isolated the compound shearilicine (61) from the strain Penicillium sp. ZO-R1-1, which had an IC50 value of less than 10 μM against L5178Y or A2780 cells, was tested against the human embryonic kidney cell line HEK-293. The results showed the highest selectivity in tests with SI (selectivity index) values in the range 3.3–8.1 and were also the most active metabolite against L5178Y cells with an IC50 value of 3.6 μM and A2780 cells with an IC50 value of 8.7 μM [42].

Fig. 5

Chemical structures of tubingensin A series

Table 5

Name, bioactivities and source of tubingensin A series

Number Compound name Biological activity Species origin References
58 Tubingensin A Anti-insect, anti-virus A. tubingensis [38]
59 Tubingensin B Cytotoxicity A. tubingensis [39]
60 Aflavazole Anti-insect A. flavus [40]
61 Shearilicine Cytotoxicity Penicillium sp. [42]

2.6 Other non-paspaline skeleton type compounds

This series contain irregular non-paspaline type compounds (Fig. 6 and Table 6). In 1992, the compound paxinorol (62), isolated from the fungus Penicillium paxilli, which was found to be toxic to mammals, and it reduced the activity behavior of mice, but returned to normal after some time [43]. In the same year, the compound sulpinine C (63) was isolated from Aspergillus sulphureus, which was weakly active against H. zea but inactive against C. hemipterus [44]. In 1992, Gloer JB and his colleagues reported the anti-insect metabolite aspernomine (64) from Aspergillus nomius, which showed moderate activity against H. zea. Incorporating this compound at 100 ppm into the standard test diet resulted in a 35% reduction in body weight gain of the test insects relative to the control. Moreover, it also exhibited cytotoxicity against three human tumor cell lines, with ED50 values of 3.09, 4.93, and 3.08 μg/mL against A-549 lung, MCF-7 breast, and HT-29 colon adenocarcinoma cell lines, respectively [45]. In 1997, petromindole (65) was isolated by Ooike M et al. from the soil fungus Petromyces [46]. In 2002, two anthelmintic IDTs, thiersinine A (66) and B (67), were isolated from an organic extract of P. thiersii NRRL 28, 147, which showed effective activity against S. frugiperda when added to standard test grains at 100 ppm, with growth compared to the control rates were reduced by 83% and 84% respectively. However, they were inactive against both Candida albicans ATCC 90, 029 and Staphylococcus aureus ATCC 29, 213 in the standard assay at 200 μg/plate [47]. In 2010, the natural products asporyzin A (68) and B (69) were isolated from Aspergillus oryzae, where 68 and 69 had lower insecticidal activity than their precursor JBIR-03, and neither of them showed any antifungal activity [25]. In 2010, the IDT JBIR-03 (70) was isolated from the fungus Dichotomyces cejpii var., which showed anti-MRSA (methicillin-resistant Staphylococcus aureus) activity and was tested at 32 and 64 mg/ml, respectively. Inhibits the growth of gram-positive and gram-negative bacteria at a concentration of any cytotoxic activity [48]. In 2013, the compound (6S, 7R, 10E, 14E)-16-(1H-indol-3-yl)-2, 6, 10, 14-tetramethylhexadeca-2, 10, 14-triene-6, 7-diol (71) was isolated from an acid fungal strain Penicillium camemberti OUCMDZ-1492, which showed significant protection against H1N1 virus-induced cytopathic with IC50 values of 34.1 μM, respectively [7]. In 2016, Gao SS et al. discovered the compound rhizovarin D (72) from Rhizomucor Mucor irregularis QEN-189, which represents the most complex member of IDT derivatives [49]. In 2018, Zhao JC et al. isolated a new 1(2), 2(18)-diseco IDT drechmerin H (73) from the fermentation broth of Drechmeria sp. This compound exhibits a significant agonistic effect on the pregnane X receptor (PXR) with an EC50 (concentration for 50% of maximal effect) value of 134.91 ± 2.01 nM [50]. In 2019, the IDT tolypocladin H (74) was isolated from the strain Tolypocladium sp. XL115, the compound is active against the fungus A. fragariae with MIC values of 6.25–50 μg/mL; also active against all bacteria tested, the MIC value is 12.5–25 μg/mL, but no cytotoxicity [51]. In 2020, Nur EAA et al. isolated a new IDT terpendole N (75) from Volutella citrinella BF-0440, but no physiological activity was found [52]. In 2021, the compound penerpene N (76) was identified from the fungus Penicillium sp. KFD28, which represents a second paxilline-type IDT with a 1, 3-dioxane ring, has a low cytotoxic effect on Hela cancer cell lines, and no antimicrobial activity was found [35]. In 2021, the compound ascandinine A (77) was isolated from the Antarctic sponge-derived fungus Aspergillus candidus HDN15-152, which has an unprecedented 2-oxabicyclo [2.2.2]octan-3-ol motif embedded in a pentacyclic system [53].

Fig. 6

Chemical structures of other types of compounds

Table 6

Name, bioactivities and source of other types of compounds

Number Compound name Biological activity Species origin References
62 Paxinorol Animal toxicity P. paxilli [43]
63 Sulpinine C Anti-insect Aspergillus sulphureus [44]
64 Aspernomine Anti-insect, anti-cancer A. Nomius [45]
65 Petromindole P. muricatus [46]
66 Thiersinine A Anti-insect P. thiersii [47]
67 Thiersinine B Anti-insect P. thiersii [47]
68 Asporyzin A Insecticide A. oryzae [25]
69 Asporyzin B Insecticide A. oryzae [25]
70 JBIR-03 Anti-MRSA D. cejpii [48]
71 (6S, 7R, 10E, 14E)-16-(1H-Indol-3-yl)-2, 6, 10, 14-tetramethylhexadeca-2, 10, 14-triene-6, 7-diol Cytotoxicity P. camemberti [7]
72 Rhizovarin D Mucor irregularis [49]
73 Drechmerin H Agonistic effect on PXR Drechmeria sp. [50]
74 Tolypocladin H Antibacterial activity Tolypocladium sp. XL115 [51]
75 Terpendole N V. citrinella BF-0440 [52]
76 Penerpene N Anti-cancer Penicillium sp. [35]
77 Ascandinine A A.candidus [53]

3 Paspaline skeleton type

3.1 Only paspaline skeleton

There are twenty-five IDT compounds containing only the paspaline skeleton (Fig. 7 and Table 7). In 1966, Arigoni D and his colleagues isolated the compound paspaline (78) from Claviceps paspali, which did not cause BK channel inhibition and tremor, but showed stronger anti-proliferative, anti-migratory, and Wnt/β-catenin inhibition than compound emindole SB [23, 54]. In the same year, Sarah et al. isolated the compound paspaline B (79) from the fungus Penicilium paxilli, which was the first oxidized analog of paspaline to be isolated, and also had tremor-causing activity for animals [55]. Paxilline (80) was first isolated from P. paxilli in 1974, and later Cole et al. reported that administration of 25 mg/kg of this compound caused severe intermittent tremors in roosters and mice [56, 57]. In 1989, Miles CO and colleagues discovered the compounds α-paxitriol (81) and β-paxitriol (82), neither of which caused tremors in mice [43]. In 1989, 1'-O-acetylpaxilline (83) was isolated from Emericella striata. When the injection concentration was 3.125 mg/kg, it could cause tremors in mice, and its tremor intensity was the same as that of paxilline. However, at the same time, it can also cause horn arch in mice [29]. In 1989, the compound 13-desoxypaxilline (84) was isolated from Emericella spp., which was active against human A-549 and HL-60 cancer cell lines, but had no antibacterial activity [35, 58]. In 1990, PC-M6 (85) was isolated from P. crustosum. The compound 85 showed moderate inhibitory activity against Staphylococcus aureus ATCC 6538, and also had activity for human gastric cancer cells [35, 59, 60]. In 1994, two compounds, 10β-hydroxy-13-desoxypaxilline (86) and 7α-hydroxy-13-desoxypaxilline (87), were isolated from the fungus P. paxilli, of which 86 showed significant resistance to human A-549 and HL-60 cancer cell lines, and it is the only paspaline-type IDTs that exhibits activity against both cell lines. 87 has tremor activity [61]. In 1995, Tomoda H et al. isolated and characterized terpendoles E (88), F (89), and G (90) from the culture broth of Albophoma yamanashiensis by using different production media [62]. They have a weak inhibitory effect on cholesterol acyltransferase (ACAT) activity, and 88 can be oxidatively modified to desoxyterpendole I (123) [63, 64]. In 1995, Belofsky et al. isolated the compound 7α-hydroxyl-13-dehydroxypaxilline (91) from Eupenicillium Shearii [65], which showed moderate inhibitory activity against Staphylococcus aureus ATCC 6538 and antibacterial activity against Bacillus subtilis ATCC 6633 (MIC = 16 μg/mL), but showed no inhibitory activity against E. coli ATCC 25, 922 and L. monocytogenes ATCC 1911 [35]. In 2009, the compound penijanthine A (92) was isolated from the fungus Penicillium janthinellum, which had no antifungal activity against Aspergillus fumigatus IFM 41, 362, Aspergillus niger IFM 41, 398, Candida albicans ATCC 90, 028 or Cryptococcus neoformans ATCC 90, 112 [66]. In 2013, 4α-demethylpaspaline-4α-carboxylic-acid (93) and 4α-demethylpaspaline-3, 4, 4α-triol (94) were isolated from an acid fungal strain Penicillium camemberti OUCMDZ-1492, and compound 94 was significant protection against H1N1 virus-induced cytopathic in MDCK cells with an IC50 value of 32.2 μM [7]. In 2013, the IDTs 3-deoxo-4β-deoxypaxilline (95) and 2'-hydroxypaxilline (96) were isolated from an acid fungal strain Penicillium camemberti OUCMDZ-1492, and compound 95 exhibited significant protection against H1N1 virus-induced cytopathic with IC50 value of 28.3 μM [7]. In 2014, the IDT 4β-deoxypenijanthine A (97) was isolated from the soil fungus Penicillium sp. CM-7, which showed no activity against human A-549 and HL-60 cancer cell lines [67]. In 2014, the IDT 4β-deoxy-1'-O-acetylpaxilline (98) was isolated from the soil fungus Penicillium sp. CM-7, which showed no effect on human A-549 and HL-60 cancer cell lines [67]. In 2019, during chemical research on the endophyte Penicillium sp. ZO-R1-1 was isolated from the medicinal plant ginger root, and the compounds 7-hydroxypaxilline-13-ene (99) and 7-methoxypaxilline (100) were discovered. Compound 99 showed cytotoxicity with IC50 values in the range of 5.3–8.1 μM [42]. In 2021, the IDT penerpene K (101) was isolated from a fermentation broth produced by adding L-tryptophan to the medium of the fungus Penicillium sp. KFD28. It has inhibitory activity against PTP1B and TCPTP, but has no antibacterial activity and cytotoxicity [35]. In 2021, the compound epi-paxilline (102) was isolated from the marine-derived fungus Penicillium sp., which has inhibitory activity against PTP1B with IC50 values of 31.5 μM, respectively [26, 35].

Fig. 7

Chemical structures of paspaline-type compounds with only a paspaline skeleton

Table 7

Name, bioactivities and source of compounds with only paspaline skeleton

Number Compound name Biological activity Species origin References
78 Paspaline Anti-cancer C. paspali [23]
79 Paspaline B Tremor activity Penicillium sp. [55]
80 Paxilline Tremor and bacteriostatic activity P. paxilli [57]
81 α-Paxitriol Tremor activity P. paxilli [43]
82 β-Paxitriol Tremor activity P. paxilli [43]
83 1'-O-Acetylpaxilline Tremor activity E. striata [29]
84 13-Desoxypaxilline Anti-cancer Emericella spp. [58]
85 PC-M6 Antibacterial activity Penicillium sp. [59]
86 10β-Hydroxy-13-desoxypaxilline Cell activity P. paxilli [61]
87 7α-Hydroxy-13-desoxypaxilline Tremor activity P. paxilli [61]
88 Terpendole E Mitotic kinesin Chaunopycnis alba [63]
89 Terpendole F Weak activity A. yamanashiensis [62]
90 Terpendole G Weak activity A. yamanashiensis [62]
91 7α-Hydroxyl-13-dehydroxypaxilline Antibacterial activity E. Shearii [65]
92 Penijanthine A P. janthinellum [66]
93 4α-Demethylpaspaline-4α-carboxylic acid Cytotoxicity P. camemberti [7]
94 4α-Demethylpaspaline-3, 4, 4α-triol Cytotoxicity P. camemberti [7]
95 3-Deoxo-4β-deoxypaxilline Cytotoxicity camemberti [7]
96 2′-Hydroxypaxilline P. camemberti [7]
97 4β-Deoxypenijanthine A Penicillium sp. [67]
98 4β-Deoxy-1′-O-acetylpaxilline Penicillium sp. [67]
99 7-Hydroxypaxilline-13-ene Cytotoxicity Penicillium sp. [42]
100 7-Methoxypaxilline Penicillium sp. [42]
101 Penerpene K Inhibitory activity against PTP1B and TCPTP Penicillium sp. [35]
102 Epipaxilline Anti-cancer Penicillium sp. [26]

3.2 F-ring modification

Based on the paspaline skeleton, its F-ring was modified by epoxidation (Fig. 8 and Table 8). In 1966, Arigoni D and his colleagues isolated the compound paspalicine (103) from Claviceps paspali, a dehydroxylated analog of paspalinine lacking tremor activity [23]. It can effectively block maxi-K (high-conductance Ca2+-activated K+) channels [24, 54]. In 1980, Gallagher RT et al. discovered the compound paspalinine (104) from Claviceps paspali, a mycotoxin that causes tremors in mice [68]. In 1993, compounds 14-hydroxypaspalinine (105) and 14-(N, N-dimethylvalyloxy)-paspalinine (106) were isolated from the fungus Aspergillus nomius. At 100 ppm levels, the two compounds resulted in a 90% reduction in body weight gain in tests against the corn roundworm H. zea. However, at this concentration, 105 does not have any effect [69]. In 1995, Huang XH et al. isolated and characterized terpendole A (107), B (108), C (109), and D (110) from Albophoma yamanashiensis and found that they showed strong inhibition of ACAT activity [70]. In 1995, Tomoda et al. isolated and characterized terpendoles H–K (111–114) from the culture broth of A. yamanashiensis using different production media [62]. 113 and 114 have moderate inhibitory effects on ACAT activity with IC50 values of 38.8 μm and 38.0 μm in rat liver microsomes, respectively, but 114 has a weaker activity [62-64]. In 1999, terpendole M (115) was isolated from perennial ryegrass (Lolium perenne) infected with the endophytic fungus Neotyphodium lolii. In standard mouse bioassays, this compound was less tremor than 109 [71]. In 2006, Junker et al. isolated and discovered the compound 14-(N, N-dimethylleucyloxy)-paspalinine (116) from Aspergillus alliaceus culture medium by optimizing the culture conditions [72]. In 2016, Gao et al. discovered the compound rhizovarins F (117) from Rhizomucor Mucor irregularis QEN-189 [49]. In 2019, Liang JH and colleagues isolated a new IDT drechmerin I (118) from the fermentation broth of Drechmeria sp., which has antibacterial activity against Bacillus subtilis with a MIC value of 200 μg/mL [73]. In 2019, during chemical research on the endophyte Penicillium sp. ZO-R1-1 isolated from the root of the medicinal plant ginger, paspalinine-13-ene (119), was discovered, which shows cytotoxicity with IC50 values in the range of 5.3–8.1 μM [42]. In 2020, the compound terpendole P (120) was isolated from the culture medium of the fungus Volutella citrinella BF-0440, which has 6 consecutive ring systems and an indole ring and can inhibit sterol O-acyltransferases 1 and 2 (SOAT1 and 2) [52]. In 2021, the compound ascandinine C (121) was isolated from the Antarctic sponge-derived fungus Aspergillus candidus HDN15-152. It is a rare IDT with a 6/5/5/6/6/6/6-fused ring system. The compound 121 has anti-influenza virus A (H1N1) activity with an IC50 value of 26 μM [53]. In 2021, the IDT penerpene L (122) was isolated from a fermentation broth produced by adding L-tryptophan to the medium of the fungus Penicillium sp. KFD28. It has inhibitory activity against PTP1B and TCPTP, but has no antibacterial activity and cytotoxicity [35]. In the same year, the IDTs ascandinine B (124) and D (125) were isolated from the Antarctic sponge-derived fungus Aspergillus candidus HDN15-152. They represent a rare IDT with a 6/5/5/6/6/6/6-fused ring system. Among them, 125 is cytotoxic to HL-60 cells with an IC50 value of 7.8 μM [53].

Fig. 8

Chemical structures of paspaline-type compounds with F-ring modification

Table 8

Name, bioactivities and source of compounds with F-ring modification

Number Compound name Biological activity Species origin References
103 Paspalicine Block maxi-K channels C. paspali [23]
104 Paspalinine Vibratory mycotoxins P. tularense [68]
105 14-Hydroxypaspalinine Insect resistance Aspergillus nomius [69]
106 14-(N, N-dimethylvalyloxy)-Paspalinine Insect resistance Aspergillus nomius [69]
107 Terpendole A ACAT inhibitors A. yamanashiensis [70]
108 Terpendole B ACAT inhibitors A. yamanashiensis [70]
109 Terpendole C Tremor activity A. yamanashiensis [70]
110 Terpendole D ACAT inhibitors A. yamanashiensis [70]
111 Terpendole H Weak activity A. yamanashiensis [62]
112 Terpendole I ACAT inhibitors A. yamanashiensis [62]
113 Terpendole J ACAT inhibitors A. yamanashiensis [62]
114 Terpendole K Tremor activity I. muelleri [62]
115 Terpendole M ACAT inhibitors N. lolii [71]
116 14-(N, N-dimethylleucyloxy)-Paspalinine Aspergillus alliaceus [72]
117 Rhizovarin F Mucor irregularis [49]
118 Drechmerin I Antibacterial activity Drechmeria sp. [73]
119 Paspalinine-13-ene Cytotoxicity Penicillium sp. [42]
120 Terpendole P Suppress SOAT Volutella citrinella [52]
121 Ascandinine C Cytotoxicity A. candidus [53]
122 Penerpene L Inhibitory activity against PTP1B and TCPTP Penicillium sp. [35]
123 Desoxyterpendole I [13]
124 Ascandinine B A. candidus [53]
125 Ascandinine D Cytotoxicity A. candidus [53]

3.3 A-ring prenylation

Based on the paspaline skeleton, the modification of isopentenyl was added to the 20, 21 or (and) 22 positions of the A ring of its indole ring (Fig. 9 and Table 9). In 1964, Wilson BJ isolated the compounds ɑ-aflatrem (126) and β-aflatrem (127) from Aspergillus flavus, which are fibrillating mycotoxins with acute neurotoxic effects [74, 75]. In 1977, Cole RJ et al. discovered the compound paspalitrem A (128) from Claviceps paspali, a toxin that can vibrate muscles [76, 77]. In 1992, compounds sulpinine A (129) and B (130) were isolated from Aspergillus sulphureus, both of which were active against H. zea but not against C. hemipterus [44]. Among them, 129 have the most potent activity. When this compound was added to the standard test diet at 100 ppm, a 96.0% reduction in body weight gain compared to the control was noted after one week, and a 10% mortality rate was also observed in this assay. 130 brought a similar weight gain reduction of 87.2%. Moreover, 129 was also cytotoxic to human lung cancer A549, breast cancer MCF7, and colon adenocarcinoma HT-29 cells with ED50 values of 25.7, 58.1, and 3.7 µg/ mL [44, 78]. In 1995, Tomoda H et al. isolated and characterized terpendole L (131) from the culture broth of Albophoma yamanashiensis by using different production media [62]. This compound has a moderate inhibitory effect on ACAT activity with an IC50 value of 32.4 μM in rat liver microsomes [62-64]. In 1996, the first systematic study of the effect of paspalitrem C (132) on the spontaneous contractile activity of a variety of mammalian smooth muscles [79], increased the spontaneous contractility of the bladder and duodenum in guinea pigs and rats, and caused tracheal tension in guinea pigs. These effects are attributed to blocking high conductance, Ca2+-activated K+ channels [77, 79]. In 2007, shearinine K (133) and J (134) were isolated and characterized from the endophytic fungus Penicillium sp. [80]. In 2013, the IDT 21, 22-diprenylpaxilline (135) was isolated from an acid fungal strain Penicillium camemberti OUCMDZ-1492, which exhibits significant protection against H1N1 virus-induced cytopathic in MDCK cells with an IC50 value of 73.3 μM [7]. In 2014, when studying JanD and AmyD protein function, the compound 20, 21-diprenylpaxilline (136) were discovered [13, 81, 82]. In 2019, the isoprene IDT tolypocladin A (137) was isolated from the fungus Tolypocladium sp., which showed no inhibitory activity against three pathogenic fungi (F. oxysporum, A. solani, and R. solani). However, it showed significant inhibitory activity against seven pathogenic fungi (A. fragariae, C. cassiicola, A. alternata, B. cinereal, C. personata, V. dahliae Kleb, and S. sclerotiorum), with MIC values of 6.25–25 μg /mL. It is also active against Bacillus cereus and Staphylococcus aureus, with MIC values of 25 and 12.5 μg/mL, respectively [51]. In 2019, two new prenylated IDTs, namely tolypocladin K (138) and L (139), were isolated from the fungus Tolypocladium sp. XL115. The compound 138 exhibits moderate antifungal activity against S. sclerotiorun, H. maydis, B. cinereal, and C. acutatum with a MIC value of 50 μg/mL [64].

Fig. 9

Chemical structures of paspaline-type compounds with A-ring prenylation

Table 9

Name, bioactivities and source of compounds with A-ring prenylation

Number Compound name Biological activity Species origin References
126 α-Aflatrem Neurotoxicity A. flavus [74]
127 β-Aflatrem Neurotoxicity A. flavus [74]
128 Aaspalitrem A Tremor muscle toxin C. paspali [76]
129 Sulpinine A Anti-insect, cytotoxic A. sulphureus [44]
130 Sulpinine B Anti-insect A. sulphureus [44]
131 Terpendole L Antibacterial activity Tolypocladium sp. [64]
132 Paspalitrem C Tremor muscle toxin Phomopsis sp. [79]
133 Shearinine K P. janthinellum [80]
134 Shearinine J Penicillium sp. [80]
135 21, 22-Diprenylpaxilline Cytotoxic P. camemberti [7]
136 20, 21-Diprenylpaxilline [81]
137 Tolypocladin A Antibacterial activity, cytotoxic Tolypocladium sp. [51]
138 Tolypocladin K Antifungal activity Tolypocladium sp. [64]
139 Tolypocladin L Tolypocladium sp. [64]

3.4 The isopentenyl group on the A ring is modified

The difference from the previous classification is that the isopentenyl group on the A ring is further modified by oxidation, halogenation, or epoxidation (Fig. 10 and Table 10). In 1977, Cole et al. discovered the compound paspalitrem B (140) from Claviceps paspali [76]. Cattle are affected by tremors (also known as "staggering") as they graze on toxic pastures; the compound identified at the highest concentration was the compound 140 (~ 150 mg/kg) in Claviceps cynodontis-infected Cynodon dactylon collected from pastures causing staggered syndrome in South African cattle herds [76, 77]. In 1990, PC-M5 (141) was isolated from Penicillium crustosum, which is toxic to PC12 cells [35, 59, 60]. In 2002, Tsuchiya et al. found the isolated and characterized compound NK12838 (142), which inhibits the activities of SOAT1 and SOAT2 with a SI value (log (IC50 for SOAT1)/(IC50 for SOAT2)) of + 0.27, but has no cytotoxicity [83, 84]. In 2016, while studying the biosynthesis of shearinine, the compound protoshearinine (143) was characterized [85]. In 2018, the compound sespelline (144) was reported while studying the biosynthesis of sespendole [86]. In 2019, new isoprenindole diterpenes tolypocladins B–G (145–150), I (151), and J (152) were isolated from the fungus Tolypocladium sp., they showed no inhibitory activity against three pathogenic fungi (F. oxysporum, A. solani and R. solani). All of them are active against A. fragariae with MIC values of 6.25–50 μg/mL, and compound 145 has weak activity against Staphylococcus aureus [51]. In 2020, the compound terpendole O (153) was isolated from the culture medium of the fungus Volutella citrinella BF-0440, which has 7 consecutive ring systems and an indole ring. It can inhibit sterol SOAT1 and 2 [52]. In 2020, Ohshiro T and colleagues isolated new compounds, termed voluhemins A (154) and B (155), from the culture broth of the fungal strain Volutella citrinella BF 0440. They have a common IDT core and two additional isoprenyl moieties, and 155 are O-methylated 154. 154 can inhibit the activities of SOAT1 and SOAT2 with a SI value of + 0.45, and 155 can selectively inhibit the SOAT2 isoenzyme. However, none of which is cytotoxic [83].

Fig. 10

Chemical structures of paspaline-type compounds in which the isopentenyl group on the A-ring is modified

Table 10

Name, bioactivities and source of compounds with the isopentenyl group on the A-ring is modified

Number Compound name Biological activity Species origin References
140 Paspalitrem B Tremor muscle toxin C. paspali [76]
141 PC-M5 Cytotoxicity P. crustosum [59]
142 NK12838 Inhibits SOAT1 and SOAT2 activity V. citrinella [84]
143 Protoshearinine [85]
144 Sespelline [86]
145 Tolypocladin B Antibacterial activity Tolypocladium sp. [51]
146 Tolypocladin C Antibacterial activity Tolypocladium sp. [51]
147 Tolypocladin D Antibacterial activity Tolypocladium sp. [51]
148 Tolypocladin E Antibacterial activity Tolypocladium sp. [51]
149 Tolypocladin F Antibacterial activity Tolypocladium sp. [51]
150 Tolypocladin G Antibacterial activity Tolypocladium sp. [51]
151 Tolypocladin I Antibacterial activity Tolypocladium sp. [51]
152 Tolypocladin J Antibacterial activity Tolypocladium sp. [51]
153 Terpendole O Suppress SOAT Volutella citrinella [52]
154 Voluhemin A Inhibits SOAT1 and SOAT2 activity V. citrinella [83]
155 Voluhemin B Inhibit SOAT2 activity V. citrinella [83]

3.5 A-ring with 6/5 member ring

The 21 and 22 positions of the A-ring of the indole ring are modified with diprenyl groups, and then further oxidatively cyclized into a 6/5-membered ring (Fig. 11 and Table 11). In 1984, Jesus et al. isolated and identified the tremor toxin janthitrems E–G (156–158) from the fungus P. janthinellum [87]. In 1992, Wilkins et al. isolated janthitrem B (159) [88]. In 1993, Penn and colleagues isolated and identified the compound janthitrem C (160) [89]. In 1995, compounds shearinines A (161) and B (162) were discovered from the fungus Eupenicillium shearii, both of which showed potent activity against H. zea and Carpophilus hemipterus [65]. 161 also induces apoptosis in human leukemia HL-60 cells, while 162 causes significant mortality in leaf disc assays against Spodoptera frugiperda [65, 90]. In 1995, Belofsky et al. discovered the compound shearinine C (163) from Eupenicillium Shearii, which can be formed from 160 through an autoxidative process, which has anti-insect activity [65]. In 2007, Smetanina OF and colleagues isolated shearinines D(164), E(165), and F(166) from marine-derived strains of the fungus Penicillium janthinellum [90]. 166 inhibits EGF-induced malignant transformation of JB6 P+ Cl 41 cells in soft agar with INCC50 (inhibition of colony number 50) equal to 13 μM concentration. It may be a strongly effective cancer preventive agent in humans or animals. 164 and 165 induce apoptosis in human leukemia HL-60 cells at a concentration of 100 μM. Moreover, the apoptosis rates of apoptotic cells are 39% and 34%, respectively, compared with control cells [80, 90]. In 2007, shearinines D–G was isolated and characterized from the endophytic fungus Penicillium sp., in which shearinine G (167) had inhibitory effects on BK channels [80]. Shearinines H (168) and I (169) were isolated and characterized from the endophytic fungus Penicillium sp. in 2007 [80]. In 2010, the compound epoxy-janthitrems I–IV (170–173) was isolated and identified from the endophyte Epichloë endophytes, and the compound epoxy-Janthitrems produced by the endophyte had strong inhibitory activity against insect larvae. However, when ryegrass plants are grown at a constant low temperatures for a long time, the concentration of the compounds in the plants is significantly reduced, and the insect resistance is less effective [91, 92]. In 2014, the compound pyrapaxilline (174) was isolated from Eupenicillium shearii. Lipopolysaccharide (LPS) increases NO production by approximately 2.5-fold over basal levels. When the mouse macrophage cell line RAW264.7 was pretreated with this compound for 2 h before LPS stimulation, it inhibited NO production by 40% at 10–30 μg/ml with no toxicity [93]. In 2018, new compounds 11, 12-epoxyjanthitrem B and 11, 12-epoxyjanthitrem C were isolated from the fungus Penicillium janthinellum, and named janthitrem A (175) and janthitrem D (176), respectively. Injecting mice with 175 at a concentration of 4 mg/kg can achieve high-intensity tremor effects in 15 min [94]. In 2019, Ariantari NP and colleagues isolated compounds shearinine P (177), 7-methoxyshearinine P (178), and shearinine Q (179) from strain Penicillium sp. ZO-R1-1. Among them, the IC50 value of 179 on L5178Y or A2780 cells is 10 μM [42]. In 2019, during chemical research on the endophyte Penicillium sp. ZO-R1-1 isolated from the medicinal plant ginger root, the compounds 7-methoxypyrapaxilline (180) and pyrapaxilline-6-ene (181) were discovered. Among them, the compound 181 showed cytotoxicity with IC50 values in the range of 5.3–8.1 μM; and also showed significant cytotoxic activity against the A2780 human ovarian cancer cell line, with IC50 values of 5.3–8.7 μM [42].

Fig. 11

Chemical structures of paspaline-type compounds with A-ring 6/5 member ring

Table 11

Name, bioactivities and source of compounds with A-ring 6/5 member ring

Number Compound name Biological activity Species origin References
156 Janthitrem E Tremor toxin P. janthinellum [87]
157 Janthitrem F Tremor toxin P. janthinellum [87]
158 Janthitrem G Tremor toxin P. janthinellum [87]
159 Janthitrem B Tremor, anti-insect activity P. janthinellum [88]
160 Janthitrem C P. janthinellum [89]
161 Shearinine A Anti-insect, cancer cell activity E. shearii [65]
162 Shearinine B Anti-insect activity E. shearii [65]
163 Shearinine C anti-insect activity E. shearii [65]
164 Shearinine D cancer cell activity P. janthinellum [80]
165 Shearinine E Anti-cancer P. janthinellum [80]
166 Shearinine F Penicillium sp. [80]
167 Shearinine G BK channel inhibition Penicillium sp. [80]
168 Shearinine H Penicillium sp. [80]
169 Shearinine I Penicillium sp. [80]
170 Epoxy-Janthitrem I Pesticide E. endophytes [91]
171 Epoxy-Janthitrem II Pesticide E. endophytes [91]
172 Epoxy-Janthitrem III Pesticide E. endophytes [91]
173 Epoxy-Janthitrem IV Pesticide E. endophytes [91]
174 Pyrapaxilline Inhibit the production of NO E. shearii [93]
175 Janthitrem A Tremor, anti-insect activity P. janthinellum [94]
176 Janthitrem D P. janthinellum [94]
177 Shearinine P Penicillium sp. [42]
178 7-Methoxyshearinine P Penicillium sp. [42]
179 Shearinine Q Penicillium sp. [42]
180 7-Methoxypyrapaxilline Penicillium sp. [42]
181 Pyrapaxilline-6-ene Cytotoxicity Penicillium sp. [42]

3.6 A-ring with 5/6 member ring

The difference from the previous type is that this type is further oxidatively cyclized into a 5/6-membered ring based on the diprenyl modification at the 20 and 21 positions of the A ring of the indole ring (Fig. 12 and Table 12). In 1981, two strong neurotoxins, lolitrems A (182) and B (183), were isolated from herbs that developed a livestock disease known as "ryegrass staggered disease." They can poison livestock with tremors that do not directly impair spatial learning and memory, but reduce voluntary movements in poisoned animals; later, perennial ryegrass toxicosis (PRGT) was prevented by limiting the concentration of 183 [95]. In 1992, lolitriol (184) was found in extracts of endophyte-infected ryegrass leaves and cultures of A. lolii [43]. Moreover, 183 is quickly degraded to compound 184, which does not cause tremors even at 20 mg/kg, so its activity is at least 20-fold lower than 183 [96]. In 1994, Christopher et al. obtained the abundant secondary compound lolitrem E (185) when 183 was purified from ryegrass staggers (RGS), which has intense BK channel activity but no tremor effect in animals [97, 98]. In 1996, Sarah et al. isolated lolitrem F (186), a stereoisomer of the vibratory mycotoxin 183, from ryegrass infected with Acremonium Lolii. The compound 186 was found to have similar potency and duration of action as 183 in standard mouse bioassays, but was slightly less active than 183 [99]. In 1997, the compound lolitrem H (187) was discovered [71]. In 1997, Sarah et al. isolated lolilline (188) from an extract of ryegrass seeds infected with the endophytic fungus Acremonium lolii, which does not have tremor effects [100]. In 1998, lolitrem N (189), lolicine A (190), and B (191) were identified in an extract of perennial ryegrass (Lolium perenne) seeds infected with the endophytic fungus Neotyphodium lolii, and they are lolitrem-like compounds [101].

Fig. 12

Chemical structures of paspaline-type compounds with A-ring 5/6 member ring

Table 12

Name, bioactivities and source of compounds with A-ring 5/6 member ring

Number Compound name Biological activity Species origin References
182 Lolitrem A Neurotoxin E. festucae [95]
183 Lolitrem B Neurotoxin E. festucae [95]
184 Lolitriol Neurotoxin Endophyte-infected ryegrass [43]
185 Lolitrem E BK channel activity Endophyte-infected perennial ryegrass [97]
186 Lolitrem F Neurotoxin L. perenne [99]
187 Lolitrem H A. lolii [71]
188 Lolilline A. lolii [100]
189 Lolitrem N Endophyte-infected ryegrass [101]
190 Lolicine A L. perenne [101]
191 Lolicine B L. perenne [101]

3.7 A-ring 4/5 or 6 membered ring

The difference between this type and the last type is that the oxidative cyclization is modified into a 4/5 or 4/6-membered ring, and even further forms an oxygen-containing 8-membered ring with the 17th position of the C ring (Fig. 13 and Table 13). In 1983, Amelia et al. isolated 6 IDTs penitrems A–F (192–197) from Penicillium crustosum, wherein the compounds 192, 194, and 197 showed the anti-cancer effect on human A-549 and HL-60 cancer cell lines [49, 102]. It was also found that all chlorinated compounds (192, 194, and 197) exhibited more vigorous activity than their chlorine-free analogs, 193, 195, and 196 [24, 49]. In 1992, the compound secopenitrem B (198) was isolated from Aspergillus sulphureus, which was active against H. zea but inactive against C. hemipterus. It reduced weight gain by 87.0%, while 198 also caused 32.0% larval mortality [44]. In 1993, Yamaguchi et al. isolated PC-M4 (199) from P. crustosum, which could be biosynthesized by PC-M6, and then added isoprenyl to give PC-M5, which had no cancer cell activity [59]. In 2011, the compound secopenitrem D (200) was isolated and characterized from P. crustosum, which caused poisoning in animals [103]. In 2016, Gao et al. discovered the compounds rhizovarins A–C (201–203) and E (204) from Rhizomucor Mucor irregularis QEN-189, which represent the most complex members of the IDT derivatives. Among them, 201 and 202 showed activity against human A-549 and HL-60 cancer cell lines, and compound 204 showed activity against the A-549 cancer cell line, but not the Hela cell line [49].

Fig. 13

Chemical structures of paspaline-type compounds with A-ring 4/5 or 6 membered ring

Table 13

Name, bioactivities and source of compounds with A-ring 4/5 or 6 membered ring

Number Compound name Biological activity Species origin References
192 Penitrem A Cancer cell activity P. crustosum [49]
193 Penitrem B Anti-proliferative, anti-migration P. crustosum [49]
194 Penitrem C Cancer cell activity P. crustosum [49]
194 Penitrem D Anti-proliferative, anti-migration P. crustosum [49]
196 Penitrem E Anti-proliferative, anti-migration P. crustosum [49]
197 Penitrem F Cancer cell activity P. crustosum [49]
198 Secopenitrem B Insect resistance A.sulphureus [44]
199 PC-M4 P. crustosum [59]
200 Secopenitrem D Poisons mammals P. crustosum [103]
201 Rhizovarin A Cytotoxicity Mucor irregularis [49]
202 Rhizovarin B Cytotoxicity Mucor irregularis [49]
203 Rhizovarin C Mucor irregularis [49]
204 Rhizovarin E Cytotoxicity Mucor irregularis [49]

4 Conclusion

This paper reviews the chemical structures of IDTs and their derivatives discovered in the past 50 years. Based on previous classifications, we divided 77 non-paspaline compounds into 6 categories according to their structural characteristics, and 127 paspaline-type compounds are divided into 7 categories according to oxidative modification. This provides convenient data for the future discovery of new compounds with similar structures or different oxidative modifications. At the same time, we also summarize the biophysiological activities of these compounds and their strong applications in pharmaceutical and agricultural markets. This also shows more compounds and provides more potent options for the development summary of future market applications.

Notes

Acknowledgements

This work was funded by the National Natural Science Foundation of China (Project No. 22077102 and 21877089), and the Shaanxi Key Laboratory of Natural Product & Chemical Biology Open Foundation (Project No. SXNPCB 2021001).

Author contributions

All authors read and approved the final manuscript.

Declarations

Competing interests

The author declares that there are no conflicts of interest associated with this work.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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  1. 1. Key Laboratory for Enzyme and Enzyme-Like Material Engineering of Heilongjiang, College of Life Science, Northeast Forestry University, Harbin, 150040, Heilongjiang, China
  2. 2. Shaanxi Key Laboratory of Natural Products and Chemical Biology, College of Chemistry and Pharmacy, Northwest A & F University, Yangling, 712100, Shaanxi, China
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