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. 2022 Jul 8;12(8):161. doi: 10.1007/s13205-022-03237-9

Anti-inflammatory alkaloids from the cold-seep-derived fungus Talaromyces helicus SCSIO41311

Mengjing Cong 1,4, Yi Zhang 1, Xinyue Feng 2, Xiaoyan Pang 1, Yonghong Liu 1, Xiaoyong Zhang 3,✉, Zhiyou Yang 2,✉, Junfeng Wang 1,4,✉
PMCID: PMC9270513  PMID: 35818470

Abstract

One new natural alkaloid, chaetominine B (1), together with twenty known compounds was isolated from the South China Sea cold-seep-derived fungus Talaromyces helicus SCSIO41311. Their structures were elucidated on the basis of nuclear magnetic resonance spectrum (NMR), mass spectrometry (MS) and ECD calculation, as well as comparing with previous literatures. Among them, twelve compounds showed potent NO inhibitory activities and two of them, azaspirofurans A (13) and fumiquinones B (21), exhibited NO inhibitory effects more than the positive control eicosapentaenoic acid (EPA) with IC50 values of 9.65 and 15.54 μM, respectively. Moreover, compound 13 attenuated LPS-induced imbalance of cytokines release such as TNF-α, IL-1β, IL-4, and IL-10. Additionally, the NMR data and absolute configuration of compound 20 were first reported.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13205-022-03237-9.

Keywords: Talaromyces helicus, Cold-seep, Anti-inflammatory, Alkaloid

Introduction

In recent years, the secondary metabolites from marine fungi have attracted more and more attention because of their diverse chemical structures and biological activities (Carroll et al. 2022). Cold seeps are the typical deep-sea ecosystems which breed special biological microorganism due to its extreme environment. Therefore, the secondary metabolites from cold-seep are more novel and diverse (Zhang et al. 2012). For example, several bioactive compounds have been generated by different fungus from the deep-sea sediment of cold-seep in the South China Sea, including acyclic peroxide derivative asperoxide A (Lü et al. 2020), ophiobolin sesterterpenoids (Chi et al. 2020), and phenol derivatives (Chi et al. 2021). During our research for secondary metabolites from cold-seep-derived fungi, a strain identified as Talaromyces helicus SCSIO41311 was studied, which led to the isolation of one new natural alkaloid, chaetominine B (1), along with twenty known compounds (Fig. 1). Herein, details of the isolation, structural elucidation, and anti-inflammatory activities of compounds (1 − 21) are described.

Fig. 1.

Fig. 1

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Structures of compounds 1–21

Experimental section

General experimental procedures

ECD spectra were obtained with a Chirascan circular dichroism spectrometer. NMR spectra were measured on a Bruker AV 500 MHz or AVANCE ш HD 700 MHz NMR spectrometer with TMS as internal standard. Chemical shifts were expressed as δ values, with J values. HR-ESI–MS data were recorded on a Bruker maXis Q-TOF in positive/negative ion-mode. HPLC was carried on Shimadzu LC-10ATvp with YMC ODS SERIES (YMC-Pack ODS-A, YMC Co. Ltd., 250 × 10 mm I.D., S-5 μm, 12 nm) and Naphthyl column (Π NAP, 250 × 10 mm I.D., COSMOSIL). The TLC plates with silica gel GF254 (0.4–0.5 mm, Qingdao Marine Chemical Factory, Qingdao, China) were used for analysis and preparative TLC. Column chromatography was carried out on silica gel (200–300 mesh, Jiangyou Silica Gel Development Co., Yantai, China), Sephadex LH-20 (40–70 μm, Amersham Pharmacia Biotech AB) and Combi Flash (Irregular C18, 40–63 μm, Santai Tech).

Fungal material

The fungal strain SCSIO 41311 was isolated from a cold-seep sediment fungus, which was collected from the South China Sea (depth 1138 m) in July 2020. It was identified by Associate Professor Xiao-Yong Zhang, College of Marine Science, South China Agricultural University as Talaromyces helicus and named as Talaromyces helicus SCSIO41311 (accession no. KT224828). A voucher specimen has been preserved in the CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China.

Fermentation and extraction

The strain was inoculated on PDA medium plates at 28℃ for 7 days. The seed medium (15 g malt powder, 2.5 g sea salt, 1000 mL distilled water, pH 7.4–7.8) was incubated under the condition of 180 r min−1 rotating shaker at 25 ℃ for 3 days. Then inoculate the cultured seed medium (3.0 mL/bottle) into 54 bottles (1L) of sterilized rice culture medium (200 g rice, 2.5 g sea salt, 250 mL distilled water) for 40 days. The fermentation was extracted with ethyl acetate (EtOAc) three times to afford a crude extract (41.0 g).

Isolation and purification

The extract was fractionated by silica gel column chromatography (CC), which was eluted with CH2Cl2 and MeOH mixed solvent in a step gradient (100:0–20:80, v/v) and separated into seven fractions (Frs. 1–7). Fr.1 was divided into seven parts (Frs. 1.1–1.7) by Combi Flash column chromatography eluting with CH3CN/H2O (0–100%). Fr.1.1 was further purified by semi-preparative HPLC (51% MeOH/H2O, 3 mL/min) to yield 1 (1.9 mg, tR 27.2 min) and 2 (4.4 mg, tR 29.5 min). Fr.1.2 was divided into five parts (Frs. 1.2.1–1.2.5) by Sephadex LH-20 (MeOH). Fr.1.2.2 was further purified by semi-preparative HPLC (46% CH3CN/H2O, 3 mL/min) to yield 12 (1.2 mg, tR 13.5 min) and 19 (1.3 mg, tR 21.1 min). Fr.1.2.3 was further purified by semi-preparative HPLC (55% CH3CN/H2O, 3 mL/min) to obtain 7 (0.5 mg, tR 11.1 min) and 6 (40.1 mg, tR 13.0 min). Fr.1.2.4 was further separated by semi-preparative HPLC (50% CH3CN/H2O, 3 mL/min) to yield 11 (7.0 mg, tR 16.7 min), 3 (4.1 mg, tR 18.4 min), and 4 (2.1 mg, tR 20.1 min). Fr.1.2.5 was further purified by semi-preparative HPLC (52% CH3CN/H2O, 3 mL/min) to gain 8 (7.66 mg, tR 12 min). Fr.3 was divided into seven parts (Frs. 3.1–3.7) by Combi Flash column chromatography eluting with CH3CN/H2O (0–100%). Fr.3.3 was further purified by semi-preparative HPLC (92% CH3CN /H2O with 0.3‰ TFA (trifluoroacetic acid), 3 mL/min) to yield 20 (5.3 mg, tR 39 min). Fr-3.4 was further separated with semi-preparative HPLC (75% CH3CN/H2O with 0.3‰ TFA, 3 mL/min) to afford four sub-fractions (Frs. 3.4.1–3.4.4). Fr.3.4.3 was further separated by semi-preparative HPLC (62% CH3CN /H2O with 0.3‰ TFA, 3 mL/min) to gain 14 (3.2 mg, tR 38 min). Fr.3.5 was further separated with semi-preparative HPLC (71% CH3CN/H2O with 0.3‰ TFA, 3 mL/min) to give five sub-fractions (Frs. 3.5.1–3.5.5). Fr.3.5.1 was further purified by semi-preparative HPLC (46% MeOH /H2O with 0.3‰ TFA, 3 mL/min) to obtain 17 (41.13 mg, tR 16 min) and 21 (4.0 mg, tR 23 min). Fr.3.5.2 was further purified by semi-preparative HPLC (40% MeOH /H2O with 0.3‰ TFA, 3 mL/min) to yield 15 (8.4 mg, tR 11.5 min). Fr.3.6 was further separated with semi-preparative HPLC (75% CH3CN/H2O, 3 mL/min) to afford four sub-fractions (Frs. 3.6.1–3.6.4). Fr.3.6.1 was further purified with semi-preparative HPLC (58% CH3CN/H2O, 3 mL/min) to afford two sub-fractions (Frs. 3.6.1.1–3.6.1.2). Fr.3.6.1.1 was further purified by semi-preparative HPLC (74% CH3CN /H2O with 0.3‰ TFA, 3 mL/min) to yield 16 (6.67 mg, tR 27 min). Fr.3.6.4 was further purified by semi-preparative HPLC (65% CH3CN/H2O with 0.3‰ TFA, 3 mL/min) to give 5 (71.11 mg, tR 30 min) and Fr.3.6.4.2. Fr.3.6.4.2 was further purified by semi-preparative HPLC (42% MeOH /H2O with 0.3‰ TFA, 3 mL/min) to yield 9 (1.48 mg, tR 26 min) and 10 (4.19 mg, tR 36 min). Fr.6 was purified by semi-preparative HPLC (72% CH3CN /H2O with 0.3‰ TFA, 3 mL/min) to yield 18 (14.38 mg, tR 21.5 min).

Structural characterization

Chaetominine B (1), colorless oils, 1H and 13C-NMR data, Table 1; CD (MeOH) Δε (nm): 10.25 (210), 1.18 (225), 3.77 (235), 0.66 (254), 1.09 (263), −2.82 (300), 0.02 (341); HR-ESI–MS m/z 435.1662 [M + H]+ (calc. for C23H23N4O5, 435.1663), 457.1472 [M + Na]+ (calc. for C23H22NaN4O5,457.1482).

Table 1.

1H- and 13C-NMR data of compounds 1 and 20

No. 1a 20b No 1a
δC δH (J in Hz) δC δH (J in Hz) δC δH (J in Hz)
1 66.6 4.94, s 13
2 83.8 5.11, s 76.7 14 36.7 2.37, d (10.2)
3 78.1 193.8 15 162.1
4 133.5 147.4 17 168.3
5 123.5 7.24, d (7.0) 142.4 18 123.0
6 112.1 6.75, d (7.9) 185.6 19 127.7 7.68, d (8.1)
7 130.7 7.17–7.14, m 59.6 3.80, s 20 128.8 7.58, t (7.6)
8 121.2 6.82–6.80, m 21.3 1.31, s 21 136.0 7.85–7.82, m
9 148.1 22 127.8 8.25, d (7.8)
10 172.8 23 148.5
11 56.8 4.33–4.30, m 25 8.15, s
12 13.7 1.55, d (6.9) 27 52.8 3.75, s
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aRecorded in CD3OD at 500 and 125 MHz

bRecorded at (d6) DMSO at 500 and 125 MHz

ECD calculations

The theoretical calculations of 1 and 20 were performed using the density functional theory (DFT) as carried out in the Gaussian 03. The preliminary conformational distributions search was performed using Frog2 online version. Further geometrical optimization was performed at the B3LYP/6-31G (d) level. Solvent effects of the MeOH were evaluated at the same DFT level using the SCRF/PCM method. TD-DFTS4 at B3LYP/6-31G (d) was employed to calculate the electronic excitation energies and rotational strengths in MeOH. The stable conformations obtained at the B3LYP/6-31G (d) level were further used in magnetic shielding constants at the B3LYP/6–311++G (2d, p) level.

Measurement of nitric oxide levels

BV2 microglia (2 × 105 cells/mL) were seeded in the plates for 12 h, pretreated with LPS (Sigma L2654, 100 ng/mL) for 0.5 h followed incubation with compounds at different concentrations (2, 20 μM) for 24 h. Cultured supernatant (100 μL) was collected and added with 100 μL of Griess reagent (1% sulfanilamide and 0.1% N-naphthyl ethylenediamine dihydrochloride in 2.5% phosphoric acid; Promega G2930, Madison, WI, USA) for 10 min in the dark at room temperature. An ELISA microplate reader was used for the measurement of absorbances at 540 nm. A standard curve was generated in the same manner using NaNO2 for quantitation.

Measurement of cytokines TNF-α, IL-1β, IL-4, and IL-10

BV2 microglia (1.5 × 105 cells/mL) were plated in DMEM medium contained with 10% fetal bovine serum for 12 h, cells were then pre-treated with 100 ng/mL LPS for 0.5 h, compound 13 (2 and 20 μM) was added for another 24 h. The supernatants were collected and enzyme-linked immunosorbent assay (ELISA; MEIMIAN, Yancheng, China) was performed for quantification of TNF-α, IL-1β, IL-4, and IL-10 according to the manufacturer's protocol.

Results and discussion

Compound 1 was obtained as colorless oil with the molecular formula as C23H22N4O5 based on its HR-ESI–MS at m/z 435.1662 [M + H]+, indicating fifteen degrees of unsaturation. The 1H NMR spectrum displayed eight aromatic protons at δH 8.25 (1H, d, J = 7.8 Hz), 7.85–7.82 (1H, m), 7.68 (1H, d, J = 8.1 Hz), 7.58 (1H, t, J = 7.6 Hz), 7.24 (1H, d, J = 7.0 Hz), 7.17–7.14 (1H, m), 6.82–6.80 (1H, m) and 6.75 (1H, d, J = 7.9 Hz); four methine protons at δH 8.15 (1H, s), 5.11 (1H, s), 4.33–4.30 (1H, m) and 2.37 (1H, d, J = 10.2 Hz); one oxygenated methyl at δH 3.75 (3H, s) and one methyl at δH 1.55 (3H, d, J = 6.9 Hz). The 13C NMR spectrum also showed three carbonyls (δC 172.8, 168.3 and 162.1).

The 1H and 13C NMR data of 1 (Table 1) closely resembled those of known compound chaetominine (2) (Jiao, et al. 2006), except for the presence of one oxygenated methyl (δC/H 52.8/3.75), one less unsaturation and some of the chemical shifts changed, such as downfield shifted for C-9 (140.41 → 148.13) and upfield shifted resonances of H-11 (4.61 → 4.33), indicating that the amide bond at position 10 of the compound 2 broken and connected to a methoxy group. This deduction was further confirmed by the HMBCs from H-12 and H-27 to C-10 (Fig. 2). As compounds 1 and 2 were co-occurring metabolites, we proposed that they would have the same biosynthetic pathway and the same corresponding centers (2R,3S,11S,14R) between them on biosynthetic grounds. Furthermore, the absolute configuration of 1 was assigned as 2R,3S,11S,14R via the electronic circular dichroism (ECD) calculations, which was well-fitted with experimental ECD curve (Fig. 3). Herein, all the 1D and 2D NMR data of 1 were consistent with those of methyl (αS,3S,4aR,9aS)-2,3,4,4a,9,9a-hexahydro-4a-hydroxy-2-oxo-3-(4-oxo-3(4H)-quinazolinyl)-1H-pyrido[2,3-b]indole-1-ethanoate, which had been previously obtained as the important precursor to synthesize chaetominine (2) (Luo, et al. 2014). To the best of our knowledge, this is the first report of chaetominine B (1) as a natural product.

Fig. 2.

Fig. 2

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Key COSY and HMBC correlations of 1

Fig. 3.

Fig. 3

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Experimental and calculated ECD spectra of 1

Compound 20 was obtained as colorless oils. The molecular formula was deduced as C8H8O5 based on its HR-ESI–MS at m/z 183.0925 [M-H]+, indicating five degrees of unsaturation. The 1D, 2D NMR spectra showed that it is fumigatin oxide (Yamamoto et al. 1965). The absolute configuration of C-1 and C-2 in 20 was revealed as 1R, 2S compared between calculated and experimental ECD data (Fig. 4). In addition, the NMR data and absolute configuration of fumigatin oxide was firstly reported.

Fig. 4.

Fig. 4

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Experimental and calculated ECD spectra of 20

According to the NMR data and comparison with the literature data, the other known compounds were identified to be chaetominine (2) (Jiao et al. 2006), tryptoquivalines F (3) (Yamazaki et al. 1978), tryptoquivalines J (4) (Yamazaki et al. 1978), isotryptoquivaline F (5) (Xue et al. 2014), fumiquinazolines F (6) (Takahashi et al. 1995), fumiquinazolines G (7) (Takahashi et al. 1995), fumiquinazolines J (8) (Zheng et al. 2012), spiro [5H,10H-dipyrrolo[1,2-α:1′,2′-d]pyrazine-2-(3H),2′-[2H]indole]-3′,5,10 (1′H)-trione (9) (Wang et al. 2008), 6-methoxyspirotryprostatin B (10) (Zhang et al. 2008), 12,13-dihydroxyfumitremorgin C (11) (Afiyatullov et al. 2004), cyclotryprostatin B (12) (Cui et al. 1997), azaspirofurans A (13) (Ren et al. 2010), 14-norpseurotin A (14) (Zhang et al. 2008), pseurotin F1 (15) (Tao et al. 2016), pseurotin A (16) (Peter Bloch 1981), 11-O methylpseurotin A (17) (Boot et al. 2007), fumigaclavine C (18) (Li et al. 2013), trypacidin (19) (Balan et al. 1965), and fumiquinones B (21) (Hayashi et al. 2007).

Nitric oxide (NO) is one of the main inflammatory mediators and plays a key role in neuro-inflammatory diseases. All of the isolated compounds with enough amount were evaluated for their inhibitory effect on NO production in LPS-induced BV2 microglial anti-inflammatory activities. Eicosapentaenoic acid (EPA) was selected as a positive control with IC50 value of 50.0 μM (Fig. 5). Based on the assay results, compared to control group, treatment with LPS significantly increased the production of NO. Most evaluated compounds except 8 significantly reduced NO production at a high concentration of 20 μM (Fig. 5). We calculated the IC50 values of compounds on NO inhibition, and compounds 13 and 21 showed more potent anti-inflammatory NO inhibitory activities than EPA with IC50 values of 9.65 and 15.54 μM, respectively. Compounds 5, 6, 11, 12, 14, 17, 18 and 19 showed moderate inhibitory activities with IC50 values of 26.51, 21.35, 24.95, 29.58, 32.37, 32.22, 23.46 and 38.62 μM, respectively. Compounds 2 and 20 exhibited weak inhibitory activities with IC50 values of 103.2 and 100.1 μM, respectively.

Fig. 5.

Fig. 5

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Effects of compounds on Lipopolysaccharide (LPS)-induced NO production in BV2 microglia. *p < 0.05, **p< 0.01, and ***p < 0.001 versus vehicle (Veh), one-way ANOVA and post hoc Dunnett’s test

In addition, we evaluated the effects of compound 13 on the LPS-induced production of TNF-α, INF-γ, IL-4, and IL-10, which are important in neuroinflammation. Compared to control group, LPS significantly increased the production of TNF-α and INF-γ, while decreased IL-4 and IL-10 in the supernatants of cultured BV2 microglia. Compound 13 treatment significantly inhibited TNF-α and INF-γ production at concentrations of 2 and 20 μM (Fig. 6A, B). In addition, compound 13 attenuated LPS-induced decrease of IL-4 and IL-10 at 2 and 20 μM, respectively (Fig. 6C, D).

Fig. 6.

Fig. 6

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Effects of compound 13 on Lipopolysaccharide (LPS)-induced cytokines release in BV2 microglia. *p < 0.05, **p < 0.01, and ***p < 0.001 versus vehicle (Veh), one-way ANOVA and post hoc Dunnett’s test

Conclusions

In summary, one new natural alkaloid, chaetominine B (1) together with twenty known compounds was isolated from the South China Sea cold-seep-derived fungus Talaromyces helicus SCSIO41311. Compounds 13 and 21 showed more potent NO inhibitory activities than EPA with IC50 values of 9.65 and 15.54 μM, respectively. Compounds 5, 6, 11, 12, 14, 17, 18 and 19 showed moderate NO inhibitory effects while compounds 2 and 20 exhibited weak NO inhibitory activities. Moreover, compound 13 significantly attenuated LPS-induced pro-inflammatory cytokines release such as TNF-α and INF-γ, while dramatically upregulated anti-inflammatory cytokines IL-4 and IL-10. Additionally, the NMR data and absolute configuration of 20 were first reported here.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 529 kb) (529.1KB, docx)

Acknowledgements

This work was financially supported by the Guangdong MEPP Funds (No. GDNRC [2021] 48), Finance Science and Technology Project of Hainan Province (ZDKJ202018), Guangdong Basic and Applied Basic Research Foundation (2021A1515011523), Guangdong-Joint Foundation of Shenzhen (2021B1515120046), Key Special Project for Introduced Talents Team of Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou) (GML2019ZD0406). We are grateful to ZH Xiao, AJ Sun, XH Zheng, Y Zhang, and X Ma in the analytical facility at SCSIO for recording spectroscopic data.

Declarations

Conflict of interest

No conflict of interest was reported by the authors.

Contributor Information

Xiaoyong Zhang, Email: zhangxiaoyong@scau.edu.cn.

Zhiyou Yang, Email: zyyang@gdou.edu.cn.

Junfeng Wang, Email: wangjunfeng@scsio.ac.cn.

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