Hydroxydiorygmone A,a New Guaiane-Sesquiterpene from the Cultured Lichen Mycobiont of Diorygma sp

Abstract

Objective: Cultured mycobiont of the Vietnamese crustose-lichen Diorygma sp. has been chemically investigated. Biological activities including cytotoxicity against HepG2 cell line, α-glucosidase inhibition, and nitric oxide inhibitory activity were evaluated. Methods: Extensive spectroscopic methods (NMR and ECD) and HRESI mass data were employed for structural elucidation. These isolates were evaluated for their cytotoxicity against HepG2 cell line, α-glucosidase inhibition, and inhibitory activity toward nitric oxide production in LPS-stimulated RAW 264.7 cells. Results: Four compounds (1–4), including a new guaiane-sesquiterpene, hydroxydiorygmone A (1), along with three known analogues, diorygmones A and B (2 and 3) and pruinosone (4), were isolated and characterized. Compound 1 showed moderate α-glucosidase inhibition with an IC₅₀ value of 160 ± 2.2 µM and significant inhibitory activity toward nitric oxide production in LPS-stimulated RAW 264.7 cells with an IC₅₀ value of 8.11 ± 0.21 µM. Others were inactive in α-glucosidase inhibitory and nitric oxide inhibitory tests. Conclusion: A new guaiane-sesquiterpene, hydroxydiorygmone A (1) was isolated and showed moderate α-glucosidase inhibition with an IC₅₀ value of 160 ± 2.2 µM and significant inhibitory activity toward nitric oxide production in LPS-stimulated RAW 264.7 cells with an IC₅₀ value of 8.11 ± 0.21 µM.

Keywords

Cultured lichen mycobiont sesquiterpenes cytotoxicity

Introduction

Lichens, a fascinating symbiotic association between fungi (mycobiont) and photosynthetic partners (photobiont), are a treasure trove for natural product discovery.¹ These unique organisms are known to produce a diverse array of structurally complex and biologically active secondary metabolites.² Recent advancements in culturing lichen mycobionts independently of the photobiont have opened exciting new avenues for exploring their biosynthetic potential.³ Mycobionts derived from lichens have produced a diverse range of secondary metabolites, some of which exhibit uniqueness and notable divergence from compounds obtained from the original lichens.^2,4,5 The chemical structures of these metabolites show homology to fungal secondary metabolites.^6–8 Diorygma crustose lichens are widely distributed in Vietnam,^5,9,10 presenting a promising source for novel natural products. However, few phytochemical investigations have been conducted. Previous research on the chemical profile of a cultured Diorygma hieroglyphicum mycobiont revealed the presence of funiculosone.¹¹ In 2022, two new guaiane-sesquiterpenes were isolated from the Diorygma sp. mycobiont in Vietnam.¹² Additionally, two more new guaiane-type compounds were isolated from mycobionts of Vietnamese D. pruinosum.⁵ Further study of this species by Le and colleagues in 2024 reported the discovery of three additional new guaiane-sesquiterpenes from D. pruinosum.¹⁰ These compounds exhibited potent antimicrobial activity against multidrug-resistant Staphylococcus aureus. All these reports indicate that lichens belonging to the Vietnamese Diorygma genus could be a valuable source of new guaiane-sesquiterpenes, encouraging us to replicate the work on cultured mycobionts of Diorygma sp. on a larger scale.¹² Our investigation of the cultured mycobiont from Diorygma sp. led to the isolation and structural elucidation of a new guaiane-sesquiterpene, hydroxydiorygmone A (1), together with three known compounds, diorygmones A and B (2 and 3)¹² and pruinosone (4)⁵ (Figure 1). To assess the biological properties of the isolates, we evaluated their α-glucosidase inhibition, cytotoxicity towards HepG2 cancer cell, and nitric oxide inhibitory activity.

Figure 1.

Chemical structures of 1-4.

Materials and Methods

General Experimental Procedures

The HRESI mass spectrum was obtained using a MicrOTOF–Q mass spectrometer coupled with an LC-Agilent 1100 LC-MSD Trap spectrometer. NMR spectra were recorded on a Bruker Avance III spectrometer (500 MHz for ¹H NMR and 125 MHz for ¹³C NMR). Experimental ECD data were recorded using a JASCO J-815 Spectropolarimeter. Gravity column chromatography was carried out on silica gel 60 (0.040-0.063 mm, Himedia). Thin-layer chromatography (TLC) was conducted on precoated silica gel 60 F₂₅₄ or silica gel 60 RP–18 F_254S (Merck), and spots were visualized by spraying with a 10% H₂SO₄ solution followed by heating.

Lichen Material

The lichen sample used in this research was obtained from the bark of tree located in Quang Ngai city (15.104 N; 108.806 E), Vietnam (approx. 9 m alt.), during March 2021. Identification of the lichen specimen as Diorygma sp. was conducted by one of the authors (T. P. G. Vo), and it is currently housed in the Herbarium of the Ho Chi Minh City University of Science, Ho Chi Minh City, Vietnam, under the registration number UE-L008.

Mycobiont Culture

This research applied the mycobiont cultivation method outlined by Do et al (2022).⁵ In brief, tiny fragments of mycobiont colonies were aseptically transferred onto the surface of MY10 medium (composed of malt extract 1%, yeast extract 0.4%, sucrose 10%, and agar 1.5%, w/v) in 100-mL flasks. These flasks were then placed in a cooled incubator (Sanyo, Japan) at 18 °C, shielded from light, for a duration of 12 weeks. Post-incubation, mycobiont colonies were carefully detached from the culture medium and subjected to drying in an oven (Memmert, Germany) at a low temperature of 45 °C. To ensure traceability, the voucher specimens of the lichen mycobiont were cataloged at Ho Chi Minh City University of Education, under registration number UE-MY03.

Extraction and Isolation

Following the method established by Nguyen et al (2023),¹² the mycobiont colonies obtained (58 g dry weight) were ground into a fine powder, followed by maceration with EtOAc (in 10 portions of 300 mL each) at room temperature. The combined extracts were concentrated using a rotary evaporator to yield a crude extract (340 mg). The resulting crude extract was fractionated by silica gel column chromatography (CC), eluted with a gradient system of n-hexane-EtOAc (4:1-1:1, v/v). This process yielded five fractions (EA1-EA5). Fraction EA1 (89 mg) was subjected to Sephadex LH-20 CC, eluted with MeOH to obtain three subfractions (EA1.1-EA1.3). EA1.3 (45 mg) was further purified using silica gel CC, eluted with n-hexane-CHCl₃-acetone-MeOH (600:40:4:0.5 v/v/v/v) to yield 1 (3.5 mg) and 2 (21 mg). Fraction EA5 (88 mg) underwent further purification using C18 reversed-phase silica gel CC, eluted with a mixture of MeOH-H₂O (2:1, v/v) to obtain 3 (15.5 mg) and 4 (33.0 mg).

Hydroxydiorygmone A (1)

Colorless oil; [α]²⁵_D+ 88 (c 0.1, CHCl₃); ¹H NMR (acetone-d₆, 500 MHz) and ¹³C NMR (acetone-d₆, 125 MHz): See Table 1. HRESIMS m/z: 233.1532 [M + H − H₂O]⁺ (calcd for [C₁₅H₂₁O₂ ]⁺, 233.1536).

Table 1.

¹H (500 MHz) and ¹³C (125 MHz) NMR Data of 1 and 2 (δ in ppm) in Acetone-d₆.

No.	1		2
No.	δ_H (J in Hz)	δ _C	δ_H (J in Hz)	δ _C
1	3.53 (m)	39.7	3.50 (m)	44.0
2	2.40 (m)	36.1	2.08 (m)	37.2
2	2.24 (m)	36.1	2.24 (m)	37.2
3	-	206.6		208.3
4	-	134.4		134.3
5	-	171.2		173.4
6	5.23 (s)	67.0	5.19 (d, 4.5)	66.9
7		148.4		147.6
8	5.48 (d, 3.0)	128.9	5.60 (dd, 6.0, 5.5)	127.7
9	5.02 (dd, 10.0, 3.0)	71.0	1.90 (ddd, 14.0, 9.0, 4.5)	32.2
9	5.02 (dd, 10.0, 3.0)	71.0	2.30 (dd, 14.0, 7.5)	32.2
10	2.35 (m)	36.8	2.55 (m)	33.7
11	2.53 (hept, 6.5)	36.8	2.44 (hept, 6.5)	36.3
12	1.13 (d, 6.5)	21.6	1.09 (d, 7.0)	22.8
13	1.12 (d, 6.5)	21.6	1.08 (d, 6.5)	22.5
14	0.88 (d, 7.0)	13.5	0.81 (d, 7.0)	16.6
15	1.64 (d, 2.0)	7.0	1.60 (d, 1.5)	8.0

Cytotoxicity Assay

The method used followed that reported by Nguyen et al (2022).¹² Briefly, HepG2 and RAW-264.7 cells in a complete medium containing DMEM (HyClone, Cytiva, USA) and 10% fetal bovine serum (FBS) were seeded into a 96-well plate at 5 × 10⁴ cells per well. The cells were then incubated at 37 °C with 5% CO₂. After culturing for 24 h, the old medium was replaced by diluted compounds (in dimethyl sulfoxide (DMSO, Sigma-Aldrich, Germany) for HepG2 cells or DMSO supplemented with lipopolysaccharide (LPS, Sigma Aldrich, Germany) for RAW-264.7 cells), positive control Doxorubicin (DOX, Fesenius Kabi, Germany), and negative control DMSO or DMSO+LPS with the corresponding concentrations as nitric oxide production assay. After 72 h of treatment, 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) was added into each well of the test plate. The plate was incubated at 37 °C with 5% CO₂ for another 3 h. DMSO was used to dissolve the crystals from the interaction between MTT and viable cells. The absorbance of samples was read at 570 nm by the ELISA Reader (BioTek, USA). Cell death (% inhibition) was estimated by the following formula:

% Inhibition = 100 - [100 \times (A_{Sample} – A_{B 1}) \div (A_{D M S O} – A_{B 2})]

Where, A_Sample: Absorbance of sample, A_DMSO: Absorbance of negative control, A_B1: Absorbance of blank of sample, A_B2: Absorbance of blank of DMSO. The IC₅₀ value and the inhibitory chart were respectively calculated and built using GraphPad Prism software (version 8.0.1, Insightful Science LLC, USA).

α-Glucosidase Inhibition Assay

A previously established protocol by Duong et al (2020),⁴ with minor adjustments, was employed to investigate the inhibitory effects of various compounds on α-glucosidase from Saccharomyces cerevisiae. A series of sample dilutions were prepared in a 5% DMSO solution, ranging from a high concentration of 200 µg/mL to a low concentration of 0.4 µg/mL. These dilutions were achieved through a two-fold serial dilution process. Separately, α-glucosidase enzyme (0.1 U/mL) and its substrate, p-nitrophenyl-α-D-glucopyranoside (4 mM), were prepared in a 0.1 M phosphate buffer solution with a pH of 6.9. The entire experiment was performed in triplicate for each sample concentration. To initiate the assay, 50 µL of each sample dilution was added to three consecutive wells on a 96-well plate. Subsequently, 40 µL of the α-glucosidase solution was added to each well. The plate was then incubated for 20 min at 37 °C. Following this incubation, 40 µL of the substrate, p-NPG, was dispensed into each well. The plate then underwent another 20-min incubation at 37 °C. Finally, the reaction was terminated by adding 130 µL of 1 M Na₂CO₃ solution to each well. The level of enzyme inhibition was assessed by measuring the absorbance of the reaction mixture at 405 nm using a microplate reader (model: CLARIOstar plus, BMG LABTECH, Ortenberg, Germany). A 5% DMSO solution served as the control, while acarbose was utilized as a standard reference inhibitor. The IC₅₀ value was determined by plotting the percentage of enzyme inhibition against the logarithm of sample concentrations using GraphPad Prism 8.0.1 software.

Measurement of nitric oxide production assay

Determination of nitric oxide (NO) production and cell viability assay were performed using the same method described in our previous reports.^13,14 The sample was analyzed in triplicate at five different concentrations around the IC₅₀ values, and the mean values were retained. N(G)-monomethyl-L-arginine (L-NMMA) was used as a positive control.

Molecular Docking

The in silico study utilized Schrodinger's Maestro software (Maestro and Schrödinger (2021), New York). Two target proteins, human PPAR-gamma (PDB: 1I7I)¹⁵ and α-glucosidase (PDB: 4J5 T),¹⁶ were obtained from the Protein Data Bank and prepared using the Protein Preparation Wizard. The human PPAR-gamma protein is a crucial target for the search for anti-inflammatory agents due to its significant role in regulating genes involved in lipid and glucose metabolism, as well as its influence on inflammatory pathways.¹⁷ Sitemap analysis¹⁸ was used for proteins without a co-crystal ligand, like 4J5 T, to detect the binding site, while for 1I7I, a grid receptor was directly made from the centroid of the co-crystal ligand. As for the 4J5 T protein,¹⁶ it is a crystal structure of processing alpha-glucosidase I, which is significant in the study on the inhibition of the alpha-glucosidase enzyme. The studied ligands were generated and modified using Ligprep (Schrödinger Release 2022-3: LigPrep. Schrödinger Inc., New York) before conducting Glide SP and XP docking procedures.¹⁹ MM-GBSA calculations were then performed on the XP output to compare with native ligands.¹⁷

Statistical Analysis

Data are expressed as the mean (±) with the standard error of the mean (SEM). Statistical significance was set at p ≤ 0.05.

Results and Discussion

Structure Elucidation

Compound 1, a colorless oil, had the molecular formula C₁₅H₂₂O₃ established by its HRESIMS through the ion peak at m/z 233.1532 [M + H − H₂O]⁺ (calcd for [C₁₅H₂₁O₂]⁺, 233.1542). Compound 1 had 15 carbon resonances defined by ¹³C NMR and HSQC spectra, including a ketone carbon (δ_C 206.6), four olefinic carbons (δ_C 171.2, 148.4, 134.4, and 128.9), two oxygenated carbons (δ_C 71.0 and 67.0), one methylene (δ_C 36.1), three methines (δ_C 39.7, 36.8, and 21.6), and four methyls (δ_C 21.6, 21.6, 13.5, and 7.0). The ¹H NMR spectrum showed an isopropenyl [δ_H 1.13 (3H, d, J = 6.5 Hz), 1.12 (3H, d, J = 6.5 Hz), 2.53 (1H, hept, J = 6.5 Hz)], a doublet methyl at δ_H 0.88 (3H, d, J = 7.0 Hz), an olefinic proton at δ_H 5.48 (1H, d, J = 3.0 Hz), and two oxygenated methines at δ_H 5.23 (1H, s) and 5.02 (1H, dd, J = 10.0, 3.0 Hz). Signals of a 2-methylcyclopent-2-en-1-one unit [δ_H 1.64 (3H, d, J = 2.0 Hz), 3.53 (m), 2.40 (m), and 2.24 (m)] were observed and confirmed by HMBC correlations of both H₃-15 (δ_H 1.64) and H₂-2 (δ_H 2.40 and 2.24) to C-3 (δ_C 206.6), C-4 (δ_C 134.4), and C-5 (δ_C 171.2) (Figure 2). Comparison of the ¹H and ¹³C NMR data of 1 with those of 2¹² (Table 1) indicated that they shared the same guaiane-type sesquiterpene skeleton, with the only difference being the occurrence of one hydroxy group at C-9. HMBC correlations of H₃-14 (δ_H 0.88) to C-9 (δ_C 71.0) and C-1 (δ_C 39.7), of H-8 (δ_H 5.48) to C-6 (δ_C 67.0), C-9, C-10 (δ_C 36.8), and of H-9 (δ_H 5.02) to C-1, C-7 (δ_C 148.4), and C-8 (δ_C 128.9) defined the position of 9-OH. The HMBC correlations of the two methyls H₃-12 (δ_H 1.13) and H₃-13 (δ_H 1.12) and of the oxygenated proton H-6 with C-7 and C-11 (δ_C 36.8) confirmed that the isopropyl group was located at C-7.

Figure 2.

Selected HMBC and NOESY correlations of 1.

The relative configuration of 1 was assigned based on the NOESY experiment and a detailed comparison of the NMR data with its closely related structure, diogrymone A (2). The NOESY correlations of H-6/H-1, H-9/H-1, H₃-14/H-1, and H₃-14/H-9 indicated that all H-1, H-6, H-9, and H₃-14 were on the same face (Figure 2). The ECD data of 1 and 2 showed high consistency, supporting the absolute configuration of 1 (Figure 3). ECD data of 2 displayed a strong negative Cotton effect (CE) at 250 nm, indicating the absolute (1R,10R) configuration. This negative CE was believed to be an indicator for determining the 1R configuration of guaiane-type sesquiterpenes.^5,10,12 Together, the complete structure of 1 was established as depicted in Figure 1, named hydroxydiogrymone A.

Figure 3.

ECD spectra of 1 and 2.

Biological Activity

The inhibitory effect of 1-4 on α-glucosidase was examined, revealing moderate activity for 1 and 4 with IC₅₀ values of 160 ± 2.2 and 255 ± 4.1 µM, respectively (the positive control acarbose 330 ± 4.2 µM). Compounds 2 and 3 exhibited no activity. A comparative analysis of the biological activity of 1–4 indicated that the incorporation of 9-OH in 1 or the 7,8-epoxide ring in 4 would enhance the activity. All isolates are weak in cytotoxicity against HepG2 cancer cell line (Figure 4). Compound 1 was selected to evaluate its NO inhibitory activity, indicating the significant result with an IC₅₀ value of 8.11 ± 0.21 µM (the positive control L-NMMA 41.3 ± 6.6 µM). The cell viability percentage of 1 against RAW-264.7 cell line was shown in Figure 5, demonstrating that 1 did not exhibit any cytotoxic effects.

Figure 4.

Cytotoxicity of 1-4 against HepG2 cell line.

Figure 5.

Cytotoxicity of 1 against RAW-264.7 cell line.

Molecular Docking

XP docking analysis revealed that both hydroxydiorygmone A (1) and pruinosone (4) possess the capability to bind to the active site of human PPAR-gamma. MM-GBSA calculations reveal that 1 and 4 exhibit binding affinities of −75.4 and −76.0 kcal/mol, respectively, which are fairly comparable to the natural ligand of the protein (−108.3 kcal/mol). However, their ability to form hydrogen bonds is notably inferior to that of the natural ligands, as indicated by the assembly results in Table 2. Compounds 1 and 4 formed hydrogen bonds with Ser 342, whereas the native ligands established stronger interactions with four hydrogen bonds to Ser 289, His 323, His 449, and Tyr 473 (Figure 6). This difference was likely due to the smaller size of the studied ligands, which may not have fully occupied the protein's binding pocket, resulting in weaker binding energies at around 65% compared to the native ligands. It was evident that hydrophobic interactions governed the binding behavior of these two ligands when their structures “blended” in the hydrophobic region of the protein, interacting with characteristic residues such as Met364, Val339, Leu340, Leu353, Gly284, Cys285, and Phe363.

Figure 6.

The binding modes of two ligands with Human PPAR-gamma protein compared to native ligand.

Table 2.

The XP Docking scores, the MMGBSA and number of H-bonds of Two Ligands in Human PPAR-Gamma Active Site.

Compound	Docking Score	Binding affinity (kcal/mol)	Number of H-bond	H-bond network
AZ 242 (Native ligand of 1I7I)	−11.7	−108.3	4	Ser 289, His 323, His 449, Tyr 473
Hydroxydiorygmone A (1)	−6.9	−75.4	1	Ser 342
Pruinosone (4)	−6.3	−76.0	1	Ser 342

XP docking analyses confirmed the binding potential of 1 and 4 to α-glucosidase's active site. They exhibited relatively favorable binding affinities of −39.5 kcal/mol and - 46.3 kcal/mol, respectively, compared to acarbose (−52.8 kcal/mol), as detailed in Table 3. According to Figure 7, compound 1 demonstrated good hydrogen bonding ability with four bonds (Arg 428, Gly 566, Trp 710, and Glu 771), while 4 formed two hydrogen bonds with Arg 428 and Trp 391. Conversely, acarbose formed five bonds (Glu 361, Asp 392, Asp 568, Tyr 709, and Glu 771). It was observed that neither of the studied ligands replicated the binding mode of acarbose, as they formed hydrogen bonds at different positions. This difference could be attributed to the grid for 4J5 T being generated from the sitemap area without the native ligand and the smaller size of the ligands compared to acarbose. As a result, suitable binding modes were adapted without replicating the binding pattern of acarbose.

Figure 7.

The binding modes of two ligands with α-glucosidase protein compared to acarbose.

Table 3.

The XP Docking scores, the MMGBSA and number of H-bonds of Two Ligands in α-Glucosidase Active Site.

Compound	Docking Score	Binding affinity (kcal/mol)	Number of H-bond	H-bond network
Acarbose	−9.6 (−9.8)*	−52.8	5	Glu 361, Asp 392, Asp 568, Tyr 709, Glu 771
Hydroxydiorygmone A (1)	−4.1 (−4.5)*	−39.5	4	Arg 428, Gly 566, Trp 710, Glu 771
Pruinosone (4)	−6.6	−46.3	2	Trp 391, Arg 428

*(in parentheses): The Glide GScore value, after state penalty compensation.

Based on the aforementioned in vitro and in silico data, compound 1 was found to exhibit strong suppression of α-glucosidase and NO production, but poor inhibition of the cancer cell line HepG2. Subsequent research ought to concentrate on the mechanisms of action and utilization of 1.

Supplemental Material

sj-docx-1-npx-10.1177_1934578X241297992 - Supplemental material for Hydroxydiorygmone A, a New Guaiane-Sesquiterpene from the Cultured Lichen Mycobiont of Diorygma sp

Supplemental material, sj-docx-1-npx-10.1177_1934578X241297992 for Hydroxydiorygmone A, a New Guaiane-Sesquiterpene from the Cultured Lichen Mycobiont of Diorygma sp by Ngoc-Hong Nguyen, Thuc-Huy Duong, Gia-Huy Duong, Huy Truong Nguyen, Thi-Hoai-Thu Nguyen, Nguyen-Hong-Nhi Phan, Thi-Phi-Giao Vo, Thi-Minh-Dinh Tran and Thi-Phuong Nguyen in Natural Product Communications

Footnotes

Acknowledgements

This work was supported by Ton Duc Thang University.

Authors’ Contributions

Conceptualization, T.P.N, N.H.N ; methodology, T.H.D, N.H.N, H.T.L; software, G.H.D, H.T.N, T.H.T.N; formal analysis, T.H.D, N.H.N, H.T.N; investigation, T.H.D, N.H.N, T.M.D.T; resources, T.P.G.V, G.H.D, N.H.N.P, T.H.T.N; data curation, T.P.G.V, N.H.N.P, T.H.T.N; writing—original draft preparation, T.M.D.T, N.H.N, T.P.N; writing—review and editing, all authors. All authors have read and agreed to the published version of the manuscript.

Availability of Data and Materials

Datasets generated in this study are available from the corresponding author on request.

Declaration of Conﬂicting Interests

The author(s) declared no potential conﬂicts of interest with respect tothe research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

Ethical Approval is not applicable for this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

Supporting Information

Supporting information accompanies this paper was found online.

ORCID iD

Huy Truong Nguyen

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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