Two New Compounds from the Insect-Derived Endophytic Penicillium Chrysogenum and Their Biological Activities Against Triple Negative Breast Cancer Cells

Abstract

Objective

Treatments for triple-negative breast cancer (TNBC) are limited to chemotherapy and a few immunotherapeutic agents, highlighting the urgent need to develop novel therapeutic strategies. Natural products, especially compounds derived from insect-associated endophytic fungi, have emerged as a potential direction for TNBC drug discovery. Based on this, this study investigates the material basis of the insect-derived endophytic fungus Penicillium chrysogenum and evaluated the anti-TNBC activities of its monomeric compounds.

Methods

An endophytic P. chrysogenum strain isolated from the intestinal tract of Periplaneta americana was fermented in a rice medium. Metabolites were extracted with ethyl acetate, and the extract was fractionated using MCI gel and Sephadex LH-20 column chromatography, followed by semi-preparative HPLC. Structural elucidation of isolates relied on spectroscopic analyses (NMR, HRESIMS). Cytotoxicity against HCC1806 and MDA-MB-231 cells was evaluated via CCK-8 assay, with IC₅₀ values determined by nonlinear regression.

Results

Ten compounds were isolated, including two new polyketide derivatives: penichrysone A (1) and penichrysone B (3), and eight known analogues. Compound 3 showed selective anti-proliferative activity against HCC1806 cells with an IC₅₀ of 51.7 µM. Structural analysis revealed that 3 was a xanthone derivative with a methylol group at C-3, and key HMBC correlations confirmed the substitution pattern. Comparative analysis of compounds 3−6 suggested that hydroxyl groups at C-2 and C-1′ are critical for bioactivity, while substitutions at H-6 or 8-OH diminished potency.

Conclusion

This study expands the chemical diversity of P. chrysogenum metabolites and identifies penichrysone B (3) as a promising lead compound for TNBC therapy.

Keywords

secondary metabolites anti-cancer triple negative breast cancer

Introduction

Breast cancer is one of the most common malignant tumors in women.¹ Although remarkable progress has been made in cancer detection, treatment, and management, it remains the leading cause of cancer-related death among women.^2–5 TNBC is the subtype with the worst prognosis among breast cancers, as it lacks targetable receptors, limiting therapeutic options to chemotherapy and a few immunotherapeutic agents.^6–8 Additionally, its high tumor heterogeneity and aggressiveness contribute to its poor outcome.^9,10 Current research on TNBC is shifting from “one-size-fits-all” treatment approaches to precision medicine, with the discovery of lead compounds from natural products emerging as one of the research hotspots.¹¹

Insect-derived medicines hold profound therapeutic value in traditional pharmacology, with Pencillium americana serving as a cornerstone in Chinese medicinal practices since its documentation in the Divine Farmer's Classic of Materia Medica. The insect has historically been employed to treat ailments such as ulcers, burns, and gastrointestinal disorders,¹² and modern studies have further unveiled its diverse bioactivities, including anti-tumor, anti-inflammatory, and tissue-regenerative properties.^13,14 While research on P. americana has predominantly focused on its intrinsic bioactive compounds—ranging from amino acids to macrolactams—a paradigm shift toward exploring microbial symbionts has emerged in recent years.^15–21 Insect-associated microorganisms, particularly endophytes, represent an underexplored reservoir of structurally novel and pharmacologically active metabolites, offering opportunities to expand the frontiers of natural product discovery. Among these symbionts, P. chrysogenum stands out as a fungal workhorse with a well-documented capacity for producing bioactive secondary metabolites.^22,23 However, its ecological role and metabolic potential within insect hosts remain poorly characterized, despite growing evidence that host-specific environments drive unique biosynthetic pathways in endophytic fungi.^24,25 This study is motivated by the hypothesis that P. chrysogenum, as a symbiont of P. americana, may yield metabolites shaped by coevolutionary interactions with its insect host, thereby contributing structurally and functionally distinct compounds to the drug discovery pipeline. Our prior work on P. chrysogenum isolated from this insect revealed its metabolic richness, prompting further systematic investigation.²⁶ Herein, we report the isolation of ten small molecules from P. chrysogenum, including two new polyketide derivatives, penichrysones A (1) and B (3), alongside eight known analogues (2, 4−10) (Figure 1). Given the reported anti-tumor properties of P. americana, compounds 1−10 were evaluated for their against TNBC.¹³ This research not only expands the chemical repertoire of P. chrysogenum but also highlights the anti-proliferative activity of 3 against TNBC. Structural elucidation and preliminary bioactivity assessments of the isolates are discussed to highlight their relevance to pharmaceutical and mechanistic studies.

Figure 1.

Chemical Structures of Compounds 1−10.

Method

General

UV spectra were recorded with a Jasco J-815 circular dichroism spectrometer (JASCO, Tokyo, Japan). For NMR spectra acquisition, the Bruker AV-400, AV-500, and AV-600 MHz spectrometer (Karlsruhe, Germany) were employed, with tetramethylsilane (TMS) serving as the internal standard. High Resolution Electrospray Ionization Mass Spectroscopy (HRESIMS) data were gathered via a Shimazu LC-20AD AB SCIEX triple TOF 5600+ MS spectrometer (Shimadzu Corporation, Tokyo, Japan). Column chromatography was carried out using MCI gel CHP 20P (75-150 μm, Mitsubishi Chemical Industries, Tokyo, Japan) and Sephadex LH-20 (Amersham Pharmacia, Uppsala, Sweden). Semi-preparative high performance liquid chromatography (HPLC) was carried out using a SEP LC-52 with an MWD UV detector equipped with a YMC-Pack C-18 column (250 mm × 10 mm, i.d., 5 μm); all the flow rate was 3 mL/min unless otherwise indicated.

Fungal Material

In November 2021, an endophytic fungal strain identified as P. chrysogenum was successfully isolated from P. americana specimens collected on Shenzhen University campus located in Guangdong Province, PR China. The strain characterization was performed through ITS sequencing analysis for precise taxonomic determination. Following isolation and identification, the authenticated strain has been deposited in the Culture Collection Center of the School of Pharmacy at Shenzhen University Medical School, Shenzhen University, PR China, for long-term preservation and future research purposes.

Extraction and Isolation

The extraction and isolation method of endophytes from the intestinal tract of P. americana was described in our previous report.²⁶ Building on our prior work, we continued the isolation of other fractions. Fr.A (1.6 g) was subjected to Sephadex LH-20 (MeOH) to obtain six portions (Fr.A.1–Fr.A.6). Of which, compound 10 (18.9 mg, t_R =13.4 min) was purified from Fr.A.1 (298.6 mg) was purified using semi-preparative HPLC (MeOH/H₂O containing 0.05% HCOOH, 25%). Similarly, compound 9 (2.2 mg, t_R = 34.9 min) was purified from Fr.A.5 (71.0 mg) washed with aqueous MeOH (containing 0.05% HCOOH, 30%). Fr.B (4.1 g) was applied to Sephadex LH-20 (MeOH) to produce three portions (Fr.B.1–Fr.B.3). Among them, purification of Fr.B.1 (155.8 mg) by semi-preparative HPLC with 70% aqueous MeOH (containing 0.05% HCOOH) led to the obtainment of compound 4 (3.0 mg, t_R = 9.2 min). Fr.C (3.1 g) was divided into three fractions (Fr.C.1–Fr.C.3) by Sephadex LH-20 (MeOH). Of which, Fr.C.3 (111.2 mg) was fractionated with semi-preparative HPLC (MeOH/H₂O, containing 0.05% HCOOH, 63%) to give compounds 6 (2.0 mg, t_R = 13.5 min), 1 (2.0 mg, t_R = 17.8 min), 8 (4.4 mg, t_R = 18.7 min), 5 (3.6 mg, t_R = 29.9 min), and two fractions (Fr.C.3.1–Fr.C.3.2). Among them, compound 7 (6.3 mg, t_R = 13.2 min) was purified from Fr.C.3.1 (30.0 mg) by semi-preparative HPLC (MeOH/H₂O containing 0.05% HCOOH, 45%). Likewise, compound 3 (2.3 mg, t_R = 18.9 min) was purified from Fr.C.3.2 (33.0 mg) by semi-preparative HPLC (MeOH/H₂O containing 0.05% formic acid, 60%). Fr.D (2.4 g) was subjected to Sephadex LH-20 (MeOH) to obtain five portions (Fr.D.1–Fr.D.5). Of which, purification of Fr.D.3 (59.1 mg) by semi-preparative HPLC with 67% aqueous MeOH (containing 0.05% HCOOH) led to the obtainment of compound 2 (23.8 mg, t_R = 13.3 min). Figure S1 shows the extraction and isolation procedures for compounds from the endophytic P. chrysogenum.

Penichrysone A (1)

Yellow solid.

UV (MeOH) λ_max (log ε) 210 (3.94), 258 (3.57), 300 (2.87) nm; UV spectrum, see Supporting Information Figure S2.

¹H NMR and ¹³C NMR data: Table 1; NMR spectra, see Supporting Information Figure S3–7.

Table 1.

The ¹H (600 MHz) and ¹³C (150 MHz) NMR Data of 1 and 3 in CD₃OD (δ in ppm, J in Hz).

No.	1		3
	δ_C (type)	δ_H (mult.)	δ_C (type)	δ_H (mult.)
1			144.8, C
2	165.7, C		141.2, C
3	112.9, CH	6.23 (s)	135.1, C
4	183.9, C		108.7, CH	6.88 (s)
4a	105.5, C		154.4, C
5	163.3, C		108.3, CH	7.06 (d, 7.5)
6	100.2, CH	6.24 (d, 2.1)	138.7, CH	7.68 (t, 7.5)
7	166.1, C		111.6, CH	6.78 (d, 7.5)
8	95.0, CH	6.36 (d, 2.1)	162.6, C
8a	160.3, C		108.7, C
9			187.5, C
9a			107.6, C
10a			157.7, C
1′	121.4, C		60.3, CH₂	4.79 (s)
2′	156.8, C
3′	114.4, CH	6.77 (d, 7.5)
4′	132.5, CH	7.21 (t, 7.5)
5′	122.4, CH	6.80 (d, 7.5)
6′	139.5, C
7′	19.9, CH₃	2.26 (s)

HRESIMS m/z 285.0745 [M + H]⁺ (calcd for C₁₆H₁₃O₅, 285.0757); HRESIMS spectrum, see Supporting Information Figure S8.

Penichrysone B (3)

Yellow solid.

UV (MeOH) λ_max (log ε) 204 (3.16), 232 (2.80), 260 (2.95), 342 (2.04), 396 (1.01) nm; UV spectrum, see Supporting Information Figure S9.

¹H NMR and ¹³C NMR: Table 1; NMR spectra, see Supporting Information Figure S10–14.

HRESIMS m/z 275.0539 [M + H]⁺ (calcd for C₁₄H₁₁O₆, 257.0550); HRESIMS spectrum, see Supporting Information Figure S15.

Cell Culture and Cell Viability Assay

HCC1806 cells (ATCC, CRL-2335) and MDA-MB-231 cells (ATCC, HTB-26), were cultured with high-glucose DMEM/F-12 (A4192001, ThermoFisher) supplemented with 15% fetal bovine serum (FBS) (2094468CP, Gibco, USA), 100 U/mL penicillin, and 100 μg/mL streptomycin at 37 °C in a humidified atmosphere with 5% CO₂. HCC1806 and MDA-MB-231 (3000 cells/well) were inoculated into 96-well plates with completed high-glucose DMEM/F-12. After overnight culture, the cells adhered to the 96-well plates, we treated them with different compounds or DMSO for 48 h. Then 90 μL of DMEM and 10 μL of Cell Count Kit-8 (CCK-8) were added into each well for 2 h at 37 °C. Finally, we used a microplate reader (BioTek, USA) to measure the absorbance of each well at 450 nm. These experimental procedures have been standardized in our laboratory.

Statistical Analyses

One-way analysis of variance (ANOVA) was performed for comparison among multiple groups. IC₅₀ values were determined by nonlinear regression. All analyses were conducted with GraphPad Prism 9.

Results

Penichrysone A (1), was obtained as a yellow solid, which was deduced to have the molecular formula C₁₆H₁₂O₅ (eleven degrees of unsaturation) by its HRESIMS based on the observed protonated molecular peak at m/z 285.0745 [M + H]⁺ (calcd for C₁₆H₁₃O₅, 285.0757). The ¹H NMR spectrum (Table 1) of 1 shows five aromatic protons [δ_H 7.21 (1H, t, J = 7.5 Hz, H-4′), 6.80 (1H, d, J = 7.5 Hz, H-5′), 6.77 (1H, d, J = 7.5 Hz, H-3′)], one olefinic proton [δ_H 6.23 (1H, s, H-3)], and one methyl at δ_H 2.26 (3H, s, H-7′). The ¹³C NMR and DEPT spectra (Table 1) of 1 show 16 carbons in resonance, including one methyl, six methines (one olefinic and five aromatic carbons), and nine quaternary carbons (one carbonyl). Compound 1 was suggested to belong to the family of flavones by its ¹H and ¹³C NMR data, and was similar to penimethavone A.²⁷ The key difference lay in the absence of a hydroxyl group at C-4′, and obseved a methine at δ_H 7.21 (1H, t, J = 7.5 Hz, H-4′), and δ_C 132.5 (CH) in 1. The ¹H–¹H COSY correlations (Figure 2) of H-3′/H-4′/H-5′, as well as HMBC (Figure 2) correlations of H-4′ (δ_H 7.21)/C-2′ (δ_C 156.8), C-6′ (δ_C 139.5) indicate the hydrogen atom was attached to C-4′. Collectively, the structure of 1 was finally elucidated as shown in Figure 1.

Figure 2.

¹H–¹H COSY () and key HMBC () correlations of 1 and 3.

Penichrysone B (3), was isolated as a yellow solid, it has a molecular formula C₁₄H₁₀O₆ (ten degrees of unsaturation) based on analysis of the HRESIMS in the positive ion mode, m/z 275.0539 [M + H]⁺ (calcd for C₁₄H₁₁O₆, 275.0550). The ¹H NMR spectrum (Table 1) of 3 shows four aromatic protons [δ_H 7.68 (1H, t, J = 7.5 Hz, H-6), 7.06 (1H, t, J = 7.5 Hz, H-5), 6.88 (1H, s, H-4), and 6.78 (1H, d, J = 7.5 Hz, H-7)]. The ¹³C NMR (Table 1) spectrum displays 14 carbons ascribed to one methylol, four methines, and nine quaternary carbons (one carbonyl). The ¹H and ¹³C NMR data suggest that compound 3 belongs to the family of xanthone. Careful analysis of the spectroscopic features suggested that compound 3 was similar to monodictyxanthone which was isolated from the marine algicolous fungus Monodictys putredinis.²⁸ The difference was the presence of a methylol [δ_H 4.79 (2H, s, H-1′), δ_C 60.3 (C-1′)] at C-3 in compound 3. The HMBC (Figure 2) correlations from H-1′ to C-2 (δ_C 141.2), C-3 (δ_C 135.1), and C-4 (δ_C 108.7) confirmed that the methylol group was attached to C-3. In addition, careful analysis of the chemical shifts of C-1 (δ_C 144.8) and C-2 (δ_C 141.2), two hydroxyl groups are determined to be connected at C-1 and C-2, respectively. Hence, the structure of compound 3 was determined as shown in Figure 1.

Eight known compounds were identified to be penimethavone A (2),²⁷ 6,8-dihydroxy-3-methyl-9-oxo-9H-xanthene-1-carboxylic acid (4),²⁹ methyl 6,8-dihydroxy-3-methyl-9-oxo-9H-xanthene-1-carboxylate (5),³⁰ penicillone C (6),³¹ endocrocin (7),²⁹ 1′-hydroxyisorhodoptilometrin (8),³² hydroxypropan-2′,3′-diol orsellinate (9),³³ and N-(2-hydroxypropanoyl)-2-aminobenzoic acid amide (10)³⁴ by comparison with literature data.

We detected the cell proliferation activity of compounds 1−10. Initial screening was performed at 40 µM, a concentration selected based on typical natural product screening ranges and pre-experimental cytotoxicity assessments to balance activity detection and cellular tolerance.^35,36 HCC1806 cells and MDA-MB-231 cells were treated with the isoaltes at a concentration of 40 μM for 48 h, and the CCK-8 assay for cell viability (Figure 3A) showed that compound 3 had a significant inhibitory effect on the proliferation of HCC1806 cells. And then, HCC1806 cells were treated with different concentrations of compound 3, and the IC₅₀ was detected to be 51.7 μM (Figure 3B).

Figure 3.

The Cell Proliferation Activity of Compounds 1−10 and the IC₅₀ of the Compound 3. A: HCC1806 Cells and MDA-MB-231 Cells Were Treated with Compounds 1−10 (40 μM) or DMSO for 48 h and Subjected to CCK-8 Assay. Data are Mean ± SD. *P < .05 (**P < .01; ***P < .001) was Considered Significant. B: HCC1806 Cells Were Treated with Different Concentrations of 3 (10 μM, 20 μM, 40 μM, and 60 μM) for 48 h and the Cell Viability was Determined by CCK-8.

Discussion

Although compound 3 exhibits anti-proliferative activity against HCC1806 cells, its potency is notably limited when compared to clinically used chemotherapeutic drugs such as paclitaxel. Specifically, the IC₅₀ value of 3 (51.7 µM) is approximately 14 800-fold higher than that of paclitaxel (3.5 nM),³⁷ highlighting a substantial gap in therapeutic potency relative to established agents. This contrast underscores the need for further optimization to enhance its efficacy for potential clinical translation. Recent studies have shown that natural product-derived lead compounds with modest initial activity can be optimized through structural modifications to improve potency, such as the development of taxane derivatives from paclitaxel.^38,39 Notably, this study did not evaluate compound 3 in in vivo tumor models or normal cell lines, leaving uncertainties about its efficacy and safety in physiological contexts.

The structure-activity relationships of compounds 3 to 6 suggest that the hydroxyl groups at C-2 and C-1′ positions may be critical active sites, as bioactivity weakens when 8-OH and H-6 are substituted by other groups. This finding is generally consistent with previous studies, which showed that hydroxyl substitution in xanthone derivatives significantly affects their anticancer activity by regulating interactions with target proteins.^40,41 Future studies using molecular docking and site-directed mutagenesis could further verify these functional groups’ role in binding to potential targets, which is overexpressed in basal-like TNBC cells (e.g., HCC1806).^42,43

Differences in receptor expression profiles between HCC1806 (basal-like) and MDA-MB-231 (mesenchymal-like) cells likely underlie the selective activity of 3.⁴² HCC1806 cells may express specific receptors or transporters with high affinity for 3, such as ATP-binding cassette transporters or integrins, which are known to mediate drug uptake in TNBC subtypes.^44,45 A recent transcriptomic analysis revealed that basal-like TNBC cells exhibit enhanced expression of EGFR and downstream signaling pathways, which could serve as potential targets for compound 3.⁴⁶ This selectivity highlights the promise of fungal metabolites in exploiting subtype-specific dependencies, a strategy gaining traction in precision oncology.⁴⁷

Moreover, the selective activity of 3 against basal-like TNBC underscores the importance of targeting TNBC heterogeneity. Recent advances in TNBC subtyping have identified at least six molecular subtypes, each with distinct therapeutic vulnerabilities.⁴⁸ Compounds like 3, which exhibit subtype-selective activity, could serve as valuable chemical tools to dissect TNBC heterogeneity and inspire the development of precision therapies. This approach resonates with recent breakthroughs in antibody-drug conjugates, such as sacituzumab govitecan, which targets Trop-2 and has shown efficacy in specific TNBC subtypes.⁴²

Conclusion

This study reports the discovery of two new polyketide derivatives, penichrysone A (1) and B (3), from the insect-derived endophytic fungus P. chrysogenum. Compound 3 demonstrates selective anti-proliferative activity against HCC1806 TNBC cells, providing a promising lead for further optimization. These findings not only expand the chemical diversity of P. chrysogenum metabolites but also validate insect-endophyte systems as a fertile ground for TNBC drug discovery.

Highlights

Two new compounds (a flavone penichrysone A and a xanthone derived penichrysone B), together with eight known compounds, were isolated from the endophytic fungus Penicillium chrysogenum derived from the insect Periplaneta americana.

All the isolated compounds were tested against human triple negative breast cancer cells (HCC1806 and MDA-MB-231).

Biological evaluation reveals that penichrysone B exhibits inhibitory activity in the proliferation of HCC1806 cells with an IC₅₀ of 51.7 μM.

Supplemental Material

sj-docx-1-npx-10.1177_1934578X251380433 - Supplemental material for Two New Compounds from the Insect-Derived Endophytic Penicillium Chrysogenum and Their Biological Activities Against Triple Negative Breast Cancer Cells

Supplemental material, sj-docx-1-npx-10.1177_1934578X251380433 for Two New Compounds from the Insect-Derived Endophytic Penicillium Chrysogenum and Their Biological Activities Against Triple Negative Breast Cancer Cells by Ke-Ming Li, Zi-Wei Zhang, Wen-Xing Zhu, Chun-Yan Zhu, Yong-Ming Yan, Guangyi Yang and Qin Luo in Natural Product Communications

Footnotes

Acknowledgments

This study was supported financially by the Shenzhen Fundamental Research Program (JCYJ20210324120213038), SZU Top Ranking Project (868/000005030322), and Sanming Project of Medicine in Shenzhen (SZZYSM202106009).

ORCID iDs

Ke-Ming Li

Chun-Yan Zhu

Yong-Ming Yan

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Sanming Project of Medicine in Shenzen (SZZYSM202106009), Shenzhen Municipal Fundamental Research Program (JCYJ20210324120213038), and SZU Top Ranking Project (868/000005030322).

Declaration of Conflicting Interests

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

Supplemental Material

Supplemental material for this article is available online.

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