Elsevier

Fitoterapia

Volume 143, June 2020, 104599
Fitoterapia

Novel secondary metabolites from the endobryophytic fungus Botrysphaeria laricina and their biological activity

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Abstract

One novel polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) hybrid metabolite, laricinin A (1), two new meroterpenoids, tricycloalternarenes X and Y (2 and 3), one new coumarin, 3,4,7-trihydroxy-6-methylcoumarin (4), together with the known ethyl acetylorsellinate (5), diorcinol K (6), and tricycloalternarenes C and D (7 and 8) were obtained from culture of the fungus Botrysphaeria laricina isolated from the moss Rhodobryum umgiganteum. The structures of the new compounds were elucidated based on extensive spectroscopic techniques including HRMS and 1D and 2D NMR measurements. The absolute configuration of compound 1 was determined by ECD calculation and it was the first example of a novel group of PKS-NRPS hybrids possessing an unprecedented methyldihydropyran-isobutylpyrrolidinone skeleton. Compounds 2, 7, and 8 showed significant quinone reductase inducing activity in Hepa 1c1c7 cells.

Graphical abstract

Chemical investigation on the endophytic fungus Botrysphaeria laricina inhabiting the moss Rhodobryum umgiganteum afforded four new compounds, including laricinin A (1), which was the first example of a polyketide synthase-nonribosomal peptide synthetase hybrid possessing an unprecedented skeleton. Some compounds showed significant quinone reductase inducing activity in Hepa 1c1c7 cells.

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Introduction

The bryophytes (mosses, liverworts, and hornworts) are nonvascular herbaceous land plants that grow on rocks, soil, or as epiphytes on the trunks and leaves of forest trees [1,2]. Since the discovery of endophytic fungi in the healthy tissues of mosses [3,4], which live within the nonvascular tissues in much the same way as those living within higher vascular plants [5], many strains have been investigated for their secondary metabolites and they have demonstrated the ability to produce compounds with diverse structures and bioactivities [[6], [7], [8], [9]].

Quinone reductase (QR) is one of the major phase II drug-metabolizing enzymes, which can be induced by a wide variety of endogenous and exogenous insults [10]. The induction of this enzyme accelerates the ability of the body to detoxify and eliminate carcinogens, which is closely related to chemoprevention. We have adopted a bioassay of measuring quinone reductase activity in Hepa 1c1c7 murine hepatoma cells [11]. In the course of our ongoing search for bioactive compounds from fungal endophytes, a strain of the fungus Botrysphaeria laricina was isolated from the healthy tissue of the moss Rhodobryum umgiganteum (Bryaceae), and the EtOAc extract of its culture on Czapek's medium exhibited significant quinone reductase inducing activity in Hepa 1c1c7 cells. Further fractionation of this extract yielded one novel PKS-NRPS hybrid metabolite, laricinin A (1), two new meroterpenoids, tricycloalternarenes X and Y (2 and 3), one new coumarin, 3,4,7-trihydroxy-6-methylcoumarin (4), together with the known ethyl acetylorsellinate (5), diorcinol K (6), and tricycloalternarenes C and D (7 and 8) (Fig. 1). The quinone reductase inducing activity of the isolates was tested and compounds 2, 7, and 8 showed significant activity. Herein, we report the isolation, structure elucidation, and bioactivity of these compounds.

Section snippets

General experimental procedures

Silica gel (200–300 mesh), C18 reversed-phase silica gel, and Sephadex LH-20 (Pharmacia Bioteck) were used for column chromatography (CC). Precoated silica gel GF254 plates (Qingdao Haiyang Chemical Co. Ltd., Qingdao, People's Republic of China) were used for thin-layer chromatography, and spots were visualized by spraying with anisaldehyde-H2SO4-acetic acid-H2O (4:6:80:100) followed by heating. UV spectra were measured with a Shimadzu UV-2550 spectrophotometer. IR spectra were recorded on a

Results and discussion

Compound 1 was isolated as a yellowish oil. It was assigned the molecular formula C14H23NO3 by the quasi molecular ion [M + H]+ peak at m/z 254.1748 (calcd for C14H24NO3, 254.1751) in the HR-ESIMS, indicative of four double bond equivalents. Its IR spectrum displayed absorption bands for the carbonyl (1695 cm−1) and hydroxy (3278 cm−1) groups. The 1H NMR data (Table 1) of 1 exhibited resonances for three methyls (δH 0.86, d, J = 6.5 Hz; 0.88, d, J = 6.5 Hz; and 1.14, d, J = 6.2 Hz), two

Declaration of Competing Interest

None.

Acknowledgements

Financial support from the National Natural Science Foundation of China (Nos. 21877071 and 81874341) is gratefully acknowledged.

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