Emestrin-type thiodiketopiperazines from Aspergillus nidulans SD-531, a fungus obtained from the deep-sea sediment of cold seep in the South China Sea

https://doi.org/10.1016/j.dsr.2023.104004Get rights and content

Highlights

  • Secondary metabolites of the deep-sea-derived Aspergillus nidulans were studied.

  • Three new and three known emestrin-type thiodiketopiperazines were characterized.

  • Emestrin, a diketopiperazine with disulfide bridge, showed potent cytotoxicity.

Abstract

Three new emestrin-type thiodiketopiperazines including didethio-11a-methylthioemestrin (1), 7′-epi-didethio-11a-methylthioemestrin (2), and 2″-desmethyl-MPC1001F (3), along with three known analogues emestrin (4), dethiosecoemestrin (5), and emestrin H (6), were isolated and identified from the culture extract of Aspergillus nidulans SD-531, a fungus obtained from the deep-sea cold seep sediment sample collected from the South China Sea. Their structures and absolute configurations were determined by spectroscopic analysis and TDDFT-ECD calculations. Compounds 36 showed antimicrobial activity against some of the tested strains, while compounds 35 had cytotoxic activity against the tumor cell line Huh 7.5. Compound 4 exhibited the strongest cytotoxic activity with an IC50 value of 0.25 μM, which was better than that of the positive control sorafenib.

Introduction

Thiodiketopiperazines (TDKPs), produced mainly by fungi, are a class of important natural products with versatile structural features and diverse bioactivities (Meng et al., 2014; Barakat et al., 2019; Zhai et al., 2020). More than ten distinct subtypes of emestrin-type TDKPs were isolated and characterized after reporting the first one in 1986 (Seya et al., 1986a; Li et al., 2016). Most of these TDKPs have been reported to possess various bioactivities such as antibacterial, antifungal, and antitumor activities (Herath et al., 2005, 2013; Jiang and Guo, 2011; Xu et al., 2013). The cold seep-derived microorganisms generally possess unique metabolic pathway and genetic background due to their adaptation to the extreme living environment in the deep sea, and thus having the potential to prepare interesting natural products, such as sulfur-containing compounds (Margesin and Schinner, 2001; Zhang and Lanoil, 2004; Skropeta and Wei, 2014). During our recently initiated program on identifying new bioactive secondary metabolites from cold seep-derived fungi (Lv et al., 2020; Yan et al., 2022; Hu et al., 2023), we performed chemical investigations on the culture extract of Aspergillus nidulans SD-531, which was obtained from the sediment samples collected from the cold seep environment in the South China Sea. As a result, three new emestrin-type thiodiketopiperazines, methylthioemestrin (1), 7′-epi-methylthioemestrin (2), and 2″-desmethyl-MPC1001F (3), together with three related known analogues, emestrin (4) (Seya et al., 1986a), dethiosecoemestrin (5) (Seya et al., 1986b), and emestrin H (6) (Li et al., 2016), were isolated and identified from the culture extract of the fungus. The structures of compounds 16 were established on the basis of spectroscopic analysis and all these compounds were tested for antimicrobial and cytotoxic activities. This paper reports the isolation, structural elucidation, and bioactivity evaluation of these compounds.

Section snippets

General experimental procedures

Ultraviolet (UV) and ECD spectra were recorded on a Lengguang Gold S54 spectrophotometer (Shanghai Lengguang Technology Co. Ltd., Shanghai, China) and a Chirascan spectropolarimeter, respectively. 1D and 2D-NMR spectra were recorded on a Bruker Avance-500 spectrometer (Bruker Biospin Group, Karlsruhe, Germany). Mass spectra were determined on an API QSTAR Pulsar 1 mass spectrometer. Analytical high performance liquid chromatography (HPLC) analysis was carried out using a Dionex HPLC system,

Results and discussion

The EtOAc extract of the fungal culture was obtained after culturing the fungus A. nidulans SD-531 on the rice solid medium. The extract was further fractionated and purified by a combination of column chromatography (CC), including silica gel, Sephadex LH-20, and Lobar LiChroprep RP-18, as well as by semi-preparative HPLC, to yield compounds 16 (Fig. 1).

Compound 1 was isolated as white powder with molecular formula C28H26N2O10S on the basis of HRESIMS data, indicating 17 degrees of

Conclusions

Three new emestrin-type thiodiketopiperazines 13 and three known analogues 46 were isolated and identified from the culture extract of cold-seep-derived fungus Aspergillus nidulans SD-531. Their structures and absolute configurations were determined by NMR spectroscopic and TDDFT-ECD calculations. Compounds 36 exhibited antimicrobial activity and cytotoxic activity indicating that they might be used as promising molecules for the development of natural antimicrobial or anti-tumor agents.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was financially supported by the Shandong Special Fund for Qingdao National Laboratory for Marine Science and Technology (2022QNLM030004-4), by the Strategic Priority Research Program of Chinese Academy of Sciences (XDA22050401), and by the National Natural Science Foundation of China (U2006203, 42076090, and 41976090). B.-G.W. acknowledges the support of the RV KEXUE of the National Major Science and Technology Infrastructure from the Chinese Academy of Sciences (for sampling). T.K.

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