北部湾珊瑚来源构巢裸胞壳菌GXIMD 02509中具有细胞毒性的一个多硫代二酮哌嗪生物碱和结构多样的芳香聚酮类化合物

An epipolythiodioxopiperazine alkaloid and diversified aromatic polyketides with cytotoxicity from the Beibu Gulf coral-derived fungus Emericella nidulans GXIMD 02509 北部湾珊瑚来源构巢裸胞壳菌GXIMD 02509中具有细胞毒性的一个多硫代二酮哌嗪生物碱和结构多样的芳香聚酮类化合物 equal first-author equal corresp equal Xiaowei LUO, luoxiaowei1991@126.com Xiaowei LUO, luoxiaowei1991@126.com luoxiaowei1991@126.com https://orcid.org/0000-0002-2114-1609 广西中医药大学， 海洋药物研究院/广西海洋药物重点实验室， 中国南宁市， 530200 广西中医药大学， 海洋药物研究院/广西海洋药物重点实验室， 中国南宁市， 530200 Institute of Marine Drugs, Guangxi Key Laboratory of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China Institute of Marine Drugs, Guangxi Key Laboratory of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China 北部湾藴育着丰富且亟待研究的海洋（微）生物资源，是活性天然产物的重要来源。本研究从涠洲岛珊瑚共附生构巢裸胞壳菌GXIMD 02509中分离获得一个多硫代二酮哌嗪生物碱和系列芳香聚酮类化合物，含一个新化合物4a- O -methoxyarugosin H ( 1 )。我们通过采用多种波、光谱学技术及对比文献方法鉴定了化合物的化学结构。化合物 1-5 、 7 和 10 对786-O、SW1990和SW480等3株肿瘤细胞增殖具抑制活性，半抑制浓度（IC 50 ）值为4.3–33.4 μmol/L。化合物emestrin J ( 10 )具有一个二硫桥键，还能够显著抑制786-O细胞克隆及迁移，诱导786-O细胞凋亡并阻滞细胞分裂在G2/M期，是一个潜在具抗肿瘤活性的先导化合物。 巢裸胞壳菌 海洋真菌 芳香聚酮 多硫代二酮哌嗪 细胞毒 Marine microorganisms, especially marine fungi, have historically proven their value as a prolific source for structurally novel and pharmacologically active secondary metabolites ( Deshmukh et al., 2018 Deshmukh et al., 2018 ; Carroll et al., 2022 Carroll et al., 2022 ). The corals constitute a dominant part of reefs with the highest biodiversity, and harbor highly diverse and abundant microbial symbionts in their tissue, skeleton, and mucus layer, with species-specific core members that are spatially partitioned across coral microhabitats ( Wang WQ et al., 2022 Wang WQ et al., 2022 ). The coral-associated fungi were very recently found to be vital producers of structurally diverse compounds, terpenes, alkaloids, peptides, aromatics, lactones, and steroids. They demonstrate a wide range of bioactivity such as anticancer, antimicrobial, and antifouling activity ( Chen et al., 2022 Chen et al., 2022 ). The genetically powerful genus Emericella (Ascomycota), which has marine and terrestrial sources, includes over 30 species and is distributed worldwide. It is considered a rich source of diverse secondary metabolites with antimicrobial activity or cytotoxicity ( Alburae et al., 2020 Alburae et al., 2020 ). Notably, Emericella nidulans , the sexual state of a classic biosynthetic strain Aspergillus nidulans , was recently reported as an important source of highly methylated polyketides ( Li et al., 2019 Li et al., 2019 ) and isoindolone-containing meroterpenoids ( Zhou et al., 2016 Zhou et al., 2016 ) with unusual skeletons. The Beibu Gulf is a semi-enclosed gulf in the northwest of the South China Sea, and harbors tremendous underexplored biodiversity in terms of both marine organisms and microorganisms; these are rich in diversified secondary metabolites ( Huang et al., 2022 Huang et al., 2022 ). In continuation of our efforts to discover interesting lead compounds from Beibu Gulf coral-derived marine fungi, a plethora of structurally novel secondary metabolites with remarkable biological activity have been recently obtained, including anti-tumor ascochlorins ( Guo et al., 2021 Guo et al., 2021 ; Luo et al., 2021 Luo et al., 2021 ) and cytochalasans ( Luo et al., 2020 Luo et al., 2020 ), anti-osteoclastogenic chlorinated polyketides ( Zhang et al., 2022 Zhang et al., 2022 ), phenolic derivatives ( Lu et al., 2022 Lu et al., 2022 ), and cyclopiazonic acid alkaloids ( Wang JM et al., 2022 Wang JM et al., 2022 ). In this study, a fungus Emericella nidulans GXIMD 02509 endemic to Weizhou coral reefs attracted our attention owing to the intriguing high-performance liquid chromatography (HPLC)-ultraviolet (UV) profiles of its extract. Subsequent chemical investigation led to the isolation of nine diverse aromatic polyketides, an epipolythiodioxopiperazine alkaloid, and a farnesylated phthalide derivative ( Fig. 1 Fig. 1 ). Several of these compounds showed cytotoxicity against three human cancer-cell lines (786-O, SW1990, and SW480). Here, the process of isolation and structural determination, as well as the cytotoxicity results, are described in detail. Compound 1 was isolated as a bright-yellow solid and was deduced with the molecular formula C 21 H 22 O 6 based on the high resolution-electrospray ionization-mass spectroscopy (HR-ESI-MS) data [M+H] + ion peak at m/z 371.1499 (calcd for C 21 H 23 O 6 , 371.1495). The UV spectrum revealed the presence of benzene chromophores with absorption bands at 203, 255, and 320 nm. The 1 H nuclear magnetic resonance (NMR) ( Table 1 Table 1 ) and heteronuclear single quantum coherence (HSQC) data for 1 displayed a series of signals, including: two hydroxyl groups attributable to 1-OH ( δ H 10.93, s) and 7-OH ( δ H 11.38, s); one aldehyde group, H-11 ( δ H 9.98, s); four aromatic or olefinic protons, H-3 ( δ H 7.12, d, J =8.5 Hz), H-4 ( δ H 6.12, d, J =8.5 Hz), H-5 ( δ H 7.16, s), and H-2' ( δ H 5.25, t, J =7.0 Hz); one methylene, H-1' ( δ H 3.28, d, J =7.0 Hz); three singlet methyls, 6-Me ( δ H 2.24, s), H 3 -4' ( δ H 1.72, s), and H 3 -5' ( δ H 2.24, s); and one methoxyl, 4a-OMe ( δ H 4.03, s). Aside from these ten corresponding hydrogen-bearing carbons, ten aromatic or olefinic (four oxygenated) carbons and a carbonyl ( δ C 198.3) remained in the 13 C NMR spectrum. NMR: nuclear magnetic resonance; HMBC: heteronuclear multiple bond correlation. Position δ C , type δ H ( J (Hz)) HMBC 1 160.4, C 2 125.2, C 3 134.9, CH 7.12, d (8.5) 1, 1' 4 105.5, CH 6.12, d (8.5) 2, 4a, 9a 4a 170.5, C 4a-OMe 53.2, CH 3 4.03, s 4a 5 128.0, CH 7.16, s 6, 6-Me, 7, 10a 6 139.8, C 6-Me 15.2, CH 3 2.24, s 5, 6, 7 7 154.8, C 8 113.7, C 8a 125.3, C 9 198.3, C 9a 103.5, C 10a 140.2, C 11 194.1, CH 9.98, s 7, 8, 8a 1' 27.8, CH 2 3.28, d (7.0) 1, 2, 3, 2', 3' 2' 121.5, CH 5.25, t (7.0) 2, 1', 4', 5' 3' 133.7, C 4' 25.9, CH 3 1.72, s 2', 3', 5' 5' 17.9, CH 3 2.24, s 2', 3', 4' 1-OH 10.93, s 1, 2, 9a 7-OH 11.38, s 6, 7, 8 This information revealed that structurally, 1 was closely related to arugosin H, which was also obtained from the marine-derived fungus Emericella nidulans var. acristata ( Kralj et al., 2006 Kralj et al., 2006 ). The main difference was the appearance of a methoxyl group ( δ H/C 4.03/53.2) at C-4a ( δ C 170.5) in 1 instead of the hydroxyl group that appears in arugosin H. This deduction was verified by the heteronuclear multiple bond correlation (HMBC) correlation from 4a-OC H 3 to C-4a ( Fig. 2 Fig. 2 ). Based on these findings, we determined that the structure of 1 was a methyl derivative of arugosin H, and accordingly assigned it a trival name: 4a- O -methoxyarugosin H (Figs. S1‍–‍S9). Compound 1 was probably an artifact produced during the isolation procedure when methanol was used as the main solvent ( Capon, 2020 Capon, 2020 ). We were able to pinpoint known compounds by comparing the physicochemical data of known compounds 2‍ –‍ 11 (supplementary information) with data from the literature. We identified pre-shamixanthone ( 2 ) ( Wu et al., 2015a Wu et al., 2015a ), cycloisoemericellin ( 3 ) ( Kawahara et al., 1988 Kawahara et al., 1988 ), sterigmatocystin ( 4 ) ( Zhu and Lin, 2007 Zhu and Lin, 2007 ), dihydrosterigmatocystin ( 5 ) ( Zhu and Lin, 2007 Zhu and Lin, 2007 ), dehydromicroperfuranone ( 6 ) ( Kralj et al., 2006 Kralj et al., 2006 ; Roux et al., 2020 Roux et al., 2020 ), varioxiranol I ( 7 ) ( Wu et al., 2015b Wu et al., 2015b ), arugosin G ( 8 ) ( Kralj et al., 2006 Kralj et al., 2006 ), arugosin C ( 9 ) ( Kawahara et al., 1988 Kawahara et al., 1988 ; El-Kashef et al., 2021 El-Kashef et al., 2021 ), emestrin J ( 10 ) ( Li et al., 2016 Li et al., 2016 ), and farnesylemefuranone D ( 11 ) ( Chi et al., 2020 Chi et al., 2020 ). Interestingly, emestrin J ( 10 ) harbors with an uncommon disulfide moiety, which was biosynthesized by a peptide cyclization pathway along with additional ring-expansion and macrocyclization ( Li et al., 2016 Li et al., 2016 ). During the course of our search for anti-tumor lead compounds from marine natural products ( Zhou et al., 2019 Zhou et al., 2019 ; Luo et al., 2021 Luo et al., 2021 ), all obtained compounds were evaluated for cytotoxicity against three human cancer cell lines, i.e., 786-O (human renal carcinoma cell), SW1990 (human pancreatic cancer cell), and SW480 (human colorectal cancer cell), along with the normal human liver cell line LO2 ( Table 2 Table 2 ). Among them, compounds 1‍ -‍ 5 , 7 , and 10 showed inhibitory activity against these cell lines, with the half maximal inhibitory concentration (IC 50 ) values ranging from 4.3 to 33.4 μmol/L. Notably, emestrin J ( 10 ) exhibited the strongest activity against these cancer cell lines, especially for 786-O (4.3 μmol/L), and was at least as potent as the positive control, cisplatin. Interestingly, two xanthone derivatives ( 4 and 5 ) displayed antiproliferative activity, with IC 50 values of 18.3 and 24.7 μmol/L against 786-O, and 19.6 and > 40 μmol/L against SW1990 cells, respectively. This revealed that the Δ 16 double bond in 4 probably promoted cytotoxic activity. All data shown above are mean±SD of three independent experiments. IC 50 : half maximal inhibitory concentration; SD: standard deviation. "‒": > 40 μmol/L. 2 Compound 4 IC 50 (μmol/L) 786-O SW1990 SW480 LO2 1 – – 32.6±1.2 – 2 – 33.2±5.1 – – 3 – 24.7±2.2 30.2±4.8 – 4 18.3±1.9 19.6±2.8 – – 5 24.7±1.8 – – – 6 – – – – 7 33.4±1.8 30.4±5.1 27.2±6.5 – 8 – – – – 9 – – – – 10 4.3±0.7 14.1±1.8 4.9±0.3 11.1±2.4 11 – – – – Cisplatin 2.5±0.6 33.8±4.7 26.7±4.6 5.2±0.6 To further evaluate the potential anti-tumor activity of 10 , we next investigated its activity against 786-O cells in cell colony and scratch wound assays. Consistent with the above-mentioned antiproliferative activity, compound 10 significantly reduced cell colony formation of 786-O cells at concentrations of 0.5 and 1.0 μmol/L (Figs. 3 3 a and 3 3 b). Also, compared with the vehicle group, compound 10 significantly suppressed migration of 786-O cells in a time- and dose‐dependent manner (Figs. 3 3 c and 3 3 d). To explore whether the antiproliferative activity of 10 was related to apoptosis, we further evaluated the compound for its effect on cell apoptosis and cell-cycle arrest in 786-O cells. The results were analyzed by flow cytometry and showed that the total apoptotic cells (early and late) induced by 10 at 24 h rose by 21.4% (2 μmol/L) and 29.5% (4 μmol/L), suggesting that 10 induced 786-O cell apoptosis in a dose-dependent manner (Figs. 4 4 a and 4 4 b). Meanwhile, the cell-cycle distribution results revealed that 10 primarily blocked the cell cycle during the G2/M phase, resulting in an inability of cells to proliferate (Figs. 4 4 c and 4 4 d). Therefore, it was clear that 10 could suppress the proliferation, colony formation, and migration of 786-O cells, and induce apoptosis, acting as a potential anti-tumor compound. In conclusion, nine aromatic polyketides, including a new one, 4a- O -methoxyarugosin H ( 1 ), along with an epipolythiodioxopiperazine alkaloid, emestrin J ( 10 ), and a farnesylated phthalide derivative, were obtained from the Beibu Gulf coral-associated fungus Emericella nidulans GXIMD 02509. We determined their structures by spectral data analysis, as well as comparison with reported data. Several of the compounds exhibit cytotoxicity against three human cancer cell lines, 786-O, SW1990, and SW480. 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Three xanthones from a marine-derived mangrove endophytic fungus . Chem Nat Compd , 43 ( 2 ): 132 - 135 . https://doi.org/10.1007/s10600-007-0062-9 https://doi.org/10.1007/s10600-007-0062-9 Three xanthones from a marine-derived mangrove endophytic fungus Xiaowei LUO and Yonghong LIU conceived the research and designed experiments. Miaoping LIN, Zhenzhou TANG, Jiaxi WANG, Humu LU, Chenwei WANG, Yanting ZHANG, Xinming LIU, and Chenghai GAO performed the experiments and analysis. Xiaowei LUO, Miaoping LIN, and Zhenzhou TANG interpreted the data and wrote the paper. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data. This research was supported by the Guangxi Natural Science Foundation (Nos. 2020GXNSFBA159001, 2020GXNSFGA297002, and 2021GXNSFAA220052), the National Natural Science Foundation of China (Nos. U20A20101 and 22007019), the Special Fund for Bagui Scholars of Guangxi (Yonghong LIU), and the Scientific Research Foundation of Guangxi University of Chinese Medicine (No. 2022C038), China. 10.1631/jzus.B2200622 1673-1581（2023）03-0275-06 林妙萍,唐振洲,王佳熹等.北部湾珊瑚来源构巢裸胞壳菌GXIMD 02509中具有细胞毒性的一个多硫代二酮哌嗪生物碱和结构多样的芳香聚酮类化合物[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2023,24(03):275-280. 林妙萍,唐振洲,王佳熹等.北部湾珊瑚来源构巢裸胞壳菌GXIMD 02509中具有细胞毒性的一个多硫代二酮哌嗪生物碱和结构多样的芳香聚酮类化合物[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2023,24(03):275-280. This research was supported by the Guangxi Natural Science Foundation (Nos. 2020GXNSFBA159001, 2020GXNSFGA297002, and 2021GXNSFAA220052), the National Natural Science Foundation of China (Nos. U20A20101 and 22007019), the Special Fund for Bagui Scholars of Guangxi (Yonghong LIU), and the Scientific Research Foundation of Guangxi University of Chinese Medicine (No. 2022C038), China. 2022-12-07 2023-01-06 2023-03-15 2023-03-14 2023-02-17 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2022 2023 浙江大学出版社 Miaoping LIN, Zhenzhou TANG, Jiaxi WANG, Humu LU, Chenwei WANG, Yanting ZHANG, Xinming LIU, Chenghai GAO, Yonghong LIU, and Xiaowei LUO declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. Compliance with ethics guidelines Supplementary information 1 Materials and methods; Figs. S1‒S9; Physicochemical data of known compounds 2‒11 浙江大学学报（英文版）（B辑：生物医学和生物技术） 3 24