1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 DOI: 10.1002/ijch.201800162 Epigenetic Manipulation Induces the Production of Coumarin-Type Secondary Metabolite from Arthrobotrys foliicola Chi-Ying Li, [a, b] I-Wen Lo, [a] Yen-Ping Hsueh, [c] Yu-Ming Chung, [a] Shih-Wei Wang, [a, d] Michal Korinek, [a, e, f] Yi- Hong Tsai, [a] Yuan-Bin Cheng, [a, g] Tsong-Long Hwang, [e, f, h] Clay C. C. Wang, [b, i] Fang-Rong Chang,* [a, j] and Yang- Chang Wu* [a, g, k] Abstract: Pursuing epigenetic manipulation approach in fungi led to the isolation of an unusual coumarin metabolite from fungi. An addition of the histone deacetylase inhibitor, suberohydroxamic acid (SBHA), to the culture medium of Arthrobotrys foliicola induced production of the coumarin-type secondary metabolite represented by a single intensive peak in the HPLC profile of the ethyl acetate extract. The compound which was identified as 4-ethyl-7-hydroxy-8- methyl-2H-chromen-2-one (1) was isolated from nature for the first time. Moreover, the investigation on the remaining part of the HPLC profile led to the separation of 6-ethyl-2,4- dihydroxy-3-methylbenzaldehyde (2) and ten 2,5-diketopiper- azine compounds (3–12). The structures of isolates were deduced by their mass and NMR spectroscopic data. The coumarin-type secondary metabolite (1) with peculiar smell induced by epigenetic stimulation is found for the first time in the Arthrobotrys species and the family Orbiliaceae. We evaluated 1 for the cytotoxic, anti-inflammatory, anti-allergic and nematocidal activities, however, it was found inactive. Keywords: Arthrobotrys foliicola · epigenetic manipulation · secondary metabolites · coumarin · 2,5-diketopiperazine 1. Introduction Fungi are important sources of natural products that are useful to humankind. Bioactive components generated by fungi have been used in pharmaceutical, food industries and agricul- ture. [1,2,3] Natural products obtained from fungi are generally cultivated under standardized laboratory growth conditions. [4] Traditional methods to explore fungal natural products usually include species collection, optimization of strains cultivation conditions, extraction, bioassay-guided fractionation, purifica- tion, and structural elucidation. However, this approach often [a] C.-Y. Li, I-W. Lo, Y.-M. Chung, S.-W. Wang, M. Korinek, Y.- H. Tsai, Y.-B. Cheng, F.-R. Chang, Y.-C. Wu Graduate Institute of Natural Products, College of Pharmacy Kaohsiung Medical University, Kaohsiung, 807, Taiwan phone: + 886-7-312-1101 (ext. 2162) phone: + 886-7-312-1101(ext. 5437) E-mail: aaronfrc@kmu.edu.tw yachwu@kmu.edu.tw [b] C.-Y. Li, C. C. C. Wang Department of Pharmacology and Pharmaceutical Sciences University of Southern California, School of Pharmacy Los Angeles, CA 90089, USA [c] Y.-P. Hsueh Institute of Molecular Biology, Academia Sinica Taipei, 11529, Taiwan [d] S.-W. Wang Department of Medicine, Mackay Medical College New Taipei City, 252, Taiwan [e] M. Korinek, T.-L. Hwang Graduate Institute of Natural Products, College of Medicine, and Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan, 33302, Taiwan [f] M. Korinek, T.-L. Hwang Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, and Graduate Institute of Health In- dustry Technology, College of Human Ecology, Chang Gung Uni- versity of Science and Technology, Taoyuan, 33302, Taiwan [g] Y.-B. Cheng, Y.-C. Wu Department of Medical Research, Kaohsiung Medical University, Kaohsiung, 807, Taiwan [h] T.-L. Hwang Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan [i] C. C. C. Wang Department of Chemistry, University of Southern California College of Letters, Arts, and Sciences, Los Angeles, CA 90089, USA [j] F.-R. Chang National Research Institute of Chinese Medicine Taipei, 112, Taiwan [k] Y.-C. Wu Research Center for Natural Products & Drug Development Kaohsiung Medical University, Kaohsiung, 807, Taiwan Supporting information for this article is available on the WWW under https://doi.org/10.1002/ijch.201800162 Isr. J. Chem. 2019, 59, 1 – 8 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 These are not the final page numbers! ÞÞ Full Paper