Bioorganic Chemistry xxx (xxxx) xxx Please cite this article as: Sui-Qun Yang, Bioorganic Chemistry, https://doi.org/10.1016/j.bioorg.2020.104477 Available online 18 November 2020 0045-2068/© 2020 Elsevier Inc. All rights reserved. Separation and confgurational assignment of stereoisomeric phenalenones from the marine mangrove-derived fungus Penicillium herquei MA-370 Sui-Qun Yang a, b , Attila M´ andi c , Xiao-Ming Li a, b , Hui Liu a , Xin Li a, b , S´ andor Bal´ azs Kir´ aly c , Tibor Kurt´ an c, * , Bin-Gui Wang a, b, d, * a Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Nanhai Road 7, Qingdao 266071, People’s Republic of China b Laboratory of Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Wenhai Road 1, Qingdao 266237, People’s Republic of China c Department of Organic Chemistry, University of Debrecen, POB 400, 4002 Debrecen, Hungary d Center for Ocean Mega-Science, Chinese Academy of Sciences, Nanhai Road 7, Qingdao 266071, People’s Republic of China A R T I C L E INFO Keywords: Marine fungi Penicillium herquei Phenalenone derivatives ACE inhibitory activity Molecular docking ABSTRACT Eight phenalenone derivatives, including four new compounds, aceneoherqueinones A and B (1 and 2), (+)-aceatrovenetinone A (3a), and (+)-aceatrovenetinone B (3d), along with four known congeners, (–)-acea- trovenetinone A (3b), (–)-aceatrovenetinone B (3c), (–)-scleroderolide (4a), and (+)-scleroderolide (4b), were characterized from the marine mangrove-derived fungus Penicillium herquei MA-370. Among them, compounds 1 and 2 are rare phenalenone derivatives featuring cyclic ether unit between C-5 and C-2 ′ . All of these compounds were subjected to chiral HPLC analysis, and the unstable stereoisomers 3a–3d, containing confgurationally labile chirality centers, were characterized by online HPLC-ECD measurements supported with TDDFT-ECD calculations. The structures of these compounds were elucidated by detailed analysis of their NMR and mass spectroscopic data, and the absolute confguration of compound 1 was confrmed by X-ray diffraction analysis, while those of compounds 2 and 3a–3d were determined by TDDFT-ECD calculations of their ECD spectra. All of the isolated compounds were tested for the inhibitory activity against angiotensin-I-converting enzyme (ACE), and compounds 1 and 2 displayed activity with IC 50 values 3.10 and 11.28 μM, respectively. The intermolecular interaction and potential binding sites of 1 and 2 with ACE were elaborated by molecular docking, showing that compound 1 bound well with ACE via hydrogen interactions with residues Ala261, Gln618, Trp621, and Asn624, while compound 2 interacted with residues Asp358 and Tyr360. 1. Introduction Phenalenone derivatives represent a unique class of polyketides consisting three condensed rings of hydroxyperinaphthenones. These compounds, reported as metabolites of higher plants and microbes [1,2], exhibited diverse and signifcant bioactivities such as antimicrobial [3], anti-HIV [4], anti-tumor [5], and anti-rheumatic effects [1]. Antimi- crobial derivatives are generally produced by fungi belonging to several genera such as Coniothyrium [2], Penicillium [3,6], Aspergillus [5], and Gremmeniella [7,8]. The fungal species Penicillium herquei has been studied for secondary metabolites since 1912 [9] and is known for the production of various phenalenone derivatives. Interestingly, different absolute confgurations of the C-2 ′ chirality center of phenalenone de- rivatives were reported in different fungal sources or even in the same fungal strain, but no chiral HPLC analysis has been applied to this type of natural products yet. Marine-derived microbes are rich sources of nat- ural products possessing diverse scaffolds and bioactivities [10]. During our ongoing investigations of marine-derived fungi for structurally unique and biologically active metabolites [11–13], the fungal strain Penicillium herquei MA-370 was isolated from the rhizospheric soil of the marine mangrove plant Rhizophora mucronata collected at Hainan Is- land. When the EtOAc extracts of the culture broth were analyzed by HPLC, a series of typical phenalenone peaks with similar UV absorption maxima around 225, 277, and 364 nm were detected, but no hit was found in our HPLC-UV database. We thus performed a large scale fermentation of this fungus in liquid medium, leading to the isolation of eight phenalenone derivatives, including four new compounds, ace- neoherqueinones A and B (1 and 2), (+)-aceatrovenetinone A (3a), and * Corresponding authors. E-mail addresses: kurtan.tibor@science.unideb.hu (T. Kurt´ an), wangbg@ms.qdio.ac.cn (B.-G. Wang). Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg https://doi.org/10.1016/j.bioorg.2020.104477 Received 13 October 2020; Received in revised form 11 November 2020; Accepted 13 November 2020