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Chemical and Biological Study of Aplysiatoxin Derivatives Showing Inhibition of Potassium Cite This: RSC Adv.,2019,9,7594 Channel Kv1.5†

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Chemical and Biological Study of Aplysiatoxin Derivatives Showing Inhibition of Potassium Cite This: RSC Adv.,2019,9,7594 Channel Kv1.5† RSC Advances View Article Online PAPER View Journal | View Issue Chemical and biological study of aplysiatoxin derivatives showing inhibition of potassium Cite this: RSC Adv.,2019,9,7594 channel Kv1.5† Yang-Hua Tang,‡ab Jing Wu,‡c Ting-Ting Fan,a Hui-Hui Zhang,a Xiao-Xia Gong,a Zheng-Yu Cao,e Jian Zhang,*c Hou-Wen Lin *d and Bing-Nan Han *a Three new aplysiatoxins, neo-debromoaplysiatoxin D (1), oscillatoxin E (2) and oscillatoxin F (3), accompanied by four known analogues (4–7), were identified from the marine cyanobacterium Lyngbya sp. Structural frames differ amongst these metabolites, and therefore we classified compounds 1 and 4– 6 as aplysiatoxins as they possess 6/12/6 and 6/10/6 tricyclic ring systems featuring a macrolactone ring, and compounds 2, 3 and 7 as oscillatoxins that feature a hexane-tetrahydropyran in a spirobicyclic system. Bioactivity experiments showed that compounds 1 and 4–6 presented significant expression of phosphor-PKCd whereas compounds 2, 5 and 7 showed the most potent blocking activity against Received 5th February 2019 Creative Commons Attribution-NonCommercial 3.0 Unported Licence. potassium channel Kv1.5 with IC values of 0.79 Æ 0.032 mM, 1.28 Æ 0.080 mM and 1.47 Æ 0.138 mM, Accepted 25th February 2019 50 respectively. Molecular docking analysis supplementing the binding interaction of oscillatoxin E (2) and DOI: 10.1039/c9ra00965e oscillatoxin F (3) with Kv1.5 showed oscillatoxin E (2) with a strong binding affinity of À37.645 kcal molÀ1 À rsc.li/rsc-advances and oscillatoxin F (3) with a weaker affinity of À32.217 kcal mol 1, further supporting the experimental data. Introduction marine cyanobacteria so far.5–14 According to their structural characteristics, the early isolated ATXs were classied into three Cyanotoxins, otherwise known as poisonous metabolites yiel- categories: aplysiatoxins possessing 6/12/6 tricyclic ring systems This article is licensed under a ded by cyanobacteria, can be classied into neurotoxins featuring a macrolactone ring (ABC ring) (e.g. aplysiatoxin, (anatoxin-a, b-methylamino alanine), hepatotoxins (micro- debromoaplysiatoxin, manauealides A–C and oscillatoxin A); cystins, nodularins), cytotoxins (cylindrospermopsin) and der- oscillatoxins featuring a hexane-tetrahydropyran of a spi- robicyclic system (AB ring) (oscillatoxin D and 30-methyl- Open Access Article. Published on 06 March 2019. Downloaded 10/1/2021 7:43:08 PM. matotoxins (lyngbyatoxin-a, aplysiatoxins) based on their mode of action.1 The aplysiatoxins (ATXs) are a class of biologically oscillatoxin D); and nhatrangins featuring an opening chain active dermatotoxins with anti-proliferative activity, tumour- (nhatrangins A and B). The main structural skeleton of ATXs promoting properties, proinammatory actions and antiviral (tricyclic ring systems) vary greatly, whilst their side chains, that activity.2–6 Initially, aplysiatoxin and debromoaplysiatoxin were contain aromatic rings, oen remain unchanged. Our research obtained from the sea hare Stylocheilus longicauda, whilst group recently isolated two new ATXs that display rare carbon further research indicated that these compounds are metabo- skeletons; neo-debromoaplysiatoxin A showing a 6/10/6 fused- lized by cyanobacteria.5,7 27 ATXs have been isolated from ring system which we grouped as an aplysiatoxin and neo- debromoaplysiatoxin B with a 6/6/6 fused ring system as an oscillatoxin. In addition to this structural novelty, these aResearch Center of Marine Biology and Natural Products, College of Life Sciences and compounds also exhibit excellent bioactivity with potent Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China. E-mail: blocking action against potassium channel Kv1.5.14 Kv1.5 has [email protected] been presumed to be a pivotal target for new treatment of atrial bDepartment of Pharmacy, Graduate School, Hunan University of Chinese Medicine, tachyarrhythmias with minimal side effects.15,16 In pursuit of Changsha 410208, People's Republic of China cDepartment of Pathophysiology, Shanghai Jiaotong University, School of Medicine, additional novel Kv1.5 inhibitors, our group isolated three new 1 Shanghai 200025, China. E-mail: [email protected] aplysiatoxins, neo-debromoaplysiatoxin D ( ) and oscillatoxin E dResearch Center for Marine Drugs, State Key Laboratory of Oncogenes and Related and F (2 and 3), and four known aplysiatoxins (4–7) from the Genes, Department of Pharmacy, Ren Ji Hospital Affiliated to Shanghai Jiao Tong cyanobacterium Lyngbya sp. extracted from the South China Sea University School of Medicine, Shanghai 200127, China. E-mail: [email protected] (Fig. 1). Due to their structural characteristics, compounds 1 e Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational and 4–6 can be classied as aplysiatoxins, with their corre- Development, China Pharmaceutical University, Nanjing, China sponding ABC ring, and 2, 3 and 7 as oscillatoxins. This report † Electronic supplementary information (ESI) available. See DOI: 10.1039/c9ra00965e details the separation, structural elucidation and biological ‡ These authors contributed equally to this work. activity of these metabolites. Herein, we demonstrate that 7594 | RSC Adv.,2019,9,7594–7600 This journal is © The Royal Society of Chemistry 2019 View Article Online Paper RSC Advances Fig. 1 Chemical structures of compounds 1–7. compounds 1 and 4–6 expressed phosphor-PKCd dramatically, This NMR spectroscopic data indicated that 1 contained but our oscillatoxins, 2, 3 and 7, lacked any activity. Impor- a tricyclic core and its' planar structure closely resembled neo- tantly, selective blocking of Kv1.5 was seen to be signicant for debromoaplysiatoxin A.14 Careful analysis of these two 2 5 7 Æ m Æ m Creative Commons Attribution-NonCommercial 3.0 Unported Licence. , and with IC50 values of 0.79 0.032 M, 1.28 0.080 M compounds' 1D and 2D NMR spectroscopic data uncovered that Æ m d and 1.47 0.138 M, respectively. an oxygenated quaternary carbon resonance of C 75.7 at C-4 in neo-debromoaplysiatoxin A was replaced by the methine reso- d d 1 Results and discussion nances of C 40.4/ H 3.29 in . The HMBC correlations from H-4 to C-3 and C-5 in 1 strongly support this assignment (Fig. 2). The The cyanobacterium Lyngbya sp. was collected in the South NOESY experiments and vicinal coupling constants were China Sea and extracted with MeOH and CH2Cl2 (1 : 1, v/v). The utilized to establish its relative stereochemistry. The large extract was suspended in aqueous MeOH and extracted with coupling constants of H-5b (J ¼ 13.4, 10.6 Hz) and the NOESY b petroleum ether, dichloromethane and ethyl acetate. To identify cross-peak of H-2/H3-24 discovered that H-2, 4, 5 and 24 were This article is licensed under a 1 10,11 b the main constituents of the extracts preliminary, a H-NMR axially oriented. The NOESY correlations from H-5 to H3-25 method was utilized to the extracts and revealed the enrich- and H3-26 suggested these protons were b-orientated, whereas ment of aplysiatoxins in the dichloromethane extract. Sequen- the a-orientation was indicated at H-5a, H-2, H-4 and H3-24, Open Access Article. Published on 06 March 2019. Downloaded 10/1/2021 7:43:08 PM. tial chromatography of dichloromethane extract on vacuum supported by the NOESY correlations of H-2/H3-24 and the large liquid chromatography (VLC) and octadecyl silica gel (ODS), coupling constants of H-5b (J ¼ 13.4, 10.6 Hz).10,11 The coupling ¼ followed by C18 reverse-phase HPLC, led to the isolation of constants of H-11 (J 10.8, 1.6 Hz) and the NOESY correlation seven aplysiatoxin derivatives including three new compounds, of H-12/H-11/H3-23 indicated that H-10 and H-11 were anti ¼ ¼ neo-debromoaplysiatoxin D (1), oscillatoxin E (2) and oscil- orientated (JH-10, H-11 10.8 Hz and JH-11,H-12 1.6 Hz). The latoxin F (3), and four known compounds (4–7). These four NOESY cross-peaks of H-11/H3-23 indicated these protons were known structures were identied as anhydrode- co-facial, while the NOESY correlations of H-9/H-10 uncovered bromoaplysiatoxin (4), debromoaplysiatoxin (5), 3-methoxyde- these hydrogens were the same side of the cyclohexane, the bromoaplysiatoxin (6) and 30-methyloscillatoxin D (7)by small coupling between H-12 and H-11 (JH-11,H-12 ¼ 1.6 Hz) and 6,10,11 comparing their spectroscopic data with the literature data. the NOESY correlations of H-11/H-12/H3-23 and H3-22/H-10 Neo-debromoaplysiatoxin D (1) was isolated as a colourless established the stereochemistry of C-12 (Fig. 3). The NOESY solid, with a molecular formula C32H46O9 indicating ten degrees correlations of H2-8/H-2 indicated that the ether oxygen at C-7 of unsaturation was established by HRESIMS. The 1H NMR was attached axially to the ring A.11 Furthermore, taking note spectrum uncovered the appearance of a 1,3-disubstituted of the structural similarities of compounds 1–7, it is likely that 13 aromatic ring at dH 7.20 (t, J ¼ 7.8 Hz), dH 6.99 (m), dH 6.88 (d, J ¼ these seven compounds have a common biosynthetic origin. 7.6 Hz) and dH 6.75 (dd, J ¼ 8.1, 2.5 Hz), four methyl doublets at The relative con guration of C-29 and C-30 in the partial dH 1.25, 1.10, 0.89 and 0.75 and three methyl singlets at dH 3.27, structure of 3,4-dihydroxyvaleric acid were consistent with that 1.02 and 0.79. The 13C and DEPT spectrum of 1 displayed seven of the known compounds 4–6 owing to their similar coupling ¼ quaternary carbons including one keto carbon (dC 211.6), two constants between H-29 and H-30 (JH-29,H-30 4.1 Hz) and d 6,10,11 1 carbonyl carbons ( C 170.9 and 169.8) and two aromatic carbons biosynthetic pathway.
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