New Trisulfated Steroids from the Vietnamese Marine Sponge Halichondria Vansoesti and Their PSA Expression and Glucose Uptake Inhibitory Activities
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marine drugs Article New Trisulfated Steroids from the Vietnamese Marine Sponge Halichondria vansoesti and Their PSA Expression and Glucose Uptake Inhibitory Activities Kseniya M. Tabakmakher 1, Tatyana N. Makarieva 1,*, Vladimir A. Denisenko 1, Roman S. Popov 1, Pavel S. Dmitrenok 1 , Sergey A. Dyshlovoy 1,2 , Boris B. Grebnev 1, Carsten Bokemeyer 2, Gunhild von Amsberg 2,3 and Nguyen X. Cuong 4 1 G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-let Vladivostoku 159, 690022 Vladivostok, Russia 2 Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany 3 Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, 20251 Hamburg, Germany 4 Institute of Marine Biochemistry, Vietnam Academy of Science and Technology (VAST), Hanoi 100000, Vietnam * Correspondence: [email protected]; Tel.: +7-950-295-6625 Received: 26 June 2019; Accepted: 24 July 2019; Published: 27 July 2019 Abstract: Seven new unusual polysulfated steroids—topsentiasterol sulfate G (1), topsentiasterol sulfate I (2), topsentiasterol sulfate H (3), bromotopsentiasterol sulfate D (4), dichlorotopsentiasterol sulfate D (8), bromochlorotopsentiasterol sulfate D (9), and 4β-hydroxyhalistanol sulfate C (10), as well as three previously described—topsentiasterol sulfate D (7), chlorotopsentiasterol sulfate D (5) and iodotopsentiasterol sulfate D (6) have been isolated from the marine sponge Halichondria vansoesti. Structures of these compounds were determined by detailed analysis of 1D- and 2D-NMR and HRESIMS data, as well as chemical transformations. The effects of the compounds on human prostate cancer cells PC-3 and 22Rv1 were investigated. Keywords: marine sponge; Halichondria vansoesti; trisulfated steroids; topsentiasterol sulfates; halistanol sulfates; anticancer activity; PSA expression; glucose uptake 1. Introduction Biologically active trisulfated steroids are characteristic secondary metabolites found in some marine sponges. These polar steroids comprise several structural subgroups in the sponges. The first compound, bearing a common 2β,3α,6α-trisulfoxy steroid nucleus, halistanol sulfate, was isolated in 1981 from the Okinawan sponge Halichondria cf. moorei [1] (Figure S1). The subgroup also includes sokotrasterol sulfate from the sponge Halichondria sp. [2], halistanol sulfates A-J and polasterol B, found in the sponges Epipolasis sp. [3,4], Pseudoaxinissa digitata [5], and Halichondria sp. [6], ophirapsranol trisulfate from Topsentiaophiraphidites [7], four sterols isolated from the sponges Trachyopsis halichondroides and Cymbastela coralliophila [8], amaranzoles A-F from Phorbas amaranthus [9,10], and topsentinol K trisulfate from the sponge Topsentia sp. [11]. Another subgroup of these metabolites consists of ibisterol sulfates and lembesterol A from the sponges Topsentia sp. [12], Xestospongia sp. [13], and Petrosia strongilata [14]. In their steroid nuclei, 2β,3α,6α-trisulfoxy functionality is combined with a C-9(11)-double bond and a methyl group at C-14. One more subgroup includes topsentiasterol sulfates A–E from the sponge Topsentia sp. [15], Sch 575867 from the deep-water sponge belonging to the family Astroscleridae [16], spheciosterol sulfates from the sponge Spheciospongia sp. [17], as well as chloro- and iodotopsentiasterol sulfates D, isolated from the sponge Topsentia sp. in our laboratory [18]. Mar. Drugs 2019, 17, 445; doi:10.3390/md17080445 www.mdpi.com/journal/marinedrugs Mar. Drugs 2019, 17, x 2 of 15 functionality is combined with a C-9(11)-double bond and a methyl group at C-14. One more subgroup includes topsentiasterol sulfates A–E from the sponge Topsentia sp. [15], Sch 575867 from the deep-water sponge belonging to the family Astroscleridae [16], spheciosterol sulfates from the Mar.sponge Drugs Spheciospongia2019, 17, 445 sp. [17], as well as chloro- and iodotopsentiasterol sulfates D, isolated from2 of the 14 sponge Topsentia sp. in our laboratory [18]. These compounds contain a common Δ9(11)-unsaturated, 4β-hydroxy-14α-methyl, 2β,3α,6α-trisulfated steroid nucleus. TheseIn compounds addition to contain unusual a common structuralD9(11) features,-unsaturated, trisulfated 4β-hydroxy-14 steroids αpossess-methyl, promising 2β,3α,6α-trisulfated biological steroidproperties nucleus. [19]. In fact, a broad range of activities has been described to trisulfate steroids such as antibacterialInadditiontounusualstructuralfeatures, [1,15,20], antifungal [15,16,21], trisulfatedsteroidspossesspromisingbiologicalproperties[ antiviral (including anti-HIV and anti-HSV effects)19]. In[5,12,13,22,23], fact, a broad rangeantiparasitic of activities [21], and has beenantiplatelet described activities to trisulfate [24]. In steroids addition, such the as inhibition antibacterial of different [1,15,20], antifungalenzymes [6,11,18], [15,16,21 ],promotion antiviral (including of angiogenesis anti-HIV [25], and and anti-HSV antitumoreffects) activity [5,12 against,13,22,23 various], antiparasitic tumor [cell21], andlines antiplatelet [7,15,17,26] activities have been [24 ].described. In addition, Thus, the the inhibition search offor different new trisulfated enzymes steroids [6,11,18], from promotion sponges, of angiogenesisincluding the [25 analyses], and antitumor of their activitychemical against structures various and tumor physiological cell lines [7 properties,,15,17,26] have continues been described. to be a Thus,promising the search area forof research. new trisulfated Hopefully, steroids this from may sponges, lead to including the development the analyses of a of new their generation chemical structures of drugs andfor a physiological broad spectrum properties, of diseases. continues to be a promising area of research. Hopefully, this may lead to the developmentIn the course of a new of our generation ongoing of interest drugs for in anew broad biologically spectrum active of diseases. secondary metabolites of marine invertebrates,In the course Halichondria of our ongoing vansoesti interest sponge, in newcollected biologically in Vietnamese active secondary waters during metabolites the 49th of scientific marine invertebrates,cruise aboard Halichondriathe R/V ‘Academic vansoesti Oparin’,sponge, was collected investigated. in Vietnamese As a result, waters ten during trisulfated the 49th steroids scientific 1–10 cruisewere isolated aboard the(Figure R/V ‘Academic1). Using NMR Oparin’, spectroscopy, was investigated. including As a1H, result, 13C, tenHSQC, trisulfated COSY, steroidsHMBC,1 and–10 wereNOESY, isolated as well (Figure as high-resolution1). Using NMR mass spectroscopy, spectrometry including and chemical1H, 13 C,transformations, HSQC, COSY, 1 HMBC,–4 and 8 and–10 NOESY,were identified as well as as high-resolution new, unusual mass analogues spectrometry of to andpsentiasterol chemical transformations,sulfates and halistanol1–4 and 8 –sulfates.10 were identifiedCompounds as new,5–7 unusualwere previously analogues known of topsentiasterol as chlorotopsen sulfatestiasterol and halistanol sulfate D, sulfates. iodotopsentiasterol Compounds 5sulfates–7 were D previously [18], and known topsentiasterol as chlorotopsentiasterol sulfate D, respectively sulfate D, iodotopsentiasterol[15]. Herein, we report sulfates the D isolation, [18], and topsentiasterolstructural elucidation, sulfate proposed D, respectively biosynthetic [15]. Herein, pathwa weys, reportand the the study isolation, of the structuralbiological elucidation,activities of proposedthe isolated biosynthetic compounds. pathways, and the study of the biological activities of the isolated compounds. 29 1:R=a 21 22 2:R=b 26 20 20 24 18 R 3:R=c 25 17 11 H 3a:R=c* 11 17 H 27 19 13 4:R=d H 1 H 1 9 14 9 14 NaO3SO 5:R=e NaO3SO 15 10 6:R=f 10 10 3 5 30 H H 7 1-9 NaO SO 7:R=g NaO SO 3 H 8:R=h 3 H HO OSO3Na 9:R=i HO OSO3Na O O O O 26 Br 25 25 26 26 26 25 25 25 26 NH OH OCH3 27 O 28 27 27 27 O 28 31 28 OH 28 OCH3 27 a b 32 28 O cdc* O O Cl I Cl Cl 26 25 26 25 26 25 26 25 26 25 O O O O 27 27 O 27 27 27 28 28 28 28 e g 28 f h i Br Cl FigureFigure 1.1. TheThe structuresstructures ofof 11−10. − 2. Results and Discussion 2. Results and Discussion Concentrated EtOH extract of the sponge Halichondria vansoesti was partitioned between aqueous Concentrated EtOH extract of the sponge Halichondria vansoesti was partitioned between EtOH and n-hexane. The aqueous EtOH-soluble materials were further applied on a reversed-phase aqueous EtOH and n-hexane. The aqueous EtOH-soluble materials were further applied on a column chromatography (YMC-gel) and eluted successively with H2O EtOH:H2O (3:7) EtOH:H2O reversed-phase column chromatography (YMC-gel) and eluted successively! with H2O!→EtOH:H2O (2:3) EtOH:H2O (1:1) EtOH:H2O (3:2) resulting in several subfractions. Subfractions obtained by (3:7)!→EtOH:H2O (2:3)!→EtOH:H2O (1:1)→EtOH:H2O (3:2) resulting in several subfractions. elution with EtOH:H2O (3:7) to EtOH:H2O (6:4) were further purified by a reversed-phase HPLC (YMC-ODS-A) to give 1, 2 and 4–10. The subfraction, eluted with H2O, was further extracted with BuOH, after which the butanol solution was concentrated and subjected to a reversed-phase HPLC (YMC-ODS-A) to obtain 3. Mar. Drugs 2019, 17, 445 3 of 14 The molecular formula of 1,C H NNa O S , was established from the [M Na] ion peak 30 44 3 14 3 3Na − − at m/z 784.1724 in the ( )-HRESIMS. In addition, the peaks at m/z 380.5927