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Lissoclibadins 8–14, polysulfur dopamine-derived alkaloids from the colonialascidian Lissoclinum cf. badiumWeifang Wanga, Ohgi Takahashia, Taiko Odab, Takahiro Nakazawaa, Kazuyo Ukaia, Remy E.P.Mangindaanc, Henki Rotinsuluc, Defny S. Wewengkanga,c, Hisayoshi Kobayashid,Sachiko Tsukamotoe, Michio Namikoshia,*aTohoku Pharmaceutical University, Aoba-ku, Sendai 981-8558, JapanbFaculty of Pharmaceutical Sciences, Keio University, Minato-ku, Tokyo 105-8512, JapancFaculty of Fisheries and Marine Science, Sam Ratulangi University, Kampus Bahu, Manado 95115, IndonesiadInstitute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, JapaneFaculty of Medical and Pharmaceutical Sciences, Kumamoto University, Oe-honmachi, Kumamoto 862-0973, Japana r t i c l e i n f oArticle history:Received 27 August 2009Received in revised form15 September 2009Accepted 15 September 2009Available online 18 September 2009Keywords:Polysulfur alkaloidTunicateStructure assignmentCytotoxicityL1210V79a b s t r a c tSeven new polysulfur alkaloids, lissoclibadins 8 (1)–14 (7), were isolated from an ascidian, Lissoclinum cf.badium, collected in Indonesia. The structures were assigned on the basis of their spectroscopic data andcomputational modeling study. Lissoclibadin 8 (1) had four identical dopamine-derived units, and this isthe first instance of a tetramer. Lissoclibadin 9 (2) was the second example of trimers next to lissoclibadin1 (8). Lissoclibadins 10 (3)–12 (5) were symmetric dimers, and 13 (6) had a dopamine and ethyl unitsconnected by sulfide and disulfide bonds. Lissoclibadin 14 (7) was a varacin-type monomer. Thesecompounds inhibited the colony formation of Chinese hamster V79 cells and cell proliferation of murineleukemia L1210 cells.? 2009 Elsevier Ltd. All rights reserved.1. IntroductionAscidians are a rich source of biologically active nitrogenoussubstances with high chemical diversity.1,2More than 80% of newcompounds from ascidians contained nitrogen, and about 70% ofnitrogenous compounds are alkaloids. During our ongoing studieson bioactive alkaloidal components from ascidians, we have iso-lated seven new polysulfur aromatic alkaloids, lissoclibadins 8 (1)–14 (7) (Fig. 1), from the colonial ascidian, Lissoclinum cf. badium,collected in Indonesia.3This ascidian gave lissoclibadins 1 (8)–7(14) and four known compound (15–18) (Fig. 1).4–6The relatedpolysulfur alkaloids derived from dopamine have been reportedfrom ascidians of the genera Eudistoma,7Lissoclinum,7–12and Poly-citor.13These alkaloids were constructed with one,7–10,12,13two,4–6,9,11,14and three4,5dopamine units. In the present investigation, weisolated a tetramer for the first time, a trimer, four dimers, anda monomer. These new compounds showed cytotoxicity againstmurine and human tumor cell lines. We report herein the isolation,structures, and bioactivity of seven new lissoclibadins (1–7).2. Results and discussionSeven newcompounds, lissoclibadins 8 (1)–14 (7), were isolatedfrom L. cf. badium collected at Manado, Indonesia, in September,2006, together with 8, 10, 11, 14, 15, 17, and 18.4–62.1. Structure of lissoclibadin 8 (1)The molecular formula (C52H76N4O8S12) and weight (1268) weredetermined from HRFABMS and NMR data (Table 1). Two sets of1Hand13C NMR signals were assigned by the analysis of1H–1H COSY,HMQC, HMBC, and NOE difference spectra of 1 to two identicalaromatic amine moieties (unit a in Fig. 2). Each unit had a hexa-substituted benzene ring and two methylenes, two OMe, an SMe,and an NMe2group. The1H–1H COSY spectrum of 1 showed theconnectivity of the two methylenes at C-7 and -8. NOEs were ob-served between H3-9/H3-10, H3-10/H3-11, and NMe2/H2-7 and -8 in* Corresponding author. Tel./fax: þ81 22 727 0219.E-mail address: mnami@tohoku-pharm.ac.jp (M. Namikoshi).Contents lists available at ScienceDirectContents lists available at ScienceDirectTetrahedronTetrahedronjournal homepage: www.elsevier.com/locate/tetjournal homepage: www.elsevier.com/locate/tet0040-4020/$ – see front matter ? 2009 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2009.09.056Tetrahedron 65 (2009) 9598–9603