Lagunamide C, a cytotoxic cyclodepsipeptide from the marine cyanobacterium Lyngbya majuscula Ashootosh Tripathi a , Jonathan Puddick b , Michele R. Prinsep b , Matthias Rottmann c , Kok Ping Chan d , David Yu-Kai Chen e , Lik Tong Tan a,⇑ a Natural Sciences and Science Education, National Institute of Education, Nanyang Technological University, 1 Nanyang Walk, Singapore 637616, Singapore b Department of Chemistry, University of Waikato, Private Bag 3105, Hamilton 3205, New Zealand c Swiss Tropical and Public Health Institute, Parasite Chemotherapy, Socinstrasse 57, CH-4002 Basel, Switzerland and University of Basel, CH-4003 Basel, Switzerland d Chemical Synthesis Laboratory, Institute of Chemical and Engineering Sciences, 11 Biopolis Way, Helios #03-08, Singapore 138667, Singapore e Department of Chemistry, Seoul National University, Gwanak-1 Gwanak-ro, Gwanak-gu, Seoul 151-742, South Korea article info Article history: Received 16 May 2011 Received in revised form 13 July 2011 Available online 6 September 2011 Keywords: Lyngbya majuscula Oscillatoriaceae Marine cyanobacteria Cytotoxicity Anti-malarial Cyclic depsipeptide abstract Lagunamide C (1) is a cytotoxic cyclodepsipeptide isolated from the marine cyanobacterium, Lyngbya majuscula, from the western lagoon of Pulau Hantu Besar, Singapore. The complete structural character- ization of the molecule was achieved by extensive NMR spectroscopic analysis as well as chemical manipulations. Several methods, including the advanced Marfey’s method, a modified method based on derivatization with Mosher’s reagents and analysis using LC–MS, and the use of 3 J H–H coupling con- stant values, were utilized for the determination of its absolute configuration. Compound 1 is related to the aurilide-class of molecules and it differs mainly in the macrocyclic structure by having a 27 mem- bered ring system due to additional methylene carbon in the polyketide moiety. Lagunamide C displayed potent cytotoxic activity against a panel of cancer cell lines, such as P388, A549, PC3, HCT8, and SK-OV3 cell lines, with IC 50 values ranging from 2.1 nM to 24.4 nM. Compound 1 also displayed significant anti- malarial activity with IC 50 value of 0.29 lM when tested against Plasmodium falciparum. In addition, lagu- namide C exhibited weak anti-swarming activity when tested at 100 ppm against the Gram-negative bacterial strain, Pseudomonas aeruginosa PA01. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Marine cyanobacteria have emerged over the past 40 years as one of the richest groups of marine organisms in producing struc- turally diverse bioactive secondary metabolites (Gerwick et al., 2001; Tan, 2007). Cyanobacterial strains belonging to Lyngbya, Symploca, and Oscillatoria genera, in particular, are prolific produc- ers of a number of structurally unique compounds with several bioactivities, such as antimicrobial, cytotoxic, and neurotoxic prop- erties (Tan, 2010; Nunnery et al., 2010). This makes marine cyano- bacterial compounds an attractive source of therapeutic agents for the treatment of cancer diseases. In recent years, a growing number of cyanobacterial natural products, including viridamides A and B (Simmons et al., 2008) and gallinamide A (Linington et al., 2009), have been shown to exhibit significant antiprotozoal activities, par- ticularly as antimalarial agents (Nunnery et al., 2010). In our quest for novel bioactive secondary metabolites from lo- cal strains of marine cyanobacteria, we chanced upon a persistent strain of filamentous marine cyanobacterium, Lyngbya majuscula Agardh ex Gomont, from the western lagoon of Pulau Hantu Besar, Singapore. Chemical investigation of its organic extract, using vacuum flash chromatography (VFC), RP-HPLC, and NMR, yielded a number of known and new bioactive secondary metabolites, including the recently reported lagunamides A and B. The present study represents a continued chemical investigation on the same cyanobacterial samples. Further examination of one of the VFC- derived fractions eluted with 100% EtOAc and subsequent RP-HPLC, resulted in the isolation of a new cytotoxic cyclic depsi- peptide, lagunamide C (1). In this study, we wish to report on the complete structural elucidation as well as the biological property of lagunamide C (1). Compound 1 shares structural similarities with the aurilide class of molecules viz., lagunamides, kulokekahi- lide-2, palau’amide, and it differs primarily in the polyketide- derived moiety as well as having a 27-membered macrocyclic ring system (Williams et al., 2003; Suenaga et al., 2004; Nakao et al., 2004; Han et al., 2006; Tripathi et al., 2010) (see Fig. 1). 2. Results and discussion Lagunamide C (1) possesses a molecular formula of C 46 H 73 N 5 O 10 as suggested by HRESIMS based on the [M+Na] + ion peak at m/z 0031-9422/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.phytochem.2011.08.019 ⇑ Corresponding author. Tel.: +65 6790 3820; fax: +65 6896 9432. E-mail address: liktong.tan@nie.edu.sg (L.T. Tan). Phytochemistry 72 (2011) 2369–2375 Contents lists available at SciVerse ScienceDirect Phytochemistry journal homepage: www.elsevier.com/locate/phytochem