Bifurcatriol, a New Antiprotozoal Acyclic Diterpene from the Brown Alga Bifurcaria Bifurcata
Total Page：16
File Type：pdf, Size：1020Kb
marine drugs Article Bifurcatriol, a New Antiprotozoal Acyclic Diterpene from the Brown Alga Bifurcaria bifurcata Vangelis Smyrniotopoulos 1, Christian Merten 2, Marcel Kaiser 3,4 and Deniz Tasdemir 1,5,* 1 School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland; [email protected] 2 Lehrstuhl für Organische Chemie 2, Ruhr-Universität Bochum, Universitätsstraße 150, 44801 Bochum, Germany; [email protected] 3 Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland; [email protected] 4 University of Basel, 4003 Basel, Switzerland 5 GEOMAR Centre for Marine Biotechnology (GEOMAR-Biotech), Research Unit Marine Natural Product Chemistry, Research Division Marine Ecology, GEOMAR Helmholtz Centre for Ocean Research Kiel, Am Kiel-Kanal 44, 24106 Kiel, Germany * Correspondence: [email protected]; Tel.: +49-431-6004430 Received: 19 June 2017; Accepted: 27 July 2017; Published: 2 August 2017 Abstract: Linear diterpenes that are commonly found in brown algae are of high chemotaxonomic and ecological importance. This study reports bifurcatriol (1), a new linear diterpene featuring two stereogenic centers isolated from the Irish brown alga Bifurcaria bifurcata. The gross structure of this new natural product was elucidated based on its spectroscopic data (IR, 1D and 2D-NMR, HRMS). Its absolute configuration was identified by experimental and computational vibrational circular dichroism (VCD) spectroscopy, combined with the calculation of 13C-NMR chemical shielding constants. Bifurcatriol (1) was tested for in vitro antiprotozoal activity towards a small panel of parasites (Plasmodium falciparum, Trypanosoma brucei rhodesiense, T. cruzi, and Leishmania donovani) and cytotoxicity against mammalian primary cells. The highest activity was exerted against the malaria parasite P. falciparum (IC50 value 0.65 µg/mL) with low cytotoxicity (IC50 value 56.6 µg/mL). To our knowledge, this is the first successful application of VCD and DP4 probability analysis of the calculated 13C-NMR chemical shifts for the simultaneous assignment of the absolute configuration of multiple stereogenic centers in a long-chain acyclic natural product. Keywords: Bifurcaria bifurcata; diterpene; marine alga; VCD; absolute configuration; antiprotozoal 1. Introduction Acyclic terpenes comprise a very small yet fundamental fraction of terpenes, the largest class of natural products with the highest structural and stereochemical diversity [1]. Terpene biosynthesis involves them as intermediates originating from enzymatic elongation and modification of few universal linear and non-chiral isoprenoid precursors [2,3]. The immense chemodiversity of terpenes finally emerges through a more evolved enzymatic machinery of additional cyclization and rearrangements as compared to the pathways of their acyclic primordial congeners [2,4]. Linear terpenes also encompass various modifications of the simple parent acyclic carbon skeletons. They display numerous ecological roles (e.g., defensive or communicational) and are represented in all terpene classes, both in terrestrial and marine macro- and micro-organisms. The properties and activities associated with these roles underline their great significance in industry, agriculture, and medicine [5–7]. Marine algal metabolites account for 13% of marine natural products, with terpenoids prevailing at a percentage over 50% [8,9]. Geranylgeraniol derivatives comprise some of the earliest compounds Mar. Drugs 2017, 15, 245; doi:10.3390/md15080245 www.mdpi.com/journal/marinedrugs Mar. Drugs 2017, 15, 245 2 of 10 Mar. Drugs 2017, 15, 245 2 of 10 compounds isolated from the order Fucales that comprise about a third of brown algal metabolites [10]. Recent literature surveys on the family Sargassaceae indicate Bifurcaria bifurcata (Velley) R. Rossisolated to be from one theof the order most Fucales prolific that sources comprise of bi aboutoactive a thirdsecondary of brown metabolites. algal metabolites This species [10 accounts]. Recent forliterature 8% of the surveys total onmetabolites the family of Sargassaceaethe family, with indicate acyclicBifurcaria diterpenes bifurcata being(Velley) the main R. constituents Ross to be one of theof the organic most prolificextracts sources [11,12]. of Many bioactive of the secondary geranylgeraniol-derived metabolites. This linear species diterpenes accounts forare 8% of ofhigh the chemotaxonomictotal metabolites ofand the family,ecological with importance acyclic diterpenes with demonstrated being the main antifouling, constituents ofantimicrobial, the organic antimitotic,extracts [11 ,12and]. Manycytotoxic of the activities geranylgeraniol-derived [11]. Unfortunately, linear unambiguous diterpenes areassignment of high chemotaxonomic of the absolute configurationand ecological of importance all stereogenic with demonstratedcenters in many antifouling, linear diterpenes antimicrobial, has not antimitotic, yet been accomplished and cytotoxic dueactivities to their [11 molecular]. Unfortunately, features unambiguous [11]. assignment of the absolute configuration of all stereogenic centersIt is in commonly many linear accepted diterpenes that has chirality, not yet been an accomplishedamplifier of molecular due to their diversity, molecular has features triggered [11]. evolutionIt is commonly in nature acceptedby rendering that chirality,most physiologica an amplifierl interactions of molecular regio- diversity, and has stereospecific triggered evolution [13,14]. Bioactivein nature secondary by rendering metabolites most physiological are principally interactions chiral compounds, regio- and stereospecificnecessitating the [13 ,unambiguous14]. Bioactive determinationsecondary metabolites of their areabsolute principally configuration chiral compounds, (AC) and necessitatingconformations, the in unambiguous order to gain determination insights into theirof their mode absolute of action configuration or biosynthetic (AC) and origin conformations, [14,15]. inThe order most to gainfrequently insights used into theirmethods mode for of designationaction or biosynthetic of the AC originin chiral [14 ,molecules15]. The most to date frequently are NMR used anisotropy methods forand designation X-ray crystallography. of the AC in However,chiral molecules their application to date are NMR in natural anisotropy products and X-ray is not crystallography. always feasible. However, The alternation their application of NMR in signalsnatural requires products the is notuse alwaysof a chiral feasible. anisotropy The alternation reagent while of NMR the signalsformation requires of a single the use crystal of a chiral is a prerequisiteanisotropy reagent for X-ray while crystallography the formation of[13]. a single The use crystal of nondestructive is a prerequisite chiroptical for X-ray crystallography methods, such [13 as]. electronicThe use of circular nondestructive dichroism chiroptical (ECD) and methods, vibrational such circular as electronic dichroism circular (VCD), dichroism as alternatives (ECD) andhas recentlyvibrational gained circular popularity. dichroism In particular, (VCD), as the alternatives combination has of recently stereochemical gained popularity. sensitivity with In particular, the rich structuralthe combination content of of stereochemical vibrational spectra sensitivity by VC withD and the Raman rich structural Optical contentActivity of (ROA) vibrational has brought spectra forwardby VCD very and reliable Raman approaches Optical Activity for the (ROA) AC determ has broughtination of forward natural veryproducts reliable [16,17]. approaches In addition, for thethe ACconformational determination sensitivity of natural of products vibrational [16, 17spectroscopy]. In addition, allowed the conformational some insights sensitivity into very of interestingvibrational conformational spectroscopy allowed variations some in insightsnatural prod intoucts very [18] interesting as well conformationalas peptides and variationsother chiral in moleculesnatural products [19–21]. [18] as well as peptides and other chiral molecules [19–21]. InIn continuation continuation of of our our investigation investigation of of chemical chemical constituents constituents of of seaweeds, seaweeds, we we isolated isolated a a new new linearlinear diterpene diterpene bifurcatriol bifurcatriol ( (11,, Figure Figure 11)) from the Irish brown alga BifurcariaBifurcaria bifurcata bifurcata. .In In this this paper, paper, we describe its isolation, structure elucidation, including including AC AC assignment, assignment, and and inin vitro vitro antiprotozoal activity.activity. Encouraged Encouraged by by the the recent recent successful successful de determinationtermination of of the the AC AC of of two two linear linear diterpenes, diterpenes, elegandiolelegandiol ( (22)) and and bifurcane bifurcane ( (33)) with with a a single single chiral chiral carbon carbon (C-13) (C-13) from from the the same same alga alga by by VCD VCD spectroscopyspectroscopy [[22],22], wewe explored explored the the applicability applicabilit ofy this of methodthis method to linear to diterpeneslinear diterpenes bearing multiplebearing multiplestereogenic stereogenic centers. The centers. VCD-based The VCD-base AC assignmentd AC assignment is further supported is further by supported13C-NMR chemicalby 13C-NMR shift chemicalcalculations shift [23 calculations]. [23]. 10 4 15 13 7 OH 16 1 17OH 18 19OH 20 1 OH OH 2 OH O 3 FigureFigure 1. 1. StructureStructure of of compounds compounds (1 (1––33)