molecules Review Secondary Metabolites from Gorgonian Corals of the Genus Eunicella: Structural Characterizations, Biological Activities, and Synthetic Approaches Dario Matulja 1, Maria Kolympadi Markovic 2, Gabriela Ambroži´c 2, Sylvain Laclef 3, Sandra Kraljevi´cPaveli´c 1,* and Dean Markovi´c 1,* 1 Department of Biotechnology, University of Rijeka, Radmile Matejˇci´c2, 51000 Rijeka, Croatia; [email protected] 2 Department of Physics and Centre for Micro- and Nanosciences and Technologies, University of Rijeka, Radmile Matejˇci´c2, 51000 Rijeka, Croatia; [email protected] (M.K.M.); [email protected] (G.A.) 3 Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources (LG2A) UMR CNRS 7378—Institut de Chimie de Picardie FR 3085, Université de Picardie Jules Verne, 33 rue Saint Leu, FR-80039 Amiens CEDEX, France; [email protected] * Correspondence: [email protected] (S.K.P.); [email protected] (D.M.); Tel.: +385-51-584-550 (S.K.P.); +385-51-584-816 (D.M.) Academic Editor: Paula B. Andrade Received: 9 December 2019; Accepted: 26 December 2019; Published: 28 December 2019 Abstract: Gorgonian corals, which belong to the genus Eunicella, are known as natural sources of diverse compounds with unique structural characteristics and interesting bioactivities both in vitro and in vivo. This review is focused primarily on the secondary metabolites isolated from various Eunicella species. The chemical structures of 64 compounds were divided into three main groups and comprehensively presented: a) terpenoids, b) sterols, and c) alkaloids and nucleosides. The observed biological activities of depicted metabolites with an impact on cytotoxic, anti-inflammatory, and antimicrobial activities were reviewed. The most promising biological activities of certain metabolites point to potential candidates for further development in pharmaceutical, cosmetic, and other industries, and are highlighted. Total synthesis or the synthetic approaches towards the desired skeletons or natural products are also summarized. Keywords: Eunicella genus; eunicellin-type diterpenes; sterols; nitrogenated compounds; cytotoxic; anti-inflammatory; antimicrobial; synthetic approaches 1. Introduction Oceans and seas cover more than 70% of the surface of our planet and, therefore, are an extensive and rich source of biotechnological potential [1]. Terrestrial organisms, mainly plants, have been widely explored and utilized to obtain novel compounds with the purpose to develop novel drugs for improved treatment for various diseases [2]. In contrast, species living in the marine environment have traditionally been used as food, contributing to human health as valuable sources of proteins, polysaccharides, amino acids, vitamins, minerals, and other micronutrients [1,3]. More than 30,000 compounds have been isolated from marine organisms since biochemical research began in the second half of the last century [4,5]. Numerous sea bioprospecting programs have been performed with the aim to search for new compounds as target leads in the drug discovery processes, emphasizing on anticancer products with improved performance and/or less severe adverse effects [2,6]. Consequently, since 1969 and the approval of cytarabine, the first marine-derived product for the treatment of leukemia, six more Molecules 2020, 25, 129; doi:10.3390/molecules25010129 www.mdpi.com/journal/molecules Molecules 2019, 24, x 2 of 26 Molecules 2020, 25, 129 2 of 26 the treatment of leukemia, six more compounds have been approved by the Food and Drug Administration (FDA) for clinical use, while dozens of others are currently in different stages of compoundspreclinical and have clinical been approvedtrials [7]. byBesides the Food anticancer and Drug activity, Administration marine natural (FDA) compounds for clinical use,have while also dozensdemonstrated of others neuroprotective, are currently in dianticardiovascular,fferent stages of preclinical antimicrobial, and clinical anti-inflammatory, trials [7]. Besides antioxidant, anticancer activity,antifouling, marine and other natural interesting compounds biological have alsoactivities demonstrated [1]. neuroprotective, anticardiovascular, antimicrobial,Marine sponges anti-inflammatory, from the phylum antioxidant, Porifera antifouling, are recognized and other among interesting the most biologicalinteresting activities organisms [1]. in bioprospectingMarine sponges as sources from the of phylum the largest Porifera number are recognizedof so far characterized among the mostmarine interesting metabolites. organisms Other ininvertebrates bioprospecting like ascnidarians sources of include the largest more number than of11,000 so far species, characterized some marineof which metabolites. are poorly Other or invertebratescompletely unexplored like cnidarians [4]. Moreover, include more corals than are 11,000 interesting species, sedentary some of which organisms are poorly that ormay completely survive unexploredharsh internal [4]. and Moreover, external corals marine are environmenta interesting sedentaryl conditions. organisms The main that mayreason survive why harshthey produce internal andvarious external secondary marine environmentalmetabolites is conditions.to protect The themselves main reason from why predatory they produce species various [4,8]. secondary These metabolitescharacteristics is to may protect be themselvesexploited fromin search predatory of novel species bioactives [4,8]. These with characteristics still unexplored may be biological exploited inmechanisms search of novel of action. bioactives with still unexplored biological mechanisms of action. Eunicella coral species belong to the orderorder Alcyonacea,Alcyonacea, familyfamily Gorgoniidae.Gorgoniidae. Gorgonian corals, also known as sea fans and soft corals, are characterizedcharacterized by their branched, fan-like structure which can bebe foundfound on on both both hard hard and and soft soft sea sea bottoms bottoms in the in Mediterranean, the Mediterranean, tropical, tropical, and subtropical and subtropical marine areasmarine [8 ,areas9]. Due [8,9]. to their Due tree-like to their morphological tree-like morp features,hological they features, provide they nutrients provide and nutrients protection and to otherprotection marine to invertebratesother marine and invertebrates vertebrates and [10]. vert Forebrates example, [10]. bacteria For example, of the genus bacteriaEndozoicomonas of the genusare keyEndozoicomonas endosymbionts are withinkey endosymbionts colonies of Eunicella within cavolinicolonies(Figure of Eunicella1) and maycavolini contribute (Figure to 1) the and coral’s may adaptationcontribute to to the the coral’s environment adaptation or to to its the metabolism environment [9,11 or]. to its metabolism [9,11]. Figure 1.1.Eunicella Eunicella cavolini cavolinifrom from the Adriaticthe Adriatic Sea (Rtina, Sea Paška(Rtina, vrata, Pašk Croatia),a vrata, geographical Croatia), geographical coordinates: Geographicalcoordinates: Geographical longitude 44 ◦longitude190140’, geographical 44°19′14′’, geographical latitude 15◦55 latitude0420’. 15°55′42′’. Recently, RaimundoRaimundo etet al.al. have analyzed genomes of 15 bacteria from 12 genera, cultivated from Eunicella sp.,sp., andand identified identified gene gene clusters clusters responsible responsible for for the the biosynthesis biosynthesis ofterpenes, of terpenes, polyketides, polyketides, and peptidesand peptides [12]. [12]. The The microorganisms microorganisms might might be also be also involved involved in symbiotic in symbiotic biosyntheses biosyntheses producing producing the ditheff erentdifferent oxygenation oxygenation and unsaturationand unsaturation patterns patter of thens naturalof the productsnatural products originating originating from Eunicella from species.Eunicella Furthermore, species. Furthermore, those symbiotic those organisms symbiotic can organisms be analyzed can by be a metagenomicanalyzed by approach,a metagenomic which allowsapproach, the which bioprospecting allows the of bioprospecting genes encoding of enzymes genes encoding or discovering enzymes of or biocatalysts discovering for of the biocatalysts synthesis offor bioactive the synthesis secondary of bioactive metabolites secondary [13–15 metabolites]. [13–15]. Eunicella cavolini (yellow gorgonian, Koch, 1887) 1887) and and EunicellaEunicella singularis singularis (white(white gorgonian, gorgonian, Esper, Esper, 1791) are thethe mostmost abundantabundant gorgoniangorgonian coralscorals inin thethe MediterraneanMediterranean marinemarine areaarea [[10].10]. The first first is recognized byby itsits orange-coloredorange-colored colonies colonies and and is is widespread widespread from from the the Tunisian Tunisian coast coast to the to Aegeanthe Aegean Sea. ItSea. can It be can found be found up to 150 up m to where 150 m it canwhere form it larger,can fo morerm larger, arborescent more coloniesarborescent due tocolonies the environmental due to the stabilityenvironmental [10,16]. stability Other Eunicella [10,16]. membersOther Eunicella mentioned members in this mentioned review are ingranulata this review(Grassho are granulataff, 1992), verrucosa(Grasshoff,(Pallas, 1992), 1766), verrucosa and labiata(Pallas,(Thomson, 1766), and 1927) labiata [17 (Thomson,]. In addition 1927) to their[17]. potentIn addition biological to their activities, potent highbiological susceptibility activities, to high climate susceptibility change, anthropogenic to climate change, influences,