Dean Marković

Background: While granulatamides A and B have been previously isolated, their biological activities have been only partially examined. The aim of this study was to synthesize granulatamide B (4b), a tryptamine-derivative naturally occurring in Eunicella coral species, using the well-known procedure of Sun and Fürstner and its 12 structural analogues by modifying the side chain, which differs in length, degree of saturation as well as number and conjugation of double bonds. background: The extreme physical and chemical conditions in the marine environment have led macro- and micro-organisms to adapt by synthesizing secondary metabolites for purposes of defense, attack, or signaling [1]. These compounds are often characterized by unique chemical structures, higher oxygen content, and the presence of halogen atoms, and thus differ significantly from compounds isolated from terrestrial organisms[2]. Because marine metabolites exhibit a wide range of biological activities, including anticancer [3], anti-inflammatory [4], antimicrobial [5], antioxidant [6] and others, they have attracted the attention of the scientific community, particularly with regard to the discovery of new compounds as potential drugs that are more potent and less toxic. Although the upsurge of marine (blue) biotechnology did not begin until the middle of the last century, more than 30,000 compounds have been isolated to date, largely due to the implementation of the extensive marine bioprospecting programs [7–9]. As a result, a large number of steroids, terpenes, phenols, polypeptides, glycosides and alkaloids have been extracted, characterized, synthesized and subjected on numerous studies of their biological effects, with a focus on anticancer activity [10]. Marine indole alkaloids include a group of different heterocyclic products that exhibit various pharmacological activities, as already described in the recent literature [11, 12]. So far, they have been isolated mainly from marine microorganisms (fungi and bacteria), sponges, bryozoans, tunicates, molluscs, red algae, mangroves and corals [11]. 2 / 21 However, the latter, are not a prolific source of these chemicals, as alkaloids account for only 4% of all metabolites studied that have been isolated from cnidarians, according to Rocha et al. [13]. Moreover, the coral microbiome may be the actual producer of indole compounds, as the indole synthesis pathway from tryptophan is well-known in bacteria [14] and 3-hydroxy-L-kynurenine, a tryptophan metabolite, has been detected in the coral genus Eunicella [15]. Nevertheless, there are more than 100 indole alkaloids obtained from the coral extracts that exhibit remarkable biological properties such as antibacterial, insecticidal and cytotoxic activities [16]. Notable among them are two N-acyl tryptamines, granulatamides A and B, isolated in 2006 from the soft coral Eunicella granulata (Grasshoff, 1992) and previously studied only on few cell lines for their antiproliferative activities [17]. Such N-fatty acyl tryptamines are a rare group of natural products that have been isolated mainly from terrestrial organisms [18–20] and for which few biological studies were conducted [21–24]. In addition to isolation from natural organisms, total synthetic approaches to the preparation of granulatamides A [25] and B [26] have also been published. Therefore, both granulatamides are important because of their interesting chemical structure consisting of 3 main components: indole nucleus, amide bond and long fatty acyl chain. The indole nucleus is a planar and aromatic heterocyclic motif that is considered a privileged structure in organic and medicinal chemistry [27–29]. Moreover, it is a pharmacophore of numerous natural and synthetic compounds that exhibit various biological activities with the potential to treat different diseases as observed in preclinical and c