Contents lists available at ScienceDirect Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox Immunomodulatory activity of marine natural products: Synthesis, spectral characterization and toxicity assessment of natural and related synthetic iodinated tyramides Miljana R. Đorđević a , Niko S. Radulović a,∗ , Nikola M. Stojanović b , Pavle J. Ranđelović c a Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia b Faculty of Medicine, University of Niš, Dr Zoran Ðinđić Boulevard 81, 18000 Niš, Serbia c Department of Physiology, Faculty of Medicine, University of Niš, Dr Zoran Đinđić Boulevard 81, 18000 Niš, Serbia ARTICLEINFO Keywords: N-(3,5-diiodo-4-methoxyphenethyl)benzamide Ascidian Toxicity Artemia salina Macrophages Immunomodulatory activities ABSTRACT The toxicity of natural marine iodoarenes or their synthetic counterparts is widely unknown despite the fact that triiodothyronine and thyroxine are members of this class. In this work we aimed to expand such knowledge on iodinated marine natural products and tested an ascidian (Didemnum rubeum) metabolite, N-(3,5-diiodo-4- methoxyphenethyl)benzamide, together with closely related synthetic iodinated tyramides: N-(2,5-diiodo-4- methoxyphenethyl)benzamide, N-(3-iodo-4-methoxyphenethyl)benzamide, N-(4-methoxyphenethyl)benzamide, and N-(3-iodo-4-methoxyphenethyl)formamide, for their efect on the viability of rat macrophages, as well as acute toxicity on Artemia salina. The tested tyramides exerted a varying degree of toxicity towards brine shrimps, but in certain cases, the determined lethal concentrations were even lower than those of known toxicants (e.g. strychnine sulfate, SDS). The toxicity was highly dependent on the structure of these mutually related com- pounds, while the natural one was shown to be the most toxic. In the case of macrophage cultures, the tested tyramides exerted much less toxicity but were found to have an efect on the functioning of these normal im- mune cells. The samples of the tyramides were obtained by synthesis, and were fully structurally and spectrally characterized, which also provided corroboration of the proposed structure of the natural product originally isolated in minute amounts. 1. Introduction Ascidians (Tunicates; Ascidiacea), also known as tunicates, are among the most frequently investigated groups of marine organisms with about 3000 reported living species (Shenkar and Swalla, 2011; Davidson, 1993). A number of tunicates, wild-harvested or cultured, are a part of the human diet in diferent parts of the world, including some European countries (Abdul Jafar Ali and Tamilselvi, 2016; Lambert et al., 2016), where they are regarded as healthy seafood high in pro- tein and low in calories. These marine invertebrate flter feeders use secondary metabolites for protection against predators and microbial pathogens, as well as intra- or interspecies interactions (Palanisamy et al., 2017). It is no wonder that ascidians represent an unusually rich source of bioactive secondary metabolites (Sri Kumaran et al., 2011). Up to now, most of the studies of their biological activities were or- iented towards the discovery of novel cytotoxic or antibiotic agents (Palanisamy et al., 2017; Watters, 2018). Ascidian metabolites (and their analogs) found clinical usage in advanced soft-tissue sarcoma, osteosarcoma, metastatic breast cancers (Yondelis ® - trabectedin and Aplidin ® - dehydrodidemnin B, respectively) (Fayette et al., 2005; González-Santiago et al., 2006). Most of these bioactive metabolites are amino acid-derived compounds of varying complexity: from oligopep- tides to simple derivatives of a single (non-essential) amino acid. Halogenated metabolites are a characteristic of marine organisms, including ascidians, and are known to commonly include chlorine and bromine, while only a small number of iodine-containing metabolites were identifed (Murphy, 2003). Iodinated natural compounds have been divided (Borrelli et al., 2004) into fve general classes of com- pounds: 1) volatile ones such as iodomethane (Itoh et al., 1997), 2) terpene derivatives (Williams et al., 2003), 3) fatty acid-related com- pounds (Dugrillon and Gaetner, 1995), 4) nucleoside derivatives (Kazlauskas et al., 1983), and 5) tyrosine-related compounds (Kigoshi et al., 1999). Among the classes, the most renown and perhaps biolo- gically most investigated, is the last one, with thyroxine and related compounds as fagpoles. Expressed through their cytotoxic efect on transformed cells, i.e. various kinds of cancer cell lines, halogenated https://doi.org/10.1016/j.fct.2018.12.039 Received 1 November 2018; Received in revised form 21 December 2018; Accepted 22 December 2018 ∗ Corresponding author. Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia. E-mail address: nikoradulovic@yahoo.com (N.S. Radulović). Food and Chemical Toxicology 125 (2019) 150–160 Available online 24 December 2018 0278-6915/ © 2018 Elsevier Ltd. All rights reserved. T