marine drugs Review Occurrence and Properties of Thiosilvatins Maria Michela Salvatore 1 , Rosario Nicoletti 2,3 , Marina DellaGreca 1 and Anna Andolfi 1,* 1 Department of Chemical Sciences, University of Naples ‘Federico II’, 80126 Naples, Italy; [email protected] (M.M.S.); [email protected] (M.D.) 2 Council for Agricultural Research and Economics, Research Centre for Olive, Citrus and Tree Fruit, 81100 Caserta, Italy; [email protected] 3 Department of Agriculture, University of Naples ‘Federico II’, 80055 Portici, Italy * Correspondence: andolfi@unina.it; Tel.: +39-081-2539179 Received: 27 September 2019; Accepted: 21 November 2019; Published: 26 November 2019 Abstract: The spread of studies on biodiversity in different environmental contexts is particularly fruitful for natural product discovery, with the finding of novel secondary metabolites and structural models, which are sometimes specific to certain organisms. Within the large class of the epipolythiodioxopiperazines, which are typical of fungi, thiosilvatins represent a homogeneous family that, so far, has been reported in low frequency in both marine and terrestrial contexts. However, recent observations indicate that these compounds have been possibly neglected in the metabolomic characterization of fungi, particularly from marine sources. Aspects concerning occurrence, bioactivities, structural, and biosynthetic properties of thiosilvatins are reviewed in this paper. Keywords: thiosilvatins; secondary metabolites; diketopiperazines; epipolythiodioxopiperazines; fungi; biological activities 1. Introduction A huge chapter on research on biodiversity is represented by studies concerning the biochemical properties of the manifold organisms which are part of natural ecosystems. Novel secondary metabolites are continuously discovered, disclosing a surprising chemodiversity in terms of both structural and biosynthetic aspects. Although most classes of compounds are spread throughout the several kingdoms of nature, a certain specificity results in some cases. An example in this respect is represented by the epipolythiodioxopiperazines (ETPs), so far only reported from fungi [1]. ETPs are a large and structurally diverse class of bioactive secondary metabolites originating from diketopiperazines and characterized by the presence of a disulfide bridge or a polysulfide dioxopiperazine six-membered ring. Due to their bioactivities, ETPs are receiving attention in recent years [2]. This review is focused on thiosilvatins, a specific family of ETPs resulting from the enzymatic assemblage of two amino acids (i.e., l-tyrosine/l-phenylalanine and glycine), generally integrated with two methylated sulfur atoms. Unlike a related family including hyalodendrin, gliovictin, and their analogues, in this homogeneous group of compounds, the pivotal nitrogen deriving from the aromatic amino acid is not engaged in structural modifications other than methylation (Figure1). Mar. Drugs 2019, 17, 664; doi:10.3390/md17120664 www.mdpi.com/journal/marinedrugs Mar.Mar. Drugs Drugs 20192019, 17, 17, x, FOR 664 2 of2 of13 14 Mar. Drugs 2019, 17, x FOR 2 of 13 Figure 1. Basic structure of thiosilvatins. Figure 1. Basic structure of thiosilvatins. The finding of natural products displaying this kind of molecular structure only started in the The finding of natural products displaying this kind of molecular structure only started in the 1980s [3],The and finding even of nowadays natural products reports aredisplaying quite infrequent. this kind Theof molecular present paper structure provides only starteda review in ofthe 1980s [3], and even nowadays reports are quite infrequent. The present paper provides a review of the the1980s current [3], andknowledge even nowadays concerning repo occurrence,rts are quite bioact infrequent.ivities, structural,The present and paper biosynthetic provides aspectsa review of of current knowledge concerning occurrence, bioactivities, structural, and biosynthetic aspects of these thesethe currentcompounds. knowledge To ensure concerning a comparative occurrence, examinat bioactionivities, of the severalstructural, structures and biosynthetic reviewed herewith, aspects of compounds. To ensure a comparative examination of the several structures reviewed herewith, the thethese name compounds. of some compounds To ensure wasa comparative adapted to examinat conformion to previouslyof the several characterized structures reviewed analogs. herewith, namethe name of some of some compounds compounds was was adapted adapted to conform to conform to previously to previously characterized characterized analogs. analogs. 2. Structures and Chemical Properties 2. Structures and Chemical Properties (3R,6R)-1,4-Dimethyl-3-(4-(3-methyl-2-butenyloxy)benzyl)-3,6-bis(methylthio)piperazine-2,5- (3R,6,6RR)-1,4-Dimethyl-3-(4-(3-methyl-2-butenyloxy)benzyl)-3,6-bis(methylthio)piperazine-2,5-dione)-1,4-Dimethyl-3-(4-(3-methyl-2-butenyloxy)benzyl)-3,6-bis(methylthio)piperazine-2,5- dione(1), the (1), founder the founder product product of this of compound this compound series, series was, isolated was isolated for the for first the time first in time 1981 in along 1981 withalong its withdione its (deprenyl1), the founder analogue product (16) [3] of. thisSubsequently, compound 1 series was named, was isolated cis-bis(methylthio)silvatin for the first time in when1981 along the deprenylwith its deprenyl analogue analogue (16)[3]. Subsequently, (16) [3]. Subsequently,1 was named 1 wascis -bis(methylthio)silvatinnamed cis-bis(methylthio)silvatin when the only when sulfur the onlybridged sulfur thiosilvatin, bridged thiosilvatin, dithiosilvatin dithiosilvatin (2), was characterized (2), was characterized and submitted and tosubmitted a reductive to a methylation reductive methylationonly sulfur giving bridged 1 and thiosilvatin, its epimer dithiosilvatin in C-6 (3) [4] ((Figure2), was 2).characterized and submitted to a reductive givingmethylation1 and giving its epimer 1 and in its C-6 epimer (3)[4] in (Figure C-6 (23).) [4] (Figure 2). 1 2 3 1 2 3 Figure 2. Structures of cis-bis(methylthio)silvatin (1, NM = 408 U), dithiosilvatin (2, NM = 378 U), Figuretrans-bis(methylthio)silvatin 2. Structures of cis-bis(methylthio)silvatin (3, NM = 408 U). (1, NM = 408 U), dithiosilvatin (2, NM = 378 U), transFigure-bis(methylthio)silvatin 2. Structures of cis-bis(methylthio)silvatin (3, NM = 408 U). (1, NM = 408 U), dithiosilvatin (2, NM = 378 U), trans-bis(methylthio)silvatin (3, NM = 408 U). The most relevant structural modifications observed in this class of compounds are in the numberThe most of sulfurs, relevant the structural degree ofmodifications methylation obse of heteroatoms,rved in this class and theof compounds presence of are a dimethyl in the The most relevant structural modifications observed in this class of compounds are in the numberallylic of chain sulfurs, (Table the3 ).degree A controversial of methylation issue of he concerningteroatoms, thiosilvatinsand the presence could of bea dimethyl represented allylic by number of sulfurs, the degree of methylation of heteroatoms, and the presence of a dimethyl allylic chainnomenclature. (Table 1). A controversial In fact, several issue compounds concerning werethiosilvatins inconsistently could be designatedrepresented with by nomenclature. trivial names, chain (Table 1). A controversial issue concerning thiosilvatins could be represented by nomenclature. Inabbreviations, fact, several compounds or according were to inconsistently the IUPAC standards, designated which with trivial generally names, are abbreviations, not linked to or the In fact, several compounds were inconsistently designated with trivial names, abbreviations, or accordingname of to the the founder IUPAC compound.standards, which For generally instance, are Sch not 54794 linked (4) to and the Sch name 54796 of the (5) founder have the according to the IUPAC standards, which generally are not linked to the name of the founder compound.same structures For instance, and stereostructures Sch 54794 ( of4) 1andand Sch3, but 54796 their (5 amino) have functions the same are structures not methylated; and compound. For instance, Sch 54794 (4) and Sch 54796 (5) have the same structures and stereostructuresconsequently, theyof 1 and could 3, but be their respectively amino functions named cis are- andnot metransthylated;-dinor-bis(methylthio)silvatin consequently, they could [5 ]. stereostructures of 1 and 3, but their amino functions are not methylated; consequently, they could beLikewise, respectivelycis-3-(4-hydroxybenzyl)-1,4-dimethyl-3,6-bis(methylthio)-2,5-piperazinedione named cis- and trans-dinor-bis(methylthio)silvatin [5]. Likewise, cis (16-3-(4-) and be respectively named cis- and trans-dinor-bis(methylthio)silvatin [5]. Likewise, cis-3-(4- hydroxybenzyl)-1,4-dimethyl-3,6-bis(methylthio)-2,5-piperazinedionetrans-6-(4-hydroxybenzyl)-1,4-dimethyl-3,6-bis(methylthio)piperazine-2,5-dione (16) (17and) were namedtrans-6-(4- in the hydroxybenzyl)-1,4-dimethyl-3,6-bis(methylthio)-2,5-piperazinedione (16) and trans-6-(4- hydroxybenzyl)-1,4-dimethyl-3,6-bis(original manuscripts according to IUPACmethylthio)piperazine-2,5-dione standards [3,6], but they could (17 be) easilywere namednamed respectively in the hydroxybenzyl)-1,4-dimethyl-3,6-bis(methylthio)piperazine-2,5-dione (17) were named in the originalcis- and manuscriptstrans-deprenyl-bis(methylthio)silvatin. according to IUPAC standards [3,6], but they could be easily named respectivelyoriginal manuscripts cis-