Natural Products Containing a NitrogenâSulfur Bond - Journal of

Review Cite This: J. Nat. Prod. 2018, 81, 423−446

pubs.acs.org/jnp

Natural Products Containing a Nitrogen−Sulfur Bond Janusz J. Petkowski,*,† William Bains,‡ and Sara Seager†,§ †

Department of Earth, Atmospheric, and Planetary Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States ‡ Rufus Scientific, 37 The Moor, Melbourn, Royston, Herts SG8 6ED, U.K. § Department of Physics, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States ABSTRACT: Only about 100 natural products are known to contain a nitrogen−sulfur (N−S) bond. This review thoroughly categorizes N−S bond-containing compounds by structural class. Information on biological source, biological activity, and biosynthesis is included, if known. We also review the role of N−S bond functional groups as post-translational modifications of amino acids in proteins and peptides, emphasizing their role in the metabolism of the cell.

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INTRODUCTION Natural products that contain a nitrogen−sulfur (N−S) bond constitute a fascinating group of compounds with enormous structural diversity. Interestingly, it is notable that N−S bonds are rarely found in biochemistry, and there are only about 100 compounds that contain N−S bonds known to be produced by life. While the community is generally aware of the rarity of the N−S bond in natural products, neither the occurrence nor the chemistry of N−S bond-containing natural products has been reviewed before. This paper provides a systematic review of this diverse group of compounds. Unique chemical properties of the N−S bond, such as its polar character and the multiple valence states of sulfur, allow for a large diversity of N−S bond-containing compounds, many of which have found crucial applications in many branches of modern industry. Industrial uses of N−S bond compounds include components of lubricating greases, dyes, and vulcanization agents.1−6 They are common in pharmaceuticals (both as active components and as intermediates in the synthesis of bioactive compounds), herbicides, fungicides, pesticides, and antimicrobial agents (e.g., antibiotics or industrial antimicrobial finishes for textiles).1,7−11 Thus, N−S bonds are functionally and biologically important to humans. This review details the biological sources and biological activities of N−S compounds, including N−S bond-containing post-translational modifications of proteins and peptides and their occurrence and functions in the cell. In some cases, these functions are well established, but in many others, they are initial hypotheses only. In many instances the hypothesized biological role is based on initial in vitro data, modeling, or structural analogy only and requires more direct experimental confirmation before being regarded as more than a suggestion. Many molecules show low specificity, low potency effects on biological systems, which are unlikely to be related to their in vivo role.12 Throughout this paper we use the term “suggested role” to © 2018 American Chemical Society and American Society of Pharmacognosy

identify such interesting initial observations or hypotheses on a molecule’s biological role. In order to be as comprehensive and clear as possible, our review of N−S bond-containing natural products has been segregated by structural class, with biosynthetic information reviewed as well, if known.

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SMALL-MOLECULE NATURAL PRODUCTS CONTAINING AN N−S BOND Sulfamates. Sulfamates are stable, water-soluble compounds that have been used in many branches of industry for more than a century.11 Sulfamates form the largest group among the N−S bond-containing natural products. This group is characterized by a S(VI) valence state of sulfur in an N−S bond, where the other valences of the central sulfur atoms are filled by bonds to oxygen. Out of approximately 100 known N−S natural compounds 73 are sulfamates. These constitute a very diverse group of secondary sulfamates, together with pyrrole and indole sulfamates, azetidinone sulfamates, and others. There are very few natural primary sulfamates known. We present each structural class of natural sulfamates below in detail. Primary Sulfamates. There are only five known, natural, primary sulfamates, all of which are adenosine nucleoside derivatives. An excellent review covering the discovery, biological activity, and total synthesis of primary sulfamate natural products was recently published.13 5′-O-Sulfamoyladenosine (1), 5′-O-sulfamoyl-2-chloroadenosine, also known as dealanylascamycin (2), 5′-O-sulfamoyl-2bromoadenosine (3), and the 7-deaza-adenosine derivative 5′-Osulfamoyltubercidin (4) were all isolated from various terrestrial actinomycetes (Streptomyces species). Halogenated adenosine nucleoside derivatives (2, 3) and the nonhalogenated deazaReceived: November 14, 2017 Published: January 24, 2018 423

DOI: 10.1021/acs.jnatprod.7b00921 J. Nat. Prod. 2018, 81, 423−446

Journal of Natural Products

Review

variant (4) were isolated from Streptomyces rishiriensis and Streptomyces mirabilis, respectively.14−19 Nucleocidin (5) was isolated from the soil microbe Streptomyces calvus.20 Nucleocidin (5) is a very interesting example of a rare natural product. Apart from the uncommon, N−S bond-containing primary sulfamate group, it contains an extremely rare fluorinated sugar moiety in its structure. So far there are only a few known fluorinated natural products, and 5 can be considered an exception even among those.21

Despite these recent breakthroughs, the full biosynthetic pathway of 5 is still unknown. Secondary Sulfamates. Secondary sulfamates populate the largest and the most structurally diverse class of natural N−S compounds. By far the most studied secondary sulfamates are heparan sulfate and heparin. Both are structurally closely related to each other and are members of the glycosaminoglycan (mucopolysaccharides) family of long unbranched polysaccharides consisting of highly negatively charged, repeating disaccharide units.30,31 Both heparan sulfate and heparin contain characteristic N-sulfo-α-D-glucosamine monosaccharide building blocks: GlcNS (7), GlcNS(6S) (8), GlcNS(3S) (9), and GlcNS(3,6S) (10).30,31

The function of heparin in animals is not fully understood, but it likely is involved in defense against invading pathogens and other foreign molecules. The heparin polymer appears to be conserved across a number of different animal species, including invertebrates.32 Heparin is released into the vasculature from secretory granules of the mast cells at the site of tissue injury.33 It is also routinely used as an anticoagulant (blood thinner).34,35 While structurally very similar to heparin (they both differ in the degree of modification of the component sugar residues, e.g., heparin has a much higher percentage of sulfonated residues), heparan sulfate has a distinct function and acts as a component of the extracellular matrix, where it provides attachment points to a variety of proteins involved in a multitude of biological processes, including cardiovascular and neural development, angiogenesis, and blood coagulation.36,37 Some studies also suggest that heparan sulfate can also be implicated in tumor metastasis and viral infection.38 The biosynthesis of heparin and heparan sulfate has been reviewed thoroughly30,39−41 and so will only be summarized here. In brief, the formation of an N−S bond in heparan sulfate (and likely in the majority of natural secondary and tertiary sulfamates) is catalyzed by amine sulfotransferases (EC 2.8.2.3) that utilize 3′-phospho-5′-adenylyl sulfate (PAPS) as a sulfonate donor to catalyze the sulfonation of either primary or secondary amines.42,43 Four amine sulfotransferases (NDSTs), belonging to a GlcNAc N-deacetylase/N-sulfotransferase family, involved in the biosynthesis of heparan sulfate have been characterized.44−48 Saxitoxins have received almost equal attention to heparin and heparan sulfate. The saxitoxin (STX) family of natural neurotoxin alkaloids contains close to 60 known compounds.49 They are often known as the paralytic shellfish toxins (PSTs) and are directly responsible for paralytic shellfish poisoning (PSP).49 STX and its analogues can be structurally classified into several classes such as nonsulfated, monosulfated, disulfated, decarbamoylated, and the recently discovered hydrophobic analogues, each with varying levels of toxicity.49 Due to their importance in

Primary sulfamates (−O−SO2NH2), together with primary sulfonamides (−SO2NH2) and primary sulfamides (−NH− SO2NH2), are well-known zinc-binding chemotypes common in some drugs, especially in efficient carbonic anhydrase (EC 4.2.1.1) inhibitors, e.g., used as diuretics or to treat glaucoma.22−25 We discuss primary sulfonamide natural products in the next section; there are no known primary sulfamide natural products. All known natural primary sulfamates have biocide activity. The diverse biological and pharmacological roles of natural primary sulfamates were reviewed in detail very recently13,22−24 and will not be expanded upon here. The biosynthetic pathway for compounds 1−4 is essentially unknown,13 although a cluster of 23 genes from Streptomyces sp. JCM9888 involved in ascamycin (6) and dealanylascamycin (2) biosynthesis was recently identified.26 Disruption of the acmE gene in the ascamycin/dealanylascamycin biosynthetic gene cluster showed that 2 is a precursor to 6, as disruption of acmE blocked biosynthesis of ascamycin (6).26 In contrast to 2, ascamycin (6) has a much narrower spectrum of antibiotic activity and was shown to be active only against a limited number of microorganisms, such as Xanthomonas spp.27 The equivalent potency of 6 and 2 in inhibiting protein synthesis in in vitro systems suggests that this limitation is likely due to limited permeability of bacterial cell membranes to 6.27 Significant progress was made in recent years regarding elucidation of the biosynthetic pathway of nucleocidin (5).28,29 The nucleocidin (5) biosynthetic gene cluster was discovered by identification of genes encoding the 5′-O-sulfamate moiety,28 and the first biosynthetic details on nucleocidin (5) assembly from isotope labeling studies were provided shortly thereafter.29 424



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dinoflagellates and freshwater cyanobacteria, which form vast blooms in many parts of the world. Out of ∼60 known STX compounds only six belong to the N−S bond-containing secondary sulfamate group: monosulfonated GTX5 (11) and GTX6 (12) and disulfonated C1 (13), C2 (14), C3 (15), and C4 (16) (see Table 1 for details on their biological sources). Secondary sulfamate saxitoxins M1 (17) and M3 (18) were isolated from mussel samples collected in eastern Canada and Angola during intense blooms of the dinoflagellates Alexandrium tamarense and Gymnodinium catenatum, respectively (Table 1).53−56 M1 (17) and M3 (18) are likely bivalve metabolites of saxitoxins produced by dinoflagellates, as they were not identified in the plankton.53 M7 (19) and M9 (20), two other mussel metabolites of secondary sulfamate saxitoxins, were recently identified in laboratory mussels grown in the presence of Alexandrium tamarense.57 All of the known N−S saxitoxins are sulfonated on the carbamate nitrogen-21 (N-21) position. The complete cyanobacterial biosynthetic pathway for the saxitoxin family has been extensively reviewed before,58−60 and the stx gene clusters, containing up to 26 open reading frames, responsible for saxitoxin biosynthesis have been identified for multiple species of cyanobacteria.61−68 Saxitoxin biosynthesis in dinoflagellates still remains somewhat elusive, although it is believed that the route of biosynthesis is similar to that in cyanobacteria.58,65,102 A PAPS-dependent

toxicology, saxitoxins are one of the most studied groups of compounds with vast literature available. Excellent reviews on the structural diversity, synthesis, mechanism of action, and toxicology of the entire family of STX compounds have been published.49−52 The primary sources for STX toxins are marine Table 1. N−S Bond-Containing Sulfamate Saxitoxins sulfamate saxitoxin GTX5 (B1), monosulfated (11)

GTX6 (B2), monosulfated (12)

C1, disulfated (13)

biological source Alexandrium catenella (Dinoflagellate) Alexandrium f undyense (Dinoflagellate) Alexandrium tamarense (Dinoflagellate) Anabaena circinalis (Cyanobacterium) Aphanizomenon f los-aquae (Cyanobacterium) Aphanizomenon gracile (Cyanobacterium) Aphanizomenon issatschenkoi (Cyanobacterium) Gymnodinium catenatum (Dinoflagellate) Pyrodinium bahamense (Dinoflagellate) Alexandrium catenella (Dinoflagellate) Alexandrium f undyense (Dinoflagellate) Alexandrium ostenfeldii (Dinoflagellate) Alexandrium tamarense (Dinoflagellate) Aphanizomenon f los-aquae (Cyanobacterium) Cylindrospermopsis raciborskii (Cyanobacterium) Gymnodinium catenatum (Dinoflagellate) Pyrodinium bahamense (Dinoflagellate) Alexandrium catenella (Dinoflagellate) Alexandrium f undyense (Dinoflagellate)

sulfamate saxitoxin

ref 69−73 74−77 53, 78 79−81 82, 83

C2, disulfated (14)

84 85, 86 55, 87−91 92 70−72, 93 76 94

C3, disulfated (15)

78 83

C4, disulfated (16)

95 55, 87−91, 96 92

M1, M3, M7, M9,

69−72 74−77

425

monosulfated monosulfated monosulfated monosulfated

(17) (18) (19) (20)

biological source Alexandrium ostenfeldii (Dinoflagellate) Alexandrium tamarense (Dinoflagellate) Anabaena circinalis (Cyanobacterium) Cylindrospermopsis raciborskii (Cyanobacterium) Gymnodinium catenatum (Dinoflagellate) Alexandrium catenella (Dinoflagellate) Alexandrium fundyense (Dinoflagellate) Alexandrium ostenfeldii (Dinoflagellate) Alexandrium tamarense (Dinoflagellate) Anabaena circinalis (Cyanobacterium) Cylindrospermopsis raciborskii (Cyanobacterium) Gymnodinium catenatum (Dinoflagellate) Alexandrium catenella (Dinoflagellate) Gymnodinium catenatum (Dinoflagellate) Alexandrium catenella (Dinoflagellate) Gymnodinium catenatum (Dinoflagellate) bivalve metabolic transformation bivalve metabolic transformation bivalve metabolic transformation bivalve metabolic transformation

ref 94 53, 73, 78, 97−99 79−81, 100 101 55, 87−91,96 69−71 74−77 94 53, 73, 78, 97−99 79−81, 100 101 55, 87−91, 96 69−72 55, 88, 96 69−72 55, 87, 88, 96 53, 55 53 57 57



Review

sulfotransferase, specific to N-21 of STX and gonyautoxins 2 and 3 (GTX2, GTX3), named N-ST, was purified from the cytosolic fraction of clonal-axenic vegetative cells of the dinoflagellate Gymnodinium catenatum. N-ST transfers a sulfonate group from PAPS to N-21 in the carbamoyl group of STX to yield GTX5 (11) or to N-21 of GTX2 or GTX3 to yield C1 (13) or C2 (14), respectively. The N-ST enzyme is specific to the N-21 position of STX, GTX2, and GTX3 and is not active toward neoSTX, GTX1, and GTX4, which contain an additional −OH group at N1.103,104 This suggests that biosynthesis of N-1 hydroxylated saxitoxins GTX6 (12), C3 (15), and C4 (16) likely involves a different sulfotransferase and that the biosynthetic pathways for saxitoxins are likely to be specific to particular toxins, and hence possibly to the organisms that make them. The medicinal applications of saxitoxins are rather limited, but at least some STXs have demonstrated pharmaceutical potential as anesthetics.49

Heterocycles based on brominated spiroisoxazolines are relatively common natural products arising from secondary metabolism of bromotyrosine.114,117,118 In contrast to other ianthesisnes, ianthesine C (29) possesses four dibromotyrosinederived moieties.112 Compound 31 is the secondary sulfamate derivative of the known natural product araplysillin-1.114 Apart from a single study showing very weak binding activity of ianthesine E to adenosine A1 receptors in a whole cell binding assay, nothing is known regarding the biological activities of compounds 29−32.115 Siladenoserinols A, B, D, F, H, and K (33−38) are secondary sulfamates from a tunicate of the family Didemnidae collected in Indonesia.119 A series of in vitro studies identified 33−38 (as well as other members of the siladenoserinol family) as potential inhibitors of an interaction between the p53 tumor suppressor and Hdm2 ubiquitin ligase (EC 6.3.2.19).119 Disruption of this interaction could lead to reactivation of the p53 and induction of apoptosis. It is not clear if this cell-killing phenomenon is the normal mode of action of the siladenoserinols, but the effect is being investigated for potential development of cytotoxic agents. A secondary sulfamate cyclodidemniserinol (39) was isolated from extracts of the Palauan ascidian Didemnum guttatum.120 Compound 39 was tested as an inhibitor of HIV-1 integrase and proposed as a potential lead compound for antiretroviral chemotherapy.120 Scleritodermin A (40) is an unusual cyclic peptide isolated from the lithistid sponge Scleritoderma nodosum.121 Compound 40 consists of a series of proteinaceous amino acids, L-proline, and L-serine, as well as the unusual, noncanonical, amino acids keto-allo-isoleucine and O-methyl-N-sulfo-D-serine and a novel conjugated thiazole group.121,122 Scleritodermin A (40) was also reported to inhibit tubulin polymerization at 10 μM concentration and showed in vitro cytotoxicity against human cancer cell lines.121 Linear Tertiary Sulfamates. Only three linear tertiary sulfamate natural compounds are known. Minalemines D−F (41−43) are tertiary sulfamate derivatives isolated from the

Some N−S compounds produced by zooplankton were identified as carriers of chemical cues that can result in changes in development and growth of algae, e.g., leading to the formation of sharp silica spikes or changes in cell wall structure, which in turn leads to reduced consumption by predators.105,106 Unicellular freshwater green algae of the genus Scenedesmus also use aliphatic sulfates and sulfamates as signaling molecules. The normally unicellular Scenedesmus morphs into multicellular cenobia (colonies) in the presence of crustacean Daphnia sp., which is a grazer of the alga.106 The grazing rate of the Scenedesmus cenobium morph is lower than that of the unicellular morph, suggesting that the metamorphosis is a self-defense mechanism acquired by the green alga and triggered by a kairomone believed to be secreted by Daphnia sp.107 Daphnia kairomones have been identified as several aliphatic sulfates and sulfamates.108−111 Scenedesmus reacts to all of the compounds 21−28 by formation of cenobia, although saturated variants 21− 26 give the most potent response; the amphiphatic character of the Daphnia kairomones 21−28 appears to be crucial for their chemical activity,108−111 more so than the specific processes based on receptor−ligand interactions. However, it is important to note that there is no final proof that these chemicals are indeed released by live daphnids, and comparisons with aliphatic sulfates from smaller grazers such as rotifers have not yet been made.106 Secondary sulfamate derivatives of brominated spiroisoxazolines, ianthesines C, D, and E (29−31) and 32 from the ianthesine family, were isolated from an Ianthella sp., a marine sponge collected in Australia,112,113 an Aplysina f ulva sponge from the Florida Keys,114 and a Pseudoceratina sp. sponge from the Great Barrier Reef.115,116 426



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Azetidinone Sulfamates. Monobactam sulfamates are a group of compounds that have received much attention since their discovery in the early 1980s (Table 2).124 The mechanism of action and biological activity of this group of compounds is Table 2. N−S Bond-Containing Naturally Occurring Sulfamate Monobactam Antibiotics sulfamate monobactam antibiotic SQ 26,180 (44) sulfazecin (SQ 26,445) (45)

MM 42842 (46) isolufazecin (47)

PB 5266A (48) PB 5266B (49) PB 5266C (50) SQ 28,332 (PB 5582A) (51) SQ 26,700 (M53B1) (52) SQ 26,812 (M138) (53) SQ 26,823 (54) SQ 26,875 (55) SQ 26,970 (M101) (56) TAN 850 (57) SQ 28,502 (58) SQ 28,503 (59)

marine tunicate Didemnun rodriguesi.123 Structures of D−F (41− 43) differ only in the length of a hydrocarbon chain. Nothing is known about their biosynthesis or function. 427

biological source

ref

Chromobacterium violaceum SC 11,378 (ATCC 31,532) Gluconobacter species SC 11,435 (ATCC 31,581) Acetobacter pasteurianus pasteurianus ATCC 6,033 Acetobacter aceti aceti ATCC 15,973 Acetobacter peroxydans ATCC 12,874 Acetobacter aceti liquefaciens ATCC 23,751 Acetobacter sp. ATCC 21,760 Gluconobacter sp. ATCC 19,357 Gluconobacter oxidans oxidans ATCC 15,178 Gluconobacter oxidans ATCC 19,441 Gluconobacter oxidans suboxydans ATCC 23,773 Gluconobacter oxidans industrialis ATCC 11,894 Pseudomonas acidophila Pseudomonas mesoacidophila Pseudomonas cocovenenans Pseudomonas mesoacidophila SB72,310 Pseudomonas acidophila Gluconobacter sp. Cytophaga johnsonae Cytophaga johnsonae Cytophaga johnsonae Flexibacter sp. SC 11,401 (ATCC 35,208) Cytophaga johnsonae Agrobacterium radiobacter SC 11,742 Agrobacterium radiobacter SC 11,742 Agrobacterium radiobacter SC 11,742 Agrobacterium radiobacter SC 11,742 Agrobacterium radiobacter SC 11,742 Pseudomonas sp. Flexibacter sp. ATCC 35,103 Flexibacter sp. ATCC 35,103

126, 127, 132, 134, 136, 137 126, 127, 130, 131, 134, 138−143

144, 145 126, 127, 134, 138− 142

146, 147 146, 147 146, 147 126, 148

126, 149, 150 126, 132, 134, 149, 150 126, 149, 150 126, 149, 150 126, 149, 150 151 126, 152 126, 152



Review

widely known and is similar to penicillin, which inhibits mucopeptide synthesis, thereby preventing proper peptidoglycan cross-linking in the bacterial cell wall. Monobactams have generally very high affinity for penicillin-binding proteins, which are essential in the final steps of the biosynthesis of peptidoglycan. The mechanism of action of monobactam antibiotics was reviewed thoroughly very recently125 and will not be expanded upon here. The antibacterial spectrum of the naturally occurring monobactams is limited to Gram-negative bacteria. However, they are intrinsically stable to β-lactamasecatalyzed hydrolysis, the most common mechanism of resistance to other β-lactam antibiotics, which is one of the reasons for their spectacular clinical success. Natural monobactams have been used successfully as scaffolds to obtain very effective synthetic derivatives.124,125 To date there are 16 known natural monobactam sulfamates (azetidin-2-one-1-sulfonates) (Table 2). These monocyclic βlactam antibiotics have a unique chemical structure characterized by the presence of a sulfonate attached to the nitrogen of a βlactam ring and a variable C-3 side chain. Some sulfamate monobactams such as naturally occurring MM 42842 (46) have an additional C-4 methyl group, which provides enhanced chemical and β-lactamase stability.126 Sulfamate monobactams have been isolated from a multitude of bacterial strains identified in soil, water, and plants such as Chromobacterium, Agrobacterium, Flexibacter, Acetobacter, Pseudomonas, and Gluconobacter.125,127−129 Table 2 provides details of their biological sources. Until the very recent discovery of the sulfazecin (45) biosynthetic gene cluster,130,131 only the biosynthetic pathway of the β-lactam ring was known for natural monobactam sulfamates.132,133 The importance of sulfur metabolism regulation for its biosynthesis suggested that the sulfamate group of monobactams is produced through PAPS.134 The sulfazecin (45) biosynthetic gene cluster is composed of 17 genes including two nonribosomal peptide synthetases, a methyltransferase, a sulfotransferase, and a dioxygenase.130,131

Monobactams are not the only known natural azetidinone ring containing sulfamates. Early studies reported a natural secondary sulfamate derivative of penicillin, antibiotic FR-900318 (60), from a fungus, Aspergillus candidus.135 FR-900318 (60) was not studied thoroughly, and it is the only example of a natural sulfamate derivative of penicillin known so far. Indole and Pyrrole Sulfamates. Pyrrole and indole sulfamates constitute the second largest group of sulfamates, with 15 compounds identified so far. Interestingly, the majority of them appear to have deterring or antifeedant properties, with several being produced by marine organisms.153−155

Three amphipathic 2-alkylpyrrole sulfamates (61−63) were isolated from the marine worm Cirriformia tentaculata. Their suggested role is defense from competitors, pathogens, or predators, including fish.156−158 Another marine pyrrole sulfamate, 2,3,4-tribromopyrrole sulfamate (64) isolated from the marine acorn worm Saccoglossus kowalevskii, could also have an antipredation purpose; however, further studies are required to conclusively prove that 64 really functions as a chemical defense against consumers.154,159 428



Review

Four indole sulfamates, ancorinolates A, B, C (65−67) and bis-ancorinolate B (68), and ancorinazole (69), an indolo[3,2a]carbazole also possessing a sulfamate group, were isolated from separate specimens of a New Zealand Ancorina sp. sponge.160 Ancorinolates A (65) and C (67) exhibited weak HIV-inhibitory activity.160

diverse collection of enzymes, although its specificity remains questionable, as no in vivo assays were performed to confirm potential pharmacological importance of 74.166,167 Compound 74 was also shown to have potential broad fungicide properties.166,167 No follow-up studies were performed to confirm those initial observations. The amine sulfotransferase responsible for the formation of the N−S bond in 74 has not been identified, but it is likely to be PAPS-dependent.168 Phosphosulfamates. Natural phosphosulfamates are represented by four natural products, phaseolotoxins (75−77) and sulphostin (78). They are characterized by an exceptionally diverse and unusual atom and bond composition. Both 75 and 78 contain a N−S bond in an uncommon sulfamate group, bonded to an equally rare triaminophosphate motif, leading to a “tract” of five heteroatoms in a row.

The skin of many Bufo spp. toads contains a number of indolealkylamines, derivatives of the deterrent bufotenine. An early study reported isolation of two members of the indole sulfamate family, O-methylbufoteninesulfamate (70) and bufoviridinesulfamate (71), from Bufo alvarius, a desert toad from Arizona.161 No further studies of 70 and 71 were undertaken after their initial isolation.

Phaseolotoxin (75) is one of the most extensively studied natural toxins. Compound 75 is produced by several strains of plant pathogens, Pseudomonas syringae pv. Phaseolicola, Pseudomonas syringae pv. Actinidiae, and Pseudomonas syringae pv. syringae strain CFBP3388.169 Phaseolotoxin (75) is composed of two characteristic moieties, a tripeptide Lornithyl-alanyl-homoarginine and triamino-phosphate sulfamate.170 Compound 75 is a phytotoxin that is responsible for inhibition of the biosynthesis of arginine and polyamines.170−174 It requires enzymatic cleavage by plant peptidases to generate the active form, octicidin, also known as PSOrn (76), which is the predominant form of the toxin in infected plant tissues. Octicidin (76) is a potent inhibitor of ornithine transcarboxylase (OCTase; EC 2.1.3.3) and ornithine decarboxylase (ODC; EC 4.1.1.17).175,176 The physiological product of OCTase is citrulline, which is a precursor of arginine, so inhibition of OCTase leads to loss of arginine production.174,177−179 The inhibition of ODC blocks biosynthesis of polyamines.176 Pseudomonas syringae pv. phaseolicola is resistant to the detrimental effect of its own toxin due to the presence of an argK gene that encodes phaseolotoxin-resistant OCTase (ROCT).180−183 Interestingly phaseolotoxin production and argK expression are temperature dependent, and no detectable amounts of phytotoxin or ROCT are produced above 28 °C.184−187

While it appears that animals seem to dominate the biochemical realm of indole and pyrrole sulfamate natural product chemistry, there have been a few reports on the isolation of several sulfamate derivatives of tryptophan in plants. Two sulfamate tryptophan derivatives, tryptorheedei A (72) and tryptorheedei B (73), were isolated from the seed kernels of Entada rheedei, a liana plant from Africa.162 Compounds 72 and 73 were suggested to have an inhibitory effect on indolamine 2,3dioxygenase (IDO) (EC 1.13.11.52), a human heme-containing enzyme that is the first enzyme in the catabolism of tryptophan to kynurenine.163 IDO expression has been linked to immune modulation and tumor survival.162,164 Sulfoglucobrassicin (74) is a sulfamate derivative of glucobrassicin isolated from a flowering plant, Isatis tinctoria, in the family Brassicaceae.165 Limited in vitro enzyme inhibition studies suggested that 74 is a moderate to strong inhibitor of a 429



Review

variety of clinically relevant synthetic drugs used as anticancer agents, diuretics, antiepileptics, and various antipsychotic drugs as well as the eponymous sulfonamide antibiotics.25,207−209 This breadth of pharmacological action shows that the sulfonamide group is compatible with specific, potent biological action, yet it seems to be excluded from life’s biochemical repertoire. Even more noticeable is that aryl sulfonamides, in which the sulfonamide group is linked to an aromatic ring, are the majority of clinically used sulfonamides, but only two natural product aryl sulfonamides are known. Taichunamide D (79) is an indole alkaloid isolated from the fungus Aspergillus taichungensis IBT 19404.210 Compound 79 contains a 1-methylsulfonyl group and is, so far, the only known example of a natural 1-methylsulfonylindole alkaloid. The 1methylsulfonyl group is also present in another rare alkaloid (80). Compound 80 is a brominated tertiary sulfonamide isolated from the North Sea bryozoan Flustra foliacea.211

The exact biosynthetic pathway of phaseolotoxin (75) is unknown, but the Pht gene cluster involved in its biosynthesis was described. A putative nonribosomal peptide synthetase gene (gene PSPPH_4550), located outside the Pht cluster, was also reported as required for phaseolotoxin production.188,189 The Pht cluster contains 23 genes.190−192 The functions of most of the Pht genes are unknown, and only a few are definitely involved in 75 biosynthesis.182,183,192−196 It is worth mentioning that one of the earlier studies reported the isolation of a natural derivative of phaseolotoxin (75), 2serinephaseolotoxin (77), from New Zealand isolates of Pseudomonas syringae pv. Phaseolicola.197,198 Compound 77 was characterized as a minor component (∼6% of the crude toxin) with equally toxic properties.197−199 Since its first isolation no new studies on 77 have been published.

There are only two known primary sulfonamides: altemicidin (81) and psammaplin C (82). Altemicidin (81) is a primary sulfonamide isolated from a strain of Streptomyces sioyaensis SA1758 from a sample of sea mud from Japan, the first reported cytotoxic alkaloid from a marine actinomycete.212−216 Altemicidin (81) is an efficient acaricidal agent against mites and showed inhibition of the growth of murine L1210 lymphoid leukemia tumor cell lines.13 Compound 81 is structurally related to two aliphatic secondary sulfonamide antibiotics, SB-203208 (83) and SB-203207 (84), that were isolated from a fermentation broth of Streptomyces sp. NCIMB405 13, although it is important to note that SB-203207 (84) may be a degradation product of SB203208 (83).217,218 SB-203207 (84) and SB-203208 (83) are potent competitive inhibitors of bacterial and mammalian isoleucyl tRNA synthetase and were also shown to be weak antibacterial agents.217,218 The second known primary sulfonamide natural product is psammaplin C (82). Compound 82 is a member of a class of compounds containing a bromotyrosine-cysteine framework isolated from the sponge Pseudoceratina purpurea.219,220 A partial biosynthesis for 82 was suggested through condensation of a bromo oxime functionalized tyrosine with a rearranged cysteine, which subsequently leads to a disulfide residue, a precursor to the sulfonamide moiety of 82.13 Compound 82 showed very promising inhibition of an important cancer-associated isozyme, human carbonic anhydrase XII zinc metalloenzyme.13 To date the only example of a natural aryl sulfonamide natural product comes from a report of the discovery of a series of sulfonyl-bridged alkaloid dimers (sulfadixiamycins A−C), isolated from a recombinant Streptomyces sp. harboring the

Sulphostin (78) is a phosphosulfamate isolated from the culture broth of Streptomyces sp. MK251-43F3.200 Compound 78 was identified as a strong dipeptidyl peptidase IV (DPP-IV; EC 3.4.14.5) inhibitor.201−204 Dipeptidyl peptidase IV is a cellsurface serine exopeptidase that selectively cleaves dipeptides from the N-terminus of target proteins.205,206 DPP-IV regulates activity of many important physiological processes, such as insulin release and modulation of thymocyte activity. Therefore, 78 is considered to be a potential therapeutic agent for type II diabetes and immune-related disorders.202,203,205,206

Sulfonamides. Sulfonamides are also characterized by hexacoordinate sulfur, but in the (+4) oxidation state, as the sulfur is bonded to one carbon atom. Sulfonamides are less common among natural products than sulfamates. There are eight known natural sulfonamides. Despite their rarity among natural products, the sulfonamide group is common in a vast 430



Review

are the second largest group (12 members) of natural products containing the N−S bond, after sulfamates. Isothiazoles. There are only a few isothiazole-containing natural products identified to date, in contrast to thiazoles, which are common in nature.231−234 Among the most studied natural products are brassilexin (87) and sinalexin (88). Both of them are very potent antifungal phytoalexins produced by cruciferous plants.235,236 Brassilexin (87) was isolated from leaves of the brown mustard Brassica juncea infected with the plant pathogenic fungus Alternaria brassicae.237 Sinalexin (88) was isolated from leaves of white mustard (Sinapis alba).238 Three other known natural isothiazoles, collismycin F (89), aulosirazole (90), and pronqodine A (91), are less studied. Collismycin F (89) is an antibiotic isolated from Streptomyces sp. strain SF 2738 and Actinomycetes sp. strain C13.239,240 Both aulosirazole (90), a cytotoxin from the blue-green alga Aulosira fertilizsima, and pronqodine A (91) are produced by Streptomyces sp. MK83295F2 and were reported to have some potential as antitumor agents.241−243 Little is known about the biosynthesis of the five known natural isothiazoles, despite the fact that this class of compounds drew much attention due to their role as phytoalexins, which are crucial in mediating the responses of cruciferous plants to several types of stress, including fungal and bacterial infections.244 The phytoalexins brassinin and cyclobrassinin were shown to be crucial intermediates in the biosynthesis of the isothiazole brassilexin (87),235,236 but nothing is known on the mechanisms of biosynthesis of other isothiazole phytoalexins. Similarly, the mechanism of biosynthesis of the collismycin F (89) isothiazole ring is not known, although a gene cluster, containing 27 open reading frames, responsible for the biosynthesis of a bipyridyl compound, collismycin A, was recently identified in Streptomyces sp. CS40, a strain isolated from the leaf-cutting ant Acromyrmex octospinosus.245 Collismycin F (89) is an isothiazole analogue of collismycin A, which also harbors a bipyridyl scaffold.239 While the mechanism of collismycin F (89) biosynthesis is still not known, it was shown that one of the crucial intermediates in biosynthesis of its analogue collismycin A involves production of an intermediate compound, termed collismycin SN (92), which contains a pyridine unit fused to an N-substituted isothiazol-3one ring.245 It is not known which of the 27 genes in the collismycin A biosynthesis cluster encodes the enzyme responsible for N−S bond formation in collismycin SN (92). It also remains to be seen if a homologous collismycin biosynthetic gene cluster exists in Streptomyces sp. SF 2738 and if it is responsible for the production of collismycin F (89).

entire xiamycin biosynthesis gene cluster.221 One of the three compounds, sulfadixiamycin A (85), was confirmed to contain an aryl sulfonamide moiety. Sulfadixiamycins were shown to exhibit moderate antimycobacterial activities and were also suggested as potential antibiotics against multidrug-resistant bacteria.221 To date there is very limited information available on the biosynthesis of sulfonamides in living organisms. It was postulated that the few, rare aliphatic sulfonamide-containing natural products that were discovered to date likely originate from incorporation of taurine-derived residues, as well as from enzymatic oxygenation of thioethers.222,223 These biosynthetic pathways however cannot be responsible for the formation of aromatic sulfonamides in the Streptomyces sp. described above.221 Indeed, it was shown that a flavin-dependent enzyme (XiaH) plays a key role in sulfadixiamycin biosynthesis.221 We also note that another aryl sulfonamide, N-butylbenzenesulfonamide (86), a compound widely used in chemical synthesis and industry, was isolated from several biological sources including an Actinoallomurus strain (Actinomycetes),224 Pseudomonas sp. (from greenhouse soil sample),225 and higher plants, specifically from roots of Angelica sinensis226 and bark of Prunus af ricana.227 It is important to note however that compound 86 is a popular synthetic plasticizer, is also used as a reagent during synthesis of sulfonyl carbamate herbicides, and is very stable and persistent in the environment.228−230 This suggests that 86 could potentially accumulate in organisms as a contaminant. Whether 86 is a true natural product rather than an environmental contaminant requires further investigation.226 Nevertheless 86 was shown to possess important biological activities, as a potential fungicide against a series of plant pathogens,225 and has been suggested as an androgen receptor antagonist in prostate cancer treatment.227 Aromatic N−S Compounds. The aromatic N−S compounds, specifically isothiazoles, thiadiazoles, and isothiazines, 431



Review

far less research done on this class of compounds, and the only known natural product containing a six-membered ring with an N−S bond is an isothiazine derivative called neamphine (98), an alkaloid isolated from the Australian marine sponge Neamphius huxleyi.251

Thiadiazoles. The second variant of aromatic N−S bondcontaining rings explored by life are the thiadiazoles. Natural thiadiazoles were extensively covered in a recent excellent review on natural products containing rings with three or more heteroatoms.246 Out of the three N−S bond-containing isomers of thiadiazoles only 1,2,4-thiadiazole derivatives are produced in nature, although very rarely. Thiadiazoles were shown to have useful biological activity, and 1,2,4-thiadiazole derivatives have been widely used in industry, e.g., as components of lubricating greases, dyes, and vulcanization agents.2−4 They are also vastly popular as pharmaceuticals, herbicides, fungicides, pesticides, and antimicrobial agents.2−4 There are only five known natural 1,2,4-thiadiazoles. Three of them are 3-amino-substituted 1,2,4-thiadiazole alkaloids from tunicates: polycarpathiamines A (93) and B (94) were isolated from Polycarpa aurata,247 and dendrodoine (95) was isolated from Dendrodoa grossularia.248 Compound 93 and compound 95 were shown to be cytotoxic at submicromolar concentrations, while compound 94 was inactive.247,248 The fourth known natural 1,2,4-thiadiazole was isolated (in two enantiomeric forms) (96a, 96b) from the cruciferous plant Isatis tinctoria (woad). 249 In contrast to tunicate thiadiazoles 93−95, compound 96 does not contain a 3-amino substituent, and it is likely that its biosynthetic pathway is completely different.247,249 The fifth known natural thiadiazole, penicilliumthiamine B (97), was identified only recently.250 Compound 97 was isolated from the culture broth of Penicillium oxalicum, a fungus found in the Chinese grasshopper Acrida cinerea.250

Other Rare N−S Bond Systems. Sulfoximines. Sulfoximines are monoaza analogues of sulfones; they are stable, watersoluble compounds with very versatile and interesting chemistry.252,253 There are only three reports to date describing the isolation of sulfoximines from natural sources, all three of which are methionine derivatives. Methionine sulfoximine (99) itself was isolated from Cnestis glabra, Cnestis polyphylla, Cnestis palala (tropical woody plants from the family Connaraceae, known for their toxicity), and Rourea orientalis,254−256 while its two phospho-derivatives (100, 101) were isolated from a Streptomyces sp.257,258 All three known natural sulfoximines have neurotoxic or antibiotic properties.174,259 Compound 99 is an inhibitor of glutamine synthetase (EC 6.3.1.2). It binds to the glutamate binding site, where it undergoes phosphorylation by ATP, which yields an irreversible, noncovalent inactivation of glutamine synthetase.260,261 Despite the fact that 99−101 have important toxicological effects, sulfoximines are very rarely used in medicine or industry and for a long time were considered only as a chemical curiosity.252,262 Only recently were some chemical properties of sulfoximines (e.g., hydrophilicity) identified as potentially useful for medicinal chemistry.253,262 Dithiazines. Dithiazines are extremely uncommon and very poorly studied, with only a single reference reporting on the chemistry of derivatives of all four possible isomers of N−S bondcontaining dithiazines.2 We discuss them here, as one highly unusual N−S bond-containing natural 1,2,3-dithiazine derivative, scorodophlone A (102), was isolated from the seeds of the tropical African tree Scorodophloeus zenkeri.263 Definitely in light of the discovery of the first (and, so far, the only) natural dithiazine, more studies are warranted on this underdeveloped branch of organic chemistry. Dithiadiazetidines. One of the most exotic natural compounds reported to date to contain an N−S bond is symploate (103) isolated from the bark of the plant Symplocos racemosa.264

Isothiazines. The six-membered ring analogues of the isothiazoles are the 1,2-thiazines (isothiazines). There has been 432



Review

widely for cellular signaling by many evolutionarily distant organisms.267 S-Nitrosothiols are generally difficult to isolate as pure compounds, although successful synthesis and isolation for many of them has been reported and is used routinely in biological applications.268 Protein S-nitrosylation is a common protein post-translational modification of cysteine residues,269 and natural S-nitroso compounds are represented mainly by S-nitroso-cysteine (105) (and peptides containing it such as S-nitroso-glutathione (106)) and S-nitroso-CoA (107)).269,270 S-Nitrosothiol formation, such as in S-nitroso-glutathione (GSNO) (106), is achieved during nitric oxide NO-dependent signaling.271−273 It is important to note, however, that other minor cellular thiols were also shown to be S-nitrosylated. S-Nitroso-cysteinylglycine (108), a metabolite of S-nitroso-glutathione (106), is generated by γ-glutamyltransferase (GGT; EC 2.3.2.2)274−276 and was suggested to mediate nitric oxide (NO) neurotransmission in the thalamic region of the brain.277 Similarly, Snitroso-homocysteine (HcyNO) (109) was implicated in nitric oxide signaling (e.g., in vascular endothelial cells).278 However, contrary to other S-nitrosylated amino acids, HcyNO can be incorporated cotranslationally into nascent protein chains, where it substitutes methionine (e.g., in hemoglobin and albumin).278,279

It contains an unprecedented 1,2,3,4-dithiadiazetidine ring. Dithiadiazetidine derivatives are an almost entirely unexplored group of organic compounds. Some synthetic work was conducted on 1,3,2,4-isomers,265 but 1,2,3,4-dithiadiazetidines are unknown, and it is very much possible that the natural product symploate is the only published molecule of this type. It remains to be seen if its structure will be confirmed by any followup experiments, but we hope that this result would encourage further studies on this rare N−S ring system.

Aminopolysulfides. The only known natural aminopolysulfide sulfinate, methyl 1-aminopentasulfide-5-sulfinate (104), has been isolated from the fresh seedpods of the tropical tree Moringa oleifera, commonly known as drumstick tree or horseradish tree.266 No information is available on chemical or medicinal properties of compound 104. HcyNO (109) also plays a central role in inactivation of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme involved in the regulation of nitric oxide synthase (NOS).280−285 Inactivation of DDAH by HcyNO (109) does not occur by transnitrosation or formation of a disulfide bond with Cys-274 in the DDAH active site, but rather by formation of an unusual N−S cross-link, N-thiosulfoximide (110) (Scheme 1).280,286 It is currently unknown if 110 is a unique modification tailored specifically to DDAH active site amino acid architecture or if there are other targets of N-thiosulfoximide cross-linking to be discovered. It is also unclear if this post-translational modification is truly irreversible, as in vitro studies suggested,281,283 either through reactivity with cellular thiols or through other means. Non-amino acid cellular thiols were also shown to be nitroslylated under physiological conditions, and their involve-

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N−S BONDS AS POST-TRANSLATIONAL MODIFICATIONS OF AMINO ACIDS IN PROTEINS AND PEPTIDES N−S bonds are found as post-translational modifications in proteins, as well as in small-molecule natural products. In this section we discuss these and what is known on their chemistry and biology. S-Nitrosothiols and Derivatives. S-Nitrosothiols are reactive derivatives of thiols. S-Nitrosothiols are a fascinating example of a specific, unusual structure that has been adapted 433



Review

Scheme 1. Proposed Mechanism of Inactivation of Dimethylarginine Dimethylaminohydrolase (DDAH) by HcyNO (109) and the Formation of the 110 Cross-Link

response, and neurotransmission290,291 opened the possibility for a “cross-talk” between H2S and NO signaling. Recently it has been shown that such “cross-talk” indeed exists and is mediated by N−S chemical species.292 H2S reacts with NO and its metabolites (e.g., S-nitrosylated proteins), yielding several biologically active, reactive, inorganic N−S compounds.293 Thionitrous acid (HSNO) (112) was the first to be discovered and proposed to be a product of the reaction of protein Snitrosothiols with H2S, capable of crossing cell membranes and facilitating further transnitrosation of proteins (e.g., hemoglobin).292 Subsequently nitrosopersulfide (−SSNO) (113), dinitrosulfite (114), and sulfinyl nitrite (115) have been proposed as other inorganic, small-molecule N−S “chemical linkers” between H2S and NO transmitter signaling pathways.293−295 Their physiological relevance however is not yet fully understood and is a subject of an ongoing heated debate.296−302 Thus, although S-nitrosylation represents only a handful of structural groups, they are ubiquitous in cells and are consequently physiologically important. Proteins can be S-nitrosylated through specific, enzymecatalyzed reactions or by uncatalyzed reaction of nitric oxide with suitably reactive thiols in the protein. Many new protein targets for S-nitrosation were identified recently either through targeted or proteome-wide approaches. Unraveling which of the cellular S-nitrosation events are a consequence of specific, catalytic targeted signaling and which are an unavoidable result of the presence of NO in the cell is crucial for full understanding of the role of both NO-mediated signal transduction and protein Snitrosation. S-Nitrosothiols are important to many aspects of cellular homeostasis, from cell proliferation to programmed cell death.268,303−305 However, the detailed mechanisms of Snitrosothiol formation in living organisms are still largely unknown, as are the details of their functions and chemical

ment in regulation of various physiological processes through controlled release of NO is currently under intensive investigation. S-Nitrosation of cysteamine to S-nitroso-cysteamine (111) was proposed to serve as an alternative nitric oxide carrier system, but it is yet to be proven to be relevant in vivo.287−289

The discovery that hydrogen sulfide (H2S) is a signaling molecule involved in the regulation of vasodilation, immune 434



Review

Scheme 2. Reduction of S-Nitroso-glutathione (106) by S-Nitroso-glutathione Reductasea

a

In the presence of physiological concentrations of glutathione (GSH), GSNHOH (116) is converted to glutathione disulfide (GSSG). Under oxidative stress conditions (no GSH) other products, such as glutathione sulfinamide (GSONH2) (118) or glutathione sulfinic acid (GSSOH), are formed.

biology.268 S-Nitroso-cysteine formation, transnitrosation reactions (i.e., the transfer of the nitroso group from GSNO or Snitroso-thioredoxin onto the target protein), and release of nitric oxide undergo sophisticated regulation and happen via a variety of mechanisms that were reviewed exhaustively.269,272,306−308 To date there are three enzymes known that contribute to the regulation of the cellular S-nitrosothiol levels through reduction of S-nitrosylated species, primarily ADH3 (glutathione-dependent formaldehyde dehydrogenase; EC 1.1.1.284),309−311 CBR 1 (carbonyl reductase 1; EC 1.1.1.184),312,313 and the recently discovered S-nitroso-CoA reductase.270 S-Nitroso reductases are conserved in the evolution from bacteria to humans.267,314,315 All three enzymes act in an analogous way to reduce S-nitrosothiols with electrons from NAD(P)H (e.g., S-nitroso-glutathione (106) or S-nitroso-CoA (107), depending on the reductase involved) to S-(N-hydroxy) intermediates (116, 117) (Schemes 2 and 3). The S-(N-hydroxy) intermediate, depending on the

is often assumed and that similar modifications in other proteins could participate in regulation of many other normal and pathological processes (Table 3).317 The stability and reactivity of sulfinamides (RS(O)NH2) has not been studied in detail; however, it was widely suggested that, in contrast to disulfide formation, sulfinamide modification of peptides and proteins is irreversible and as such is one of the major contributors to the damage that results from oxidative stress.318−325 Other, more recent studies, however, suggest that sulfinamides may be hydrolyzed to the respective sulfinic acid (RSO2H), albeit slowly,326 or react further with excess thiols to form thiosulfinates (RS(O)SR),327,328 which can be subsequently reverted to free thiols under physiologically relevant conditions.326,329−331 Under prolonged oxidative stress conditions, e.g., as a result of hypochlorous acid release during the immune response, sulfinamides can undergo further oxidation to sulfonamides. This oxidation of glutathione results in a cyclic intramolecular structure (122).332−335 The functional or physiological relevance is however not known (Table 3).

Scheme 3. Enzymatic Reaction Catalyzed by S-Nitroso-CoA Reductases

redox state of the cell (excess or scarcity of free thiols), decomposes to the corresponding disulfide and hydroxylamine (under normal physiological conditions) or to the sulfinamide (118, 119), if excess thiols are not present (Scheme 2).311,316 Sulfinamides formed as a result of S-nitrosothiol metabolism in an environment lacking free thiols are postulated to form bonds between Cys-thiols and Lys-amines as a natural consequence of HOCl protein oxidation during inflammation, both within the same protein chain and between different proteins.317 In one example (calcium binding protein S100A8) the oxidized sulfinamide variant of the protein (129) retained normal physiological functions as a chemotactic agent for neutrophils and monocytes, which is utilized during inflammatory conditions.317 It is thus possible that physiologically relevant sulfinamide formation in cells is much more widespread than it

Sulfenamides. Sulfenamides are compounds containing an N−S bond between a trivalent nitrogen and a bivalent sulfur1,351 435



Review

Table 3. In Vitro Generated, N−S Bond-Containing, Protein and Peptide Post-Translational Modifications and Cross-Links with Unconfirmed Physiological Role N−S modified residue cysteine sulfinamide (120) cysteine sulfohydroxamic acid (121) glutathione sulfonamide (122) Cys-Arg sulfenamide cross-link (128) Cys-Lys sulfenamide cross-link (124) Cys-Lys sulfinamide cross-link (129) Cys-Lys sulfonamide cross-link (130) 1,2-thiazolidin-3-one sulfinamide (134) sulfonamide 1,2thiazolidin-3-one (135) Met-Lys sulfilimine cross-link (131, 132) S-nitrocysteine (136) S-nitroglutathione (137) a

proposed physiological role

ref

nitroxyl-induced formation of sulfinamides in proteins (e.g., in human platelet proteins; cysteine proteases; phospholamban) nitroxyl-induced modification of unmodified C-terminal cysteine residues HOCl generated by the myeloperoxidase−H2O2−Cl− neutrophil system during inflammatory conditions HOCl generated by the myeloperoxidase−H2O2−Cl− neutrophil system during inflammatory conditions

331, 336− 338 337, 339 333−335, 340, 341 332

HOCl generated by the myeloperoxidase−H2O2−Cl− neutrophil system during inflammatory conditions; formed, upon binding 332, 342, to a sulbactam inhibitor, in the active site of the S70C variant of SHV-1 β-lactamase from Klebsiella pneumoniae 343a HOCl generated by the myeloperoxidase−H2O2−Cl− neutrophil system during inflammatory conditions 317, 332a HOCl generated by the myeloperoxidase−H2O2−Cl− neutrophil system during inflammatory conditions

332, 344

H2O2-mediated oxidative stress; formation upon oxidation of residue 123 H2O2-mediated oxidative stress; formation upon oxidation of residue 123

330, 345, 346 330

HOBr and bromoamine-mediated formation upon activation of granulocytes at sites of inflammation

347, 348a

intermediate step in NO release from nitroglycerine by aldehyde dehydrogenase-2 product of the reaction between peroxynitrite (ONOO−) and glutathione that generates nitric oxide

349 350

Evidence for physiological relevance is available; see text for details.

and are so rare in natural compounds that only a few examples are known. By far the most notable example of natural sulfenamide is a cyclic 1,2-thiazolidin-3-one (123) identified in several proteins, as a cellular response to oxidative stress, both in bacteria and eukaryotes.352,353 Residue 123 exists only in proteins, in contrast to the S-nitrosylation discussed above, which also occurs in small peptides.

Increasing evidence suggests that the cellular redox state is involved in regulating activity of a plethora of proteins through reversible oxidization of the catalytic cysteines.354−357 Oxidative stress agents (like H2O2) could lead to formation of sulfenic acid (Cys-SOH) followed by irreversible oxidation of critical catalytic cysteines to sulfinic (Cys-SO2H) and sulfonic (Cys-SO3H) acids.358 Such overoxidation renders affected proteins irreversibly inactive.354−357 Formation of cyclic sulfenamides (123) allows for protection of crucial cysteine residues from irreversible oxidation.330,359−361 Cyclic sulfenamides control the activity of distinct signaling and oxidative stress response pathways in eukaryotes and bacteria alike.352,353 Upon oxidative stress catalytic cysteines of many proteins, e.g., PTB1B and RPTPR tyrosine phosphatases, USP 19 deubiquitinase, and OhrR

Scheme 4. Role of Cyclic Sulfenamide in Oxidative Stress Response (ROS)a

a

Cyclic sulfenamide 123 is formed as a protective measure from irreversible oxidation of catalytic cysteine (Cys-215) in the PTPB1 phosphatase active site. (I) Exposure of the catalytic Cys-215 of PTPB1 to H2O2 leads to formation of a sulfenic acid (R-SOH), which undergoes (II) intramolecular cyclization with a neighboring amino group, resulting in formation of a cyclic sulfenamide. (III) Reduction of 123 is possible through controlled reaction with cellular glutathione, first by formation of a mixed disulfide, which is subsequently reduced by glutaredoxin. 436



Review

Scheme 5. Proposed Mechanism of Formation of a Sulfenamide Cross-Link (124) in the NemR Transcriptional Regulator upon Oxidative Stress Induced by Reactive Chlorine Species (RCS)

transcription repressor, become targets of a nucleophilic attack by a nearby backbone amide group, which leads to the formation of a cyclic sulfenamide (Scheme 4).330,362−367 The formation of the cyclic sulfenamide is fully reversible, by formation of a mixed disulfide with glutathione, which is subsequently reduced by a glutaredoxin enzyme. It is unclear how many other redoxsensitive cysteine residues undergo cyclic sulfenamide formation in vitro or in vivo, but it is suggested that there could be hundreds in human cells alone.353 Oxidative stress is also responsible for formation of another unique protein sulfenamide, secondary linear sulfenamide 124 in aerobic bacteria (Scheme 5), again produced uniquely within existing protein structures. Reactive chlorine species (RCS), such as hypochlorous acid or N-chlorotaurine, are oxidants produced by the innate immune system as a response to microbial attack.344,368 Escherichia coli transcriptional repressor NemR senses RCS by the formation of a sulfenamide bond between conserved cysteine and lysine residues, which is, similarly to cyclic sulfenamides, fully reversible by thiol-reducing agents.342,368 Formation of an N−S bond between Cys and Lys residues leads to alteration of NemR DNA binding affinity and consequently turns on oxidative stress response genes.342 Formation of a secondary linear sulfenamide in NemR is so far the only reported example of a functional redox thiol switch regulating protein function by formation of a cysteine−lysine sulfenamide bond. Nevertheless, based on the high evolutionary conservation of Cys and Lys residues participating in formation of a sulfenamide N−S bond among NemR homologues from diverse bacterial genera, it is likely that regulatory sulfenamide bond formation might be a relatively common redox switch mechanism. There is no evidence for this, however, at least in part because the functions of most NemR homologues are not known.342 Protein sulfenamides are not the only examples of natural sulfenamides. To date, there are two known examples of a peptide-derived sulfenamide produced by life (isolated from Allium sativum), scordinines A and B (125 and 126), which contain a guanidinium sulfenamide derivative of cysteine called thiocornine (127).369−371 High doses of scordinines have been reported to reduce the induction of liver cancers in rats by hydroxylamine.372,373 Sulfilimines (Sulfimides). Sulfilimines are monoaza derivatives of sulfones.374 Similar to the S-nitrosothiols discussed

above, sulfilimines are a rare structural type that have a critical role in cellular metabolism. The stability of the S(IV)N bond depends heavily on the nature of the substituents on nitrogen and sulfur.375,376 Industrial and medicinal interest in sulfilimines has been limited to some applications in polymer chemistry,375 although they have been explored as potential bactericidal, herbicidal, or pharmacological 437



Review

Formation of dehydromethionine requires a sufficiently basic, free, amino group to achieve efficient nucleophilic attack on sulfur; therefore it is unlikely to occur with protonated and Nterminally modified methionine residues385 or methionine residues present within the polypeptide chain.384,385,387 The role of formation of N-terminal dehydromethionine during inflammation is not known, but dehydromethione could be involved in some capacity in the global redox regulation of the cell. Despite the fact that cellular thiols such as glutathione are capable of reducing free dehydromethionine, its half-life in physiological conditions is measured in minutes to hours.388 This opens the possibility for dehydromethionine and similar sulfilimines to have a sufficient lifetime in vivo to allow their use in the cellular redox processes.388 In vitro studies on model peptides suggest that both intra- and intermolecular sulfilimine bonds could form, in both their protonated and neutral forms, in the cellular environment,347 although their true abundance in cells and overall stability over longer time scales (e.g., due to hydrolysis or to reactivity with cellular thiols) is sometimes doubted (Table 3).389 It is also important to consider that halogen-activated formation of sulfilimines in proteins and peptides likely competes with the generation of numerous other N−S bond structures, such as sulfinamides or sulfonamides, that differ in their degree of sulfur oxidation and nitrogen protonation,317,332 which might in the end further limit their overall impact on redox metabolism (Table 3).

reagents.375 The main application of sulfilimines is in stereoselective synthesis.377−379 The sulfilimine bond (NS) is a true rarity in natural products, and, so far, until the recent discovery of a sulfilimine NS bond in type IV collagen (131) (Figure1), the only natural sulfilimines were detected upon oxidation of N-terminal methionine residues in proteins by reactive halides generated by mammalian heme peroxidases during neutrophil and eosinophil activation.380−382 Although it was long believed that oxidation of methionine by hypochlorous acid, hypobromous acid, N-chloramines, and N-bromamines yields exclusively methioninesulfoxide, it was recently shown that dehydromethionine residues383 (133) are major products in these reactions.384,385 Dehydromethionine contains a five-membered ring joined by an N−S[+] bond which has a strong double bond character and functionally can be considered as an NS bond.386

By far the most studied natural sulfilimine cross-link is found in type IV collagen. Type IV collagen is a main constituent of basement membranes that underlie epithelia in metazoa from sponges to humans. It provides signaling cues critical for regulation of cell function and behavior as well as tissue morphogenesis and homeostasis. Studies of Drosophila and bovine tissues showed that the collagen IV scaffold is stabilized by covalent sulfilimine bonds (131) that cross-link hydroxylysine-211 (Hyl-211) and 438



Review

Figure 1. Formation of a sulfilimine cross-link in collagen IV.390 Oxidation of bromide to HOBr by peroxidasin results in formation of a bromosulfonium group at Met-93. The −S-Br group acts as a reactive intermediate to form sulfilimine cross-links in the collagen IV NC1 hexamer.

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STRUCTURE REVISIONS OF N−S COMPOUNDS Reports of nitrogen−sulfur bonds in a small number of compounds have subsequently been found to be incorrect. For completeness, we summarize below three structure revisions of compounds originally thought to contain N−S bonds. The structures of haplosamates A and B, isolated from a Cribrochalina sp. marine sponge, were initially proposed to contain a sulfamate ester group. They turned out to be unusual phosphorylated sterol sulfates, rather unusual in terms of their atom diversity.404,405 Such extraordinary atom diversity is often a cause of structure misassignments, in addition to the fact that many natural products are isolated in minute quantities. Similarly, the structure of N-mercapto-4-formylcarbostyril, which was allegedly isolated from Pseudomonas f luorescens strain G308,406 was questioned, not only on the basis of chemical properties of N-thiols (compounds with a free −SH group bound to nitrogen tend to be unstable at ambient temperatures6,407), but also on the grounds of wrong interpretation of the spectroscopic data.408 N-Mercapto-4-formylcarbostyril was revised to aeruginaldehyde.408 We note however that many publicly available, as well as commercial, natural product repositories still contain the wrong structures and appear not to be updated.

methionine-93 (Met-93) residues at the interface of adjacent triple helical protomers (Figure 1).348,391,392 The biosynthetic route of formation of the sulfilimine bond in collagen IV was only recently unraveled.390,393 Heme peroxidasin-catalyzed oxidation of bromide generates hypobromous acid (HOBr), which, through a bromosulfonium-ion intermediate, cross-links Met-93 and Hyl-211 to form a sulfilimine (Figure 1).394−398 Formation of the sulfilimine bond is strictly dependent on Br− ions. Substitution of Br− with Cl− results in methionine sulfoxide formation, instead of the NS cross-link, and prevents establishment of proper intermolecular connections between collagen protomers.394 The exact molecular mechanism by which peroxidasin utilizes HOBr to cross-link collagen IV while simultaneously avoiding collateral damage to nearby basement membrane proteins is not understood.399 The exact functional importance of specific hypohalous acid-mediated modifications of extracellular matrix proteins needs to be addressed in more detail as well, especially in light of recent studies suggesting that the improper assembly or cleavage of the sulfilimine cross-links in collagen IV could be responsible for the etiology of certain autoimmune diseases.395,400 Clearly, however, the precedent of the formation of the sulfilimine cross-link in collagen IV shows that hypohalous acid oxidative reactions may be beneficial and should not be considered as uniformly deleterious.399 It remains to be seen if collagen IV sulfilimine is a true exception in life’s chemistry or if there are more natural molecules that utilize this type of bond. Recent studies suggest that the sulfilimine cross-link is conserved throughout Eumetazoa and likely originated as early as 500 Mya at the divergence of Porifera and Cnidaria.401 The heme-dependent peroxidasin enzyme responsible for the formation of the NS bond is also evolutionarily conserved throughout the Metazoa,401,402 as is the utilization of hypohalous acids in extracellular matrix formation, organogenesis, and tissue evolution.403

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CONCLUSIONS We described the occurrence, biological roles, and biosynthesis (if known) of over 100 small-molecule natural products and protein post-translational modifications that contain a nitrogen− sulfur bond. N−S natural compounds span several very diverse structural classes, isolated from many different species, both bacterial and eukaryotic, inhabiting many environments, both marine and terrestrial. N−S chemicals possess an impressive array of biological activities reflected by their vast applications in various branches of industry. N−S bond-containing functional groups confer high biological potency and specificity on 439



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molecules; indeed the first widely used synthetic antibiotic was a sulfonamide called prontosil (and its metabolite prontalbin, first patented as early as 1909, predating even penicillin).409,410 Thus, the wide use of N−S chemistry in industry and in pharmaceuticals supports the idea that nature can use N−S bonds to a powerful effect. We hope that this review stimulates further research into this interesting class of natural compounds.

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(23) Supuran, C. T.; Scozzafava, A.; Casini, A. Med. Res. Rev. 2003, 23, 146−189. (24) Poulsen, S.-A.; Davis, R. A. In Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications; Frost, S. C.; McKenna, R., Eds.; Springer Netherlands: Dordrecht, 2014; pp 325− 347. (25) Supuran, C. T. Nat. Rev. Drug Discovery 2008, 7, 168−181. (26) Zhao, C.; Qi, J.; Tao, W.; He, L.; Xu, W.; Chan, J.; Deng, Z. PLoS One 2014, 9, e114722. (27) Osada, H.; Isono, K. Antimicrob. Agents Chemother. 1985, 27, 230−233. (28) Zhu, X. M.; Hackl, S.; Thaker, M. N.; Kalan, L.; Weber, C.; Urgast, D. S.; Krupp, E. M.; Brewer, A.; Vanner, S.; Szawiola, A.; Yim, G.; Feldmann, J.; Bechthold, A.; Wright, G. D.; Zechel, D. L. ChemBioChem 2015, 16, 2498−2506. (29) Bartholome, A.; Janso, J. E.; Reilly, U.; O’Hagan, D. Org. Biomol. Chem. 2017, 15, 61−64. (30) Rabenstein, D. L. Nat. Prod. Rep. 2002, 19, 312−331. (31) Pomin, V. H. Glycobiology 2014, 24, 991−1003. (32) Medeiros, G. F.; Mendes, A.; Castro, R. A.; Bau, E. C.; Nader, H. B.; Dietrich, C. P. Biochim. Biophys. Acta, Gen. Subj. 2000, 1475, 287−94. (33) Nader, H. B.; Chavante, S. F.; dos-Santos, E. A.; Oliveira, T. W.; de-Paiva, J. F.; Jeronimo, S. M.; Medeiros, G. F.; de-Abreu, L. R.; Leite, E. L.; de-Sousa-Filho, J. F.; Castro, R. A.; Toma, L.; Tersariol, I. L.; Porcionatto, M. A.; Dietrich, C. P. Braz. J. Med. Biol. Res. 1999, 32, 529− 38. (34) Harter, K.; Levine, M.; Henderson, S. O. West. J. Emerg. Med. 2015, 16, 11−17. (35) Alhazzani, W.; Lim, W.; Jaeschke, R. Z.; Murad, M. H.; Cade, J.; Cook, D. J. Crit. Care Med. 2013, 41, 2088−98. (36) Poulain, F. E.; Yost, H. J. Development 2015, 142, 3456. (37) Nakato, H.; Li, J. P. In International Review of Cell and Molecular Biology; Jeon, K. W., Ed.; Academic Press, 2016; Vol. 325, pp 275−293. (38) Sarrazin, S.; Lamanna, W. C.; Esko, J. D. Cold Spring Harbor Perspect. Biol. 2011, 3, a004952. (39) Carlsson, P.; Kjellén, L. In Heparin - A Century of Progress; Lever, R.; Mulloy, B.; Page, C. P., Eds.; Springer: Berlin, Heidelberg, 2012; pp 23−41. (40) Sasisekharan, R.; Venkataraman, G. Curr. Opin. Chem. Biol. 2000, 4, 626−31. (41) Sugahara, K.; Kitagawa, H. IUBMB Life 2002, 54, 163−175. (42) Ramaswamy, S. G.; Jakoby, W. B. J. Biol. Chem. 1987, 262, 10039− 43. (43) Duffel, M. W. In Comprehensive Toxicology (Second Edition), Elsevier: Oxford, 2010; pp 367−384. (44) Humphries, D. E.; Sullivan, B. M.; Aleixo, M. D.; Stow, J. L. Biochem. J. 1997, 325 (2), 351−7. (45) Humphries, D. E.; Lanciotti, J.; Karlinsky, J. B. Biochem. J. 1998, 332 (2), 303−7. (46) Aikawa, J.-i.; Esko, J. D. J. Biol. Chem. 1999, 274, 2690−2695. (47) Aikawa, J.; Grobe, K.; Tsujimoto, M.; Esko, J. D. J. Biol. Chem. 2001, 276, 5876−82. (48) Dixon, J.; Loftus, S. K.; Gladwin, A. J.; Scambler, P. J.; Wasmuth, J. J.; Dixon, M. J. Genomics 1995, 26, 239−244. (49) Wiese, M.; D’Agostino, P. M.; Mihali, T. K.; Moffitt, M. C.; Neilan, B. A. Mar. Drugs 2010, 8, 2185−2211. (50) Llewellyn, L. E. Nat. Prod. Rep. 2006, 23, 200−222. (51) Cusick, K. D.; Sayler, G. S. Mar. Drugs 2013, 11, 991−1018. (52) Thottumkara, A. P.; Parsons, W. H.; Du Bois, J. Angew. Chem., Int. Ed. 2014, 53, 5760−5784. (53) Dell’Aversano, C.; Walter, J. A.; Burton, I. W.; Stirling, D. J.; Fattorusso, E.; Quilliam, M. A. J. Nat. Prod. 2008, 71, 1518−1523. (54) Vale, P.; Rangel, I.; Silva, B.; Coelho, P.; Vilar, A. Toxicon 2009, 53, 176−83. (55) Vale, P. Toxicon 2010, 55, 162−165. (56) Vale, P. Phytochem. Rev. 2010, 9, 525−535. (57) Ding, L.; Qiu, J.; Li, A. J. Agric. Food Chem. 2017, 65, 5494−5502. (58) Shimizu, Y.; Kobayashi, M.; Genenah, A.; Ichihara, N. In Seafood Toxins; American Chemical Society, 1984; Vol. 262, pp 151−160.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Janusz J. Petkowski: 0000-0002-1921-4848 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank MIT and the MIT Amar G. Bose Research Grant for support. We thank J. Petkowska for help with figure preparation.

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REFERENCES

(1) Craine, L.; Raban, M. Chem. Rev. 1989, 89, 689−712. (2) Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic Chemistry; Elsevier, 1984. (3) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Comprehensive Heterocyclic Chemistry II; Elsevier, 1996. (4) Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K. Comprehensive Heterocyclic Chemistry III; Elsevier, 2008. (5) Fachmann, H.-J.; Jotter, R.; Kubny, A.; Wagner, J. Sulfur-Nitrogen Compounds: Compounds with Sulfur of Oxidation Number IV, 8th ed.; Springer-Verlag: Berlin, Heidelberg, 1989; pp XVI, 276. (6) Fachmann, H.-J.; Jotter, R.; Kubny, A. Sulfur-Nitrogen Compounds: Compounds with Sulfur of Oxidation Number II, 8th ed.; Springer-Verlag: Berlin, Heidelberg, 1994; pp XXIV, 325. (7) Villalba, M. L.; Enrique, A. V.; Higgs, J.; Castaño, R. A.; Goicoechea, S.; Taborda, F. D.; Gavernet, L.; Lick, I. D.; Marder, M.; Bruno Blanch, L. E. Eur. J. Pharmacol. 2016, 774, 55−63. (8) Winum, J.-Y.; Scozzafava, A.; Montero, J.-L.; Supuran, C. T. Med. Res. Rev. 2005, 25, 186−228. (9) Winum, J.-Y.; Scozzafava, A.; Montero, J.-L.; Supuran, C. T. Med. Res. Rev. 2006, 26, 767−792. (10) Kolaczek, A.; Fusiarz, I.; Lawecka, J.; Branowska, D. Chemik 2014, 68, 620−628. (11) Lesch, J. E. The First Miracle Drugs: How the Sulfa Drugs Transformed Medicine; Oxford University Press, 2006. (12) Bains, W. BMC Syst. Biol. 2016, 10, 19. (13) Mujumdar, P.; Poulsen, S.-A. J. Nat. Prod. 2015, 78, 1470−1477. (14) Kristinsson, H.; Nebel, K.; O’Sullivan, A. C.; Pachlatko, J. P.; Yamaguchi, Y. In Synthesis and Chemistry of Agrochemicals IV; American Chemical Society, 1995; Vol. 584, pp 206−219. (15) Rengaraju, S.; Narayanan, S.; Ganju, P. L.; Amin, M. A.; Iyengar, M. R. S.; Sasaki, T.; Miyadoh, S.; Shomura, T.; Sezaki, M.; Kojima, M. Meiji Seika Kenkyu Nenpo 1986, 25, 49−55. (16) Takahashi, E.; Osugi, K. 5'-O-Sulfamoyladenosine antibiotics. : Patent JP 63051398, 1988. (17) Iwata, M.; Sasaki, T.; Iwamatsu, H.; Miyadoh, S.; Tachibana, K.; Matsumoto, K.; Shomura, T.; Sezaki, M.; Watanabe, T. Meiji Seika Kenkyu Nenpo 1987, 26, 17−22. (18) Takahashi, E.; Beppu, T. J. Antibiot. 1982, 35, 939−47. (19) Anzai, K.; Nakamura, G.; Suzuki, S. J. Antibiot. 1957, 10, 201−204. (20) Hewitt, R. I.; Gumble, A. R.; Taylor, L. H.; Wallace, W. S. Antibiot. Annu. 1956, 722−729. (21) O’Hagan, D.; Harper, D. J. Fluorine Chem. 1999, 100, 127−133. (22) Supuran, C. T.; Briganti, F.; Tilli, S.; Chegwidden, W. R.; Scozzafava, A. Bioorg. Med. Chem. 2001, 9, 703−714. 440



Review

(59) Wang, D.-Z.; Zhang, S.-F.; Zhang, Y.; Lin, L. J. Proteomics 2016, 135, 132−140. (60) D’Agostino, P. M.; Moffitt, M. C.; Neilan, B. A. In Toxins and Biologically Active Compounds from Microalgae, Vol. 1; Rossini, G. P., Ed.; CRC Press, 2014; pp 251−280. (61) Kellmann, R.; Mihali, T. K.; Jeon, Y. J.; Pickford, R.; Pomati, F.; Neilan, B. A. Appl. Environ. Microbiol. 2008, 74, 4044−4053. (62) Stucken, K.; John, U.; Cembella, A.; Murillo, A. A.; Soto-Liebe, K.; Fuentes-Valdés, J. J.; Friedel, M.; Plominsky, A. M.; Vásquez, M.; Glöckner, G. PLoS One 2010, 5, e9235. (63) Mihali, T. K.; Kellmann, R.; Neilan, B. A. BMC Biochem. 2009, 10, 8. (64) Mihali, T. K.; Carmichael, W. W.; Neilan, B. A. PLoS One 2011, 6, e14657. (65) Kellmann, R.; Neilan, B. A. J. Phycol. 2007, 43, 497−508. (66) Savela, H.; Spoof, L.; Hö ysniemi, N.; Vehniäinen, M.; Mankiewicz-Boczek, J.; Jurczak, T.; Kokociński, M.; Meriluoto, J. Adv. Oceanogr. Limnol. 2017, DOI: 10.4081/aiol.2017.6319. (67) Murray, S. A.; Mihali, T. K.; Neilan, B. A. Mol. Biol. Evol. 2011, 28, 1173−1182. (68) Moustafa, A.; Loram, J. E.; Hackett, J. D.; Anderson, D. M.; Plumley, F. G.; Bhattacharya, D. PLoS One 2009, 4, e5758. (69) Sebastián, C. R.; Etheridge, S. M.; Cook, P. A.; O’Ryan, C.; Pitcher, G. C. Phycologia 2005, 44, 49−60. (70) Krock, B.; Seguel, C. G.; Cembella, A. D. Harmful Algae 2007, 6, 734−744. (71) Navarro, J. M.; Muñoz, M. G.; Contreras, A. M. Harmful Algae 2006, 5, 762−769. (72) Samsur, M.; Yamaguchi, Y.; Sagara, T.; Takatani, T.; Arakawa, O.; Noguchi, T. Toxicon 2006, 48, 323−330. (73) Montoya, N. G.; Fulco, V. K.; Carignan, M. O.; Carreto, J. I. Toxicon 2010, 56, 1408−1418. (74) Poulton, N. J.; Keafer, B. A.; Anderson, D. M. Deep Sea Res., Part II 2005, 52, 2501−2521. (75) Anderson, D. M.; Kulis, D. M.; Sullivan, J. J.; Hall, S. Toxicon 1990, 28, 885−893. (76) Jaime, E.; Gerdts, G.; Luckas, B. Harmful Algae 2007, 6, 308−316. (77) Deeds, J. R.; Petitpas, C. M.; Shue, V.; White, K. D.; Keafer, B. A.; McGillicuddy, D. J.; Milligan, P. J.; Anderson, D. M.; Turner, J. T. Deep Sea Res., Part II 2014, 103, 329−349. (78) Yu, R. C.; Hummert, C.; Luckas, B.; Qian, P. Y.; Li, J.; Zhou, M. J. Chromatographia 1998, 48, 671−676. (79) Llewellyn, L. E.; Negri, A. P.; Doyle, J.; Baker, P. D.; Beltran, E. C.; Neilan, B. A. Environ. Sci. Technol. 2001, 35, 1445−1451. (80) Velzeboer, R. M. A.; Baker, P. D.; Rositano, J.; Heresztyn, T.; Codd, G. A.; Raggett, S. L. Phycologia 2000, 39, 395−407. (81) Negri, A. P.; Jones, G. J. Toxicon 1995, 33, 667−678. (82) Dias, E.; Pereira, P.; Franca, S. J. Phycol. 2002, 38, 705−712. (83) Pereira, P.; Onodera, H.; Andrinolo, D. o.; Franca, S.; Araújo, F.; Lagos, N.; Oshima, Y. Toxicon 2000, 38, 1689−1702. (84) Ballot, A.; Fastner, J.; Wiedner, C. Appl. Environ. Microbiol. 2010, 76, 1173−1180. (85) Ferreira, F. M. B.; Soler, J. M. F.; Fidalgo, M. L.; Fernández-Vila, P. Toxicon 2001, 39, 757−761. (86) Nogueira, I. C. G.; Pereira, P.; Dias, E.; Pflugmacher, S.; Wiegand, C.; Franca, S.; Vasconcelos, V. M. Toxicon 2004, 44, 773−780. (87) Costa, P. R.; Robertson, A.; Quilliam, M. A. Mar. Drugs 2015, 13, 2046−2062. (88) Oshima, Y.; Blackburn, S. I.; Hallegraeff, G. M. Mar. Biol. 1993, 116, 471−476. (89) Oh, S. J.; Matsuyama, Y.; Yoon, Y. H.; Miyamura, K.; Choi, C. G.; Yang, H. s.; Kang, I. J. J. Fac. Agr., Kyushu Univ. 2010, 55, 47−54. (90) Gárate-Lizárraga, I.; Bustillos-Guzmán, J. J.; Morquecho, L.; Band-Schmidt, C. J.; Alonso-Rodríguez, R.; Erler, K.; Luckas, B.; ReyesSalinas, A.; Góngora-González, D. T. Mar. Pollut. Bull. 2005, 50, 211− 217. (91) Bustillos-Guzmán, J. J.; Band-Schmidt, C. J.; Durán-Riveroll, L. M.; Hernández-Sandoval, F. E.; López-Cortés, D. J.; Núñez-Vázquez, E.

J.; Cembella, A.; Krock, B. Food Addit. Contam., Part A 2015, 32, 381− 394. (92) Usup, G.; Kulis, D. M.; Anderson, D. M. Nat. Toxins 1994, 2, 254−262. (93) Siu, G. K. Y.; Young, M. L. C.; Chan, D. K. O. Hydrobiologia 1997, 352, 117−140. (94) Hansen, P. J.; Cembella, A. D.; Moestrup, Ø. J. Phycol. 1992, 28, 597−603. (95) Molica, R.; Onodera, H.; García, C.; Rivas, M.; Andrinolo, D.; Nascimento, S.; Meguro, H.; Oshima, Y.; Azevedo, S.; Lagos, N. Phycologia 2002, 41, 606−611. (96) Negri, A. P.; Bolch, C. J. S.; Geier, S.; Green, D. H.; Park, T.-G.; Blackburn, S. I. Harmful Algae 2007, 6, 774−780. (97) Parkhill, J.-P.; Cembella, A. J. Plankton Res. 1999, 21, 939−955. (98) Ichimi, K.; Suzuki, T.; Ito, A. J. Exp. Mar. Biol. Ecol. 2002, 273, 51− 60. (99) Shimada, H.; Motylkova, I. V.; Mogilnikova, T. A.; Mikami, K.; Kimura, M. Plankt. Bent. Res. 2011, 6, 35−41. (100) Testé, V.; Briand, J.-F.; Nicholson, B. C.; Puiseux-Dao, S. J. Appl. Phycol. 2002, 14, 399−407. (101) Pomati, F.; Moffitt, M. C.; Cavaliere, R.; Neilan, B. A. Biochim. Biophys. Acta, Gen. Subj. 2004, 1674, 60−67. (102) Shimizu, Y. Chem. Rev. 1993, 93, 1685−1698. (103) Sako, Y.; Yoshida, T.; Uchida, A.; Arakawa, O.; Noguchi, T.; Ishida, Y. J. Phycol. 2001, 37, 1044−1051. (104) Wang, D.; Zhang, S.; Hong, H. Chin. J. Oceanol. Limnol. 2007, 25, 227−234. (105) Roccuzzo, S.; Beckerman, A. P.; Pandhal, J. Biotechnol. Lett. 2016, 38, 1983−1990. (106) Van Donk, E.; Ianora, A.; Vos, M. Hydrobiologia 2011, 668, 3− 19. (107) O’Donnell, D. R.; Fey, S. B.; Cottingham, K. L. J. Plankton Res. 2013, 35, 191−200. (108) Yasumoto, K.; Nishigami, A.; Yasumoto, M.; Kasai, F.; Okada, Y.; Kusumi, T.; Ooi, T. Tetrahedron Lett. 2005, 46, 4765−4767. (109) Yasumoto, K.; Nishigami, A.; Kasai, F.; Kusumi, T.; Ooi, T. Chem. Pharm. Bull. 2006, 54, 271−274. (110) Yasumoto, K.; Nishigami, A.; Aoi, H.; Tsuchihashi, C.; Kasai, F.; Kusumi, T.; Ooi, T. Chem. Pharm. Bull. 2008, 56, 133−136. (111) Yasumoto, K.; Nishigami, A.; Aoi, H.; Tsuchihashi, C.; Kasai, F.; Kusumi, T.; Ooi, T. Chem. Pharm. Bull. 2008, 56, 129−132. (112) Okamoto, Y.; Ojika, M.; Kato, S.; Sakagami, Y. Tetrahedron 2000, 56, 5813−5818. (113) Motti, C. A.; Freckelton, M. L.; Tapiolas, D. M.; Willis, R. H. J. Nat. Prod. 2009, 72, 290−294. (114) Rogers, E. W.; Molinski, T. F. J. Nat. Prod. 2007, 70, 1191−1194. (115) Kalaitzis, J. A.; Leone, P. d. A.; Hooper, J. N. A.; Quinn, R. J. Nat. Prod. Res. 2008, 22, 1257−1263. (116) Kalaitzis, J. A.; Davis, R. A.; Quinn, R. J. Magn. Reson. Chem. 2012, 50, 749−754. (117) Peng, J.; Li, J.; Hamann, M. T. Alkaloids. Chemistry and biology 2005, 61, 59−262. (118) Lira, N. S.; Montes, R. C.; Tavares, J. F.; Silva, M. S. d.; Cunha, E. V. L. d.; Athayde-Filho, P. F. d.; Rodrigues, L. C.; Dias, C. d. S.; BarbosaFilho, J. M. Mar. Drugs 2011, 9 (9), 2316. (119) Nakamura, Y.; Kato, H.; Nishikawa, T.; Iwasaki, N.; Suwa, Y.; Rotinsulu, H.; Losung, F.; Maarisit, W.; Mangindaan, R. E. P.; Morioka, H.; Yokosawa, H.; Tsukamoto, S. Org. Lett. 2013, 15, 322−325. (120) Mitchell, S. S.; Rhodes, D.; Bushman, F. D.; Faulkner, D. J. Org. Lett. 2000, 2, 1605−1607. (121) Schmidt, E. W.; Raventos-Suarez, C.; Bifano, M.; Menendez, A. T.; Fairchild, C. R.; Faulkner, D. J. J. Nat. Prod. 2004, 67, 475−478. (122) Liu, S.; Cui, Y.-M.; Nan, F.-J. Org. Lett. 2008, 10, 3765−3768. (123) Expósito, M. A.; López, B.; Fernández, R.; Vázquez, M.; Debitus, C.; Iglesias, T.; Jiménez, C.; Quiñoá, E.; Riguera, R. Tetrahedron 1998, 54, 7539−7550. (124) Bassetti, M.; Righi, E.; Viscoli, C. Expert Opin. Invest. Drugs 2008, 17, 285−296. 441



Review

(125) Decuyper, L.; Jukič, M.; Sosič, I.; Ž ula, A.; D’Hooghe, M.; Gobec, S. Med. Res. Rev. 2017, DOI: 10.1002/med.21443. (126) Sykes, R. B.; Bonner, D. P. Clin. Infect. Dis. 1985, 7, S579−S593. (127) Sykes, R. B.; Cimarusti, C. M.; Bonner, D. P.; Bush, K.; Floyd, D. M.; Georgopapadakou, N. H.; Koster, W. H.; Liu, W. C.; Parker, W. L.; Principe, P. A.; Rathnum, M. L.; Slusarchyk, W. A.; Trejo, W. H.; Wells, J. S. Nature 1981, 291, 489−491. (128) Parker, W. L.; O’Sullivan, J.; Sykes, R. B. In Advances in Applied Microbiology; Laskin, A. I., Ed.; Academic Press, 1986; Vol. 31, pp 181− 205. (129) Brewer, N. S.; Hellinger, W. C. Mayo Clin. Proc. 1991, 66, 1152− 1157. (130) Li, R.; Oliver, R. A.; Townsend, C. A. Cell Chem. Biol. 2017, 24, 24−34. (131) Braga, D.; Lackner, G. Cell Chem. Biol. 2017, 24, 1−2. (132) O’Sullivan, J.; Gillum, A. M.; Aklonis, C. A.; Souser, M. L.; Sykes, R. B. Antimicrob. Agents Chemother. 1982, 21, 558−64. (133) Tahlan, K.; Jensen, S. E. J. Antibiot. 2013, 66, 401−410. (134) O’Sullivan, J.; Souser, M. L.; Kao, C. C.; Aklonis, C. A. Antimicrob. Agents Chemother. 1983, 23, 598−602. (135) Yamashita, M.; Hashimoto, S.; Ezaki, M.; Iwami, M.; Komori, T.; Kohsaka, M.; Imanaka, H. J. Antibiot. 1983, 36, 1774−1776. (136) Georgopapadakou, N. H.; Smith, S. A.; Cimarusti, C. M. Eur. J. Biochem. 1982, 124, 507−512. (137) Wells, J. S.; Trejo, W. H.; Principe, P. A.; Bush, K.; Georgopapadakou, N.; Bonner, D. P.; Sykes, R. B. J. Antibiot. 1982, 35, 184−8. (138) Asai, M.; Haibara, K.; Muroi, M.; Kintaka, K.; Kishi, T. J. Antibiot. 1981, 34, 621−7. (139) Imada, A.; Kitano, K.; Kintaka, K.; Muroi, M.; Asai, M. Nature 1981, 289, 590−1. (140) Kintaka, K.; Haibara, K.; Asai, M.; Imada, A. J. Antibiot. 1981, 34, 1081−9. (141) Matsuo, T.; Masuya, H.; Sugawara, T.; Kawano, Y.; Noguchi, N.; Ochiai, M. Chem. Pharm. Bull. 1983, 31, 2200−2208. (142) Matsuo, T.; Sugawara, T.; Masuya, H.; Kawano, Y.; Noguchi, N.; Ochiai, M. Chem. Pharm. Bull. 1983, 31, 1874−84. (143) Kamiya, K.; Takamoto, M.; Wada, Y.; Asai, M. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1981, 37, 1626−1628. (144) Box, S. J.; Brown, A. G.; Gilpin, M. L.; Gwynn, M. N.; Spear, S. R. J. Antibiot. 1988, 41, 7−12. (145) Gwynn, M. N.; Box, S. J.; Brown, A. G.; Gilpin, M. L. J. Antibiot. 1988, 41, 1−6. (146) Kato, T.; Hinoo, H.; Shoji, J.; Matsumoto, K.; Tanimoto, T.; Hattori, T.; Hirooka, K.; Kondo, E. J. Antibiot. 1987, 40, 135−8. (147) Kato, T.; Hinoo, H.; Terui, Y.; Nishikawa, J.; Nakagawa, Y.; Ikenishi, Y.; Shoji, J. J. Antibiot. 1987, 40, 139−44. (148) Singh, P. D.; Johnson, J. H.; Ward, P. C.; Wells, J. S.; Trejo, W. H.; Sykes, R. B. J. Antibiot. 1983, 36, 1245−51. (149) Parker, W. L.; Rathnum, M. L. J. Antibiot. 1982, 35, 300−5. (150) Wells, J. S.; Trejo, W. H.; Principe, P. A.; Bush, K.; Georgopapadakou, N.; Bonner, D. P.; Sykes, R. B. J. Antibiot. 1982, 35, 295−9. (151) Katayama, N.; Koyama, K.; Nozaki, Y.; Harada, S.; Ono, H. J. Takeda Res. Lab. 1987, 46, 62−68. (152) Cooper, R.; Bush, K.; Principe, P. A.; Trejo, W. H.; Wells, J. S.; Sykes, R. B. J. Antibiot. 1983, 36, 1252−7. (153) Garson, M. J. In Comprehensive Natural Products II; Elsevier: Oxford, 2010; pp 503−537. (154) Kicklighter, C. E.; Kubanek, J.; Hay, M. E. Limnol. Oceanogr. 2004, 49, 430−441. (155) Pawlik, J. R. In Handbook of Marine Natural Products; Fattorusso, E.; Gerwick, W. H.; Taglialatela-Scafati, O., Eds.; Springer Netherlands: Dordrecht, 2012; pp 677−710. (156) Kicklighter, C. E.; Kubanek, J.; Barsby, T.; Hay, M. E. Mar. Ecol.: Prog. Ser. 2003, 263, 299−306. (157) Barsby, T.; Kicklighter, C. E.; Hay, M. E.; Sullards, M. C.; Kubanek, J. J. Nat. Prod. 2003, 66, 1110−1112.

(158) Meredith, T. L.; Cowart, J. D.; Henkel, T. P.; Pawlik, J. R. J. Exp. Mar. Biol. Ecol. 2007, 353, 198−202. (159) Fielman, K. T.; Targett, N. M. Mar. Ecol.: Prog. Ser. 1995, 116, 125−136. (160) Meragelman, K. M.; West, L. M.; Northcote, P. T.; Pannell, L. K.; McKee, T. C.; Boyd, M. R. J. Org. Chem. 2002, 67, 6671−6677. (161) Erspamer, V.; Vitali, T.; Roseghini, M.; Cei, J. M. Biochem. Pharmacol. 1967, 16, 1149−1164. (162) Nzowa, L. K.; Teponno, R. B.; Tapondjou, L. A.; Verotta, L.; Liao, Z.; Graham, D.; Zink, M. C.; Barboni, L. Fitoterapia 2013, 87, 37− 42. (163) Opitz, C. A.; Litzenburger, U. M.; Sahm, F.; Ott, M.; Tritschler, I.; Trump, S.; Schumacher, T.; Jestaedt, L.; Schrenk, D.; Weller, M.; Jugold, M.; Guillemin, G. J.; Miller, C. L.; Lutz, C.; Radlwimmer, B.; Lehmann, I.; von Deimling, A.; Wick, W.; Platten, M. Nature 2011, 478, 197−203. (164) Munn, D. H.; Mellor, A. L. Trends Immunol. 2013, 34, 137−143. (165) Elliott, M. C.; Stowe, B. B. Phytochemistry 1970, 9, 1629−1632. (166) Ahmad, I.; Fatima, I. J. Enzyme Inhib. Med. Chem. 2008, 23, 313− 316. (167) Ahmad, I.; Fatima, I.; Afza, N.; Malik, A.; Lodhi, M. A.; Choudhary, M. I. J. Enzyme Inhib. Med. Chem. 2008, 23, 918−921. (168) Mahadevan, S.; Stowe, B. B. In Plant Growth Substances 1970: Proceedings of the 7th International Conference on Plant Growth Substances Held in Canberra, Australia, December 7−11, 1970; Carr, D. J., Ed.; Springer: Berlin, Heidelberg, 1972; pp 117−126. (169) Arrebola, E.; Cazorla, F. M.; Perez-García, A.; de Vicente, A. Toxins 2011, 3, 1089−1110. (170) Moore, R. E.; Niemczura, W. P.; Kwok, O. C. H.; Patil, S. S. Tetrahedron Lett. 1984, 25, 3931−3934. (171) Tourte, C.; Manceau, C. Eur. J. Plant Pathol. 1995, 101, 483− 490. (172) Tamura, K.; Imamura, M.; Yoneyama, K.; Kohno, Y.; Takikawa, Y.; Yamaguchi, I.; Takahashi, H. Physiol. Mol. Plant Pathol. 2002, 60, 207−214. (173) Mitchell, R. E. Phytochemistry 1976, 15, 1941−1947. (174) Duke, S. O.; Dayan, F. E. Toxins 2011, 3, 1038. (175) Ferguson, A. R.; Johnston, J. S. Physiol. Plant Pathol. 1980, 16, 269−275. (176) Bachmann, A. S.; Matile, P.; Slusarenko, A. J. Physiol. Mol. Plant Pathol. 1998, 53, 287−299. (177) Mitchell, R. E.; Johnston, J. S.; Ferguson, A. R. Physiol. Plant Pathol. 1981, 19, 227−235. (178) Templeton, M. D.; Sullivan, P. A.; Shepherd, M. G. Biochem. J. 1984, 224, 379−388. (179) Templeton, M. D.; Reinhardt, L. A.; Collyer, C. A.; Mitchell, R. E.; Cleland, W. W. Biochemistry 2005, 44, 4408−4415. (180) Ferguson, A. R.; Johnston, J. S.; Mitchell, R. E. FEMS Microbiol. Lett. 1980, 7, 123−125. (181) Staskawicz, B. J.; Panopoulos, N. J.; Hoogenraad, N. J. J. Bacteriol. 1980, 142, 720−723. (182) Hatziloukas, E.; Panopoulos, N. J. J. Bacteriol. 1992, 174, 5895− 5909. (183) Mosqueda, G.; Van den Broeck, G.; Saucedo, O.; Bailey, A. M.; Alvarez-Morales, A.; Herrera-Estrella, L. Mol. Gen. Genet. 1990, 222, 461−6. (184) Nüske, J.; Fritsche, W. J. Basic Microbiol. 1989, 29, 441−447. (185) Jahn, O.; Sauerstein, J.; Reuter, G. J. Basic Microbiol. 1985, 25, 543−6. (186) Jahn, O.; Sauerstein, J.; Reuter, G. Arch. Microbiol. 1987, 147, 174−8. (187) Aguilera, S.; Alvarez-Morales, A.; Murillo, J.; Hernández-Flores, J. L.; Bravo, J.; De la Torre-Zavala, S. PLoS One 2017, 12, e0178441. (188) De la Torre-Zavala, S.; Aguilera, S.; Ibarra-Laclette, E.; Hernandez-Flores, J. L.; Hernandez-Morales, A.; Murillo, J.; AlvarezMorales, A. Res. Microbiol. 2011, 162, 488−98. (189) Arrebola, E.; Cazorla, F. M.; Pérez-García, A.; Vicente, A. d. Genes 2011, 2, 640. 442



Review

(221) Baunach, M.; Ding, L.; Willing, K.; Hertweck, C. Angew. Chem., Int. Ed. 2015, 54, 13279−13283. (222) Horinouchi, M.; Kasuga, K.; Nojiri, H.; Yamane, H.; Omori, T. FEMS Microbiol. Lett. 1997, 155, 99−105. (223) Zhou, X.; Chen, X.; Jin, Y.; Marko, I. E. Chem. - Asian J. 2012, 7, 2253−7. (224) Pozzi, R.; Simone, M.; Mazzetti, C.; Maffioli, S.; Monciardini, P.; Cavaletti, L.; Bamonte, R.; Sosio, M.; Donadio, S. J. Antibiot. 2011, 64, 133−9. (225) Kim, K. K.; Kang, J. G.; Moon, S. S.; Kang, K. Y. J. Antibiot. 2000, 53, 131−6. (226) Deng, S.; Chen, S. N.; Yao, P.; Nikolic, D.; van Breemen, R. B.; Bolton, J. L.; Fong, H. H.; Farnsworth, N. R.; Pauli, G. F. J. Nat. Prod. 2006, 69, 536−41. (227) Roell, D.; Baniahmad, A. Mol. Cell. Endocrinol. 2011, 332, 1−8. (228) Huppert, N.; Würtele, M.; Hahn, H. H. Fresenius' J. Anal. Chem. 1998, 362, 529−536. (229) Poliakova, O. V.; Lebedev, A. T.; Hänninen, O. Toxicol. Environ. Chem. 2000, 75, 181−194. (230) Strong, M. J.; Garruto, R. M.; Wolff, A. V.; Chou, S. M.; Fox, S. D.; Yanagihara, R. Acta Neuropathol. 1991, 81, 235−41. (231) Jin, Z. Nat. Prod. Rep. 2013, 30, 869−915. (232) Melby, J. O.; Nard, N. J.; Mitchell, D. A. Curr. Opin. Chem. Biol. 2011, 15, 369−78. (233) Rouf, A.; Tanyeli, C. Eur. J. Med. Chem. 2015, 97, 911−27. (234) Davyt, D.; Serra, G. Mar. Drugs 2010, 8, 2755−2780. (235) Pedras, M. S. C.; Suchy, M. Org. Biomol. Chem. 2005, 3, 2002− 2007. (236) Pedras, M. S. C.; Okanga, F. I.; Zaharia, I. L.; Khan, A. Q. Phytochemistry 2000, 53, 161−176. (237) Devys, M.; Barbier, M.; Loiselet, I.; Rouxel, T.; Sarniguet, A.; Kollmann, A.; Bousquet, J.-F. Tetrahedron Lett. 1988, 29, 6447−6448. (238) Soledade, M.; Pedras, C.; Smith, K. C. Phytochemistry 1997, 46, 833−837. (239) Gomi, S.; Amano S Fau - Sato, E.; Sato E Fau - Miyadoh, S.; Miyadoh S Fau - Kodama, Y.; Kodama, Y. J. Antibiot. 1994, 47, 1385. (240) Wang, H. Studies On Antimicrobial Components From Fermentation Broth Of C-411b and C13 Actinomycetes. Master Thesis, Northwest Agriculture and Forestry University, China, 2013. (241) Stratmann, K.; Belli, J.; Jensen, C. M.; Moore, R. E.; Patterson, G. M. L. J. Org. Chem. 1994, 59, 6279−6281. (242) Nakae, K.; Adachi, H.; Sawa, R.; Hosokawa, N.; Hatano, M.; Igarashi, M.; Nishimura, Y.; Akamatsu, Y.; Nomoto, A. J. Nat. Prod. 2013, 76, 510−515. (243) Blunt, C. E.; Torcuk, C.; Liu, Y.; Lewis, W.; Siegel, D.; Ross, D.; Moody, C. J. Angew. Chem., Int. Ed. 2015, 54, 8740−8745. (244) Brooks, C. J. W.; Watson, D. G. Nat. Prod. Rep. 1985, 2, 427− 459. (245) Garcia, I.; Vior, N. M.; Braña, A. F.; González-Sabin, J.; Rohr, J.; Moris, F.; Méndez, C.; Salas; José, A. Chem. Biol. 2012, 19, 399−413. (246) Davison, E. K.; Sperry, J. J. Nat. Prod. 2017, 80, 3060−3079. (247) Pham, C.-D.; Weber, H.; Hartmann, R.; Wray, V.; Lin, W.; Lai, D.; Proksch, P. Org. Lett. 2013, 15, 2230−2233. (248) Heitz, S.; Durgeat, M.; Guyot, M.; Brassy, C.; Bachet, B. Tetrahedron Lett. 1980, 21, 1457−1458. (249) Chen, M.; Lin, S.; Li, L.; Zhu, C.; Wang, X.; Wang, Y.; Jiang, B.; Wang, S.; Li, Y.; Jiang, J.; Shi, J. Org. Lett. 2012, 14, 5668−5671. (250) Yang, Z.; Huang, N.; Xu, B.; Huang, W.; Xie, T.; Cheng, F.; Zou, K. Molecules 2016, 21, 232. (251) de Silva, E. D.; Racok, J. S.; Andersen, R. J.; Allen, T. M.; Brinen, L. S.; Clardy, J. Tetrahedron Lett. 1991, 32, 2707−2710. (252) Reggelin, M.; Zur, C. Synthesis 2000, 2000, 1−64. (253) Frings, M.; Bolm, C.; Blum, A.; Gnamm, C. Eur. J. Med. Chem. 2017, 126, 225−245. (254) Murakoshi, I.; Sekine, T.; Maeshima, K.; Ikegami, F.; Yoshinaga, K.; Fujii, Y.; Okonogi, S. Chem. Pharm. Bull. 1993, 41, 388−390. (255) Jeannoda, V. L. R.; Rakoto-Ranoromalala, D. A. D.; Valisolalao, J.; Creppy, E. E.; Dirheimer, G. J. Ethnopharmacol. 1985, 14, 11−17. (256) Bentley, R. Chem. Soc. Rev. 2005, 34, 609−624.

(190) Aguilera, S.; López-López, K.; Nieto, Y.; Garcidueñas-Piña, R.; Hernández-Guzmán, G.; Hernández-Flores, J. L.; Murillo, J.; AlvarezMorales, A. J. Bacteriol. 2007, 189, 2834−2843. (191) López-López, K.; Hernández-Flores, J. L.; Cruz-Aguilar, M.; Alvarez-Morales, A. J. Bacteriol. 2004, 186, 146−153. (192) Chen, L.; Li, P.; Deng, Z.; Zhao, C. Sci. Rep. 2015, 5, 12892. (193) Hernández-Guzmán, G.; Alvarez-Morales, A. Mol. Plant-Microbe Interact. 2001, 14, 545−554. (194) Hatziloukas, E.; Panopoulos, N. J.; Delis, S.; Prosen, D. E.; Schaad, N. W. Gene 1995, 166, 83−87. (195) Zhang, Y. X.; Patil, S. S. Mol. Plant-Microbe Interact. 1997, 10, 947−960. (196) Arai, T.; Kino, K. Biosci., Biotechnol., Biochem. 2008, 72, 3048− 3050. (197) Mitchell, R. E.; Parsons, E. A. Phytochemistry 1977, 16, 280−281. (198) Mitchell, R. E.; Bieleski, R. L. Plant Physiol. 1977, 60, 723−729. (199) Graniti, A.; Durbin, R. D.; Ballio, A. In Cell to Cell Signals in Plants and Animals: Progress Report; Neuhoff, V.; Friend, J., Eds.; Springer: Berlin, Heidelberg, 1991; pp 3−14. (200) Akiyama, T.; Abe, M.; Harada, S.; Kojima, F.; Sawa, R.; Takahashi, Y.; Naganawa, H.; Homma, Y.; Hamada, M.; Yamaguchi, A.; Aoyagi, T.; Muraoka, Y.; Takeuchi, T. J. Antibiot. 2001, 54, 744−6. (201) Abe, M.; Akiyama, T.; Nakamura, H.; Kojima, F.; Harada, S.; Muraoka, Y. J. Nat. Prod. 2004, 67, 999−1004. (202) Abe, M.; Abe, F.; Nishimura, C.; Ichimura, E.; Ogasawara, A.; Ichinei, M.; Muraoka, Y.; Saino, T. J. Antibiot. 2005, 58, 111−117. (203) Abe, M.; Akiyama, T.; Umezawa, Y.; Yamamoto, K.; Nagai, M.; Yamazaki, H.; Ichikawa, Y.-i.; Muraoka, Y. Bioorg. Med. Chem. 2005, 13, 785−797. (204) Abe, M.; Nagai, M.; Yamamoto, K.; Yamazaki, H.; Koga, I.; Satoh, Y.; Muraoka, Y.; Kurashige, S.; Ichikawa, Y.-i. Org. Process Res. Dev. 2005, 9, 570−576. (205) Augustyns, K.; Bal, G.; Thonus, G.; Belyaev, A.; Zhang, X. M.; Bollaert, W.; Lambeir, A. M.; Durinx, C.; Goossens, F.; Haemers, A. Curr. Med. Chem. 1999, 6, 311−27. (206) De Meester, I.; Korom, S.; Van Damme, J.; Scharpe, S. Immunol. Today 1999, 20, 367−75. (207) Connor, E. E. Prim. Care Update Ob. Gyns. 1998, 5, 32−35. (208) Carta, F.; Scozzafava, A.; Supuran, C. T. Expert Opin. Ther. Pat. 2012, 22, 747−758. (209) Scozzafava, A.; Carta, F.; Supuran, C. T. Expert Opin. Ther. Pat. 2013, 23, 203−213. (210) Kagiyama, I.; Kato, H.; Nehira, T.; Frisvad, J. C.; Sherman, D. H.; Williams, R. M.; Tsukamoto, S. Angew. Chem., Int. Ed. 2016, 55, 1128− 32. (211) Peters, L.; König, G. M.; Terlau, H.; Wright, A. D. J. Nat. Prod. 2002, 65, 1633−1637. (212) Takahashi, A.; Ikeda, D.; Nakamura, H.; Naganawa, H.; Kurasawa, S.; Okami, Y.; Takeuchi, T.; Iitaka, Y. J. Antibiot. 1989, 42, 1562−6. (213) Takahashi, A.; Kurasawa, S.; Ikeda, D.; Okami, Y.; Takeuchi, T. J. Antibiot. 1989, 42, 1556−61. (214) Takahashi, A.; Naganawa, H.; Ikeda, D.; Okami, Y. Tetrahedron 1991, 47, 3621−3632. (215) Kende, A. S.; Liu, K.; Jos Brands, K. M. J. Am. Chem. Soc. 1995, 117, 10597−10598. (216) Hirooka, Y.; Ikeuchi, K.; Kawamoto, Y.; Akao, Y.; Furuta, T.; Asakawa, T.; Inai, M.; Wakimoto, T.; Fukuyama, T.; Kan, T. Org. Lett. 2014, 16, 1646−9. (217) Stefanska, A. L.; Cassels, R.; Ready, S. J.; Warr, S. R. J. Antibiot. 2000, 53, 357−63. (218) Houge-Frydrych, C. S.; Gilpin, M. L.; Skett, P. W.; Tyler, J. W. J. Antibiot. 2000, 53, 364−72. (219) Jiménez, C.; Crews, P. Tetrahedron 1991, 47, 2097−2102. (220) Piña, I. C.; Gautschi, J. T.; Wang, G.-Y.-S.; Sanders, M. L.; Schmitz, F. J.; France, D.; Cornell-Kennon, S.; Sambucetti, L. C.; Remiszewski, S. W.; Perez, L. B.; Bair, K. W.; Crews, P. J. Org. Chem. 2003, 68, 3866−3873. 443



Review

(257) Pruess, D. L.; Scannell, J. P.; Ax, H. A.; Kellett, M.; Weiss, F. J. Antibiot. 1973, 26, 261−6. (258) Diddens, H.; Dorgerloh, M.; Zahner, H. J. Antibiot. 1979, 32, 87−90. (259) Ghoddoussi, F.; Galloway, M. P.; Jambekar, A.; Bame, M.; Needleman, R.; Brusilow, W. S. J. Neurol. Sci. 2010, 290, 41−7. (260) Liaw, S. H.; Eisenberg, D. Biochemistry 1994, 33, 675−81. (261) Eisenberg, D.; Gill, H. S.; Pfluegl, G. M. U.; Rotstein, S. H. Biochim. Biophys. Acta, Protein Struct. Mol. Enzymol. 2000, 1477, 122− 145. (262) Lücking, U. Angew. Chem., Int. Ed. 2013, 52, 9399−9408. (263) Songue, J. L.; Azebaze, A. G. B.; Vardamides, J. C.; Ndom, J. C.; Blond, A.; Meyer, M.; Dongo, E.; Ngando Mpondo, T. Bull. Chem. Soc. Ethiop. 2006, 20, 173−176. (264) Abbasi, M. A.; Ahmad, V. U.; Zubair, M.; Abid Rashid, M.; Nahar Khan, S.; Farooq, U.; Choudhary, M. I.; Zeller, K.-P. Heterocycles 2005, 65, 1837−1842. (265) Clemens, D. H. 2, 4-di-t-alkyl-1, 3, 2, 4-dithiadiazetidines. Patent US3365495A, 1968. (266) Faizi, S.; Siddiqui, B. S.; Saleem, R.; Noor, F.; Husnain, S. J. Nat. Prod. 1997, 60, 1317−1321. (267) Liu, L.; Hausladen, A.; Zeng, M.; Que, L.; Heitman, J.; Stamler, J. S. Nature 2001, 410, 490−494. (268) Broniowska, K. A.; Hogg, N. Antioxid. Redox Signaling 2012, 17, 969−80. (269) Gould, N.; Doulias, P.-T.; Tenopoulou, M.; Raju, K.; Ischiropoulos, H. J. Biol. Chem. 2013, 288, 26473−26479. (270) Anand, P.; Hausladen, A.; Wang, Y.-J.; Zhang, G.-F.; Stomberski, C.; Brunengraber, H.; Hess, D. T.; Stamler, J. S. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 18572−18577. (271) Liu, L.; Yan, Y.; Zeng, M.; Zhang, J.; Hanes, M. A.; Ahearn, G.; McMahon, T. J.; Dickfeld, T.; Marshall, H. E.; Que, L. G.; Stamler, J. S. Cell 2004, 116, 617−628. (272) Smith, B. C.; Marletta, M. A. Curr. Opin. Chem. Biol. 2012, 16, 498−506. (273) Steffen, M.; Sarkela, T. M.; Gybina, A. A.; Steele, T. W.; Trasseth, N. J.; Kuehl, D.; Giulivi, C. Biochem. J. 2001, 356, 395−402. (274) Angeli, V.; Tacito, A.; Paolicchi, A.; Barsacchi, R.; Franzini, M.; Baldassini, R.; Vecoli, C.; Pompella, A.; Bramanti, E. Arch. Biochem. Biophys. 2009, 481, 191−196. (275) Hogg, N.; Singh, R. J.; Konorev, E.; Joseph, J.; Kalyanaraman, B. Biochem. J. 1997, 323, 477−481. (276) Bramanti, E.; Angeli, V.; Franzini, M.; Vecoli, C.; Baldassini, R.; Paolicchi, A.; Barsacchi, R.; Pompella, A. Arch. Biochem. Biophys. 2009, 487, 146−152. (277) Salt, T. E.; Zhang, H.; Mayer, B.; Benz, B.; Binns, K. E.; Do, K. Q. Eur. J. Neurosci. 2000, 12, 3919−3925. (278) Jakubowski, H. Clin. Chem. Lab. Med. 2003, 41, 1462−6. (279) Jakubowski, H. J. Biol. Chem. 2000, 275, 21813−21816. (280) Knipp, M.; Braun, O.; Vašaḱ , M. J. Am. Chem. Soc. 2005, 127, 2372−2373. (281) Braun, O.; Knipp, M.; Chesnov, S.; Vasak, M. Protein Sci. 2007, 16, 1522−34. (282) Wang, Y. Controlling Nitric Oxide (NO) Overproduction: Nω, Nω-Dimethylarginine Dimethylaminohydrolase (DDAH) as a Novel Drug Target. Ph.D. Thesis, 2010. (283) Hong, L.; Fast, W. J. Biol. Chem. 2007, 282, 34684−34692. (284) Li, Z.; Kulakova, L.; Li, L.; Galkin, A.; Zhao, Z.; Nash, T. E.; Mariano, P. S.; Herzberg, O.; Dunaway-Mariano, D. Bioorg. Chem. 2009, 37, 149−61. (285) Murphy, R. B.; Tommasi, S.; Lewis, B. C.; Mangoni, A. A. Molecules 2016, 21, 61510.3390/molecules21050615. (286) Frey, D.; Braun, O.; Briand, C.; Vašaḱ , M.; Grütter, M. G. Structure 2006, 14, 901−911. (287) Morakinyo, M. K. S-Nitrosothiols: Formation, Decomposition, Reactivity and Possible Physiological Effects; Portland State University, 2010.

(288) Morakinyo, M. K.; Chipinda, I.; Hettick, J.; Siegel, P. D.; Abramson, J.; Strongin, R.; Martincigh, B. S.; Simoyi, R. H. Can. J. Chem. 2012, 9, 724−738. (289) Mbiya, W. Kinetics and Mechanism of S-Nitrosation and Oxidation of Cysteamine by Peroxynitrite; Portland State University, 2013. (290) Kabil, O.; Banerjee, R. Antioxid. Redox Signaling 2013, 20, 770− 782. (291) Filipovic, M. R. Handb. Exp. Pharmacol. 2015, 230, 29−59. (292) Filipovic, M. R.; Miljkovic, J. L.; Nauser, T.; Royzen, M.; Klos, K.; Shubina, T.; Koppenol, W. H.; Lippard, S. J.; Ivanović-Burmazović, I. J. Am. Chem. Soc. 2012, 134, 12016−12027. (293) Cortese-Krott, M. M.; Kuhnle, G. G. C.; Dyson, A.; Fernandez, B. O.; Grman, M.; DuMond, J. F.; Barrow, M. P.; McLeod, G.; Nakagawa, H.; Ondrias, K.; Nagy, P.; King, S. B.; Saavedra, J. E.; Keefer, L. K.; Singer, M.; Kelm, M.; Butler, A. R.; Feelisch, M. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, E4651−E4660. (294) Marcolongo, J. P.; Morzan, U. N.; Zeida, A.; Scherlis, D. A.; Olabe, J. A. Phys. Chem. Chem. Phys. 2016, 18, 30047−30052. (295) Filipovic, M. R.; Miljkovic, J.; Allgäuer, A.; Chaurio, R.; Shubina, T.; Herrmann, M.; Ivanovic-Burmazovic, I. Biochem. J. 2011, 441, 609. (296) Wedmann, R.; Zahl, A.; Shubina, T. E.; Dürr, M.; Heinemann, F. W.; Bugenhagen, B. E. C.; Burger, P.; Ivanovic-Burmazovic, I.; Filipovic, M. R. Inorg. Chem. 2015, 54, 9367−9380. (297) Wedmann, R.; Ivanovic-Burmazovic, I.; Filipovic, M. R. Interface Focus 2017, 7, 2016013910.1098/rsfs.2016.0139. (298) Bolden, C.; King, S. B.; Kim-Shapiro, D. B. Free Radical Biol. Med. 2016, 99, 418−425. (299) Cortese-Krott, M. M.; Butler, A. R.; Woollins, J. D.; Feelisch, M. Dalton Transactions 2016, 45, 5908−5919. (300) Cortese-Krott, M. M.; Fernandez, B. O.; Santos, J. L. T.; Mergia, E.; Grman, M.; Nagy, P.; Kelm, M.; Butler, A.; Feelisch, M. Redox Biol. 2014, 2, 234−244. (301) Cortese-Krott, M. M.; Kuhnle, G. G. C.; Dyson, A.; Fernandez, B. O.; Grman, M.; Barrow, M. P.; McLeod, G.; Ondrias, K.; Nagy, P.; Singer, M.; Kelm, M.; Butler, A. R.; Feelisch, M. BMC Pharmacol. Toxicol. 2015, 16, A42−A42. (302) Cortese-Krott, M. M.; Pullmann, D.; Feelisch, M. Pharmacol. Res. 2016, 113, 490−499. (303) Lee, U.; Wie, C.; Fernandez, B. O.; Feelisch, M.; Vierling, E. Plant Cell 2008, 20, 786−802. (304) Wünsche, H.; Baldwin, I. T.; Wu, J. J. Exp. Bot. 2011, 62, 4605− 4616. (305) Xu, S.; Guerra, D.; Lee, U.; Vierling, E. Front. Plant Sci. 2013, 4.10.3389/fpls.2013.00430 (306) Zhang, Y.; Hogg, N. Free Radical Biol. Med. 2005, 38, 831−838. (307) Hess, D. T.; Matsumoto, A.; Kim, S.-O.; Marshall, H. E.; Stamler, J. S. Nat. Rev. Mol. Cell Biol. 2005, 6, 150−166. (308) Seth, D.; Stamler, J. S. Curr. Opin. Chem. Biol. 2011, 15, 129− 136. (309) Jensen, D. E.; Belka, G. K.; Du Bois, G. C. Biochem. J. 1998, 331 (2), 659−68. (310) Kubienova, L.; Kopecny, D.; Tylichova, M.; Briozzo, P.; Skopalova, J.; Sebela, M.; Navratil, M.; Tache, R.; Luhova, L.; Barroso, J. B.; Petrivalsky, M. Biochimie 2013, 95, 889−902. (311) Guerra, D.; Ballard, K.; Truebridge, I.; Vierling, E. Biochemistry 2016, 55, 2452−2464. (312) Bateman, R. L.; Rauh, D.; Tavshanjian, B.; Shokat, K. M. J. Biol. Chem. 2008, 283, 35756−35762. (313) Staab, C. A.; Hartmanová, T.; El-Hawari, Y.; Ebert, B.; Kisiela, M.; Wsol, V.; Martin, H.-J.; Maser, E. Chem.-Biol. Interact. 2011, 191, 95−103. (314) Tichá, T.; Č inčalová, L.; Kopečný, D.; Sedlárǒ vá, M.; Kopečná, M.; Luhová, L.; Petřivalský, M. Nitric Oxide 2017, 68, 68−76. (315) Corpas, F.; Alché, J.; Barroso, J. Front. Plant Sci. 2013, 410.3389/ fpls.2013.00126. (316) Barnett, S. D.; Buxton, I. L. O. Crit. Rev. Biochem. Mol. Biol. 2017, 52, 340−354. (317) Raftery, M. J.; Yang, Z.; Valenzuela, S. M.; Geczy, C. L. J. Biol. Chem. 2001, 276, 33393−33401. 444



Review

(318) Hedberg, J. J.; Griffiths, W. J.; Nilsson, S. J.; Hoog, J. O. Eur. J. Biochem. 2003, 270, 1249−56. (319) Fukuto, J. M.; Carrington, S. J. Antioxid. Redox Signaling 2011, 14, 1649−57. (320) Väan̈ änen, A. J.; Kankuri, E.; Rauhala, P. Free Radical Biol. Med. 2005, 38, 1102−1111. (321) Väan̈ änen, A. J.; Salmenperä, P.; Hukkanen, M.; Rauhala, P.; Kankuri, E. Free Radical Biol. Med. 2006, 41, 120−131. (322) Lopez, B. E.; Rodriguez, C. E.; Pribadi, M.; Cook, N. M.; Shinyashiki, M.; Fukuto, J. M. Arch. Biochem. Biophys. 2005, 442, 140− 148. (323) Lopez, B. E.; Wink, D. A.; Fukuto, J. M. Arch. Biochem. Biophys. 2007, 465, 430−436. (324) Cook, N. M.; Shinyashiki, M.; Jackson, M. I.; Leal, F. A.; Fukuto, J. M. Arch. Biochem. Biophys. 2003, 410, 89−95. (325) Froehlich, J. P.; Mahaney, J. E.; Keceli, G.; Pavlos, C. M.; Goldstein, R.; Redwood, A. J.; Sumbilla, C.; Lee, D. I.; Tocchetti, C. G.; Kass, D. A.; Paolocci, N.; Toscano, J. P. Biochemistry 2008, 47, 13150− 13152. (326) Keceli, G.; Toscano, J. P. Biochemistry 2012, 51, 4206−4216. (327) Wong, P. S. Y.; Hyun, J.; Fukuto, J. M.; Shirota, F. N.; DeMaster, E. G.; Shoeman, D. W.; Nagasawa, H. T. Biochemistry 1998, 37, 5362− 5371. (328) Johnson, G. M.; Chozinski, T. J.; Gallagher, E. S.; Aspinwall, C. A.; Miranda, K. M. Free Radical Biol. Med. 2014, 0, 299−307. (329) Keceli, G.; Moore, C. D.; Labonte, J. W.; Toscano, J. P. Biochemistry 2013, 52, 7387−7396. (330) Sivaramakrishnan, S.; Cummings, A. H.; Gates, K. S. Bioorg. Med. Chem. Lett. 2010, 20, 444−447. (331) Keceli, G.; Toscano, J. P. FASEB J.. 2015, 29. (332) Fu, X.; Mueller, D. M.; Heinecke, J. W. Biochemistry 2002, 41, 1293−1301. (333) Pullar, J. M.; Vissers, M. C. M.; Winterbourn, C. C. J. Biol. Chem. 2001, 276, 22120−22125. (334) Harwood, D. T.; Kettle, A. J.; Winterbourn, C. C. Biochem. J. 2006, 399, 161−8. (335) Harwood, D. T.; Nimmo, S. L.; Kettle, A. J.; Winterbourn, C. C.; Ashby, M. T. Chem. Res. Toxicol. 2008, 21, 1011−6. (336) Hoffman, M. D.; Walsh, G. M.; Rogalski, J. C.; Kast, J. Mol. Cell. Proteomics 2009, 8, 887−903. (337) Keceli, G. Investigation of HNO-Induced Modifications in Various Systems; Johns Hopkins University, 2014. (338) Keceli, G.; Moore, C. D.; Toscano, J. P. Bioorg. Med. Chem. Lett. 2014, 24, 3710−3713. (339) Keceli, G.; Toscano, J. P. Biochemistry 2014, 53, 3689−3698. (340) Yuan, W.; Wang, Y.; Heinecke, J. W.; Fu, X. J. Biol. Chem. 2009, 284, 26908−26917. (341) Winterbourn, C. C.; Brennan, S. O. Biochem. J. 1997, 326, 87− 92. (342) Gray, M. J.; Li, Y.; Leichert, L. I.-O.; Xu, Z.; Jakob, U. Antioxid. Redox Signaling 2015, 23, 747−754. (343) Rodkey, E. A.; Drawz, S. M.; Sampson, J. M.; Bethel, C. R.; Bonomo, R. A.; van den Akker, F. J. Am. Chem. Soc. 2012, 134, 16798− 16804. (344) Gray, M. J.; Wholey, W.-Y.; Jakob, U. Annu. Rev. Microbiol. 2013, 67, 141−160. (345) Salmeen, A.; Barford, D. Antioxid. Redox Signaling 2005, 7, 560− 77. (346) Shetty, V.; Neubert, T. A. J. Am. Soc. Mass Spectrom. 2009, 20, 1540−1548. (347) Ronsein, G. E.; Winterbourn, C. C.; Di Mascio, P.; Kettle, A. J. Free Radical Biol. Med. 2014, 70, 278−287. (348) Vanacore, R.; Ham, A.-J. L.; Voehler, M.; Sanders, C. R.; Conrads, T. P.; Veenstra, T. D.; Sharpless, K. B.; Dawson, P. E.; Hudson, B. G. Science 2009, 325, 1230−1234. (349) Lang, B. S.; Gorren, A. C.; Oberdorfer, G.; Wenzl, M. V.; Furdui, C. M.; Poole, L. B.; Mayer, B.; Gruber, K. J. Biol. Chem. 2012, 287, 38124−34.

(350) Balazy, M.; Kaminski, P. M.; Mao, K.; Tan, J.; Wolin, M. S. J. Biol. Chem. 1998, 273, 32009−32015. (351) Koval, I. V. Russ. J. Org. Chem. 1996, 32, 1239−1270. (352) Dubbs, J. M.; Mongkolsuk, S. J. Bacteriol. 2012, 194, 5495−5503. (353) Defelipe, L. A.; Lanzarotti, E.; Gauto, D.; Marti, M. A.; Turjanski, A. G. PLoS Comput. Biol. 2015, 11, e1004051. (354) Groitl, B.; Jakob, U. Biochim. Biophys. Acta, Proteins Proteomics 2014, 1844, 1335−1343. (355) Meng, F.-G.; Zhang, Z.-Y. Biochim. Biophys. Acta, Proteins Proteomics 2013, 1834, 464−469. (356) Jones, D. P.; Go, Y.-M. Curr. Opin. Chem. Biol. 2011, 15, 103− 112. (357) Go, Y.-M.; Chandler, J. D.; Jones, D. P. Free Radical Biol. Med. 2015, 84, 227−245. (358) To date there is only one example known of the reduction of a sulfinic acid in biological systems. This process, however, is strictly dependent on ATP. See: Jönsson, T. J.; Murray, M. S.; Johnson, L. C.; Lowther, W. T. J. Biol. Chem. 2008, 283, 23846−23851. Jönsson, T. J.; Murray, M. S.; Johnson, L. C.; Poole, L. B.; Lowther, W. T. Biochemistry 2005, 44, 8634−8642. and Rhee, S. G.; Chae, H. Z.; Kim, K. Free Radical Biol. Med. 2005, 38, 1543−1552. (359) Sarma, B. K.; Mugesh, G. J. Am. Chem. Soc. 2007, 129, 8872− 8881. (360) Gupta, V.; Carroll, K. S. Biochim. Biophys. Acta, Gen. Subj. 2014, 1840, 847−875. (361) den Hertog, J.; Groen, A.; van der Wijk, T. Arch. Biochem. Biophys. 2005, 434, 11−15. (362) Salmeen, A.; Andersen, J. N.; Myers, M. P.; Meng, T.-C.; Hinks, J. A.; Tonks, N. K.; Barford, D. Nature 2003, 423, 769−773. (363) van Montfort, R. L. M.; Congreve, M.; Tisi, D.; Carr, R.; Jhoti, H. Nature 2003, 423, 773−777. (364) Yang, J.; Groen, A.; Lemeer, S.; Jans, A.; Slijper, M.; Roe, S. M.; den Hertog, J.; Barford, D. Biochemistry 2007, 46, 709−719. (365) Lee, J.-G.; Baek, K.; Soetandyo, N.; Ye, Y. Nat. Commun. 2013, 4, 1568. (366) Chi, B. K.; Gronau, K.; Mäder, U.; Hessling, B.; Becher, D.; Antelmann, H. Mol. Cell. Proteomics 2011, 1010.1074/ mcp.M111.009506. (367) Lee, J.-W.; Soonsanga, S.; Helmann, J. D. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 8743−8748. (368) Gray, M. J.; Wholey, W.-Y.; Parker, B. W.; Kim, M.; Jakob, U. J. Biol. Chem. 2013, 288, 13789−13798. (369) Kominato, K. Chem. Pharm. Bull. 1969, 17, 2198−208. (370) Kominato, K.; Kominato, Y. U.S. Patent US3626003, 1971. (371) Kominato, K.; Kominato, Y. Google Patents: Process for the production of thiocornine. US3626003, 1973. (372) Watanabe, T.; Sugie, S.; Okamoto, K.; Rahman, K. M. W.; Ushida, J.; Mori, H. Jpn. J. Cancer Res. 2001, 92, 603−609. (373) Omar, S. H.; Al-Wabel, N. A. Saudi Pharm. J. 2010, 18, 51−58. (374) Gilchrist, T. L.; Moody, C. J. Chem. Rev. 1977, 77, 409−435. (375) Koval, I. V. Russ. Chem. Rev. 1990, 59, 819. (376) Marzag, H.; Schuler, M.; Tatibouët, A.; Reboul, V. Eur. J. Org. Chem. 2017, 2017, 896−900. (377) Bizet, V.; Hendriks, C. M. M.; Bolm, C. Chem. Soc. Rev. 2015, 44, 3378−3390. (378) Elsegood, M. R. J.; Holmes, K. E.; Kelly, P. F.; Parr, J.; Stonehouse, J. M. New J. Chem. 2002, 26, 202−206. (379) Taylor, P. C. Sulfur Rep. 1999, 21, 241−280. (380) Davies, M. J. J. Clin. Biochem. Nutr. 2011, 48, 8−19. (381) Dhawan, V. In Studies on Respiratory Disorders; Ganguly, N. K.; Jindal, S. K.; Biswal, S.; Barnes, P. J.; Pawankar, R., Eds.; Springer: New York, NY, 2014; pp 27−47. (382) Winterbourn, C. C. Nat. Chem. Biol. 2008, 4, 278−286. (383) It is worth mentioning that an analogous compound, dehydroselenomethionine, was postulated to form from a selenium analogue of methionine (selenomethionine) upon treatment with HOCl or N-chloramines (but not with hydrogen peroxide). Similarly to the N−S bond in dehydromethionine, the N−Se bond in dehydroselenomethionine likely undergoes reduction by cellular thiols 445



Review

to selenomethionine. See: Carroll, L. D. Modulation of Oxidative Damage by Selenium Compounds; University of Sydney, 2015. (384) Peskin, A. V.; Turner, R.; Maghzal, G. J.; Winterbourn, C. C.; Kettle, A. J. Biochemistry 2009, 48, 10175−10182. (385) Beal, J. L.; Foster, S. B.; Ashby, M. T. Biochemistry 2009, 48, 11142−11148. (386) Glass, R. S.; Duchek, J. R. J. Am. Chem. Soc. 1976, 98, 965−969. (387) Liu, F. Dynamics and Kinetics of Singlet Oxygen Mediated Oxidation of Methionine in the Gas Phase, Hydrated Clusters and Solution; The City Uiniversity of New York, 2015. (388) Young, P. R.; Briedis, A. V. Biochim. Biophys. Acta, Gen. Subj. 1988, 967, 318−321. (389) Ončaḱ , M.; Berka, K.; Slavíček, P. ChemPhysChem 2011, 12, 3449−3457. (390) Weiss, S. J. Nat. Chem. Biol. 2012, 8, 740−741. (391) Robertson, W. E.; Rose, K. L.; Hudson, B. G.; Vanacore, R. M. J. Biol. Chem. 2014, 289, 25601−25610. (392) Cummings, C. F. Formation and Function of Collagen IV Sulfilimine Bonds; Vanderbilt University, 2013. (393) Bhave, G.; Cummings, C. F.; Vanacore, R. M.; Kumagai-Cresse, C.; Ero-Tolliver, I. A.; Rafi, M.; Kang, J. S.; Pedchenko, V. P.; Fessler, L. I.; Fessler, J. H.; Hudson, B. G. Nat. Chem. Biol. 2012, 8, 784−790. (394) McCall, A. S.; Cummings; Christopher, F.; Bhave, G.; Vanacore, R.; Page-McCaw, A.; Hudson, B. G. Cell 2014, 157, 1380−1392. (395) McCall, A. S. The Role of Peroxidasin in Basement Membrane Physiology and Human Disease; Vanderbilt University, 2015. (396) Péterfi, Z.; Geiszt, M. Trends Biochem. Sci. 2014, 39, 305−307. (397) Lázár, E.; Péterfi, Z.; Sirokmány, G.; Kovács, H. A.; Klement, E.; Medzihradszky, K. F.; Geiszt, M. Free Radical Biol. Med. 2015, 83, 273− 282. (398) Paumann-Page, M.; Katz, R.-S.; Bellei, M.; Schwartz, I.; Edenhofer, E.; Sevcnikar, B.; Soudi, M.; Hofbauer, S.; Battistuzzi, G.; Furtmüller, P. G.; Obinger, C. J. Biol. Chem. 2017, 292, 4583−4592. (399) Colon, S.; Page-McCaw, P.; Bhave, G. Antioxid. Redox Signaling 2017, 27, 839. (400) Vanacore, R.; Pedchenko, V.; Bhave, G.; Hudson, B. G. Clin. Exp. Immunol. 2011, 164, 4−6. (401) Fidler, A. L.; Vanacore, R. M.; Chetyrkin, S. V.; Pedchenko, V. K.; Bhave, G.; Yin, V. P.; Stothers, C. L.; Rose, K. L.; McDonald, W. H.; Clark, T. A.; Borza, D.-B.; Steele, R. E.; Ivy, M. T.; Aspirnauts, T.; Hudson, J. K.; Hudson, B. G. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 331−336. (402) Ero-Tolliver, I. A.; Hudson, B. G.; Bhave, G. J. Biol. Chem. 2015, 290, 21741−21748. (403) Fidler, A. L.; Darris, C. E.; Chetyrkin, S. V.; Pedchenko, V. K.; Boudko, S. P.; Brown, K. L.; Gray Jerome, W.; Hudson, J. K.; Rokas, A.; Hudson, B. G. eLife 2017, 6, e24176. (404) Qureshi, A.; Faulkner, D. J. Tetrahedron 1999, 55, 8323−8330. (405) Fujita, M.; Nakao, Y.; Matsunaga, S.; Seiki, M.; Itoh, Y.; van Soest, R. W. M.; Heubes, M.; Faulkner, D. J.; Fusetani, N. Tetrahedron 2001, 57, 3885−3890. (406) Fakhouri, W.; Walker, F.; Vogler, B.; Armbruster, W.; Buchenauer, H. Phytochemistry 2001, 58, 1297−1303. (407) Christophersen, C.; Hammerich, O. Nat. Prod. Commun. 2011, 6, 921−2. (408) Ye, L.; Cornelis, P.; Guillemyn, K.; Ballet, S.; Hammerich, O. Nat. Prod. Commun. 2014, 9, 789−94. (409) Hörlein, H. Prontalbin. German Patent No. 226239, 1909. (410) Torok, E.; Moran, E.; Cooke, F. Oxford Handbook of Infectious Diseases and Microbiology; Oxford University Press, 2009.

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