3-Bromotyrosine

Protein tyrosine residues constitute key targets for peroxynitrite-mediated nitrations. Attack of various free radicals (ONOO-, N02 ) upon tyrosine generates 3-nitrotyrosine, which can be measured immunologically or by GC/MS or HPLC techniques. The detection of 3-nitrotyrosine was considered a biomarker of peroxynitrite action in vivo. Similarly, attack of HOC1 and HOBr on tyrosine generates chlorotyro-sine and bromotyrosine, respectively, both of which are measured most accurately by GC-MS. 

Psammaplin A (208) Symmetrical bromotyrosine- derived disulfide Panobinostat (LBH-589) (209) Oncology Inhibits histone deacetylase (HDAC) Phase T/IT/ITT Novartis 945,946... 

McCulloch MWB, Coombs GS, Banerjee N, Bugni TS, Cannon KM, Harper MK, Veltri CA, Virshup DM. (2009) Psammaplin A as a general activator of cell-based signaling assays via HDAC inhibition and studies on some bromotyrosine derivatives. Bioorg Med Chem 17 2189-2198. 

There are also some natural products that were identified as inhibitors of DNMTs [87]. Certain disulfide bromotyrosine derivatives, such as psammaplin... 

Interestingly, treating bromotyrosine with TFAA in an autoclave at 80-120 °C, affords the corresponding 5(2//)-oxazolone that was used as an intermediate in the synthesis of psammaplin. ... 

Verongula gigantea Hyatt, Verongida, Porif. verongamine (bromotyrosine metabolite)/histamine Hj receptor antagonist Mierzwa 1994... 

Miozwa, R. King, A. Conova, M.A. Tozzi, S. Puar, M.S. Patel, M. Coval, S.J. Pomponi, S.A. (1994) Vaongamine, a novel bromotyrosine-daived histamine H4-antagonist from the marine sponge Verongula gigantea. J. Nat. Prod., 57, 175-177. 

Similarly, Aplysina sp.(Fig. 10.7), which show a dramatic change in color from yellow to black when exposed to air, contain cytotoxic compounds including bromotyrosine-derivative alkaloids, purealidins (Ishibashi et ah, 1991 Yagi et ah, 1993), aplysamine 2 (Xynas and Capon, 1989), and purpuramin G (Fattorusso et ah, 1970 Fig. 10.8). 

Ishibashi, M., Tsuda, M., Ohizumi, Y., Sasaki, T., and Kobayashi, J. (1991). Purealidin A, a new cytotoxic bromotyrosine-derived alkaloid from the Okinawan marine sponge Psammaplysilla purea. Experientia 47, 299-300. 

Maru, N., Koyama, T., Ohno, O., Yamada, K., and Uemura, D. (2010a). Sunabedine, a novel toxic bromotyrosine-derivative alkaloid from Okinawan sponge, order Verongida. ELeterocycles 82, 371-375. 

Xynas, R. and Capon, R. J. (1989). Two new bromotyrosine-derived metabolites from an Australian marine sponge, Aplysina sp. Aust. ]. Chem. 42,1427-1433. 

Yagi, H., Matsunaga, S., and Fusetani, N. (1993). Purpuramines A-I, new bromotyrosine-derived metabolites from the marine sponge Psammaplysilla purpurea. Tetrahedron 49, 3749-3754. 

Four minor metabolites, psammaplins B-D (503-505) and presammaplin A (506) were isolated from Psammaplysilla purpurea, in addition to psammaplin A (500). Psammaplin B (503) is a thiocyanate bromotyrosine derivative, while psammaplin C (502) is a sulfanamide. Psammaplin D (505) displayed antimicrobial activity and mild tyrosine kinase inhibition [429]. The psammaplins Ai (507) and A2 (508) and aplysinellins A (509) and B (510) were isolated from Aplysinella rhax from both Pohnpei and Palau. These compounds inhibit famesyl protein transferase and leucine aminopeptidase [430]. Another sample of A. rhax from the Great Barrier Reef, Australia contained psammaplin A 11 -sulfate (511) and bisaprasin ll -sulfate (512), both of which inhibited [3H]-l,3-dipropyl-8-cyclopentylxanthine binding to rat brain adenosine Ai receptors [431]. 

Other biologically active bromotyrosine-derived metabolites of marine origin include aeroplysinin, Fig. (48) as cytotoxic and tyrosine kinase inhibitor [382,383], fistularin isolated from Aplysina circheri which exhibited antiviral activity [384], and ceratinamides A and B, antifouling metabolites from Pseudoceratina purpurea [385],... 

Although marine organisms produce a large number of isocyanates, isothiocyanates, and formamides, the corresponding thiocyanates have rarely been encountered. Indeed, the thiocyanate functionality has only been found in six sesquiterpenes (263-268), in four tricyclic quinoline alkaloids (271-274), and in psamaplin B (172) (included in the bromotyrosine derivatives discussed in the disulfide/polysulfide section). They have been found in marine sponges, as well as in nudibranches and tunicates. 

While there exist too many syntheses of bromotyrosine alkaloids to delineate here, two illustrative examples are those of moloka iamine (1865) and the mycothiol-S -conjugate amidase inhibitor 2068 (1866). 

The Okinawan sponge Psammaplysilla purea that contains purealidins M-0 (2004-2006) also yields purealidins J (2078), K (2079), L (2080), P (2081), Q (2082), and R (2083) (1835). Purealidin J (2078) is the antipode of pseudocer-atinine A (2089). The Indian sponge Psammaplysilla purpurea, which is the source of purpurealidins F-H (2018-2020) and other bromotyrosines (vide supra), also contains purpurealidins A (2084), B (2085), C (2086), and D (2087) (1842). A Caribbean Pseudoceratina sponge has afforded the simple carboxylic acid 2088 (1868). The New Caledonian sponge Pseudoceratina verrucosa, which is the source of pseudoceratinine B (1990), also contains pseudo-ceratinines A (2089) and C (2090), the absolute configurations of which are shown (1829). 

Fig. 3.31 Aplysina archeri, a Caribbean sponge containing several bromotyrosines, including 2100 and archerine (2101) (Photo J. R. Pawlik)...

Several syntheses of the bromotyrosine spiroisoxazolines have been described (1893-1895), but a full survey of these synthetic efforts cannot be covered here. 

These novel tetrameric bromotyrosine metabolites display a range of biological activities, including effects on calcium channels (1900), lipoxygenase inhibition (1772), tumor angiogenesis inhibition (1901), and endothelial cell anti-proliferation (1902). Syntheses of several bastadins have been accomplished (1903,1904). 

In contrast to MPO, eosinophil peroxidase (EPO) prefers to oxidize plasma level bromide (20-100 pM) to hypobromous acid (HOBr) and several biological targets are implicated, including nucleic acids and nucleosides (1480, 1482, 2376), proteins (1812, 1813, 2377, 2378), unsaturated fatty acids (2379), and low-density lipoprotein (2380, 2381). This EPO-dependent bromination is suggested to be involved in the pathogenesis of asthma (2382). Accordingly, both 3-bromotyrosine and 3,5-dibromotyrosine (1812,1813) are produced by EPO-induced bromination of tyrosine residues in lung tissue (1813, 2382). 

Fig. 6.1 Aplysina fistularis, a sponge rich in bromophenols and bromotyrosines (Photo F. J. Schmitz)...

Wu W, Chen Y, d Avignon A, Hazen SL (1999) 3-Bromotyrosine and 3,5-Dibromotyrosine Are Major Products of Protein Oxidation by Eosinophil Peroxidase Potential Markers for Eosinophil-Dependent Tissue Injury in Vivo. Biochemistry 38 3538... 

Benharref A, Pais M, Debitus C (1996) Bromotyrosine Alkaloids from the Sponge Pseudoceratina verrucosa. J Nat Prod 59 177... 

Fusetani N, Masuda Y, Nakao Y, Matsunaga S, van Soest RWM (2001) Three New Bromotyrosine Derivatives Lethal to Crab from the Marine Sponge, Pseudoceratina purpurea. Tetrahedron 57 7507... 

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