Aplysina bromotyrosines

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). 

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

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],... 

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

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

Ciminiello P, Dell Aversano C, Fattorusso E, Magno S (2001) Archerine, a Novel Anti-Histaminic Bromotyrosine-Derived Compound from the Caribbean Marine Sponge Aplysina archeri. Eur J Org Chem 55... 

Encamacion RD, Sandoval E, Malmstr0m J, Christophersen C (2000) Calafianin, a Bromotyrosine Derivative from the Marine Sponge Aplysina gerardogreeni. J Nat Prod 63 874... 

Undoubtedly the most structurally and biogenetically intriguing bromotyrosines are the many spirocyclohexadienyl isoxazoles, which are too numerous to describe fully here [1[. Of those examples containing a single spiro unit, recently isolated compounds include ianthesine A (84) from the Australian sponge lanthdla sp. [72], caissarine A (85) from a Brazilian Aplysina caissara [73], and the unnamed 86 from an Australian non-verongid sponge Oceanapia sp. ]74]. 

Archerine. Cimninello and co-workers reported the isolation and structural characterization of the complex bromotyrosine-derived imidazole alkaloid archerine (62) that was isolated from the Caribbean marine sponge Aplysina archeri. The authors used long-range correlation data to assemble four substructural fragments,... 

The above described rationale of SAR can be exemplified by the bioactivities of the bromotyrosine derivatives, aeroplysinin-1 and dienone, as well as their complicated molecular substrates aerophobin-1 and isofistularin-3, isolated from the Mediterranean sponge, Aplysina aerophoba. Aeroplysinin-1 and dienone exhibit pronounced biological activity whereas aerophobin-1 and isofistularin-3 were always inactive when tested in equimolar concentrations [23]. Aeroplysinin-1 and dienone are antibiotically active against a broad spectrum of marine bacteria such as Vibrio, Micrococcus, and Alteromonas species [24] and are also cytotoxic to Ehrlich ascites tumour cells and HeLa tumour cells in the microculture tetrazolium (MTT) and clonogenic assays [25]. In these assays, it has been demonstrated that the free radical transformation of aeroplysinin-1 and dienone to its semiquinone structures are responsible for the cytotoxicity [25], Aeroplysinin-1 and dienone are the pharmacophores of aerophobin-1 and isofistularin-3. 

Sponges of the order Verongida contain numerous metabolites having a spiroisoxazoline system, which can be derived from bromotyrosine. A. from Aplysina fis-tularis, C24H26Br4N40s, Mr 818.11, mp. 134-137 °C, [o]d +252° psammaplysin A from Psammaplysilla purpurea with a 1,6-dioxa-2-aza[4,6]undecane system ... 

Silva, M.M., Bergamasco, J., Lira, S.P., Lopes, N.P., Hajdu, E Peixinho, S., and Berlinck, R.G.S. (2010) Dereplication of bromotyrosine-derived metabolites by LC-PDA-MS and analysis of the chemical profile of 14 Aplysina sponge specimens from the Brazilian coastline. Aust. J. Chem., 63,886-894. 

Acosta, A.L. and Rodriguez, A.D. (1992) 11-Oxoaerothionine a cytotoxic antitumor bromotyrosine-derived alkaloid from the Caribbean marine sponge Aplysina lacunosa. J. Nat. Prod., 55, 1007-1012. 

Ciminiello, P., Dell Aversano, C., Fattorusso, E., and Magno, S. (2001) Archerine, a novel anti-histaminic bromotyrosine-derived compound from the Caribbean marine sponge Aplysina archeri. Eur. J. Org. Chem., 55-60. 

Rodriguez, A.D. and Pina, I.C. (1993) The structures of aplysinamisines I, II, and III new bromotyrosine-derived alkaloids from the Caribbean sponge Aplysina cauliformis. J. Nat. Prod., 56, 907-914. 

The metabolites isolated from some species of Notaspidea, being strictly carnivorous, reflect their dietary origin. Thus, the Mediterranean species Tylodina perversa, which consumes mainly the sponge Aplysina (= Veron ) aero-phoba, yielded structures characteristic of verongid sponges, such as uranidine and some bromotyrosine derivatives (see Chapter 19 and Teeyapant et al, 1993 Cimino and Sodano, 1994 Thoms et al, 2003). 

The isolation of aplysinimine (20) is remarkable because this alkaloid could be considered as a possible precursor of other bromo compounds obtained from Aplysina sponges. Aplysinolide (19) has an unusual a,/S-unsaturated side chain. Another bromotyrosine derivative containing an a,/S-unsaturated side chain is aplysinadiene (21), isolated from Aplysina aerophoba (20). The structure was determined by comparison of the NMR data with the synthesized isomers 21a and 21b. Structure 21c was precluded due to the interaction of the bromine atom with the butenylide side chain (21). 

Different iV-methylation derivatives of moloka iamine, aplysamine 1 (54) 44), purealidin F (55), and G (56) 45), were obtained from an Australian sponge Aplysina sp. and the Okinawan sponge Pscanmaplysilla purea, respectively. 3,5-Dibromo-4-(3-dimethylaminopropoxy)phenethyl carbamic acid methyl ester (57) and its salt 58 were obtained as the first bromotyrosine derivatives containing a carbamate group from an Indian sample of Psammaplysilla purpurea 46), along with 59 47,48). 

Calafianin (78), isolated from the Mexican sponge Aplysina gerardogreeni, is the only bromotyrosine derivative containing an epoxy group (30). 

This class of bromotyrosine derivatives contains one spirocyclohexadienylisoxazo-line ring system. The first two alkaloids in this class are fistularin-1 (94) and fistularin-2 (95) isolated from the marine sponge Aplysina fistularis forma fulva by Gopichand and Schmitz in 1979 (68). Both compounds contain a spirocyclohexadienyhsoxazoline, a bromotyramine, and a C3 unit. 

Carney and Rinehart reported the results of additional feeding experiments in the marine sponge Aplysina fistularis in 1995 184). U- " C -L-tyrosine, U- C -L-3-bromotyrosine, and U C -L-3,5-dibromotyrosine were incorporated into both the dienone 1 and aeroplysinin-1 (14), and methyl- " C -methionine was specifically incorporated into the O-methyl group of aeroplysinin-1. In contrast to expectations, tyrosine was incorporated more efficiently than 3-bromotyrosine, which is in turn incorporated more efficiently than 3,5-dibromotyrosine. This may result from the bulky bromines interfering with the permeability of the precursors across cell membranes. It was surprising that methyl- " C -L-methyltyrosine, (methyl- C -L-3,5-dibromo-0-methyltyrosine, 3-bromo-4-hydroxybenzyl cyanide, and 3,5-dibromo-4-hydroxybenzyl cyanide were not incorporated into the dienone 1 and aeroplysinin-1 (14). Both 3-bromo-4-hydroxybenzyl cyanide and 3,5-dibromo-4-hydroxybenzyl cyanide have been identified as metabolites of A. fistularis 185), and their involvement as a potential precursor to the dienone 1 seems reasonable. The possible reasons for the lack of incorporation into 1 and 14, aside from the possibility of their not being part at the biosynthetic path, are poor transport of the halogenated nitriles across cell membranes, or poor solubility of the nitriles in sea water 184). 

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