Cytotoxicity bromotyrosine derivatives

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. 

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). 

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],... 

Bromotyrosine-derived metabolites are often encountered in marine sponges of the families Aplysinidae and Pseudocer-atidae, in particular Pseudoceratina (= Psammaplysilla) purpurea. They show a variety of biological activities, which include antimicrobial, enzyme inhibitory, and antifouling activities. Psammaplysin A (47) is antimicrobial, cytotoxic, and antifouling, whereas psammaplin A (48) is an inhibitor of histone deacetylase (2). The marine sponge lanthella basta synthesizes at least 25 bastadins that are linear or cyclic peptides composed of four bromotyrosine residues [bastadin 5 (49)] and show antimicrobial, cytotoxic, and enzyme inhibitory activities as well as interaction with Ca + channels (21). 

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. 

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. 

Purealidin C (192) was isolated from the Okinawan sponge P. purea, which exhibited cytotoxic, antifungal, and antimicrobial activities ( 4), Tokaradines A (193) and B (194), isolated from Pseudoceratina purpurea, are rare examples of marine bromotyrosine-derived metabolites containing an A-substituted pyridinium group. 

Most of the bis-spirocyclohexadienyhsoxazoline type of bromotyrosine derivatives tested exhibited moderate cytotoxicity against different cancer cell lines. These include fistularin-3 (79) (68), 11-oxoaerothionin (72) (64), ll-ep/-fistularin-3 (81) (70), 11-oxofistularin (82) (72), isofistularin-3 (80) (72), and ll-deoxyfistularin-3 (86) (73). 11-Oxoaerothionin (72) is the most potent agent and showed pronounced selective cytotoxic activity toward the human colon HCT cell line at a limited concentration range of 0.01-0.1 pg/mL (64). 

Purealidins, which are single spirocyclohexadienylisoxazoline or oxime type of bromotyrosine derivatives, exhibited moderate to strong cytotoxicity, among which purealidin N (150) is very potent against K1210 and KB cells with IC50 values of 0.07 and 0.074 pg/mL, respectively (79,84,104). 

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