Anthracyclines metal complexes

In this case, the duplex formation is commonly detected in connection with the use of appropriate electroactive hybridization indicators such as cationic metal complexes (Co(phen)33+, Co(bpy)33+, [Cu(phen)2]2+, Ru(bpy)32+ among others [18-22,32]), or organic compounds (anthracyclines, phenoth-iazine, etc. [15,24,25,28,29]). These compounds interact in different ways with ss- or dsDNA but preferentially with dsDNA undergoing reversible... 

There are now more than forty drugs approved for the treatment of human cancer in the United States. Considering the thousands of compounds that have been tested as candidate antitumor agents, this is a highly select group. Among them are two drugs that require a metal ion as part of their structures. One is the simple metal complex cis-diamminedichloroplatinum(ii). The other, bleomycin, is a natural product that must form an iron complex to display cytotoxicity. In addition, two anthracycline natural products, doxorubicin or adriamycin, and daunomycin, may also function as iron complexes or utilize cellular iron in an indirect way in their mechanisms of action. 

Metallation of anthracyclines releases protons, and using a of 10.0 for the first phenolic group, Martin calculated log values (for M + H2L M(HL) + H", where H2L refers to the neutral ligand) of 11.0 and 7.3 for Fe " and Cu ", respectively [81]. Metal ion binding must take into account possible formation of hydroxo and polymeric metal complexes at basic pH, and such events make analysis difficult, e.g. a polymeric 1 1 complex CuL forms at high pH [84]. With variation of pH and molar ratio, various complexes are formed between the ligand and these metals. The 2 1 Cu(HL)2 adduct predominates at 5 < pH < 8 [84, 86], with a reported log P = 16.66 [84], which seems high in comparison to the value of 7.3 reported [81]. Resonance Raman spectroscopy has been particularly useful in analysis of these systems and studies on the Cu(II)— adriamycin—DNA adduct indicated that an intercalated adduct could be formed [87]. 

The kinetics of removal of iron(III) from its complexes with the aminocarboxylate-anthraquinone analytical reagent calcein and with the antitumor anthracycline doxorubicin by l,2-dimethyl-3-hydroxy-4-pyridinone (LI, (251) with R = R = Me) have been monitored. Rate constants for metal removal are almost independent of the concentration of the replacing ligand, indicating dissociative mechanisms they are approximately 1 x 10 s for displacement from doxorubin and between 12 x 10 s and 2 x 10 s from calcein. 

Anthracydines have several modes of action leading to anticancer activity. They intercalate between base pairs in DNA, interfering with nucleic acid synthesis. Anthracydines also inhibit DNA topoisomerases I and II, which leads to DNA double-strand breaks. In addition, doxorubicin and daunorubicin may form complexes with metals such as iron. Although these metal-anthracycline complexes result in oxygen free radical formation, which may contribute to antitumor activity, membrane damage incurred from the free radicals is thought to be the mechanism responsible for... 

D. was the first anthracycline to be used clinically in chemotherapy for malignant tumors, however it has strong cardiotoxic side effects. The mechanism of action is complex intercalation into dna, inhibition of topoisomerase II, chelating agent for metal ions such as Fe and Cu, participation in redox reactions, effects on membrane functions. D. also shows anti-Hlv activity. 

Doxorubicin and other anthracyclines, such as daunorubicin, are believed to exhibit their antineoplastic activity through inhibition of topoisomerase II activity. This appears to occur in the absence of significant metal binding by the anthracyclines. Doxorubicin can, however, bind with iron(III) and this results in the formation of a redox-active complex that may cause untoward effects (Myers et al. 1986). Doxorubicin-iron(III) complexes have been shown to oxidatively damage membranes and inactivate protein kinase C, but the biological signficance of this is not well understood (Hannun et al. 1989). 

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