Adriamycin metallation

Chaires JB, Herrera JE, Waring MJ (1990) Preferential binding of daunomycin to 5-ATCG and 5-ATGC sequences revealed footprinting, titration experiment. Biochemistry 29 6145-6153 Chakrabarti S, Mahmood A, Kassis AI, Bump EA, Jones AG, Makrigiorgos GM (1996) Generation of hydroxyl radicals by nucleohistone-bound metal-adriamycin complexes. Free Radic Res... 

An alternative focus based on known antitumor activity of adriamycin-type systems stimulated the synthesis of the aza-anthraquinones 599 and 600 (Scheme 177) (84CC897). Thus, synergistic chloro-oxazoline directed metalation of 597 with methyllithium followed by treatment with 2,5-dimethoxybenzaldehyde and acid-promoted cyclization provided the lactone 598. Radical bromination and base-induced hydrolysis gave an intermediate keto acid which, upon Friedel-Crafts cyclization with methanesulfonic acid, led to the aza-anthraquinone 599 in modest yield. The azanaphthacene dione 600 was prepared by an analogous series of reactions starting with 597. 

The anthracyciinone class of anticancer compounds (which includes daunomycin and adriamycin) can be made using a mercury (I I )-promoted alkyne hydration. You saw the synthesis of alkynes in this class on Chapter 9 where we discussed additions of metallated alkynes to ketones. Here is the final step in a synthesis of the anticancer compound deoxydaunomycinone the alkyne is hydrated using Hg2+ in dilute sulfuric acid the sulfuric acid also catalyses the hydrolysis of the phenolic acetate to give the final product. 

The scleral plug is a device that is implanted through a sclerotomy at the pars plana it releases the drug intravitreally (Fig. 4). Its shape is similar to that of a metallic scleral plug, which is used temporarily during pars plana vitrectomy. Controlled release of doxorubicin hydrochloride [adriamycin (ADR)] (15,16), GCV (3,4,17,19,21), fluconazole (18), 5-fluorouracil (20), and tacrolimus (FK506) (22) have been reported. 

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. 

Cyclosporine-induced nephropathy was reduced by administration of Chinese salvia extract to rats (Peng et al. 2006 Qiao et al. 2001). Extracts of Chinese salvia attenuated adriamycin-induced cardiac and hepatic toxicity in healthy rats (You et al. 2007) and vanadium-induced gastrointestinal stress and metal accumulation in diabetic rats (Zhang etal.2008). 

Myers C, Gianni L, Zweier J, Muindi J, Sinha BK, Eliot H (1986) Role of iron in adriamycin biochemistry. Fed Proc 45 2792-2797 Naganuma A, Satoh M, Koyama Y, Imura N (1985) Protective effect of metallothionein inducing metals on lethal toxicity of cis-diamminedichloroplatinum in mice. Toxicol Lett 24 203-207... 

In relation to other established and clinically-used drugs, such as adriamycin and 5-fluorouracil, cisplatin shows at least equivalent activity in the NCI tumour panel [7], Table 2.II, and indeed this favorable comparison stresses the potential for metal-based drugs. 

Fig. 7.3. Structures of the metal binding antibiotics adriamycin (doxorubicin), R = CH3 (74), daunorubicin, R = H (74) and streptonigrin (75).

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]. 

Antibiotics such as streptonigrin and the anthracycUnes also bind metals and cleave DNA and metal ion involvement through similar mechanisms to that of bleomycin is possible. In the case of the clinically-used adriamycin, the acute cardiotoxicity may have as a chemical cause free radical damage produced by an iron—drug interaction. 

Adriamycin and daunomycin (fig. 3) are two antibiotics currently highly investigated because of their effectiveness against malignant cells. The interaction of daunomycin with lanthanide chlorides (Eu, Gd, Tb, Yb) yields complexes that have been analyzed by Mariam and Wells (1984) and Mariam et al. (1984) by spectrophotometry and NMR spectroscopy. Molar ratio and continuous-variation methods indicate the presence of predominantly a ML2 species at metal-to-ligand ratios less than one MjL and ML species are also present. Proton spin-lattice relaxation time and linewidth measurements utilizing the relaxation probe Gd(III) indicate that the primary coordination site is in the 11,12-positions. 

Chakrabarti, S. Mahmood, A. Kassis, A. 1. Bump, E. A. Jones, A. G. Makrigiorgos, G. M. Generation of hydroxyl radicals by nucleohistone-bound metal-adriamycin complexes. Free Radical Res. 1996, 25, 207-220. 

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