Daunomycin and

P. Cieplak, S. N. Rao, P. D. J. Grootenhuis, and P. A. Kollman, Free energy calculation on base specificity of drug-DNA interactions Application to daunomycin and acridine intercalation into DNA, Biopol. 29 717 (1990). 

Perhaps a bit more subtle than those agents that react chemically with DNA are those that insert themselves between the stacked bases of the DNA double helix— intercalation. This alters the regular structure of the DNA molecule and may lead, for instance, to inhibition of mRNA synthesis. The structures of the intercalcating agents are generally quite complex and I will spare you the complexity. However, three names may be familiar—dactinomycin (Actinomycin D), daunorubicin (daunomycin), and doxorubicin (Adriamycin)— and intercalation is how they work. All three are natural products and were isolated from the fermentation broths of Streptomyces species. 

Free daunomycin and not PEG-conjugated hposomes containing daunomycin, disappear rapidly from the circulation. Plasma clearance of the hposome was reduced 66-fold by PEG-conjugation. Coupling 29 0X26 monoclonal antibodies per PEG-liposome partially reversed the effect of PEG-conjugation on plasma clearance. 

Figure 14 Diagram of the daunomycin-d(C6TAC6) complex showing the intermolecular interactions which include intercalation and hydrogen bonds. Note that there are two hydrogen bonds between 09 of daunomycin and N2 and N3 of 62.

Figure 5-23 Stereoscopic drawing showing a molecule of daunomycin (Fig. 5-22) intercalated between two base pairs in a molecule of double-helical DNA, d(CGTACG). Nitrogen and oxygen atoms are shown as dots. From Quigley et al.220 Both daunomycin and adriamycin (doxorubicin 14-hydroxy-daunomycin) are important but seriously toxic anticancer drugs.

Frazier, A. A., and K. K. Karukstis. 1997. Investigation of competitive binding between daunomycin and verapamil or genistein in AOT reverse micell dastracts of 213th ACS National Meeting, 262. 

Karukstis, K. K., E. H. Z. Thompson, J. A. Whiles, and R. J. Rosenfeld. 1998. Partitioning of daunomycin and doxorubicin in AOT reverse micelle Abstracts of 215th ACS National Meetil1i j3. 

Duncan, R., P. Kopeckova-Rejmanova, J. Strohalm, I. Hume, H. C. Cable, J. Pohl, J. B. Lloyd, and J. Kopecek. 1987. Anticancer agents coupled1e(2-hydroxypropyl)methacrylamide copolymers. I. Evaluation of daunomycin and puromycin conjugates/itro. Br. J. Cancei55 165-174. 

Daunorubicin (Daunomycin and Cerubidine) and doxorubicin (Adriamycin) bind to and cause the intercalation of the DNA molecule, thereby inhibiting DNA template function. They also provoke DNA chain scission and chromosomal damage. Daunorubicin is useful in treating patients with acute lymphocytic or acute granulocytic leukemia. Adriamycin is useful in cases of solid tumors such as sarcoma, metastatic breast cancer, and thyroid cancer. These agents cause stomatitis, alopecia, myelosuppression, and cardiac abnormalities ranging from arrhythmias to cardiomyopathy. 

Daunorubicin (Daunomycin and Cerubidine) and doxorubicin (Adriamycin) bind to and cause the intercalation of the DNA molecule, thereby inhibiting DNA template function. They also provoke DNA chain scission and chromosomal damage. 

An improved total synthesis of the aglycone (180) of 11-deoxyadriamycin-type antibiotics, which show stronger antineoplastic activity and/or less car-diotoxicity than daunomycin and adriamycin, was accomplished by applying the method to dihydroxyacetone (180) from ethynylcarbinol (182), prepared by strong base-induced cycloaddition of the substituted tetrahydrohomophthalic anhydride (181) [137], using PIFA [78] (Scheme 46). 

Daunomycin and its analog adriamycin are in clinical use as potent antitumor agents in combination chemotherapy against acute lymphocytic leukemia. It has been suggested that the antitumor properties are associated with intercalation of the anthracycline ring of the antibiotic into the DNA of rapidly proliferating neoplastic cells and subsequent blocking of RNA synthesis (72-75). [5]... 

Daunomycin and adriamycin bind to DNA with similar binding constants of t.2.5 x 10 M- in 0.1 M buffer, pH 7.0 at 20°C, with one anthracycline antibiotic bound per six nucleotides at maximum intercalative binding (80,81). The binding constant is dependent on the salt concentration and decreases by a factor of 5 on proceeding from 0.1 M to 1.0 M NaCl solution (82). 

A third focus has been directed toward incorporation of conventional PET radionuclides nC or 18F into existing substrates or inhibitors known to interact with Pgp [113-115]. This strategy has been employed to produce various PET agents, including 1 -colchicine, 11C-verapamil, nC-daunomycin, and uC/18F-paclitaxel[115-123]. While promising data have been generated, some of these PET agents suffer from modest radiochemical yields and others from complex pharmacokinetics in vivo mediated, at least in part, by rapid metabolism of the radiolabeled compounds. 

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. 

Figure 13.10. Structure of daunorabicin (daunomycin) and its intercalation into DNA (a), and catalytic formation of peroxide anions by iron complexed to it (b). Reactive oxygen species released in the immediate vicinity of the DNA will form strand breaks and also promote formation of covalent adducts of daimorabicin and DNA that involve the amino group of the former.

Gray PJ, Philips DR. Ultraviolet photoirradiation of daunomycin and DNA-daunomycin complexes. Photochem Photobiol 1981 (33) 297-303. 

Hurwitz, E. Levy, R. Maron, R. Wilchek, M. Arnon, R. Sela, M. The covalent binding of daunomycin and adriamycin to antibodies, with retention of both drug and antibody activities. Cancer Res. 1975, 55, 1175-1181. 

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