Summary
The chromophore-modified derivative of doxorubicin, 4-demethyl-6-0-methyl-doxorubicin, has been tested for antitumor activity in a range of experimental murine tumor systems. In contrast to the inactive 6-0-methyl derivative of daunorubicin, 4-demethyl-6-0-methyl-doxorubicin provided antitumor effects comparable to that of the parent compound. In addition, detailed DNA-interaction studies showed that the doxorubicin derivative retains the ability to bind DNA by the intercalation mechanism. However, the binding affinity was appreciably reduced following structural modification in the anthraquinone chromophore. On the basis of the proposed models of intercalation, these results could be rationalized in terms of steric influence of the bulky methoxy group. The results of this study are in agreement with the correlation already observed between DNA binding and relative antitumor activity of anthracyclines.
Similar content being viewed by others
References
Carter SK: Adriamycin. A review. JNCI 55:1265–1274, 1975
Zunino F, Gambetta R, Di Marco A, Velcich A, Zaccara A, Quadrifoglio F, Crescenzi V: The interaction of adriamycin and its beta anomer with DNA. Biochim Biophys Acta 476:38–46, 1977
Zunino F, Di Marco A, Zaccara A: Molecular structural effects involved in the interaction of anthracyclines with DNA. Chem Biol Interact 24:217–225, 1979
Myers CE: Antitumor antibiotics. I. Anthracyclines. In HM Pinedo (ed): Cancer Chemotherapy. Excerpta Medica, Amsterdam, 1980, pp 66–83
Neidle S, Sanderson MR: The interactions of daunomycin and adriamycin with nucleic acids. In: Neidle S, Waring MJ (eds): Molecular aspects of anti-cancer drug action. Mac-Millan, London, 1983, pp 35–55
Brown JR: New natural, semisynthetic and synthetic anthracycline drugs. In: Neidle S, Waring MJ (eds): Molecular aspects of anti-cancer drug action MacMillan, London, 1983, pp 57–92
Tritton T, Yee G: The anticancer agent adriamycin can be actively cytotoxic without entering cells. Science 217:248–250, 1982
Quadrifoglio F, Ciana A, Manzini G, Zaccara A, Zunino F: Influence of some chromophore substituents on the intercalation of anthracycline antibiotics into DNA. Int J Biol Macromol 4:413–418, 1982
Zunino F, Casazza AM, Pratesi G, Formelli F, Di Marco A: Effect of methylation of aglycone hydroxyl groups on the biological and biochemical properties of daunorubicin. Biochem Pharmacol 30:1856–1858, 1981
Arcamone F, Cassinelli G, Penco S: Recent developments in the chemistry of doxorubicin and related anthracycline glycosides. In: Elkhadem HS (ed): Anthracycline antibiotics. Academic Press, 1982, pp 59–73
Festy B, Sturm J, Daune M: Interaction between hydroxystilbamidine and DNA. I. Binding isotherms and thermodynamics of the association. Biochim Biophys Acta 407:24–42, 1975
Scatchard G: The attraction of proteins for small molecules and ions. Ann NY Acad Sci 51:660–672, 1949
Waring M: Variation of the supercoils in closed circular DNA by binding of antibiotics and drugs: Evidence for molecular models involving intercalation. J Mol Biol 54:247–279, 1970
Geran RI, Greenberg NH, MacDonald MM, Schumacher AM, Abbott BJ: Protocols of screening chemical agents and natural products against animal tumors and other biological systems. Cancer Chemother Rep 3:1–88, 1972
Di Marco A, Lenaz L, Casazza AM, Scarpinato BM: Activity of adriamycin (NSC-123127) and daunomycin (NSC-82151) against mouse mammary carcinoma. Cancer Chemother Rep 56:153–161, 1972
Zunino F, Giuliani F, Savi G, Dasdia T, Gambetta R: Antitumor activity of daunorubicin linked to poly-L-aspartic acid. Int J Cancer 30:465–470, 1982
Bertazzoli C, Bellini O, Magrini U, Tosana MG: Quantitative experimental evaluation of adriamycin cardiotoxicity in the mouse. Cancer Treat Rep 63:1877–1883, 1979
Zunino F, Di Marco A, Zaccara A, Gambetta RA: The interaction of daunorubicin and doxorubicin with DNA and chromatin. Biochim Biophys Acta 607:206–214, 1980
Patel DJ, Kozlowski SA, Rice JA: Hydrogen bonding, overlap geometry, and sequence specificity in anthracycline antitumor antibiotic-DNA complexes in solution. Proc Natl Acad Sci USA 78:3333–3337, 1981
Quigley GJ, Wang AHJ, Ughetto G, Van Der Marel G, Van Boom JH, Rich A: Molecular structure of an anticancer drug-DNA complex: Daunomycin plus d(CpGpTpAp-CpG). Proc Natl Acad Sci USA 77:7204–7208, 1980
Masi P, Suarato S, Giardino P, Iraci G, Bernardi L, Arcamone F: 4-Demethoxy-4-hydroxydaunorubicin 6-methyl ether and 11-methyl ether, two active isomers of daunorubicin. Farmaco [Sci] 35:347–356, 1980
Henry DW: Structure-activity relationships among daunorubicin and adriamycin analogs. Cancer Treat Rep 63:845–854, 1979
Bachur NR, Gordon SL, Gee MV: Anthracycline antibiotic augmentation of microsomal electron transport and free radical formation. Mol Pharmacol 13:901–910, 1977
Bachur NR, Gordon SL, Gee MV: A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Cancer Res 38:1745–1750, 1978
Doroshow JH: Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res 43:460–472, 1983
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Zunino, F., Barbieri, B., Bellini, O. et al. Biochemical and biological activity of the anthracycline analog, 4-demethyl-6-0-methyl-doxorubicin. Invest New Drugs 4, 17–23 (1986). https://doi.org/10.1007/BF00172011
Issue Date:
DOI: https://doi.org/10.1007/BF00172011