Abstract
A number of fluorine containing derivatives of daunomycin and Adriamycin have been synthesised with a fluorine substituent located on the C-9 side chain. They included the p-trifluoromethyl-(4) and p-fluorobenzoate (3) esters of Adriamycin and the trifluoro-ethyl-hydrazones of Adriamycin (2) and daunomycin (1). The less polar derivatives (esters 3 and 4) appear to enter HeLa cells more readily than the polar derivatives (hydrazones 1 and 2) as indicated by the rates and extent of cellular uptake and the uptake was by facilitated diffusion. All four fluorinated derivatives were less active than their parent anthracyclines, but the difference was less pronounced when considering specific potency. The fluorinated derivatives (1–4) behaved sufficiently similar to daunomycin and Adriamycin to enable their use as fluorine probes in 19F NMR physicochemical and cellular studies of anthracyclines.
Similar content being viewed by others
References
Davis HL, Von Hoff DD, Henney JE and Rozencweig M: Role of antitumor antibiotics in current oncologic practice. In: Antitumor Antibiotics, Carter SK, Umezawa H, Douros J and Sakurai Y (Eds), Springer-Verlag, Berlin, 1978, pp 21–29
Goldin A, Venditti JM, MacDonald JS, Muggia FM, Henney JE and de Vitta Jr VT: Current results of the screen- ing program at the Division of Cancer Treatment, National Cancer Institute, Europ J Cancer 17:129–142, 1981
Zbinden G, Bachmann E and Holderegger C: Model systems for cardiac effects of anthracyclines. Antibiot Chemother 23:255–270, 1978
Brown JR: New natural, semisynthetic and synthetic anthra- cycline drugs. In: Neidle S and Waring MJ (Eds) Molecular aspects of anti-cancer drug action. The Macmillan Press Limited, Great Britain, pp 57–92, 1983
Arcamone F: Daunomycin and related antibiotics. Topics Antibiotic Chem 2:103–239, 1978
Neidle S: Interaction of daunomycin and related antibiotics with biological receptors. Topics Antibiotic Chem 2:242–278, 1978
Arcamone F, Franceschi G, Minghetti A, Penco S, Redaelli SJ, DiMarco A, Casazza AM, Dasdia T, DiFonzo G, Guiliani F, Lenaz L, Necco A and Soranzo C: Synthesis and biological evaluation of some 14–0-acyl derivatives of Adria- mycin. J Med Chem 17:335–337, 1974
Maral M, Ponsinet G and Jolies G: Etude de l'activite anti- tumorale experimental d'un nouvel antibiotique semi-syn- thethique: la rubidazone. C R Acad Sc Paris, Series D, 275: 301–304, 1972
Skovsgaard T: Carrier-mediated transport of daunorubicin, Adriamycin and rubidazone in Ehrlich ascites tumour cells. Biochem Pharmacol 27:1221–1227, 1978
Chandler CJ, Phillips DR, Brownlee RTC and Reiss JA: Ammonium bicarbonate mediated high-performance liquid chromatography resolution of bis-anthracyclines. J Chro- matog 348:179–186, 1986
Schwartz HS: Mechanisms of selective cytotoxicity of Adri- amycin, daunomycin and related anthracyclines. In: Neidle S and Waring MJ (Eds) Molecular aspects of anti-cancer drug action. The Macmillan Press Limited, Great Britain, pp 93–125, 1983
Bachur NR, Steel M, Meriwether WD and Hildebrand RC: Cellular pharmacodynamics of several anthracycline antibi- otics. J Med Chem 19:651–654, 1976
Sirotnak FM, Chello PL and Brockman RW: Potential for exploitation of transport systems in anticancer drug design. In: DeVita T and Busch H (Eds), Cancer Drug Development, Academic Press, New York, pp 382–447, 1979
Henry DW: Adriamycin. In: Sartorelli AC (Ed) Am Cancer Soc Symp, Series 30, American Chemical Society, Washington, pp 15–57, 1976
Arcamone F: Doxorubicin: Anticancer antibiotics, Medicinal Chemistry Series Vol 17, Academic Press, New York, 1981
Wilson WD and Jones RL: Intercalating drugs: DNA binding and molecular pharmacology. Adv Pharmacol Chemother 18:177–222, 1981
Cain BF: The role of structure-activity studies in the design of antitumor agents. Cancer Chemother Rep 59:679–683, 1975
Kessel D: Biologic properties of three anthracyclines as a function of lipophilicity. Biochem Pharmacol 28:3028–3030, 1979
Yamamoto K, Acton EM and Henry DW: Antitumor activity of some derivatives of daunorubicin at the amino and methyl ketone functions. J Med Chem 15:872–875, 1972
Hansch L, Leo A, Unger SH, Kim KH, Nikaitani D and Lien EJ: “Aromatic” substituent constants for structureactivity correlations. J Med Chem 16:1207–1216, 1973
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Tonkin, K.C., Brownlee, R.T.C., Zunino, F. et al. Fluorinated anthracyclines: Synthesis and biological activity. Invest New Drugs 8, 1–6 (1990). https://doi.org/10.1007/BF00216918
Issue Date:
DOI: https://doi.org/10.1007/BF00216918