Summary
Four fluorine containing derivatives of anthracyclines (daunomycin and adriamycin) were synthesised, and comprised C-13, 1,1,1-trifluoroethyl-hydrazones of each anthracycline, and C-14 4-F and 4-CF3-benzoate esters of adriamycin. All four derivatives intercalated into DNA in a manner similar to their parent anthracycline. The ester derivatives exhibited 3–4-fold higher binding affinity to DNA, and slower DNA dissociation kinetics than adriamycin. This stabilisation derives from additional contacts of the C-14 side chain to the DNA minor groove. The hydrazone derivatives showed lower binding affinity to DNA, and dissociated from DNA 3–4 times faster than the parent compound. The 19F resonance of the bound drug was broadened to 120 Hz and shifted 60 Hz downfield (0.32 ppm) relative to the sharp (7.5 Hz) peak of the free drug. These values imply a rapid exchange between the free and DNA bound forms (DNA lifetime > 5 ms), with the fluorine group residing in a hydrophobic region in close contact with the DNA minor groove. The 4–8 fold lesser specific potency of the ester derivatives supports the concept that DNA binding is an important factor, but not sole determinant of biological activity of these analogues.
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References
Arcamone F: Doxorubicin anticancer antibiotics, Academic Press, New York, pp 1–369, 1981
El Khadem HS: Anthracycline antibiotics, Academic Press, New York, pp 1–282, 1982
Schwartz HS: Mechanisms of selective cytotoxicity of adriamycin, 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
Valentini L, Nicolella V, Vannini E, Menozzi M, Penco S, Arcamone F: Association of anthracycline derivatives with DNA: A fluorescence study. Il Farmaco Ed Sci 40:377–390, 1985
Fritzsche H, Berg H: Analysis of equilibrium, kinetic and structural data of anthracycline-DNA interaction. Gazz Chim Ital 117:331–352, 1987
Zbinden G, Bachmann E, Holderegger C: Model systems for cardiac effects of anthracyclines. Antibiot Chemother 23:255–270, 1978
Brown JR: New natural, semisynthetic and synthetic anthracycline 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
Tonkin KC, Brownless RTC, Zunino F, Phillips DR: Fluorinated anthracyclines: Synthesis and biological activity. Investig New Drugs 8:1–6, 1990
Bloomfield VA, Crothers DM, Tinoco Jr I: Physical chemistry of nucleic acids. Harper and Row, New York, pp 442–445, 1974
Wilson WD, Jones RL: Intercalating drugs: DNA binding and molecular pharmacology. Adv Pharmacol Chemother 18: 177–222, 1981
Wilson WD, Keel RA, Jones RL, Mosher CW: Viscometric analysis of the interaction of bisphenanthridium compounds with closed circular supercoiled and linear DNA. Nucleic Acids Res 10:4093–4106, 1982
Neidle S: Interaction of daunomycin and related antibiotics with biological receptors. Topics Antibiotic Chem 2:242–278, 1978
Gianni L, Corden BJ, Myers CE: The biochemical basis of anthracycline toxicity and antitumour activity. Rev Biochem Toxicol 5:1–82, 1982
McGhee JD, von Hippel PH: Theoretical aspects of DNA-protein interactions: cooperative and non-cooperative binding of large ligands to a one-dimensional homogenous lattice. J Mol Biol 86:469–489, 1974
Dougherty G, Pigram WJ: Spectroscopic analysis of drugnucleic acid interactions. CRC Crit Rev Biochem 103–132,1982
Chaires JB, Dattagupta N and Crothers DM: Studies on interaction of anthracycline antibiotics and DNA: Equilibrium binding studies on interaction of daunomycin with DNA. Biochemistry 21:3933–3940, 1982
Chaires JB, Dattagupta N, Crothers DM: Kinetics of the daunomycin-DNA interaction. Biochemistry 24:260–267, 1985
Gandecha B, Brown JR: Dissociation kinetics of DNAanthracycline and DNA-anthraquinone complexes determined by stopped-flow spectrophotometry. Biochem Pharmacol 34:733–736, 1985
Fox KR, Brasset C, Waring MJ: Kinetics of dissociation of nogalamycin from DNA: comparison with other anthracycline antibiotics. Biochim Biophys Acta 840:383–392, 1985
Krishnamoorthy CR, Yen S, Smith JC, Lown JW, Wilson WD: Stopped-flow kinetic analysis of the interaction of anthraquinone anticancer drugs with calf thymus DNA, poly[d(G-C)].poly[d(G-C] and poly[d(A-T)].poly[d(A-T)]. Biochemistry 25:5933–5940, 1986
Phillips DR, Grief PC, Boston RC: Daunomycin-DNA dissociation kinetics. Molec Pharmacol 33:225–230, 1988
Bolton PH, Mirau PA, Shafer RH, James TL: Interaction of the antimalarial drug fluoroquine with DNA, tRNA and poly(A): 19F-NMR chemical shift and relaxation, optical absorption and fluorescence studies. Biopolymers 20:435–449, 1981
Feigon J, Denny WA, Leupin W and Kearns DR: The interaction of antitumor drugs with natural DNA: A 1H NMR study of binding mode and kinetics. J Med Chem 27:450–465, 1984
Chaires JB, Dattagupta and Crothers DM: Self-association of daunomycin. Biochemistry 21:2927–2932, 1982
Arcamone F: The development of new antitumour anthracyclines. In: Cassady JM and Douros JD (eds), Anticancer agents based on natural product models. Academic Press, New York, pp 1–42, 1980
Quigley GJ, Wang AH, Ughetto G, der Marel G, van Broom JH, Rich A: Molecular structure of an anti-cancer drug-DNA complex: Daunomycin plus d(CpGpTpApCpG). Proc Natl Acad Sci USA 77:7204–7208, 1980
Wang AH, Ughetto, Quigley GJ, Rich A: Interactions between an anthracycline antibiotic and DNA: Molecular structure of daunomycin complexed to d(CpGpTpApCpG) at 1.2 A resolution. Biochemistry 26:1152–1163, 1987
Holbrook SR, Wang AH, Rich A, Kim S: Local mobility of nucleic acids as determined from crystallographic data. III. A daunomycin-DNA complex. J. Mol Biol 199:349–357, 1988
Capranico G, Penco S, Tinelli S and Zunino F: Role of DNA breakage in cytotoxicity of doxorubicin, 9-deoxydaunorubi-cin and 4-demethyl-6-deoxydaunorubicin in murine leukaemia P388 cells. Cancer Res, in press
Capranico G, Zunino F, Kohn KW and Pommier Y: Se-quence selective topisomerase II inhibition by anthracycline derivatives in SV40 DNA: Relationship with DNA binding affinity and toxicity. Biochemistry, in press.
Davis AW, Phillips DR: A defined molecular weight distribution of DNA after extensive sonication. Eur J Biochem 173:179–183, 1978
Boston RC, Greif PC, Berman M: Conversational SAAM — an interactive program for kinetic analysis of biological systems. Comput Programs Biomed 13:111–119, 1981
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Tonkin, K.C., Boston, R.C., Brownlee, R.T.C. et al. Fluorinated anthracyclines: interactions with DNA. Invest New Drugs 8, 355–363 (1990). https://doi.org/10.1007/BF00198591
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DOI: https://doi.org/10.1007/BF00198591