caa a22 4500 465789900 CHVBK 20180323112020.0 cr unu---uuuuu 170327e19901101xx s 000 0 eng 10.1007/BF00198591 doi (NATIONALLICENCE)springer-10.1007/BF00198591 Fluorinated anthracyclines: interactions with DNA [Elektronische Daten] [Ken Tonkin, Ray Boston, Robert Brownlee, Don Phillips] 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. Kluwer Academic Publishers, 1990 fluorinated anthracyclines nationallicence adriamycin nationallicence DNA interaction nationallicence dissociation kinetics nationallicence fluorine NMR nationallicence intercalation nationallicence Tonkin Ken Department of Biochemistry, La Trobe University, 3083, Bundoora, Victoria, Australia aut Boston Ray Computer Science Program, Murdoch University, 6008, Murdoch, Western Australia, Australia aut Brownlee Robert Department of Chemistry, La Trobe University, 3083, Bundoora, Victoria, Australia aut Phillips Don Department of Biochemistry, La Trobe University, 3083, Bundoora, Victoria, Australia aut Investigational New Drugs Kluwer Academic Publishers 8/4(1990-11-01), 355-363 0167-6997 8:4<355 1990 8 10637 https://doi.org/10.1007/BF00198591 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00198591 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Tonkin Ken Department of Biochemistry, La Trobe University, 3083, Bundoora, Victoria, Australia aut NATIONALLICENCE 700 1- Boston Ray Computer Science Program, Murdoch University, 6008, Murdoch, Western Australia, Australia aut NATIONALLICENCE 700 1- Brownlee Robert Department of Chemistry, La Trobe University, 3083, Bundoora, Victoria, Australia aut NATIONALLICENCE 700 1- Phillips Don Department of Biochemistry, La Trobe University, 3083, Bundoora, Victoria, Australia aut NATIONALLICENCE 773 0- Investigational New Drugs Kluwer Academic Publishers 8/4(1990-11-01), 355-363 0167-6997 8:4<355 1990 8 10637 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer