title: A fluorescence study examining how 14-valerate side chain substitution modulates anthracycline binding to small unilamellar phospholipid vesicles.
abstract: The intrinsic fluorescence properties of the anthracycline antitumor antibiotics were studied in an effort to understand how 14-valerate side chain substitution modulates drug associations with small unilamellar phospholipid vesicles (SUVs) under near physiological conditions. Drug location and dynamics in fluid-phase dimyristoylphosphatidylcholine (DMPC) bilayers were evaluated for several analogs; accessibilities of bound fluorophores to membrane-impermeable iodide were evaluated in quenching experiments, while the diffusive motions of these agents were studied using lifetime-resolved anisotropy plots. The bulky and hydrophobic valerate substituent was found to further hinder the rotations experienced by a bound drug molecule, with apparent limiting anisotropy (a infinity) values showing increases of 13-82% upon valerate group substitution. In addition, the bimolecular quenching rate constants (unit, 10(9) M-1.s-1) for membrane-bound adriamycin (1.4), N-trifluoroacetyladriamycin (0.4), and their corresponding valerate-substituted analogs (kq values of 1.1 and 0.5, respectively) reveal that the side chain is a weak modulator of fluorophore penetration into the bilayer, with stronger modulation being achieved through amino group substitution. Similar results were obtained for drugs bound to negatively-charged dimyristoylphosphatidylglycerol (DMPG) bilayers. Finally, comparison of the equilibrium binding affinities of the various congeners for electroneutral DMPC versus negatively-charged DMPG bilayers demonstrate that positively-charged parent anthracyclines display high levels of selective binding to negatively-charged phospholipids, unlike valerate-substituted analogs which display no such selectivity. The modulation of anthracycline-membrane interactions achieved through valerate substitution offers potential explanations, at least in part, for some of the novel biological properties of valerate-containing anthracyclines.
authors.affiliation: Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010-0269.
authors.forename: T G
authors.initials: TG
authors.lastname: Burke
authors.forename: M
authors.initials: M
authors.lastname: Israel
authors.forename: R
authors.initials: R
authors.lastname: Seshadri
authors.forename: J H
authors.initials: JH
authors.lastname: Doroshow
mesh_terms: D000903:Antibiotics, Antineoplastic; D004134:Dimyristoylphosphatidylcholine; D066298:In Vitro Techniques; D008563:Membrane Lipids; D010715:Phosphatidylglycerols; D010743:Phospholipids; D012995:Solubility; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D014631:Valerates
chemical_list: D000903:Antibiotics, Antineoplastic; D008563:Membrane Lipids; D010715:Phosphatidylglycerols; D010743:Phospholipids; D014631:Valerates; C002773:dimyristoylphosphatidylglycerol; D004134:Dimyristoylphosphatidylcholine