title: Halogenation of drugs enhances membrane binding and permeation.
abstract: Halogenation of drugs is commonly used to enhance membrane binding and permeation. We quantify the effect of replacing a hydrogen residue by a chlorine or a trifluoromethyl residue in position C-2 of promazine, perazine, and perphenazine analogues. Moreover, we investigate the influence of the position (C-6 and C-7) of residue CF(3) in benzopyranols. The twelve drugs are characterized by surface activity measurements, which yield the cross-sectional area, the air-water partition coefficient, and the critical micelle concentration. By using the first two parameters (A(D) and K(aw)) and the appropriate membrane packing density, the lipid-water partition coefficients, are calculated in excellent agreement with the lipid-water partition coefficients measured by means of isothermal titration calorimetry for small unilamellar vesicles of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. Replacement of a hydrogen residue by a chlorine and a trifluoromethyl residue enhances the free energy of partitioning into the lipid membrane, on average by deltaG(lw) approximately -1.3 or -4.5 kJ mol(-1), respectively, and the permeability coefficient by a factor of approximately 2 or approximately 9, respectively. Despite exhibiting practically identical hydrophobicities, the two benzopyranol analogues differ in their permeability coefficients by almost an order of magnitude; this is due to their different cross-sectional areas at the air-water and lipid-water interfaces.
authors.affiliation: Biophysical Chemistry, Biozentrum, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland.
authors.forename: Grégori
authors.initials: G
authors.lastname: Gerebtzoff
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Li-Blatter
authors.forename: Holger
authors.initials: H
authors.lastname: Fischer
authors.forename: Adrian
authors.initials: A
authors.lastname: Frentzel
authors.forename: Anna
authors.initials: A
authors.lastname: Seelig
mesh_terms: D001578:Benzopyrans / Q000737:chemistry / Q000378:metabolism; D006219:Halogens / Q000737:chemistry* / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008563:Membrane Lipids / Q000737:chemistry* / Q000378:metabolism; D008823:Micelles; D015394:Molecular Structure; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D010640:Phenothiazines / Q000737:chemistry / Q000378:metabolism; D013499:Surface Properties; D014867:Water / Q000737:chemistry
chemical_list: D001578:Benzopyrans; D006219:Halogens; D006575:Heterocyclic Compounds, 3-Ring; D008563:Membrane Lipids; D008823:Micelles; D004364:Pharmaceutical Preparations; D010640:Phenothiazines; D014867:Water