title: Predicting the phospholipophilicity of monoprotic positively charged amines.
abstract: The sorption affinity of eighty-six charged amine structures to phospholipid monolayers (log KIAM) was determined using immobilized artificial membrane high-performance liquid chromatography (IAM-HPLC). The amine compounds covered the most prevalent types of polar groups, widely ranged in structural complexity, and included forty-seven pharmaceuticals, as well as several narcotics and pesticides. Amine type specific corrective increments were used to align log KIAMdata with bilayer membrane sorption coefficients (KMW(IAM)). Using predicted sorption affinities of neutral amines, we evaluated the difference (scaling factor ΔMW) with the measured log KMW(IAM) for cationic amines. The ΔMWvalues were highly variable, ranging from -2.37 to +2.3 log units. For each amine type, polar amines showed lower ΔMWvalues than hydrocarbon based amines (CxHyN+). COSMOmic software was used to directly calculate the partitioning coefficient of ionic structures into a phospholipid bilayer (KDMPC-W,cation), including quaternary ammonium compounds. The resulting root mean square error (RMSE) between log KDMPC-W,cationand log KMW(IAM) was 0.83 for all eighty-six polar amines, and 0.47 for sixty-eight CxHyN+amines. The polar amines were then split into five groups depending on polarity and structural complexity, and corrective increments for each group were defined to improve COSMOmic predictions. Excluding only the group with sixteen complex amine structures (≥4 polar groups, Mw> 400, including several macrolide antibiotics), the resulting RMSE for corrected KDMPC-W,cationvalues improved to 0.45 log units for the remaining set of 138 polar and CxHyN+amines.
authors.affiliation: Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 104, 3508 TD Utrecht, The Netherlands.
authors.forename: S T J
authors.identifier: http://orcid.org/0000-0002-1193-1850
authors.initials: ST
authors.lastname: Droge
authors.affiliation: Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 104, 3508 TD Utrecht, The Netherlands.
authors.forename: J L M
authors.initials: JL
authors.lastname: Hermens
authors.affiliation: Safety and Environmental Assurance Centre, Unilever, Sharnbrook, Bedford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Gutsell
authors.affiliation: Safety and Environmental Assurance Centre, Unilever, Sharnbrook, Bedford, UK.
authors.forename: J
authors.initials: J
authors.lastname: Rabone
authors.affiliation: Safety and Environmental Assurance Centre, Unilever, Sharnbrook, Bedford, UK.
authors.forename: G
authors.initials: G
authors.lastname: Hodges
mesh_terms: D000327:Adsorption; D000588:Amines / Q000737:chemistry*; D002412:Cations; D002851:Chromatography, High Pressure Liquid; D008567:Membranes, Artificial; D010743:Phospholipids / Q000737:chemistry*; D000644:Quaternary Ammonium Compounds
chemical_list: D000588:Amines; D002412:Cations; D008567:Membranes, Artificial; D010743:Phospholipids; D000644:Quaternary Ammonium Compounds