title: Study of lipophilicity and membrane partition of 4-hydroxycoumarins by HPLC and PCA.
abstract: Physicochemical properties provide reliable guidance in optimization of pharmacological efficiency and ADME profile of small chemical compounds. Their high-throughput determination is regularly based on application of HPLC techniques. In this study CHI and CHI IAM of 32 4-hydroxycoumarin analogs were measured by HPLC with methanol gradient at pHs 2.8 and 7.0. Results were analyzed by PCA in terms of computed descriptors in order to identify space for optimization of their phospholipids affinity and lipophilicity for which predictive software failed to produce reliable estimations. The chromatographic behavior of studied 4-hydroxycoumarins was typical of acidic compounds. The CHI(2.8), CHI(7.0), CHI IAM(2.8) and CHI IAM(7.0) values were all considerably cross-correlated in accordance with their prevailing lipophilic character. Structure-retention relationship (SRR) analysis furthermore revealed that H-bond accepting capacity and dipolar interactions with methanol generally shorten their retention times. However, deviations from the linear trends were noticed for R3/R5-substituted derivatives able to form intramolecular contacts with the 4-O(H) group and characterized by more uniform electron density at 2-O and 4-O atoms and quite different acidity/H-bond donating capacity than the rest of derivatives. Thus, CHI and CHI IAM determinations and SRR analysis are fast and efficiently pointed to ways of modifying biological activities of 4-hydroxycoumarins.
authors.affiliation: Galapagos Research Center Ltd, Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
authors.forename: Marina
authors.initials: M
authors.lastname: Ilijaš
authors.forename: Ivica
authors.initials: I
authors.lastname: Malnar
authors.forename: Vesna
authors.initials: V
authors.lastname: Gabelica Marković
authors.forename: Višnja
authors.initials: V
authors.lastname: Stepanić
mesh_terms: D015110:4-Hydroxycoumarins / Q000032:analysis* / Q000737:chemistry; D000925:Anticoagulants / Q000032:analysis* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D010743:Phospholipids / Q000737:chemistry; D025341:Principal Component Analysis / Q000379:methods*; D015203:Reproducibility of Results
chemical_list: D015110:4-Hydroxycoumarins; D000925:Anticoagulants; D010743:Phospholipids