title: Multivariate assessment of lipophilicity scales-computational and reversed phase thin-layer chromatographic indices.
abstract: Needs for fast, yet reliable means of assessing the lipophilicities of diverse compounds resulted in the development of various in silico and chromatographic approaches that are faster, cheaper, and greener compared to the traditional shake-flask method. However, at present no accepted "standard" approach exists for their comparison and selection of the most appropriate one(s). This is of utmost importance when it comes to the development of new lipophilicity indices, or the assessment of the lipophilicity of newly synthesized compounds. In this study, 50 well-known, diverse compounds of significant pharmaceutical and environmental importance have been selected and examined. Octanol-water partition coefficients have been measured with the shake-flask method for most of them. Their retentions have been studied in typical reversed thin-layer chromatographic systems, involving the most frequently employed stationary phases (octadecyl- and cyano-modified silica), and acetonitrile and methanol as mobile phase constituents. Twelve computationally estimated logP-s and twenty chromatographic indices together with the shake-flask octanol-water partition coefficient have been investigated with classical chemometric approaches-such as principal component analysis (PCA), hierarchical cluster analysis (HCA), Pearson's and Spearman's correlation matrices, as well as novel non-parametric methods: sum of ranking differences (SRD) and generalized pairwise correlation method (GPCM). Novel SRD and GPCM methods have been introduced based on the Comparisons with One VAriable (lipophilicity metric) at a Time (COVAT). For the visualization of COVAT results, a heatmap format was introduced. Analysis of variance (ANOVA) was applied to reveal the dominant factors between computational logPs and various chromatographic measures. In consensus-based comparisons, the shake-flask method performed the best, closely followed by computational estimates, while the chromatographic estimates often overlap with in silico assessments, mostly with methods involving octadecyl-modified silica stationary phases. The ones that employ cyano-modified silica perform generally worse. The introduction of alternative coloring schemes for the covariance matrices and SRD/GPCM heatmaps enables the discovery of intrinsic relationships among lipophilicity scales and the selection of best/worst measures. Closest to the recommended logKOW values are ClogP and the first principal component scores obtained on octadecyl-silica stationary phase in combination with methanol-water mobile phase, while the usage of slopes derived from Soczewinski-Matyisik equation should be avoided.
authors.affiliation: Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia.
authors.forename: Filip
authors.initials: F
authors.lastname: Andrić
authors.affiliation: Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest XI., Magyar Tudósok krt. 2, Hungary.
authors.forename: Dávid
authors.initials: D
authors.lastname: Bajusz
authors.affiliation: Plasma Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest XI., Magyar Tudósok krt. 2, Hungary; Department of Applied Chemistry, Faculty of Food Science, Szent István University of Budapest, H-1118 Budapest XI., Villányi út 29-43, Hungary.
authors.forename: Anita
authors.initials: A
authors.lastname: Rácz
authors.affiliation: Institute of Chemistry, Technology and Metallurgy, Njegoševa 12, 11000 Belgrade, Serbia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Šegan
authors.affiliation: Plasma Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest XI., Magyar Tudósok krt. 2, Hungary. Electronic address: heberger.karoly@ttk.mta.hu.
authors.forename: Károly
authors.initials: K
authors.lastname: Héberger
mesh_terms: D056148:Chromatography, Reverse-Phase / Q000379:methods*; D002855:Chromatography, Thin Layer / Q000379:methods*; D016000:Cluster Analysis; D004785:Environmental Pollutants / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry*; D008956:Models, Chemical; D015999:Multivariate Analysis; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D025341:Principal Component Analysis; D012995:Solubility
chemical_list: D004785:Environmental Pollutants; D008055:Lipids; D004364:Pharmaceutical Preparations
keywords: Benzodiazepines; Comparison with one variable at a time—COVAT; Generalized pairwise correlation method—GPCM; Heatmap; Lipophilicity; Phenols; Polyaromatic hydrocarbons; Reversed-phase thin-layer chromatography; Sum of ranking differences—SRD