Study of the Lipophilic Character of Xanthine and Adenosine Derivatives: II. Relationships Between Log K', RM and Log P Values

Abstract

The log k' values of a series of xanthine and adenosine derivatives were measured by means of a reversed-phase HPLC. The HPLC data were shown to be well correlated with previously reported R_M and R_MC18 values. The equations describing the relationships log k'/R_M and log k'/R_MC18 allowed the calculation of the log k' values of some compounds, which were not tested in the HPLC system. Since the relationship log k'/log P is very close to the previously described relationships R_M/log P and R_MC18/log P one can conclude that reversed-phase TLC and HPLC are very similar in describing the lipophilicity of the compounds.     

The Correlations between Capacity Factors k′ and RM Values in Liquid Column and Thin-Layer Chromatography

Abstract

The purpose of this studie being carried out is to define some regularities between Thin-layer and Liquid Column Chromatography; i.e. between experimental obtained and theotetical calculated R_M-values and experimental obtained logk-values for some non-active organic substances in mixed binary solvents systems. It was studied the kind these correlations change with changing mobile phase compositions. The present paper is a certain aspect of new studies on possibilities of the use Thin-layer Chromato-graphy as a pilot technique for Liquid Column Chromatography (1,2). In a study on the optimization of chromatographic process it is necessary to define the correlations between R_M-values which characterize the retention in TLC and k′-values which characterize the retention in in LCC.

In the paper the changes of these correlations with the changes of mobile phase compositions are studied. The conformity between theoretical calculated and experimental obtained R_M-values of chromatographed substances for differemt mobile phase compositions are investigated. A good agreement between theoretical and experimental data makes possible to foresee on the basis of the correlations between log k′- and R_M-values the retention in column chromatography.     

Rm Values, retention times and π values of a series of potentially mutagenic nitroimidazo[2,1-b]thiazoles

The R_m values and retention times of a series of nitroimidazo[2,1-b]thiazoles were obtained by means of thin-layer and high-performance liquid chromatography, respectively. Extrapolated R_m and log k′ values were correlated in a statistically significant way with π values calculated according to the literature.     

Molecular Modeling for Mobile Phase Optimization in RP-HPLC

Abstract

The applicability of molecular parameters calculated on the bases of molecular mechanics have been investigated for the prediction of reversed-phase retention behavior of structurally unrelated series of drug molecules. Non-polar, non-polar unsaturated and polar surface areas, surface energies, dipole moments, van der Waals radii and hydrophobicity values expressed by the logarithm of the octanol/water partition coefficients have been calculated from the molecular structure. The reversed-phase retention behavior was described by the slope and the intercept of the straight lines obtained by plotting the log k¹ values against the acetonitrile concentration of the mobile phase. The acetonitrile concentration (OP%₀) which was needed for the log k¹ = 0 retention was also calculated from the slope and intercept values. Step-wise linear regression analyses have been applied for revealing the correlations between the investigated parameters. The slope values could be described by the difference of the non-polar and non-polar accessible surface areas or by the total surface energy values and the van der Waals radii. The intercept values could be described by the hydrophobicity parameter, the slope and the reciprocal values of dipole moment. The acetonitrile concentration for the log k'=O retention (OP%₀) could have been calculated from the hydrophobicity and the non-polar unsaturated surface area values of the investigated compounds.     

LC and Principal Component Analysis in the Lipophilicity Study of Seven Angiotensin II-AT1 Receptor Antagonists (Sartans)

Seven sartans have been chromatographed with acetonitrile-buffer and methanol–buffer in different proportions as mobile phases. The retention values, log k or R _M were extrapolated to zero organic modifier content to obtain the log k _w or R _MW values. Calibration equations were obtained for standards of known lipophilicity. A simple method employing a gradient procedure of 10–100% acetonitrile or methanol in 60 min and standards of the extreme lipophilicity was also elaborated. Chromatographic log P values were compared to those calculated by use of different software products. Finally, principal component analysis was performed to explore and visualize similarities and differences among the drugs and among the methods.

     

LC and Principal Component Analysis in the Lipophilicity Study of Seven Angiotensin II-AT1 Receptor Antagonists (Sartans)

Seven sartans have been chromatographed with acetonitrile-buffer and methanol–buffer in different proportions as mobile phases. The retention values, log k or R _M were extrapolated to zero organic modifier content to obtain the log k _w or R _MW values. Calibration equations were obtained for standards of known lipophilicity. A simple method employing a gradient procedure of 10–100% acetonitrile or methanol in 60 min and standards of the extreme lipophilicity was also elaborated. Chromatographic log P values were compared to those calculated by use of different software products. Finally, principal component analysis was performed to explore and visualize similarities and differences among the drugs and among the methods.     

Determination of Lipophilic Character of a Series of Dermorphin-Related Oligopeptioes by Means of Reversed-Phase HPLC

Abstract

In recent times there has been a growing interest in the determination of chromatographic parameters of lipophilicity with regard to their use in the study of quantitative structure-activity relationship (1, 2). Very good correlations had been shown between the chromatographic parameters and the log P or π values as a measure of the partition coefficient between octanol and water (2). The reversed phase TLC R_m values in two different chromatographic systems and the reversed-phase HPLC log k′ values of a series of dermorphin-related oligopeptides have been previously determined (3, 4). The purpose of the present work was to study the relationship between log k′ values on one hand and R_m or ^Σπ values on the other one in view of QSAR studies. In fact the discovery of enkephalin and endorphins with high affinities for opioid receptors added new dimensions to the study of structure-activity relationship of opioid agonists (5, 6, 7, 8).     

Lipophilicity Evaluation of the Products Obtained in the Reaction of N3-Substituted Amidrazones with cis-1,2-Cyclohexanedicarboxylic Anhydride

The lipophilicity of the novel 12 products of the reaction of N³-substituted amidrazones with cis-1,2-cyclohexanedicarboxylic anhydride (4 linear, 4 triazole-like and 4 isoindole ones) with potential pharmacologic activity was evaluated by thin layer and liquid chromatography. Using organic-aqueous eluent systems (with methanol or acetonitrile) on RP18 plates and C18 column, a linear relationship between the volume fraction of modifiers and the retention indices was obtained. The retention values, log k or R _M were extrapolated to zero organic modifier content to obtain the log k _w or R _MW values. 12 compounds with known literature lipophilicity were used as a calibration dataset. The results were compared in a multivariate way with in silico methods (ALOGPs, AC_logP, AB/LogP, COSMOFrag, miLogP, ALOGP, MLOGP, KOWWIN, XLOGP3).

     

Lipophilicity Evaluation of the Products Obtained in the Reaction of N3-Substituted Amidrazones with cis-1,2-Cyclohexanedicarboxylic Anhydride

The lipophilicity of the novel 12 products of the reaction of N³-substituted amidrazones with cis-1,2-cyclohexanedicarboxylic anhydride (4 linear, 4 triazole-like and 4 isoindole ones) with potential pharmacologic activity was evaluated by thin layer and liquid chromatography. Using organic-aqueous eluent systems (with methanol or acetonitrile) on RP18 plates and C18 column, a linear relationship between the volume fraction of modifiers and the retention indices was obtained. The retention values, log k or R _M were extrapolated to zero organic modifier content to obtain the log k _w or R _MW values. 12 compounds with known literature lipophilicity were used as a calibration dataset. The results were compared in a multivariate way with in silico methods (ALOGPs, AC_logP, AB/LogP, COSMOFrag, miLogP, ALOGP, MLOGP, KOWWIN, XLOGP3).     

Centrifugal Partition Chromatography. V. Octanol-Water Partition Coefficients,Direct and Indirect Determination

Abstract

Octanol-water partition coefficients (K_oct) are one of the accepted physico-chemical parameters for predicting the biological effects of organic chemicals. It is demonstrated that centrifugal partition chromatography (CPC) can be used to determine directly the K_oct values from about 0.003 to 300. The mobile phase must be water and the stationary phase must be octanol for accurate determination of the larger K_oct values. To reduce retention times and volumes, the stationary phase volume can be decreased. This can be done using an original mode: the “underload” mode. The “underloading” procedure is described. To extend the K_oct range which can be determine by CPC, the system hexane (60%) octanol (40%)-water was used. A single linear relationship between log K in this system and log K_oct was established allowing to determine the K_oct values up to 1000 (log K_oct=3).     

Electrostatic interactions in normal and reversed-phase high-performance thin-layer chromatography. Preliminary experiments

Summary The retention behaviour of five polycyclic aromatic hydrocarbons having nearly equal ionization potentials but different molecular polarizability values was investigated using normal and reversed-phase high-performance TLC systems. Homologous series of hydrocarbons and n-alcohols were applied as the mobile phases. The electrostatic interactions operating in these chromatographic systems were analysed by studying the relationship between the log 1/R_F values and the molecular polarizabilities of solutes and solvents.     

Predicting retention data using the slope of the log adjusted retention time vs. carbon number plot for n-alkanes

Summary The slope of the n-alkane log plot dt′_R/dn_c (t′_R=adjusted retention time; n_c=carbon number) for a stationary phase can be used to obtain the retention index of an unidentified substance in a chromatogram containing only one peak with a known retention index, or to predict the retention time of a substance from that of a different homolog in the same series. It can also be used to translate retention indices into relative retention time, partition coefficient or specific retention volume. Published values of the slope are collected and critically evaluated. Equations are deduced that predict its approximate value at a specified temperature given the value at only one other temperature.     

Chromatographic Evaluation of the Lipophilic Properties of Selected Pesticides

Monolinuron, chlortoluron, diuron, isoproturon, linuron, diflubenzuron, dimefuron, teflubenzuron, and lufenuron have been chromatographed on an RP-HPLC column and on RP-HPTLC plates with methanol–water in different volume proportions as mobile phases. The retention values log k, and R_M were extrapolated to zero methanol content. Chromatographic lipophilicities (log k_w, R_Mw, _o(HPLC), and _{o (TLC)}) were compared with measured (log P_exp) partition coefficients and with values (A log Ps, IA log P, C log P, log P_Kowin, and x log P) calculated by use of five different software products. The most significant correlations were found between the chromatographic lipophilicities and C log P values. Satisfactory linear correlation was also obtained between lipophilicity (log k_w, R_Mw) and the valence Gutman index (M).     

Determination of lipophilicity of γ‐butyrolactone derivatives with anticonvulsant and analgesic activity using micellar electrokinetic chromatography

The lipophilicity of a library of 30 derivatives of dihydrofuran‐2(3H)‐one (γ‐butyrolactone) was determined by MEKC. Calibration curve prepared for ten reference drugs enabled to calculate partition coefficient (log P) for novel compounds. The results of MEKC analysis were compared with lipophilicity coefficients determined by RP‐TLC (R_M0) and computational (Mlog P, Clog P) methods. Good correlation was observed between the results obtained by both experimental methods: the MEKC parameters log k and relative lipophilicity R_MO. The relationship between determined log P values and results of the computational prediction was weaker. Analysis of the relationship between lipophilicity and anticonvulsant activity showed statistically significant differences between mean values of log P coefficients for group of active (2.18) and inactive (1.51) compounds in the maximal electroshock test.     

Lipophilicity of Some Preservatives Estimated by RP-TLC Using Stationary Phases with Different Polarity

Lipophilcity of some preservatives was determined by reversed phase high performance thin layer chromatography (RP-HPTLC) using methanol–water mixtures in different volume proportions as mobile phase on three stationary phases of different polarity: RP-18F_254s, RP-18WF_254s and CNF_254s plates. The R _M values decreased linearly with increasing methanol concentration in the mobile phase in all cases. The regression determination coefficients obtained for all stationary phases were excellent (higher than 0.98 in most cases). The chromatographic behavior of the preservatives on the RP-HPTLC plates used in this study is similar and in a very good agreement with their polarity. Good chromatographic regularities found for retention factors and by applying principal component analysis for all three types of stationary phases indicate that the same lipophilic interactions are dominants in all cases. The relationships between different RP-HPTLC retention parameters (R _M0 , b, scores of R _F -PC1/R _F and scores of R _M -PC1/R _M ) and various calculated log P values of the same preservatives show highly significant correlations for all types of stationary phases.     

Determination of lipophilicity for antitumor acridinone derivatives supported by gradient high-performance liquid chromatography method

The lipophilicity values of selected acridinone (imidazoacridinone and triazoloacridinone) derivatives were measured by gradient reversed-phase high-performance liquid chromatography (RP-HPLC) using a C18 stationary phase with a water/acetonitrile mixture as a mobile phase. The retention times obtained served as input data and appropriate log k_w values (i.e., the retention factor log k_w extrapolated to 0% organic modifier) as an alternative to log P were calculated using the DryLab program. The relationships between the lipophilicity (log k_w) and the chemical structure of the studied compounds, as well as correlation between experimentally determined lipophilicities (log k_w) and log P data calculated using some commonly available software, are discussed.     

Retention behavior of high performance ion chromatography using binary eluants

The retention behavior of high performance ion chromatography using binary eluants is given. The relationship between log(t_R) and log(1/[E]) is linear, which has been demonstrated experimentally with mixed anion solution.     

Gas chromatographic analysis of C1–C4 nitroparaffins. Separation and identification

Summary The separation of C₁–C₄ nitroparaffins on SE-30, PEGA and Porapak R stationary phases was investigated. The nitroparaffin mixture was obtained from a real technological process. The best separation was achieved on Porapak R at 190°C. The fact that each peak obtained from this column corresponded to a single compound was checked by utilizing the linear relationship between the peak widths and the adjusted retention times (t _R ). Peak identification was carried out using the chromatographic data only, with help of plots of log t _R vs. carbon number and log t _R vs. boiling point; some of the results were also confirmed with comparing the retention times with those of pure substances and IR investigation of the collected chromatographic fraction.     

Correlation between hydrophobicity of amino acids and retention data in reversed-phase liquid chromatography with micellar eluents

Summary Hydrophobic character is usually expressed in terms of the partition coefficient in 1-octanol-water (log P_o/w). However, measurement of this coefficient is often problematic. Retention in micellar liquid chromatography is mainly due to hydrophobic interactions and can also be used as an index of hydrophobicity. A hydrophobicity scale was established with retention data foro-phthalaldehyde (OPA)-N-acetyl-L-cysteine (NAC) amino acid derivatives, using the glycine derivative as reference. Since the OPA-NAC derivatives only differ in the nature of R₁ in the amino acid (R₁CH (COOH)NH₂), in the absence of electrostatic interactions the hydrophobic character of the substituent was responsible for retention. Linear relationships were obtained between log of the ratiok′ of amino acid derivatives:k′ of the glycine derivative for a given mobile phase, and logP _o/w for the R₁ substituent. Good correlations were also found for phenylthiohydantoin amino acid derivatives.