QSAR characterization of new synthesized hydantoins with antiproliferative activity.

Hydantois have been identified as constituents of a number of pharmacologically active molecules. In the present study, we have examined in vitro antiproliferative activity against human colon cancer cell lines HCT-116 of three series of 3-(4-substituted benzyl)-hydantoins with various substituent attached in position 5 of the hydantoin ring. Since the investigated compounds have recently been synthesized and show antiproliferative activity, a good understanding of the properties of the potential drug responsible for their pharmacokinetics is an important goal for their further development. One of the important properties is lipophilicity. Lipophilicity has been assessed by reversed-phase liquid chromatography (high-performance thin-layer chromatography and high-pressure liquid chromatography) by means of direct and indirect (using calibration curve) methods. Chromatographic lipophilicity indices in addition to calculated logP values were compared by hierarchical cluster analysis. The linear solvation energy relationship approach was used to understand and compare the types and relative strength of the molecular interactions that occur in the chromatographic as well as in the n-octanol-water partitioning systems. Finally, correlation between in silico pharmacokinetic predictors and antiproliferative activity was examined. Preliminary quantitative structure-activity relationship modeling indicates that pharmacokinetic predictors capture only one-quarter of all chemical features that are important for antiproliferative activity itself. Among selected descriptors are chromatographic lipophilicity indices.

RP-HPTLC Data in Correlation Studies of a 5-Arylidene-2,4-Thiazolidinedione Derivatives.

Thiazolidinediones show a large scale of biological activities as a result of ability to perform interactions with a variety of biological targets. Modeling properties of newly synthesized thiazolidinediones is important for both understanding their activity and predicting their interactions. In the paper the chromatographic retention data determined in various RP chromatographic systems (stationary phases RP-CN and RP-18; six aqueous binary mobile phases modified with acetonitrile, methanol, ethanol, propanol, acetone and dioxane) were considered for 13 new 5-arylidene-2,4-thiazolidinediones. In this article, three attempts to find suitable quantitative structure-retention relationship (QSRR) models that quantify retention as a function ofmolecular descriptors had been presented. Models built for RP-18 show generally better multiple R but are also mostly monoparametric with logP as the dominant descriptor. More informative from the standpoint of molecular interactions are QSRR models for RP-CN. The quality of those models depends of the mobile phase modifier (the best was obtained for acetone and the worst for propanol as modifier). Since all QSRR models use extrapolated retention as a property which is indirectly connected with plasma protein binding further assessment of plasma protein binding should be based on extrapolated retention on a RP-CN stationary phase instead of standard RP-18.

Chemometric study of retention indices of some thiazolidinediones derivatives in two low polarity stationary phases.

Application of chemometric methods in the study of the retention indices of thirteen 5-arylidene-2,4- thiazolidinediones in two low polarity high-performance thin-layer chromatographic (HPTLC) stationary phases (RP-18 and RP-CN) and six aqueous mobile phases. Principal component analysis classified chromatographic systems into four specific groups while one system remained non-classified. Hierarchical clustering analysis enabled grouping of the chromatographic systems into three clusters, and the studied compounds into three main classes. The color map enabled more in-depth interpretation of the relationships between the studied compounds and HPTLC systems applied.

Structure-retention relationship study of HPLC data of antiepileptic hydantoin analogues.

In the study, 18 antiepileptic hydantoin analogues were investigated by means of reversed-phase HPLC on C-18 stationary phase and eluent acetonitrile-water. Quantitative structure-retention relationship (QSRR) study has been applied in order to understand factors that affect the retention which is closely correlated to the activity (ED50 values). To overview the compounds for similarities and dissimilarities principal component analysis (PCA) has been applied. Six multiple linear regression models based on the most relevant descriptors were developed. Descriptors for MLR were selected according to variable importance calculated by partial least squares (PLS) analysis. Besides ALOGP the most important is aromatic ratio for mobile phases with more than 45% of acetonitrile, as well as electrotopological states when the % of acetonitrile is less than 40%. High agreement between experimental and predicted retention, obtained in the validation procedure, indicated the good quality of the derived QSRR models. For individual linear models, crossvalidation squared correlation coefficients (Q²) ranging from 0.697 to 0.837 were obtained. The residual values (difference between observed and calculated) agreed well within experimental error. Additionally, models were compared in terms of the smallest residual value by recently developed method of ranking based on the sum of ranking differences (SRD).

Chemometric characterization of s-triazine derivatives in relation to structural parameters and biological activity.

OBJECTIVE: In this study 14 newly synthesized s-triazine derivatives were investigated by means of reversed-phase thin-layer chromatography (TLC) on C-18 stationary and five different mobile phases: acetone-water, acetonitrile-water, methanol-water, 2-propanol-water, and tetrahydrofuran-water. METHODS: Principal component analysis (PCA) was performed to explore and visualize similarities and differences among the compounds and among the mobile phases. Observations from the PCA were supported using hierarchical cluster analysis (HCA). RESULTS: Physicochemical parameters that are significant for activity, that is, absorption, distribution, and bonding for different receptors in target tissues were calculated. CONCLUSION: Highly predictive models, describing quantitative relationships between chromatographic retention and parameters that influence activity, were obtained using partial least squares (PLS) method.

Retention data from reverse-phase high-performance thin-layer chromatography in characterization of some bis-salicylic acid derivatives.

The chromatographic behaviour of salicylic acid derivatives was investigated using reversed-phase high performance thin-layer chromatography (RP HPTLC) with methanol-water and dioxane-water binary mixtures as mobile phase in order to establish relationships between chromatographic data and selected physico-chemical parameters that are related to ADME (absorption, distribution, metabolism and elimination). Some of the investigated compounds were screened for antioxidant activity. Examination of chromatographic behaviour revealed a linear correlation between R(M) values and the volume fraction of mobile phase modifier. Obtained R(M)(0) values were correlated with lipophilicity, solubility, human intestinal absorption, plasma-protein binding, and blood-brain barrier data. The comparison among chromatographic data obtained by two mobile phase was performed with a statistical technique, principle component analysis.

HPTLC chromatography of androstene derivates. Application of normal phase thin-layer chromatographic retention data in QSAR studies.

The chromatographic behavior of seven 16-oximino derivatives of 3beta-hydropxy-5-androstene have been investigated using the normal-phase (NP) HPTLC chromatographic mode of the type silica-non-polar diluent (benzene)-polar modifier (acetonitrile, ethyl acetate, or dioxane). The linear relationship between the retention constants (R(M)) and the logarithm of the organic modifier content in the mobile phase allowed for the calculation of R(M)0 values. The influence of substituent in the molecule on extrapolated retention data is discussed. To better understand the retention mechanism in the separation of androstene compounds, the functional group contributions (tauX) were compared with Hansch substituent constants (pi). An attempt to quantitate the lipophilicity of the investigated compounds using normal phase thin-layer chromatographic R(M)0 value was made. Also, the relative lipophilicity values determined previously by RPC as well as activity were compared with NPC data.

Evaluation of lipophilicity of some benzimidazole and benztriazole derivatives by RP HPTLC and PCA.

The lipophilic character of some benzimidazole and benztriazole derivatives was studied. The classical R(Mo) values were compared with the factors scores obtained by principal component analysis (PCA) based also onto the TLC retention data. The very high correlation between the R(Mo) values and slopes (specific hydrophobic surface area) indicated as usually that this group of compounds could be considered as a homologous series independently of their structural heterogeneity. It is emphasized once again that this procedure can not be a rational and objective way for congeneric studies because always there is a high correlation between slope and intercept. The reliability of the factor scores values as lipophilic indices are shown by their high correlation with the classical R(Mo) values. In addition, the 'lipophilicity chart' described by the first two components has the effect of separating compounds from each other most effectively from the congeneric aspect point of view. The most lipophilic compounds appeared to be the benzimidazole derivatives.

Evaluation of the predictive power of calculation procedure for molecular hydrophobicity of some estradiol derivates.

Several calculation procedures for log P values based on the fragmental and atomic contributions are compared with experimental reversed-phase liquid chromatography (RPLC) retention of estradiol derivates. The RPLC experiments were performed on HPTLC and HPLC commercially available stationary phases. Binary solvent mixtures of methanol-water and acetonitrile-water were used as mobile phases. The correlation between log P and various chromatographically obtained hydrophobicity parameters (R(M)0, log k(w) and phi0) are quantified. The R(M)0, i.e., log k(w) were obtained by linear extrapolation of retention to 0% organic modifier. Phi0 values were obtained from the slopes and intercepts of such linear relationship. The mutual relationship between phi(0,MeOH) and phi(0,ACN) values of the compounds were discussed. The obtained statistical results can be summarized in the following order of reliabilities for different log P calculation methods: Broto>ACD/logP>Crippen>Rekker>Viswanadhan.