Toward steroidal anticancer drugs: Non-parametric and 3D-QSAR modeling of 17-picolyl and 17-picolinylidene androstanes with antiproliferative activity on breast adenocarcinoma cells.

The present study is aimed to analyze lipophilicity and ADMET profiles, and to develop field based 3D-QSAR and ligand-based pharmacophore hypothesis for a series of 17α-picolyl and 17(E)-picolinylidene androstane derivatives in order to give detailed structural insights and to highlight important binding features of novel androstane derivatives, as compounds with antiproliferative activity toward breast adenocarcinoma cells. This study can provide guidelines for the rational design of novel potent compounds. Sum of ranking differences (SRD), as a non-parametric method, was applied for compounds ranking. 3D-QSAR methods, including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), were applied to predict the antiproliferative effect on breast adenocarcinoma cells and provide the regions in space where interactive fields may influence the activity. The compounds are ranked so the compounds with the most favorable ADME and lipophilicity features together with significant anticancer activity can be distinguished. The established 3D-QSAR model could be used for design of new compounds with antiproliferative activity on the human ER- breast adenocarcinoma cells. The pharmacophore model is able to accurately predict antiproliferative activity. Generally, the present study provides significant guidelines for further selection, synthesis and rational design of new highly potential androstane derivatives as anticancer drugs.

Chemometrics approach based on chromatographic behavior, in silico characterization and molecular docking study of steroid analogs with biomedical importance.

Physicochemical characterization of steroid analogs (triazole, tetrazole, toluenesulfonylhydrazide, nitrile, dinitrile and dione) is considered to be a very important step in further drug selection. This study applies to the determination of lipophilicity of previously synthesized steroid derivatives using reversed-phase high-performance liquid chromatography (RP HPLC). Chemometric aspect of chromatographic lipophilicity is given throughout multiple linear regression (MLR) quantitative structure-retention relationships (QSRR) approach. Minimal inhibitory concentration (MIC) is determined for two steroid derivatives possessing antimicrobial activity against Staphylococcus aureus. Molecular docking study was performed in order to identify the compound with the most promising potential as human cytochrome P450 CYP17A1inhibitor. Identified 3ß-hydroxyandrost-5-eno[16,17-d]-1,2,3-triazole (I.2.) could be recommended for further trials for anticancer drugs and subjected to the absorption, distribution, metabolism, excretion and toxicity (ADMET) evaluation.

A comparative study of chromatographic behavior and lipophilicity of selected natural styryl lactones, their derivatives and analogues.

This study is based on the analyses of the retention behavior of selected natural styryl lactones and their synthetic analogues in reversed-phase high-performance liquid chromatography. Chromatographic separations were achieved applying ZORBAX SB-C18 column and two different mobile phases: methanol-water and acetonitrile-water. Chromatographic lipophilicity of the analyzed compounds was defined by logk0 constant and correlated with in silico molecular descriptors. According to the statistical validation parameters, obtained results indicate that the presented linear and multiple quantitative structure-retention relationship models can successfully predict the chromatographic lipophilicity of structurally similar compounds. Hierarchical cluster analyses (HCA) was applied in order to group similar compounds according to their chromatographic and in silico lipophilicity. It can be concluded that chromatographic systems with methanol-water were better for modelling of logk0. Modelling was performed in order to characterize compounds regarding their lipophilicity profiles as future drug candidates.

Lipophilicity estimation and characterization of selected steroid derivatives of biomedical importance applying RP HPLC.

The present paper deals with chromatographic lipophilicity determination of twenty-nine selected steroid derivatives using reversed-phase high-performance liquid chromatography (RP HPLC) combined with two mobile phase, acetonitrile-water and methanol-water. Chromatographic behavior of four groups (triazole and tetrazole, toluenesulfonylhydrazide, nitrile and dinitrile and dione) of selected steroid derivatives was studied. Investigated compounds were grouped using principal component analysis (PCA) according to their logk values for both mobile phases. Grouping was in the very good accordance with the polarity and lipophilicity of the investigated compounds. QSRR (quantitative structure-retention relationship) approach was used to model chromatographic lipophilicity behavior using molecular descriptors. Modeling was performed using linear regression (LR) and multiple linear regression (MLR) methods. The most influential molecular descriptors were lipophilicity descriptors that are important for molecules ability to pass through biological membranes and geometrical descriptors. All established LR-QSRR and MLR-QSRR models were statistically validated by standards, cross- and external validation parameters as well as with two graphical methods. According to all these assessments, MLR models were better for chromatographic lipophilicity prediction. It was shown that chromatographic systems with methanol-water were better for modeling of logk than systems with acetonitrile-water, as well as the systems that contained lower volume fractions of organic component in mobile phase. Modeling was performed in order to obtain lipophilicity profiles of investigated compounds as future drug candidates of biomedical importance.