Biomedical subjects

Roman Kaliszan

Publications and source records attributed to Roman Kaliszan.

29 records · Page 2Linked to original sources

PubMed2004

High-throughput evaluation of lipophilicity and acidity by new gradient HPLC methods.

There is a need for fast testing of drug candidates for properties of pharmacokinetics and pharmacodynamics importance, in particular lipophilicity and acidity. These two parameters can conveniently be estimated by gradient reversed-phase HPLC. Appropriate conventional organic solvent gradient and the new pH gradient HPLC procedures are presented. The chromatographic parameter of lipophilicity, log kw, can be determined from two organic solvent gradient runs instead of 6-8 runs necessary in the standard isocratic (polycratic) approach. The newly introduced pH gradient reversed-phase HPLC consists in a programmed increase during the chromatographic run of the eluting power of the mobile phase with regards to ionizable analytes. The eluting strength of the mobile phase increases due to its increasing (in case of acidic analytes) or decreasing (basic analytes) pH, whereas the content of organic modifier remains constant. It has been theoretically and experimentally demonstrated that the pKa and log kw values can be evaluated based on retention data from a pH gradient run, combined with appropriate data from two organic solvent gradient runs. The gradient HPLC-derived log kw parameters correlate well with analogous parameters determined isocratically as well as with reference lipophilicity parameter log P (logarithm of n-octanol/water partition coefficient). Also, the HPLC-derived pKa parameters correlate to the literature pKa values (w(w)pKa), conventionally determined by titrations in water. The approach described allows rapid and high-throughput assessment of log kw and pKa for large series of drugs candidates, also when the analytes are available in a form of mixture, e.g. produced by combinatorial synthesis.

Chemical Phenomena↗

PubMed2003

New approaches to chromatographic determination of lipophilicity of xenobiotics.

Liquid chromatography and capillary electrophoresis are unique tools for fast and efficient modeling of pharmacokinetic properties of drug candidates. Therefore numerous new separation methods and procedures have very recently been introduced to facilitate the high-throughput screening of biopartitioning features of xenobiotics. This report is a concise, up-to-date review of progress in the chromatographic assessments of data of importance for medicinal chemistry and molecular pharmacology.

Chromatography, High Pressure Liquid↗

PubMed2003

Predictive approaches to gradient retention based on analyte structural descriptors from calculation chemistry.

Quantitative structure retention relationships (QSRRs) were applied to predict reversed-phase HPLC gradient retention. The performance of the recently recommended QSRR models was compared. One tested model is based on structural descriptors from molecular modeling. To quantitatively characterize the structure of analytes the following three structural descriptors are employed: total dipole moment, electron excess charge of the most negatively charged atom and water-accessible molecular surface area. Reliability of the resulting gradient retention time predictions was compared to that provided by the models relating retention to the theoretically calculated logarithm of n-octanol-water partition coefficient, log P. The requested values of log P were obtained using three commercially available softwares. The predicted retention parameters were compared for a series of structurally diversified small molecular mass analytes. It has been demonstrated that the retention predictions from both the molecular modeling descriptors-based and the log P-based QSRR are characterized by similar errors. It has been hypothesized that the optimization of separation based on QSRRs and the linear solvent strength theory might be of practical analytical value.

Chromatography, High Pressure Liquid↗

PubMed2003

Chromatographic retention parameters in medicinal chemistry and molecular pharmacology.

The importance of lipophilicity for pharmacological and toxicological potency of xenobiotics has been recognized for a century. The reference lipophilicity scale is defined by the logarithm of partition coefficient, log P, determined in the l-octanol-water partition system. The tediousness of determinations and limited interlaboratory reproducibility of log P, on one hand, and the observations of linear relationship between log P and chromatographic retention parameters, on the other hand, gave rise to the substitution of the former by the readily available chromatographic data. Since its introduction, the reversed-phase high - performance liquid chromatography (HPLC), which has been viewed in terms of partition of a solute between a polar, aqueous mobile phase and a nonpolar stationary phase appeared especially suitable for lipophilicity (hydrophobicity) determination. The method got wide acceptance and has officially been recommended by the OECD. Fundamental relationships between chromatographic parameters are reviewed from the point of view of convenient and reliable lipophilicity measurements. The advantages and disadvantages of the stationary phase materials, which are presently employed for the determination of lipophilicity as well as those of specific HPLC systems and procedures, are critically reported. The literature on the application of chromatographic and electrochromatographic methods for assessment of lipophilicity of xenobiotics is reviewed. A separate paragraph is devoted to interpretation of retention parameters from HPLC systems comprising biomacromolecules. Role of lipophilicity in drug-biomacromolecule interactions is discussed in terms of quantitative structure-retention relationships (QSRR). Finally, reports are analyzed on systemic information which can be extracted by multivariate methods of data processing, like principal component analysis (PCA), from sets of lipophilicity parameters determined in diverse HPLC systems.

Chemical Phenomena↗

PubMed2002

Quantitative structure-retention relationships in comparative studies of behavior of stationary phases under high-performance liquid chromatography and capillary electrochromatography conditions.

Quantitative structure-retention relationships (QSRR) have been employed in studying the molecular mechanism of chromatographic separations under pressure- (HPLC) and electro-driven (CEC) conditions. Logarithms of retention factors corresponding to zero percent of organic modifier in aqueous eluent, log k(w), were determined on eight reversed-phase stationary phases under both HPLC and CEC conditions at similar eluent flow velocities. QSRR equations describing log k(w) in terms of linear solvation energy relationship (LSER) parameters of analytes, in terms of simple structural descriptors acquired by calculation chemistry, and in terms of logarithms of n-octanol-water partition coefficients, were derived. Parameters of corresponding QSRR equations for individual stationary phases were compared for both HPLC andCEC modes and the resulting similarities and differences in retention mechanisms were discussed. It has been concluded that at least in the case of regular neutral analytes the specific inputs to separation mechanism due to the electric field in CEC are of secondary importance.

Chromatography, High Pressure Liquid↗

PubMed2002

Lipophilicity and pKa estimates from gradient high-performance liquid chromatography.

The linear-solvent strength (LSS) model of gradient elution has been applied to estimate parameters of lipophilicity and acidity of a series of drugs and model chemicals. Apparent pKa values and log kw values for individual analytes were determined in 2-3 gradient runs. The first experiment (or first two experiments) uses a wide-range organic modifier gradient with pH chosen for suppressed ionization of the analyte. The result of this experiment allows an estimate of contents of organic modifier of the mobile phase (%B) providing the required retention coefficient, k, for the non-ionized analyte. The following experiment is carried out with the latter %B and a pH-gradient of the aqueous component of the eluent that is sufficient to overlap the possible pKa-value of the analyte. The initial pH of the buffer used to make the mobile phase is selected to insure that the analyte is in non-ionized form. The resulting retention time allows an estimate of PKa in a solvent of the selected %B. At the same time, estimates of log kw can also be obtained. The log kw parameter obtained from gradient HPLC by the approach proposed correlated well with the corresponding value obtained by standard procedure of extrapolation of retention data determined in a series of isocratic measurements. Correlation between log kw and the reference parameter of lipophilicity, log P, was very good for a series of test analytes and satisfactory for a structurally diverse series of drugs. The approach supported with specific detection procedures can be recommended for fast screening of lipophilicity of individual components of complex mixtures like those produced by combinatorial chemistry. The values of pKa obtained in a study were found to correlate with the literature pKa data determined in water for a set of aniline derivatives studied. In case of a series of drugs the correlation was less than moderate if the general procedure of pKa determination was applied.

Chromatography, High Pressure Liquid↗

PubMed2002

Combination of linear solvent strength model and quantitative structure-retention relationships as a comprehensive procedure of approximate prediction of retention in gradient liquid chromatography.

Quantitative structure-retention relationships (QSRR) combined with the linear solvent strength (LSS) model are demonstrated to provide approximate predictions of gradient reversed-phase high-performance liquid chromatography (HPLC) retention time for any structurally defined analyte on a once characterized column. The approach requires at first the determination of retention times for a predesigned model series of 15 analytes in two gradient runs. Then by employing the LSS theory a given HPLC system of interest is quantitatively characterized. Structure of the model analytes is next described quantitatively by means of three structural descriptors from standard molecular modeling: total dipole moment, electron excess charge of the most negatively charged atom and water-accessible molecular surface area. With those data the general QSRR equations are derived which describe gradient retention times of the model analytes in the specific column/eluent system. Having now the structural descriptors for any analyte to be chromatographed in such a characterized HPLC system, one employs respective general QSRR equations to calculate its expected gradient retention time at given gradient conditions by means of appropriate LSS equations. Additionally, the chromatographic parameters log kw and S can be calculated and retention coefficients corresponding to chosen isocratic conditions evaluated. The approach provides retention predictions which can be treated as a first approximation of actual data. Predictions are not yet precise enough for practical separation purposes but can be of use in rational modification of analytical conditions aimed at optimization of separations.

Chromatography, High Pressure Liquid↗

PubMed2002

Quantitative structure-retention relationships in affinity high-performance liquid chromatography.

In this report the affinity high-performance liquid chromatography data, which were determined on silica-based human serum albumin, alpha1-acid glycoprotein, keratin, collagen, melanin, amylose tris(3,5-dimethylphenylcarbamate), and basic fatty acid binding protein columns, are discussed. Using a quantitative structure-retention relationship (QSRR) approach the affinity data were interpreted in terms of structural requirements of specific binding sites on biomacromolecules. The unique chromatographic properties of immobilized artificial membrane and cholesterol stationary phases were also analyzed from the point of view of mimicking biological processes. It has been demonstrated that chemometric processing of appropriately designed sets of chromatographic data derived in systems comprising biomolecules provides information of relevance for molecular pharmacology and rational drug design.

Cholesterol↗

PubMedDate not supplied

Prediction of peptide retention at different HPLC conditions from multiple linear regression models.

To quantitatively characterize the structure of a peptide and to predict its gradient retention time at given HPLC conditions three structural descriptors are used: (i) logarithm of the sum of retention times of the amino acids composing the peptide, log SumAA, (ii) logarithm of the van der Waals volume of the peptide, log VDW(Vol), (iii) and the logarithm of the peptide's calculated n-octanol-water partition coefficient, clog P. The log SumAA descriptor is obtained from empirical data for 20 natural amino acids, determined in a given HPLC system. The two other descriptors are calculated from the peptides' structural formulas using molecular modeling methods. The quantitative structure-retention relationships (QSRR), build by multiple linear regression, describe HPLC retention of peptide on a given chromatographic system on which the retention of the 20 amino acids was predetermined. A structurally diversified series of 98 peptides was employed. The predicted gradient retention times on several chromatographic systems were in good agreement with the experimental data. The QSRR equations, derived for a given system operated at variable gradient times and temperatures allowed for the prediction of peptide retention in that system. Matching the experimental HPLC retention to the theoretically predicted for a presumed peptide could facilitate original protein identification in proteomics. In conjunction with MS data, prediction of the retention time for a given peptide might be used to improve the confidence of peptide identifications and to increase the number of correctly identified peptides.

Amino Acid Sequence↗

PubMedDate not supplied

Quantitative structure-activity relationships study of a series of imidazole derivatives as potential new antifungal drugs.

The Quantitative Structure-Activity Relationships (QSAR) has been developed to relate antifungal activity against Candida albicans and Rhodotorula glutinis of new imidazole derivatives with their physico-chemical and structural properties. For 265 imidazole derivatives the most significant statistically equations has been obtained with correlation coefficients R=0.800 and R=0.820 in case of activity against Ca. and Rh.g., respectively. The overall antifungal activity has been described by means of size and bulkiness related parameters as well as polar and lipophilic interactions. The significance of lipophilicity in terms of n-octanol/water partition coefficient, ClogP, on antifungal potency against both fungi has been investigated. QSAR equations for different classes of antifungal activity have been obtained. With a very high probability level (92% and 96%) the weak or very weak antifungal potency against C.a. can be determined and thus the number of required experiments can be reduced.

Antifungal Agents↗

PubMedDate not supplied

Imidazoline receptors in relaxation of acetylcholine-constricted isolated rat jejunum.

Since 20 years the concept of specific imidazoline receptors has remained controversial. The problem with imidazoline receptors is mostly due to their functional similarity to alpha-adrenoceptors. In this work, a pharmacodynamic model of isolated rat jejunum longitudinal muscle strips constricted with acetylcholine (Ach) was applied to separate functional properties of the two types of receptors. Relaxation of the preparation was measured as a function of concentration of 2-(benzofuranyl)-2-imidazoline (2-BFI), a specific imidazoline I2 receptor ligand, cirazoline, a potent I2 receptor ligand and alpha1-adrenoceptor agonist, phenylephrine, an agonist of alpha1-adrenoceptor, moxonidine, a ligand of I1 receptor, efaroxan, a ligand of I3 receptor and 5-bromo-6-(imidazoline-2-yl-amino)quinoxaline (UK14304), an agonist of alpha2-adrenoceptor. Next, the effects of a series of imidazoline-and/or alpha-adrenoceptor-binding drugs (prazosin, yohimbine, RS79948, RX821002, idazoxan and efaroxan) on the relaxation of the Ach-constricted rat jejunum strips, induced by 2-BFI, cirazoline or phenylephrine, were studied. The obtained results demonstrate the involvement of the postsynaptic imidazoline receptors in rat jejunum motility. These receptors are of I2 subtype and are linked to alpha-adrenoceptors of the predominantly alpha1 subtype. The alpha1 receptors dominate functionally over the I2 in the isolated rat jejnum. The proposed model might be useful in search for more specific new drugs.

Acetylcholine↗