Current Computer - Aided Drug Design - Volume 2, Issue 4, 2006

Lipophilicity is the molecular property, which plays a prominent role in the mutual interactions of biologically active substances. Therefore, it is not surprising that lipophilicity has been in the focus of attention at the study of the influence of external compounds on living bodies. The first attempts - more than century ago - to find the relationships between biological activity and lipid solubility are connected with the works of Mayer and Overton. The great contribution to the parametrization of lipophilicity and its use in the analysis of structure-biological activity relationships belongs to Hansch, Fujita and Leo and later to Rekker and Nys. The importance of lipophilicity for the behavior of the substance in biological system is derived from its driving force in the transport of compound from the site of administration to the site of action (pharmacokinetics) and with the similar weight on the ligand-receptor interactions at the targeted site (pharmacodynamics). Nevertheless, some difference exists between both cases: in the ligand-receptor binding, lipophilicity is manifested itself first of all by the hydrophobic interactions among the nonpolar parts of both molecules. The 1-octanol-water partitioning system was chosen as an arbitrary standard for the expression of lipophilicity. The standard shake-flask technique for the determination of partition coefficients, which is sometimes labourious and for highly lipophilic compounds inaccurate, can be substituted by various chromatographic techniques. TLC, HPLC, capillary electromigration chromatography (CEC) or immobilized artificial membrane (IAM) chromatography, usually in the reversed-phase mode, are the typical examples. In these experimental conditions, the mandatory requirement is fulfiled and the adsorption mechanism of retention is predominantly suppressed. Using lipophilicity parameters, we have to keep in mind the golden rule of QSAR analyses, that the more homogenous series of compounds is studied, the simpler and relevant results are achieved. The review contributions submitted to this issue can be divided to three categories. M. Charton and V. Khadikar with coworkers drew the attention to the theoretical computation of log P values using empirical, nonexperimental quantities. M. Charton utilized the hydrogen bonding contributions to lipophilicity and V. Khadikar summarized the recent results concerning the relations between topology of molecules and their lipophilicity. The next two contributions, i.e. of A. Nasal and R. Kaliszan and F. Barbato are devoted to the recent progress in the chromatographic methods in the evaluation of lipophilicity. Both contributions are comprehensive and offer the comparative view on the experimental results and techniques presented - HPLC methods in the first one and IAM chromatography in the second one. The last but not least contribution from M. Cronin is dealt with the influence of lipophilicity on toxic properties of chemical substances. The use of QSAR methodology in this field is of a great importance for the chemical and pharmaceutical industries and environmental sciences in general.

Modern methods of organic synthesis allow an exponential increase in the number of compounds for screening as drug candidates, often as multicomponent mixture. That requires procedures for assessing lipophilicity parameters that are rapid and can be employed with very small samples. Especially suitable appear to be the methods providing the data needed without prior isolation of an individual component of a mixture. Chromatographic and electrochromatographic techniques are unique with that respect. This review will assess how is the progress in the chromatographic determination of lipophilicity parameters, which could be interesting from the point of view of search for new drugs. In the first paragraph the correlations between measures of lipophilicity from RP HPLC and the n-octanol-water partition coefficient are discussed. Then modern HPLC stationary phases employed in lipophilicity determination are briefly presented. The further paragraphs present the base of gradient HPLC technique employed in lipophilicity evaluation and the very recent results of correlation studies between chromatographic lipophilicity parameters and drug bioactivity data. Finally, the recent applications of electrochromatographic methods in assessment of lipophilicity of xenobiotics are described.

This review discusses Immobilised Artificial Membrane (IAM) HPLC technique in terms of the structure of IAM phases, experimental methods, and information content. In a first part, the relations between pharmacokinetics and lipophilicity are discussed. Lipophilicity in n-octanol of ionisable compounds is shortly examined as a base for further discussion. Particular emphasis is placed on the meaning of phospholipids as partition phases and on the HPLC partitioning techniques. The next part presents structural information on IAM columns. The influence of experimental conditions on IAM-HPLC parameters is also examined. Particular attention is paid to the relations between IAM data and other lipophilicity parameters: IAM data are compared to lipophilicity in n-octanol and partition in liposomes. In the last part, the effectiveness of IAM data to predict bioactivity data is discussed in terms of relationships found with data of i) permeability across Caco-2 cells and passive intestinal absorption, ii) penetration across the blood-brain barrier, iii) pharmacokinetics, iv) various other pharmacological activities, and v) transdermal transport. Based on the studies reported, IAM-HPLC appears as a suitable technique to achieve data of partition in biomembranes. As compared to lipophilicity in n-octanol, IAM data for ionised compounds are distinctive. As compared to partition in liposomes, IAM technique is much faster and more reproducible.

Hydrogen bonding parameters for QSAR are reviewed. Forty five hydrogen bonding parameters for hydrogen acceptor groups and fifteen for hydrogen acceptor and donor groups for substituents bonded to sp2 hybridized carbon atoms (ήXPh) were derived from1-octanol/water partition coefficients by the method previously used for substituents bonded to sp3 hybridized carbon atoms (ήXAk). The parameters derived from log PO/W values for substituted benzenes are applicable to any data set in which substituents are bonded to sp2 hybridized carbon atoms. In aqueous solutions a leveling effect occurs with regard to groups that are hydrogen donors. Thus, groups that are both hydrogen donors and acceptors in aqueous solutions function only as hydrogen acceptors. Colinearity exists between bond moment and hydrogen bonding parameters which may mask the dependence of log PO/W on the former. Partition coefficients of substituted cyclopropanes are probably a function of ήXPh rather than of ήXAk. A study of a data set of 1-substituted naphthalenes showed no significant interaction between a substituent in position 1 and the carbon atom in position 8. Partition coefficients are a function of polarizability, hydrogen bonding, and in some cases, bond moment; the first two effects are dominant. For a data set XG where G is the skeletal group to which the substituent X is bonded the polarizability of both X and G is important.

This review describes topology of the molecule and lipophilicity in that several examples of topological estimation of lipophilicity of the molecule are discussed critically. In doing so, the earlier non-topology methods used to estimate lipophilicity was first discussed critically. Usually, lipophilicity is referred to as partition of organic compound between octanol-water systems, however, some other solvent-systems were also examined topologically. All the proposed models were confirmed by variety of statistical analyses.

The influence of hydrophobicity on toxic potency has been known for over a century. This paper summarises some of the key areas where hydrophobicity, in the form of the logarithm of the octanol-water partition coefficient (log P), is incorporated into quantitative structure-activity relationships (QSARs) for toxicity. Log P is frequently seen in QSARs for acute aquatic toxicity, especially for chemicals acting by non-reactive (i.e. in the absence of covalent binding) mechanisms of action.Within the narcoticmode of acute toxicity, a number of QSARs based on log P have been derived for different mechanisms such as non-polar and polar narcoses. For reactive chemicals, hydrophobicity is important for transport and distribution, such that hydrophobicity based QSARs may be derived for covalently binding chemicals with “constant” reactivity. Due to its contribution to pharmacokinetics, log P is also found in models for other mammalian toxicities such carcinogenicity and skin sensitisation.

Miroslav Kuchar studied organic chemistry at Prague Institute of Chemical Technology, Department of Macromolecular Chemistry, from where he graduated in 1958. He finished his postgraduate studies from the Research Institute for Pharmacy and Biochemistry, completing his PhD on medicinal chemistry in 1969. Moreover, he received his DSc degree in 1993 from Charles University with the dissertation on the use of QSAR for the development of new anti-inflammatory arylalkanoic acids. He worked for his entire professional research career in the Research Institute for Pharmacy and Biochemistry from 1963 to 1989 as a research scientist and as a senior research scientist at the Department of the synthesis of anti-inflammatory compounds; from 1990, he held the post as the head of this department. In 1993, he became the Director for research and development and was active at this position till 2003. Currently, he is working as a consultant at the pharmaceutical company Zentiva. Dr. Kuchar is active as a referee in the Collection of Czechoslovak Chemical Communications, Journal of Chromatography, Current Computer-Aided Drug Design and Grant Agency of Czech Republic. He became the scientific evaluator of European Committee, Brussels, in 1999 as a member of two panels of 5th and 6th Framework Programmes. He is a member of Editorial Board of Current Computer-Aided Drug Design. Then, he was appointed as a member of Scientific Council of Charles University in 1999. The research interests of Dr. Kuchar include research and development of non-steroidal anti-inflammatory compounds and the utilization of QSAR in this field, especially in the group of arylalkanoic acids. Now, his attention is focused on the compounds affecting biosynthesis and/or biological functions of leukotrienes, and on the compounds with anticytokine mechanism of action. The additional interest has been devoted to the parametrization of lipophilicity and the use of chromatography for this purpose. Dr. Kuchar is an author of 119 original and review papers, 23 patents and 4 monographs. During 1984 and 1992, he edited the 1st and 2nd Telesymposia on QSAR (J.R.Prous, International Publishers, Barcelona), some selected publications are cited below. SELECTED PUBLICATIONS Kuchar M., Tomková H., Rejholec V., Korhonen I.O.O.; Gas-liquid chromatography and lipophilicity of esters of benzoic acids: Enthalpy-enthropy compensation; J. Chromatogr. 1987, 398, 43. Kuchar M., Kraus E., Rejholec V., Miller V.; Enthalpy-entropy compensation in reversed phase HPLC of the series of aryloxoalkanoic and arylhydroxyalkanoic acids; J. Chromatogr. 1988, 449, 391. Kuchar M., Jelínková M.; Some problems of chromatographic evaluation of lipophilicity; 2nd Telesymposium on QSAR in Design of Bioactive Compounds ( Kuchar M., Biagi G.L., Hopfinger A., Pliska V. Eds), J.R.Prous Publishers, Barcelona 1992, pp. 65. Kuchar M., Poppová M., Panajotovová V., Vosátka V., Zunová H., Príhoda M.; Derivatives of 4-(2',4'-difluorobiphenyl-4- yl)-2-methyl-4-oxobutanoic acid (flobufen) ; Coll. Czech. Chem. Commun. 1994, 59, 2705. Kuchar M., Poppová M., Jandera A., Panajotovová V., Zunová H., Budesínsky M., Tomková H., Jegorov A., Taimr J.; Chiral forms of Flobufen and its metabolite: Synthesis and basic biological properties; Coll. Czech. Chem. Commun. 1997, 62, 498. Panajotova V., Anderová E., Jandera A., Kuchar M.; Pharmacological profile of the novel potent antirheumatic flobufen; Azneim.-Forsch. 1997, 47, 648. Kuchar M., Culíková K., Panajotovová V., Brunová B., Jandera A., KmonícekV.; 2,4-Di- hydroxyacetophenone derivatives - antileukotrienics with multiple mechanism of action; Coll. Czech. Chem. Commun. 1998, 63, 103. Trejtnar F., Wsol W., Szotáková B., Skálová L., Pávek P., Kuchar M.; Stereoselective pharmacokinetics of Flobufen in rats; Chirality 1999, 11, 781. Kuchar M., KmonícekV., Panajotova V., Jandera A., Brunová B., Junek R., Bucharová V., Cejka J., Satínsky D.; Derivatives of phenylsulfanyl benzoic acids with multiple antileukotrienic activity; Coll. Czech. Chem. Commun. 2004, 69, 2098. Kuchar M., Brunová B., Junek R., Rödling R., Hájícekj., Panajotová V., Jandera A.; The antileukotrienic derivatives and homologues of (quinolin-2-ylmethoxy)sulfanylbenzoic acids with reduced lipophilicity; Coll. Czech. Chem. Commun. 2005, 70, 1357. Bulej P., Kuchar M., Panajotová V., Jegorov A.; Pharmacological profile of 4-(2',4'-difluorobiphenyl-4-yl)-2-methylbutyric acid (deoxoflobufen); Arzneim.-Forsch. 2005, 55, 466. Junek R., Brunová B., Kverka M., Jandera A., Kuchar M.; Antileukotrienic N-arylethyl-2-arylacetamides in the treatment of ulcerative colitis, Eur. J. Med. Chem. 2006, 41, in press.