Structure-1 -octanol-water partition coefficient relationships

Two approaches to quantify/fQ, i.e., to establish a quantitative relationship between the structural features of a compoimd and its properties, are described in this section quantitative structure-property relationships (QSPR) and linear free energy relationships (LFER) cf. Section 3.4.2.2). The LFER approach is important for historical reasons because it contributed the first attempt to predict the property of a compound from an analysis of its structure. LFERs can be established only for congeneric series of compounds, i.e., sets of compounds that share the same skeleton and only have variations in the substituents attached to this skeleton. As examples of a QSPR approach, currently available methods for the prediction of the octanol/water partition coefficient, log P, and of aqueous solubility, log S, of organic compoimds are described in Section 10.1.4 and Section 10.15, respectively. 

There is a continuing effort to extend the long-established concept of quantitative-structure-activity-relationships (QSARs) to quantitative-structure-property relationships (QSPRs) to compute all relevant environmental physical-chemical properties (such as aqueous solubility, vapor pressure, octanol-water partition coefficient, Henry s law constant, bioconcentration factor (BCF), sorption coefficient and environmental reaction rate constants from molecular structure). 

The octanol-water partition coefficient, Kow, is the most widely used descriptor of hydrophobicity in quantitative structure activity relationships (QSAR), which are used to describe sorption to organic matter, soil, and sediments [15], bioaccumulation [104], and toxicity [105 107J. Octanol is an amphiphilic bulk solvent with a molar volume of 0.12 dm3 mol when saturated with water. In the octanol-water system, octanol contains 2.3 mol dm 3 of water (one molecule of water per four molecules of octanol) and water is saturated with 4.5 x 10-3 mol dm 3 octanol. Octanol is more suitable than any other solvent system (for) mimicking biological membranes and organic matter properties, because it contains an aliphatic alkyl chain for pure van der Waals interactions plus the alcohol group, which can act as a hydrogen donor and acceptor. 

Octanol/water partition coefficients, Pow, which measure the relative solubilities of solutes in octanol and in water, are widely used as descriptors in quantitative structure-activity relationships (QSAR), for example in pharmacological and toxicological applications.49 Since experimental values of these are not always available, a number of procedures for predicting them have been proposed (see references in Brinck et al.).50... 

Molecular connectivity indices are desirable as potential explanatory variables because they can be calculated for a nominal cost (fractions of a second by computer) and they describe fundamental relationships about chemical structure. That Is, they describe how non-hydrogen atoms of a molecule are "connected". Here we are most concerned with the statistical properties of molecular connectivity Indices for a large set of chemicals In TSCA and the presentation of the results of multivariate analyses using these Indices as explanatory variables to understand several properties important to environmental chemists. We will focus on two properties for which we have a relatively large data base (1) biodegradation as measured by the percentage of theoretical 5-day biochemical oxygen demand (B0D)( 11), and (2) n-octanol/water partition coefficient or hereafter termed log P (12). 

Drug binding is enhanced by hydrophobicity in that portion of the drug that binds to the pocket toe. Quantitative structure-activity relationship (QSAR) analysis of these compounds have consistently shown that the most predictive parameter of antiviral activity is a measure of hydrophobicity, the octanol water partition coefficient (logP) [80,82,85]. These studies have also consistently shown that there is no apparent correlation between electrostatic potential or dipole moment and potency. 

This area is a development in the usage of NDDO models that emphasizes their utility for large-scale problems. Structure-activity relationships (SARs) are widely used in the pharmaceutical industry to understand how the various features of biologically active molecules contribute to their activity. SARs typically take the form of equations, often linear equations, that quantify activity as a function of variables associated with the molecules. The molecular variables could include, for instance, molecular weight, dipole moment, hydrophobic surface area, octanol-water partition coefficient, vapor pressure, various descriptors associated with molecular geometry, etc. For example, Cramer, Famini, and Lowrey (1993) found a strong correlation (r = 0.958) between various computed properties for 44 alkylammonium ions and their ability to act as acetylcholinesterase inhibitors according to the equation... 

Figure 1.1.1 Examples of property estimation techniques (Sw = water solubility Kow = octanol-water partition coefficient). Chlorobenzene is the query compound. F are fragment or atom constants / is a property-property or a structure-property relationship.

Three general classes of estimation method are in frequent use. The first exploits the considerable data on octanol water partition coefficient Kow and the well developed estimation methods for that quantity by seeking a relationship between solubility and KqW. The second attempts to relate molecular structure to solubility by a variety of techniques involving counting bonds or groups or calculating molecular volumes, areas, or other topological indices such as connectivity. 

Chen, J., Xie, Q., Zhao, Y., Yan, Y., Yang, F. (2001) Quantitative structure-property relationship studies on n-octanol/water partitioning coefficients of PCDD/Fs. Chemosphere 44, 1369-1374. 

An advantage of defining the problem in this manner is that the partition coefficient has become a central property in quantitative structure-activity relationships (QSAR) and a large data base of P values is available in the medicinal chemistry literature (22-24). In particular, if a correlation (Equation 15) between the polymer-water and octanol-water partition coefficients can be established for a series of solutes, it becomes possible to utilize log P (oc-tanol/water) value as a reference point from which to calculate the polymer-water value. 

Common unspecific mode of action of all organic compounds has been taken up in quantitative structure-activity relationships (QSARs see Chapter 5) as the concept of baseline toxicity and in toxicokinetics as the body burden concept (see Chapter 2). Baseline toxicity refers to the idea that a minimum toxicity expectation may be formulated for any given organic compound based on considerations of a compound s partition properties between hydrophilic and lipophilic chemicals (e.g., between water and octanol). Commonly, this is expressed in terms of the octanol-water partition coefficient (K0,J of a chemical. The partition coefficient allows estimations of a local concentration or body burden for each individual chemical in the mixture. Assuming that this produces the same toxic effect (disturbances of cell membranes), it is then possible to anticipate joint narcotic action by adding together the respective local concentrations or body burdens for each individual mixture component. 

Generic chemical class data are often relevant to assessing potential toxicity and should be a part of any evaluation. The relevant information includes structure-activity relationships and physical-chemical properties, such as melting point, boiling point, solubility, and octanol-water partition coefficient. Physical-chemical properties affect an agent s absorption, tissue distribution, biotransformation, and degradation in the body. 

Britton, K.B., Grant, C.L. (1988). Prediction of octanol-water partition coefficients of organophosphates. Evaluation of structure-function relationships. Special Report 88-11. US Department of the Army, Corps of Engineers Cold Regions Research and Engineering Laboratory, Hanover, NH. 

From this log value we estimated by means of a Quantitative Structure-Activity Relationship (QSAR) of Mackay [345] a BCFw for musk xylene of about 3,800 and a BCFl of 79,200 for this compound in fish [346]. The predicted BCFw of musk ketone (log K(, = 4.20 [344]) was 760 and the BCFl 15,800 [346]. These data, the chemical structures, n-octanol/water partition coefficients (log Ko s)... 

A convenient point of departure is that of the increasingly popular quantitative structure activity relationships (QSAR) mentioned above [696,699,11], which derive adsorbate-adsorbent interaction indices from, for example, water solubility data, molecular connectivities [697], n-octanol-water partition coefficients, reversed-phase liquid chromatography capacity factors [723], or linear solvation energy relationships (LSER). 

Most structure-permeation evaluations of transdermal transport indicate the strong relationship between a chemical s permeability coefficient across the skin (Aip) and its lipophilicity. Potts and Guy analyzed a diverse database of skin penetration data, comprising 91 compounds and developed a simple relation indicating that Kp depended only on lipophilicity, as measured by the chemical s octanol-water partition coefficient (P), and molecular weight (MW) ... 

Alvarez-Nunez and Yalkowsky showed that the molar micellar partition coefficient is related to the octanol-water partition coefficient for a structurally diverse set of pharmaceutically important compounds through the relationship... 

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