Biological lipophilicity correlations

In 1868 two Scottish scientists, Crum Brown and Fraser [4] recognized that a relation exists between the physiological action of a substance and its chemical composition and constitution. That recognition was in effect the birth of the science that has come to be known as quantitative structure-activity relationship (QSAR) studies a QSAR is a mathematical equation that relates a biological or other property to structural and/or physicochemical properties of a series of (usually) related compounds. Shortly afterwards, Richardson [5] showed that the narcotic effect of primary aliphatic alcohols varied with their molecular weight, and in 1893 Richet [6] observed that the toxicities of a variety of simple polar chemicals such as alcohols, ethers, and ketones were inversely correlated with their aqueous solubilities. Probably the best known of the very early work in the field was that of Overton [7] and Meyer [8], who found that the narcotic effect of simple chemicals increased with their oil-water partition coefficient and postulated that this reflected the partitioning of a chemical between the aqueous exobiophase and a lipophilic receptor. This, as it turned out, was most prescient, for about 70% of published QSARs contain a term relating to partition coefficient [9]. 

The E-state indices [72, 73] were developed to cover both topological and valence states of atoms. These indices were successfully used to build correlations between the structure and activity for different physicochemical and biological properties [72]. New applications of this methodology are also extensively reviewed in Ghapter 4. Several articles by different authors demonstrated the applicability of these indices for lipophilicity predictions [74—83]. 

The trend toward decreased stability of compounds with increased lipophilicity and MW is obvious. This analysis can provide information about the roles of these two properties in contributing to clearance for this series. Again, the important question for hit triage decision making is how the hypothesized structure-clearance trends correlate to the property trends for other relevant biological properties. 

Cholesterol as well as unsaturated or saturated hydrocarbon chains are used as lipophilic lipid anchors. Although Cl 8-hydrocarbon chains (oleoyl or oleyl unit) are only used in unsaturated compounds, structural variations with C14-, C16-, or even Cl 8-hydrocarbon chains in saturated compounds are known (27). The lipophilic units are linked with a parent structure (usually glycerol) via ether (e.g., DOTMA) or ester bridges (e.g., DOTAP). Ester bridges are often used to create the linkage to avoid cytotoxicity, because ether bonds are more difficult to break down biologically than ester bonds (58). Substances that are easy to decompose and are therefore often used as a spacer are carbamate units (29) [e.g., 3p-[A-(A, A -dimethylaminoethyl)carbamoyl]-cholesterol (DC-Chol)], amide units, or phosphate esters. However, a direct correlation between toxicity and the... 

The close agreement between the experimental and calculated (Equation 9) ratios of 18 2/18 3 support exclusion of the 4-hydroxylphenyl analogue from the calculations. Examination of Equation 9 shows an interdependence between the biological activity and the hydrophobic properties of the chemical used, commonly found with many QSAR equations. This interdependent relationship is determined by the and terms, respectively. These terms control phenomena of hydrophobic interactions with receptors and phenomena of transport and distribution within the total biological systems. The occurrence of squared terms of the hydrophobic parameter in structure-activity correlations has been explained on the assumption that the compound has to penetrate several lipophilic-hydrophilic barriers or compartments on its way to the site of action (16, 17). This is consistent with the uptake of pyridazinones by roots and sbsequent translocation to the shoots (chloroplast) as the site of action (13). 

Lipophilicity is an important physicochemical descriptor used in correlating chemical stmcture with biological activity. It is traditionally expressed as the logarithm of the partition coefficient (i.e., log Aqw) of the solute between n-octanol and the aqueous phase, thus representing the rate of concentrations of a compound (X) in M-octanol and water, that is,... 

Hansch equation A Hansch equation is a linear free-energy relationship that correlates biological activity (log 1/C) to molecular and substituent parameters. The parameters describe properties such as sterics, lipophilicity, and electronic effects, and the coefficients on the parameters determine the relative importance of each parameter. 

Unger, S.H., Chiang, G.H. (1981) Octanol-physiological buffer distribution coefficients of lipophilic amines by reversed-phase high-performance liquid chromatography and their correlation with biological activity. J. Med. Chem. 24(3), 262-270. 

PURPOSE AND RATIONALE Lipophilicity expressed as logPow correlates with membrane affinity and other biological properties as summarised in Kern s (2001) review on physicochemical profiling. However, the interfacial (anisotropic) character of bilayer membranes and the ionisable phospholipid head groups of biological membranes influence the partition properties of drugs. These... 

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