Hansch hydrophobicity parameters

As noted by the original authors (Dorovska et al., 1972), and cited by Fersht (1985), there is an excellent linear correlation between log/ccat/KM and the Hansch hydrophobicity parameters (v) of the side chains (Fig. 9, A), except for the two branched side chains (valine and isoleucine residues). However, since the ku values for the esters do vary somewhat (Table A6.8), the values of pKrs do not correlate as strongly with ir (Fig. 9, B). Moreover, the plot shows distinct curvature which probably indicates the onset of a saturation effect due to the physical limits of the Sj binding pocket, adjacent to the enzyme s active site. Still, the points for valine and isoleucine deviate below the others, suggesting that the pocket has a relatively narrow opening. 

Table 1.3 Hansch hydrophobicity parameters for monosubstituted benzenes [54, 55]...

Five new pyridazinones were synthesized with substitutions in the two-position of the phenyl ring as given in Table II. Using the Hansch approach, correlations were made between the experimentally determined 18 2/18 3 ratios and the values and a,a values taken out of the data collection of Hansch and Leo (15) (Table II and Equations 1-3). The hydrophobic parameter is derived from the 1-octanol/water partition coefficient and o is the Hammett electronic parameter. 

Based on the earlier work of Meyer and Overton, who showed that the narcotic effect of anesthetics was related to their oil/water partition coefficients, Hansch and his co-workers have demonstrated unequivocally the importance of hydrophobic parameters such as log P (where P is, usually, the octanol/water partition coefficient) in QSAR analysis.28 The so-called classical QSAR approach, pioneered by Hansch, involves stepwise multiple regression analysis (MRA) in the generation of activity correlations with structural descriptors, such as physicochemical parameters (log P, molar refractivity, etc.) or substituent constants such as ir, a, and Es (where these represent hydrophobic, electronic, and steric effects, respectively). The Hansch approach has been very successful in accurately predicting effects in many biological systems, some of which have been subsequently rationalized by inspection of the three-dimensional structures of receptor proteins.28 The use of log P (and its associated substituent parameter, tr) is very important in toxicity,29-32 as well as in other forms of bioactivity, because of the role of hydrophobicity in molecular transport across cell membranes and other biological barriers. 

The activity of 1,1jl-trifluoro 3-mercapto substituted phenyl propan-2-ones was not simply correlated with MR alone, therefore, a combination of Hammett a constant, Taft steric parameter (Eg) and Hansch hydrophobic constant (x) was included in the regression analysis. "Equation 36" was found to be of the best fit for compounds substituted in the meta and para positions. 

Furthermore, an empirical hydrophobicity parameter derived from measurements of the distribution of a solute between two immiscible liquids should be mentioned cf. Section 2.2.7 dealing with hydrophobic interactions. The hydrophobic or lipophilic character of organic compounds plays an important role in their abihty to interfere with biochemical systems. Therefore, systematic efforts have been made to obtain numerically defined constants to assess the hydrophobic character of organic compounds. A hydrophobicity parameter which has proven quite valuable in the fields of toxicology, pharmacology, and environmental science is the Hansch-Leo 1-octanollwater partition coefficient TiTo/w or Pq/w as defined in Eq. (7-12),... 

Using 1-octanol/water partition coefficients for aromatic solutes, Hansch also defined a hydrophobicity parameter tix for organic substituents X according to Eq. (7-12a) [145-147],... 

As the equations show, linear correlations with the variables tr and a gave satisfactory results. This is certainly a simplification resulting from limited variance in the substituents. One would assume that square terms of the hydrophobic parameter are necessary in every correlation with biological activity not only to account for the random walk penetration process as in the original derivation of his equation by Hansch, but also, or even predominantly, as a description of the fact that numerous indifferent hydrophobic sites within the biological system compete with the site of action for the active molecule. In a first attempt we calculated regression equations for our hydrazones with the molecular parameter... 

Fife and Xin (35) found that, under PTC conditions, the reaction between benzoyl chloride and a mixture of 1.0 equivalent of sodium p-toluate and 1.0 equivalent of sodium isobutyrate in the presence of 0,1 equivalent of pyridine 1-oxide gave an anhydride product mixture that contained approximately twice as much benzoic p-toluic anhydride as benzoic isobutyric anhydride on a molar basis (equation 7). Therefore, the process must include an important component that selects for the more lipophilic p-toluate ion. The differential partitioning of the competing carboxylate ions at the di-chloromethane-water interface is a reasonable explanation for this observed selectivity, because product composition correlates with the Hansch (39) hydrophobicity parameters for competing carboxylate ions (40). 

Hansch, C. Leo, A. The hydrophobic parameter measurement and calculation. In Exploring QSAR Fundamentals and Applications in Chemistry and Biology Heller, S.R., Ed. American Chemical Society Washington, 1995 97-122. 

External structural variables usually derived from physicochemical information measured on external reference populations, such as the electronic, steric and hydrophobic parameters used in Hansch s method (7). 

Clayton and Purcell have illustrated the predictive utility of this method when applied to selected butyrylcholinesterase inhibitors (94). They obtained quantitative correlations using group dipole moments, and /x in addition to hydrophobic parameters. In addition, Hansch and co-workers have used Taft steric parameters (Es) (60) and pKa values to obtain excellent correlations in various systems (84). E8 has recently been shown to be quantitatively related to van der Waal s radii for symmetrical top-like substituents (98) while pKa values have been used as a measure of electron density distributions (99). Fukuto and co-workers combined Tafts Es and a parameters in a physicochemical approach to the mode of action of organophosphorus insecticides (95). 

Paracyclophanes.—Reactions catalysed by paracyclophanes have been reviewed, and their rates shown to correlate with the hydrophobic Hansch n parameter. Although several spectral studies have suggested that water-soluble paracyclophanes form inclusion complexes with hydrophobic substrates in aqueous solution, there has been no direct evidence. Crystalline complexes have now been isolated and X-ray analysis shows that the guest is fully mcluded within the cavity of the host. ... 

Hansch et al. have used the hemolytic substituent constants, Er, of Yamamoto and Otsu for correlations with antibacterial activity against E. ooli for a series of chloramphenicol derivatives. To determine the importance of electronic effects relative to hydrophobic properties, the authors performed regression analyses on the data of Garrett et al. Using Er derived from free-radical reactions and the hydrophobic parameter, it, of Hansch, they obtained eq 1 and eq 2... 

Steric Parameters - The steric parameter, E, of Taft has been employed by Kutter and Hansch in the correlation of the molecular structure of some phenoxyethylcyclopropylamine monoamine oxidase inhibitors and diphenhydramine antihistamines with their activity. For the types of biological activity investigated it was found that the Taft Eg was more important in the correlation than was either the electronic parameter of Hammett, a, or the hydrophobic parameter of Hansch. Their results led Kutter and Hansch to conclude that the binding of substituent groups of moderate size into a macro-molecular pouch may well be, at least over a limited range, a continuous linear process. This would negate the all-or-none situation which sometimes arises from the "lock and key" theory of enzyme-substrate interaction. ... 

Absorption into the non-polar phase, e.g., lipids, is a second putative mechanism. Partitioning between the milieu and aquatic organisms is controlled by favorable changes in thermodynamic free energy as these hydrophobic compounds leave water (Mackay and Peterson 1982 Hansch et al. 1968 Mackay 1979). Thus, any QSAR model based on hydrophobic parameters for organotin describes dose rather than mechanisms. 

Putting aside issues of the molecular origin of hydrophobic effect , the more significant issue is the extent to which desolvation contributes to overall binding thermodynamics. A variety of experimental methodologies to evaluate the magnitude of this effect exist. The most commonly used tools are Hansch transfer parameters [30, 31]. Briefly, a series of eompounds are partitioned between water and water-saturated octanol. The value n is then derived for a substitutent according to the expression ... 

Hansch-Leo hydrophobic substituent parameter Hammett sigma constants Modtried Swam Lupton constants... 

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