Positional Isomerism

Positional isomerism is a geometric factor of obvious significance in lipophilicity. In fact, it may be convenient to distinguish between:

• Regioisomerism, which relates positional isomers whose interconversion is a high-energy process.

• Tautomerism, which involves the low-energy migration of a proton from one heteroatom to another.

The example discussed in section is a fit illustration of the importance of positional isomerism in the lipophilicity of bisubstituted benzenes. Similarly, the proximity effects discussed in sections and are obviously critically dependent on the number of interconnecting atoms. The same applies to the possibility of forming internal H-bonds or even hydrophilic collapse (sections and, to partial charge neutralizations (section, to various other proximity effect (sections and, and to the possibility of forming hydrophobic interactions or even hydrophobic collapse (sections and

There are also a few examples in the literature where tautomerism was studied per se as a factor influencing lipophilicity. A case in point is that of proxibarbal, an antimigraine drug that exists in ring-chain tautomeric equilibrium with the two diastereomers of valofan (Fig. 8). Because the interconversion is rather rapid (tm ~ 150 min at pH 7.4 and 20 °C), direct measurement of partition coefficients is not feasible. In con-

cis-valofan proxibarbal frans-valofan

Figure 8. The equilibrium between proxibarbal and its ring-chain tautomers cis- and trans-valofan. Only relative configurations are implied.

cis-valofan proxibarbal frans-valofan

Figure 8. The equilibrium between proxibarbal and its ring-chain tautomers cis- and trans-valofan. Only relative configurations are implied.

trast, a kinetic study allowed rate constants of interconversion and transfer to be determined simultaneously, affording the following log Poct values: proxibarbal —0.05, cis-valofan 0.28, and irans-valofan 0.41 [24], The differences between tautomers are not very large (0.33 and 0.46), but they are most probably due to differences in the H-bonding capacity of proxibarbal and valofan. A modest difference between diastereo-mers is also noted, a factor discussed in the following section.

4.4.2 Stereoisomerism

Stereoisomerism is another geometric factor of obvious significance in lipophilicity. Again, it is convenient to distinguish between:

• Diastereomerism, which relates diastereomers whose interconversion is a high-energy process.

• Conformational isomerism, which involves the low-energy interconversion of stereoisomers.

Systematic investigations on the compared lipophilicity of diastereomers are few. In one study, 36 pairs of diastereomers were compared [25]. The differences in log P values ranged from 0.0 to 1.0. While no quantitative interpretation proved possible, the data showed that the water-accessible surface area, and not the H-bonding capacity, was the major structural determinant in the differences of lipophilicity between relatively rigid diastereomers containing one or two polar groups. This was interpreted as a consequence of the perturbation of hydrophobic hydration exerted by the polar groups at an endo or a syn position, leading to a decrease in hydrophobicity.

Several examples discussed in section 4.3 aptly illustrate the significance of conformational factors on lipophilicity. This is particularly true for the possibility of forming internal H-bonds or even hydrophilic collapse (sections, and Proximity effects between polar and nonpolar groups (sections and, as well as the possibility of forming hydrophobic bonds or even hydrophobic collapse (sections and, are also discussed above.

Other studies can be found in the literature whose specific aim was to examine relations between lipophilicity and conformational behavior [26]. For example, a series of iV-hydroxyureas (R-NH-CO-NR'-OH) showed complex tautomeric and conformational behavior depending on the nature of R and R' (H, n-alkyl or branched alkyl) [27, 28]. The major factor ultimately influencing lipophilicity was the possibility of forming or not an internal H-bond between the carbonyl oxygen and the hydroxyl proton. Solutes able for structural reasons to form this bond proved more lipophilic than those unable to form it.

4.4.3 Ionization

The possibility for a solute to exist in neutral or charged states will obviously have a major impact on its partitioning behavior. First, the solute will exhibit pH-dependent partitioning, making it indispensable to distinguish between its partition coefficients

(solvent-dependent) and its distribution coefficients (pH- and solvent-dependent) [3] (see also Chapter 7). Second - and more relevant to the present context - the fact that a polar group exists in a neutral or charged state may dramatically alter the intramolecular interactions involving this group. Thus, ionization will affect electronic conjugation (section 4.3.1), proximity effects between polar groups (section, internal H-bonds (section, internal ionic bonds and other ionic interactions (section, hydrophilic collapse (section, and the shielding of nonpolar groups by polar groups (section In addition and indirectly, the various steric/ hydrophobic effects (section 4.4.3) will also be affected.

4.4.4 Molecular Size and Chameleonic Behavior

In a most stimulating account, Jiang has commented on aggregation and self-coiling in organic molecules, stressing their major significance in the functioning of biomolecules and biomacromolecules [29]. The point to be made here is that the phenomenon of self-coiling is a capital one not only for endogenous compounds, but also for drugs and other xenobiotics and their metabolites. For a variety of (presumably historical) reasons, medicinal chemists refer to hydrophobic collapse rather than self-coiling, the term hydrophilic collapse being a more recent acquisition (section

Self-coiling, be it due to hydrophobic or to hydrophilic collapse, requires a certain number of structural conditions to be fulfilled, namely functionalities, flexibility and size. In other words, the compound must a) contain the necessary functional groups, b) be flexible enough for these functional groups to interact via electrostatic and/or hydrophobic forces, and c) a large enough for collapse to occur at all (see section

As a result of hydrophobic and/or hydrophilic collapse, a solute may become more polar in polar solvents and more lipophilic in lipidie solvents. In effect, such a solute to some extent adapts its lipophilicity to that of the medium, thereby behaving analogously to a chameleon, which changes color to resemble that of the environment.

An example of chameleonic behaviour can be found with the two major metabolites of morphine, namely its 3-O-glucuronide and its 6-O-glucuronide. In a RP-HPLC system, these two conjugates displayed a much higher than expected lipophilicity which could explain some of their rather unusual pharmacokinetic properties. Conformational analysis and computation of the MLP (see chapter 12) suggested that these compounds can indeed adopt two low-energy conformations, namely a population of folded conformers with partly masked polar groups and increased hydrophobic surface, and a population of extended conformers with maximally exposed polar groups and minimized hydrophobic surface [30, 31]. These two metabolites are exemplary in that they do fulfil the three conditions listed above for chameleonic behavior to be displayed at all. However, it must be noted that morphine O-glucuronides do not appear to display a higher than expected lipophilicity in octanol/water systems, in agreement with the arguments discussed in section



Figure 9. Interrelated factors influencing intramolecular interactions, intermolecular forces and partitioning.
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