Fluorine-hydrogen isosterism

TABLE 15.17 Fluorine-Hydrogen Isosterism. Observe the Comparable Sizes of the Two Atoms, whereas Chlorine is Close to the Methyl and Trifluoromethyl ... 

Table 13.11 Fluorine-hydrogen isosterism. Observe the comparable sizes of the two atoms, whereas chlorine is close to the methyl and trifluoromethyl...

Isosteric substitution of the C-2 hydrogen atom of valproic acid (12) with a fluorine atom affords 2-fluorovalproic acid (22), which causes significantly less hepatoxicity than valproic acid, although a reduction in anticonvulsant properties is also observed [59, 60]. The hepatoxicity of 12 involves hepatic cytochrome P450-mediated metabolism to its 4-ene metabolite (14), which undergoes further metabolism, specifically mitchondrial (3-oxidation, to provide ( )-2-propyl-2,4-pentadienoic add (23), a reactive electrophilic metabolite [59, 60]. 

One type of isosteric substitution that should have tremendous potential in the design of safer commercial chemicals is replacement of hydrogen with fluorine. Since many bioactivation mechanisms of chemicals involve cytochrome P450-mediated hydrogen atom abstraction to yield toxic metabolites, it would seem plausible that replacement of such a hydrogen atom with fluorine would provide a safer isosteric analog, without affecting commercial efficacy. 

This has been found to be the case with valproic acid (2-propylpentanoic acid) (12), which is hepatotoxic, and 2-fluorovalproic add (22), which is much less hepatotoxic, discussed in Sedion 4.3.1. The hepatoxidty of 12 involves cytochrome P450 abstraction of its C-2 hydrogen atom. The C-2 fluorine atom of 22 cannot be removed by cytochrome P450 metabolism. It would be interesting to observe if the same isosteric replacement would reduce the hepatoxidty of other carboxylic acids, such as the widely used 2-ethylhexanoic add. 

Recently, Ojima et al. described the synthesis of some taxanes with C-13 fluorine-substituted isoserine side chains. In pharmaceutical practices, the fluorine atom is usually introduced as an isosteric atom of the hydrogen atom, but it showed higher or sometimes unique activity against its hydrogen-containing counterparts. Flourine also blocks the metabolism of the parent molecule, which led to the... 

The final class of fluorinated artificial nucleobases are non-hydrogen-bond-ing isosteres of the natural bases, first described by Kool. The first such... 

Although fluorine does not have the same valency as hydrogen, it is often considered an isostere of that atom since it is virtually the same size. Replacement of a hydrogen atom with a fluorine atom will therefore have little steric effect, but since the fluorine is strongly electronegative, the electronic effect may be dramatic. 

For a long time, fluorine has been considered as a bio-isostere of hydrogen, which is no more true. Indeed, fluorine is very different from hydrogen, with a van der Waals radius comparable to that of oxygen, it induces an increase in lipophilicity and its electronegativity is the highest in the periodic classification. 

Why was it that only the fluorobenzoic acids and the thiophenes were apparently incorporated In the case of the former, this may reflect the probability that fluorobenzoic acid is structurally the most similar of the analogs to the natural substrate. Fluorine is a fairly inert atom and isosteric with hydrogen. It is not so clear why the thiophenes should have been incorporated. 

One of the most common monovalent isosteric replacements is the substitution of hydrogen with fluorine [7]. These atoms have similar van der Waals radii but different electronic effects, fluorine being the most electronegative element in the periodic table. Due to the high strength of the C—F bond, fluorine is often introduced to achieve metabolic stability. Moreover, due to its high electronegativity, fluorine can be introduced to reduce basicity of proximal amines or increase acidity of proximal adds and also to introduce a conformational bias in molecules. 

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