Fluorine biological function

Most reports concerning 2//-pyran-2-ones (a-pyrones) involve non-fluorinated derivatives, which perform important biological functions in nature and have unlimited synthetic potential for the construction of a variety of arenes and heteroarenes [28], However, very few deal with 2-pyrones containing fluoroalkyl groups. It is evident that the C-2, C-4 and C-6 positions of the 2-pyranone ring are electrophilic in nature and prone to nucleophilic attack. The presence of polyfluoroalkyl substituents on the pyrone ring favours these reactions. At the same time, R -containing 2-pyrones behave as cyclic dienes in cycloadditions. 

Incorporation of fluorine into a biological substrate opens a spectral window for viewmg biomolecular structure and dynamics in solution With mmimal background mletference, fluonne NMR can provide clear spectral information for fluorme conlainmg macromolecules, in contrast to an indecipherable mass of signals from proton or carbon NMR Whether the fluonnated unit is termed a probe, tag, marker, or reporter group, its function is the same to act as a beacon of spectral information... 

The beneficial effect of fluorine atoms on hydrolytic stability has been demonstrated with synthetic prostaglandin (SC-46275). This compound possesses an antisecretory activity that protects the stomach mucous membrane. However, its clinical development was too problematic because of the instability of the tertiary allyl alcohol function in acidic media (epimerization, dehydration, etc). A fluorine atom has been introduced on the C-16 methyl to inhibit the formation of the allylic carbocation (Figure 4.39). The fluoroanalogue possesses the same biological activity but does not undergo any degradation or rearrangement, and it epimerizes only slowly. 

While the amino acid, which has been replaced by its fluorinated analogue, is essential for the functionality of the protein, some biological consequences can occur. Thus, incorporation of 2-F-His into mammalian proteins (4-F-His cannot be incorporated), in cell culture or invivo, is accompanied by inhibition of the induction of several enzymes (e.g., inhibition of acetyltransferase activity of the pineal gland). This probably stems from the formation of defective or inactive enzymes. Indeed, histidine plays an important role in the nucleophilic and acid-base processes connected to the catalytic activity of numerous enzymes. 

The biotransformation of organofluorine materials into optically active functionalized fluo-rinated materials along with a discussion on the effect of fluorine atom(s) during enantio-selective and/or diastereoselective transformations is described. The ability of microorganisms to discriminate between enantiomers is particularly important regarding resolution and asymmetric synthesis. Furthermore, the use of chiral fluorinated materials in the design and preparation of new types of biologically active materials is discussed. 

Protected and unprotected indole derivatives dissolved in hydrogen fluoride are also fluorinated by 18F-F. The relatively stable melatonin (10), a neurohormone responsible for the biological clock and other brain functions, gave only the 6-[l8F]fluoro derivative 11, but even the more fragile 5-hydroxytryptophan (12) could be fluorinated under these conditions resulting in a mixture of 4- and 6-[l8F]fluorohydroxytryptophan 13.54... 

The a,a-difluoro Reformatsky reagent has been applied extensively to the preparation of compounds containing the -CF2C(0)- group and its derivatives,2 since this functionality often confers enhanced biological activity. Typical examples include the preparation of selectively fluorinated thromboxane A2 analogues24 and the preparation of a difluoro-y-lactone intermediate which was subsequently converted to l-(2-deoxy-2,2-difluororibofuranosyl) pyrimidine nucleosides (Equation 4.10).25... 

Dihydroxyphenylalanine (DOPA) (99) is produced by tyrosine hydroxylase-catalyzed hydroxylation of Tyr. Recent interest in the use of [18F]-6-F-DOPA (100) as a PET scanning agent for regional dopaminergic brain function is based on its conversion, in the brain, to [,8F]-6-F-dopamine (101)161. The fact that fluorine in the 6-position of DOPA, dopamine and other catecholamines retards methylation by catechol-O-methyl transferase presumably increases the biological half-life of the tracer. In contrast, fluorine in the 5-position increases the rate of methylation162. 

A His residue is often found at the active site of enzymes where it functions as a catalyst in acid-base and nucleophilic processes. Substitution of fluorine on His reduces the pKa by about 5 pH units, and this dramatic drop in basicity is reflected in altered biological properties of FHis-containing proteins. The presence of 2-FHis in cell cultures inhibits the stimulation of several enzymes, for example, the stimulation of pineal gland A-acetyltransferase activity, in cell culture and in vivo. This stimulation is accompanied by His and cyclohex-imide-sensitive incorporation of 2-FHis into cellular protein192,193. A direct comparison of His and 2-F-His in mouse L cells showed that the analogue is incorporated at about 17% the efficiency of the parent194.4-FHis showed none of the above biological activity. 

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