The difference in the medical properties of the enantiomers of many chiral drugs is a well-known fact. This is a big problem, since most drugs are still used in the form of racemates. The latter is connected with the difficulties of separation. One of the most prominent representatives of drugs in which enantiomers differ not only in degree but also in the directions of therapeutic activity are nonsteroidal anti-inflammatory drugs (NSAIDs). Naproxen is one of the NSAIDs that is available in the form of S isomer only. His R analogue does not exhibit anti-inflammatory properties but has a therapeutic activity in other directions. To understand the reasons of the difference in naproxen (NPX) enantiomers medical activity in this work original approach has been developed. The interaction of (S)- and (R)-NPX with chiral donors in linked systems – dyads have been investigated. These model systems are believed to simulate NPX enantiomers binding with chiral amino acid residues located in active sites of COXs enzymes. Idea is that upon binding some kind of diastereomers analogs are formed. In diastereomers, as it is known, enantiomers may exhibit different reactivities. Spin chemistry and photochemistry study of photoinduced charge transfer (CT) between (S)- and (R)-NPX and (S)-tryptophan and (S)-N-methylpyrrolidine linked by different bridges has shown the stereoselectivity of partial and full CT. The exciplex quantum yields and the rates of its formation are larger for the dyads containing (R)-NPX that let us suggest the greater contribution from CT processes with (R)-optical isomer. This is consistent with fact that (R)-NPX is more active in the processes of the chiral metabolism by the action of cytochrome P450 known to involve electron transfer. Really, (R)-NPX is slightly more active in oxidative metabolism .However, in the enzymatic chiral inversion of NPX-CoA esters by AMACR and other transferases (R)-isomer demonstrates appreciably greater activity than the (S)-analog. (S)-isomer - drug naproxen, according to above results, has to exhibit a more reversible binding with the amino acid donors that is an agreement with the results of biochemical research. In order to establish the nature of abovementioned stereoselectivity in processes with participation of S and R NPX another physical method - spin chemistry was used. The comparison of spin chemistry experimental results with calculation has shown that the reason of difference in R and S reactivity in ET is the distinction of spin density distribution in paramagnetic form of (R,S)- and (S,S)-diastereomers. This result is directly related to the reactivity of the enantiomers since the spin density and the electron density distributions correlate with each other. For example, the formation of hydrogen bonds between naproxen and amino acid residues in the active site of COX can be dependent on the electron density distribution of the enantiomers. The use of this approach also let us to discover the radical path of chiral inversion of R naproxen and detect short-lived radicals responsible for the phototoxicity of another drug, ketoprofen.
The work was supported by the Russian Science Foundation (18-13-00047).
Presentation Learning Outcome
• The potential practical significance of these results is the realization of why the enantiomers of naproxen differ from each other. The lack of such knowledge is a big problem for pharmacology.
• Taking into account that the scope of the NSAIDs is constantly expanding, one can hope that the knowledge of the nature of the differences between the enantiomers will serve to search for new areas of their activity.
• In addition, this report will serve as a source of new knowledge, since the foregoing approach to studying the properties of chiral drugs is completely original.