TY - CHAP

T1 - Physico-chemical approach to the study of naproxen enantiomers

AU - Ageeva, Aleksandra A.

AU - Khramtsova, Ekaterina A.

AU - Plyusnin, Viktor F.

AU - Miranda, Miguel A.

AU - Leshina, Tatyana V.

PY - 2018/7/11

Y1 - 2018/7/11

N2 - To understand reasons for the difference in naproxen (NPX), enantiomers medical activity original approach has been developed. In this chapter the interaction of (S) and (R)-NPX with chiral donors in linked systems - dyads have been described. These model systems are believed to simulate NPX enantiomers binding with chiral amino acid residues located in active sites of COX 1, 2. According to the authors' point of view, 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 been performed. Herewith, rate constants of individual steps of NPX excited state quenching by donors and fluorescence quantum yields of local excited states and exciplex have shown stereoselectivity. The scale of this effect depends on the bridge's length, structure and solvent permittivity. Exciplex quantum yields and rates of its formation are larger for dyads containing (R)-NPX that let us suggest the greater contribution from CT processes with (R)-optical isomer. Actually, (R)-NPX is slightly more active in oxidative metabolism under the action of cytochrome P- 450. 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 amino acid donors that is an agreement with the results of biochemical research. In order to establish the nature of abovementioned stereoselectivity, CIDNP effects detected in the electron transfer of diastereomers have been analyzed. By the example of two dyads CIDNP enhancement coefficients were demonstrated to differ markedly for (R,S) and (S,S)-diastereomers. The differences of enhancement coefficients was explained by the distinction of spin density distribution in the paramagnetic form of (R,S) and (S,S)-diastereomers. Since the spin and electron density distributions correlate with each other, this result is directly related to the reactivity of enantiomers.

AB - To understand reasons for the difference in naproxen (NPX), enantiomers medical activity original approach has been developed. In this chapter the interaction of (S) and (R)-NPX with chiral donors in linked systems - dyads have been described. These model systems are believed to simulate NPX enantiomers binding with chiral amino acid residues located in active sites of COX 1, 2. According to the authors' point of view, 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 been performed. Herewith, rate constants of individual steps of NPX excited state quenching by donors and fluorescence quantum yields of local excited states and exciplex have shown stereoselectivity. The scale of this effect depends on the bridge's length, structure and solvent permittivity. Exciplex quantum yields and rates of its formation are larger for dyads containing (R)-NPX that let us suggest the greater contribution from CT processes with (R)-optical isomer. Actually, (R)-NPX is slightly more active in oxidative metabolism under the action of cytochrome P- 450. 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 amino acid donors that is an agreement with the results of biochemical research. In order to establish the nature of abovementioned stereoselectivity, CIDNP effects detected in the electron transfer of diastereomers have been analyzed. By the example of two dyads CIDNP enhancement coefficients were demonstrated to differ markedly for (R,S) and (S,S)-diastereomers. The differences of enhancement coefficients was explained by the distinction of spin density distribution in the paramagnetic form of (R,S) and (S,S)-diastereomers. Since the spin and electron density distributions correlate with each other, this result is directly related to the reactivity of enantiomers.

KW - CIDNP

KW - Diastereomers

KW - Donor-acceptor dyads

KW - Electron transfer

KW - Fluorescence

KW - Stereoselectivity

UR - http://www.scopus.com/inward/record.url?scp=85058915288&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/3f038785-ca63-3bf2-a732-e47958c9284a/

M3 - Chapter

AN - SCOPUS:85058915288

SN - 9781536141290

SP - 35

EP - 66

BT - Naproxen: Chemistry, Clinical Aspects and Effects

PB - Nova Science Publishers, Inc.

ER -