Impact of Non-Covalent Interactions of Chiral Linked Systems in Solution on Photoinduced Electron Transfer Efficiency.

It is well-known that non-covalent interactions play an essential role in the functioning of biomolecules in living organisms. The significant attention of researchers is focused on the mechanisms of associates formation and the role of the chiral configuration of proteins, peptides, and amino acids in the association. We have recently demonstrated the unique sensitivity of chemically induced dynamic nuclear polarization (CIDNP) formed in photoinduced electron transfer (PET) in chiral donor-acceptor dyads to non-covalent interactions of its diastereomers in solutions. The present study further develops the approach for quantitatively analyzing the factors that determine the association by examples of dimerization of the diastereomers with the RS, SR, and SS optical configurations. It has been shown that, under the UV irradiation of dyads, CIDNP is formed in associates, namely, homodimers (SS-SS), (SR-SR), and heterodimers (SS-SR) of diastereomers. In particular, the efficiency of PET in homo-, heterodimers, and monomers of dyads completely determines the forms of dependences of the CIDNP enhancement coefficient ratio of SS and RS, SR configurations on the ratio of diastereomer concentrations. We expect that the use of such a correlation can be useful in identifying small-sized associates in peptides, which is still a problem.

Photoinduced Processes in Lysine-Tryptophan-Lysine Tripeptide with L and D Tryptophan.

Optical isomers of short peptide Lysine-Tryptophan-Lysine (Lys-{L/D-Trp}-Lys) and Lys-Trp-Lys with an acetate counter-ion were used to study photoinduced intramolecular and intermolecular processes of interest in photobiology. A comparison of L- and D-amino acid reactivity is also the focus of scientists' attention in various specialties because today, the presence of amyloid proteins with D-amino acids in the human brain is considered one of the leading causes of Alzheimer's disease. Since aggregated amyloids, mainly Aß42, are highly disordered peptides that cannot be studied with traditional NMR and X-ray techniques, it is trending to explore the reasons for differences between L- and D-amino acids using short peptides, as in our article. Using NMR, chemically induced dynamic nuclear polarization (CIDNP) and fluorescence techniques allowed us to detect the influence of tryptophan (Trp) optical configuration on the peptides fluorescence quantum yields, bimolecular quenching rates of Trp excited state, and the photocleavage products formation. Thus, compared with the D-analog, the L-isomer shows a greater Trp excited state quenching efficiency with the electron transfer (ET) mechanism. There are experimental confirmations of the hypothesis about photoinduced ET between Trp and the CONH peptide bond, as well as between Trp and another amide group.

New Aspects of the Antioxidant Activity of Glycyrrhizin Revealed by the CIDNP Technique.

Electron transfer plays a crucial role in ROS generation in living systems. Molecular oxygen acts as the terminal electron acceptor in the respiratory chains of aerobic organisms. Two main mechanisms of antioxidant defense by exogenous antioxidants are usually considered. The first is the inhibition of ROS generation, and the second is the trapping of free radicals. In the present study, we have elucidated both these mechanisms of antioxidant activity of glycyrrhizin (GL), the main active component of licorice root, using the chemically induced dynamic nuclear polarization (CIDNP) technique. First, it was shown that GL is capable of capturing a solvated electron, thereby preventing its capture by molecular oxygen. Second, we studied the effect of glycyrrhizin on the behavior of free radicals generated by UV irradiation of xenobiotic, NSAID-naproxen in solution. The structure of the glycyrrhizin paramagnetic intermediates formed after the capture of a solvated electron was established from a photo-CIDNP study of the model system-the dianion of 5-sulfosalicylic acid and DFT calculations.

Chiral Linked Systems as a Model for Understanding D-Amino Acids Influence on the Structure and Properties of Amyloid Peptides.

In this review, we provide an illustration of the idea discussed in the literature of using model compounds to study the effect of substitution of L- for D-amino acid residues in amyloid peptides. The need for modeling is due to the inability to study highly disordered peptides by traditional methods (high-field NMR, X-ray). At the same time, the appearance of such peptides, where L-amino acids are partially replaced by D-analogs is one of the main causes of Alzheimer's disease. The review presents examples of the use diastereomers with L-/D-tryptophan in model process-photoinduced electron transfer (ET) for studying differences in reactivity and structure of systems with L- and D-optical isomers. The combined application of spin effects, including those calculated using the original theory, fluorescence techniques and molecular modeling has demonstrated a real difference in the structure and efficiency of ET in diastereomers with L-/D-tryptophan residues. In addition, the review compared the factors governing chiral inversion in model metallopeptides and Aß42 amyloid.

Role of Chiral Configuration in the Photoinduced Interaction of D- and L-Tryptophan with Optical Isomers of Ketoprofen in Linked Systems.

The study of the L- and D-amino acid properties in proteins and peptides has attracted considerable attention in recent years, as the replacement of even one L-amino acid by its D-analogue due to aging of the body is resulted in a number of pathological conditions, including Alzheimer's and Parkinson's diseases. A recent trend is using short model systems to study the peculiarities of proteins with D-amino acids. In this report, the comparison of the excited states quenching of L- and D-tryptophan (Trp) in a model donor-acceptor dyad with (R)- and (S)-ketoprofen (KP-Trp) was carried out by photochemically induced dynamic nuclear polarization (CIDNP) and fluorescence spectroscopy. Quenching of the Trp excited states, which occurs via two mechanisms: prevailing resonance energy transfer (RET) and electron transfer (ET), indeed demonstrates some peculiarities for all three studied configurations of the dyad: (R,S)-, (S,R)-, and (S,S)-. Thus, the ET efficiency is identical for (S,R)- and (R,S)-enantiomers, while RET differs by 1.6 times. For (S,S)-, the CIDNP coefficient is almost an order of magnitude greater than for (R,S)- and (S,R)-. To understand the source of this difference, hyperpolarization of (S,S)-and (R,S)- has been calculated using theory involving the electron dipole-dipole interaction in the secular equation.

Optical Configuration Effect on the Structure and Reactivity of Diastereomers Revealed by Spin Effects and Molecular Dynamics Calculations.

The peculiarities of spin effects in photoinduced electron transfer (ET) in diastereomers of donor-acceptor dyads are considered in order to study the influence of chirality on reactivity. Thus, the spin selectivity-the difference between the enhancement coefficients of chemically induced dynamic nuclear polarization (CIDNP)-of the dyad's diastereomers reflects the difference in the spin density distribution in its paramagnetic precursors that appears upon UV irradiation. In addition, the CIDNP coefficient itself has demonstrated a high sensitivity to the change of chiral centers: when one center is changed, the hyperpolarization of all polarized nuclei of the molecule is affected. The article analyzes the experimental values of spin selectivity based on CIDNP calculations and molecular dynamic modeling data in order to reveal the effect of optical configuration on the structure and reactivity of diastereomers. In this way, we succeeded in tracing the differences in dyads with L- and D-tryptophan as an electron donor. Since the replacement of L-amino acid with D-analog in specific proteins is believed to be the cause of Alzheimer's and Parkinson's diseases, spin effects and molecular dynamic simulation in model dyads can be a useful tool for investigating the nature of this phenomenon.

Stereoselectivity of Electron and Energy Transfer in the Quenching of (S/R)-Ketoprofen-(S)-Tryptophan Dyad Excited State.

Photoinduced elementary processes in chiral linked systems, consisting of drugs and tryptophan (Trp) residues, attract considerable attention due to several aspects. First of all, these are models that allow one to trace the full and partial charge transfer underlying the binding of drugs to enzymes and receptors. On the other hand, Trp fluorescence is widely used to establish the structure and conformational mobility of proteins due to its high sensitivity to the microenvironment. Therefore, the study of mechanisms of Trp fluorescence quenching in various systems has both fundamental and practical interest. An analysis of the photo-chemically induced dynamic nuclear polarization (CIDNP) and Trp fluorescence quenching in (R/S)-ketoprofen-(S)-tryptophan ((S/R)-KP-(S)-Trp) dyad carried out in this work allowed us to trace the intramolecular reversible electron transfer (ET) and obtain evidence in favor of the resonance energy transfer (RET). The fraction of dyad's singlet excited state, quenched via ET, was shown to be 7.5 times greater for the (S,S)-diastereomer than for the (R,S) analog. At the same time, the ratio of the fluorescence quantum yields shows that quenching effectiveness of (S,S)-diastereomer to be 5.4 times lower than for the (R,S) analog. It means that the main mechanism of Trp fluorescence quenching in (S/R)-KP-(S)-Trp dyad is RET.

Role of Association in Chiral Catalysis: From Asymmetric Synthesis to Spin Selectivity.

The origin of biomolecules in the pre-biological period is still a matter of debate, as is the unclarified nature of the differences in enantiomer properties, especially for the medically important activity of chiral drugs. With regards to the first issue, significant progress was made in the last decade of the 20th century through experimental confirmation of Frank's popular theory on chiral catalysis in spontaneous asymmetric synthesis. Soai examined the chiral catalysis of the alkylation of achiral aldehydes by achiral reagents. Attempts to model this process demonstrated the key role of chiral compounds associates as templates for chiral synthesis. However, the elementary mechanism of alkylation and the role of free radicals in this process are still incompletely understood. Meanwhile, the influence of external magnetic fields on chiral enrichment in the radical path of alkylation has been predicted. In addition, the role of chiral dyad association in another radical process, electron transfer (ET), has been recently demonstrated by the following methods: chemically induced dynamic nuclear polarisation (CIDNP), NMR spectroscopy, XRD and photochemistry. The CIDNP analysis of ET in two dyads has revealed a phenomenon first observed for chiral systems, spin selectivity, which results in the difference between the CIDNP enhancement coefficients of dyad diastereomers. These dyads are linked systems consisting of the widespread drug (S)-naproxen (NPX) or its R analogue and electron donors, namely, (S)-tryptophan and (S)-N-methylpyrrolidine. Because NPX is one of the most striking examples of the difference in the therapeutic properties of enantiomers, the appearance of spin selectivity in dyads with (S)- and (R)-NPX and S donors can shed light on the chemical nature of these differences. This review is devoted to discussing the chemical nature of spin selectivity and the role of chiral associates in the chiral catalysis of an elementary radical reaction: ET in chiral dyads.

Spin Selectivity in Chiral Linked Systems.

This work has shown spin selectivity in electron transfer (ET) of diastereomers of (R,S)-naproxen-(S)-N-methylpyrrolidine and (R,S)-naproxen-(S)-tryptophan dyads. Photoinduced ET in these dyads is interesting because of the still unexplained phenomenon of stereoselectivity in the drug activity of enantiomers. The chemically induced dynamic nuclear polarization (CIDNP) enhancement coefficients of (R,S)-diastereomers are double those of the (S,S)-analogue. These facts are also interesting because spin effects are among the most sensitive, even to small changes in spin and molecular dynamics of paramagnetic particles. Therefore, CIDNP reflects the difference in magnetoresonance parameters (hyperfine interaction constants (HFIs), g-factor difference) and lifetimes of the paramagnetic forms of (R,S)- and (S,S)-diastereomers. The difference in HFI values for diastereomers has been confirmed by a comparison of CIDNP experimental enhancement coefficients with those calculated. Additionally, the dependence of the CIDNP enhancement coefficients on diastereomer concentration has been observed for the naproxen-N-methylpyrrolidine dyad. This has been explained by the participation of ET in homo-(R,S-R,S or S,S-S,S) and hetero-(R,S-S,S) dimers of dyads. In this case, the effectivity of ET, and consequently, CIDNP, is supposed to be different for (R,S)- and (S,S)-homodimers, heterodimers, and monomers. The possibility of dyad dimer formation has been demonstrated by using high-resolution X-ray and NMR spectroscopy techniques.

A photochemical approach for evaluating the reactivity of substituted lappaconitines.

Lappaconitine (LC) is a natural diterpenoid alkaloid (DTA), acting as a human heart sodium channel blocker and possessing a wide range of biological activities, the cellular and molecular mechanisms of which are widely studied. This interest is due to the fact that various representatives of this DTA class show opposite biological activities. The possible reasons for this difference seem to be related to the peculiarities of the substituent effect on the drug-receptor binding process. In this work, the influence of substituents on the reactivity of LC and its derivatives has been studied by using elementary processes of photodecomposition. The given approach includes the joint analysis of the photophysical properties of the studied systems and their photodecomposition quantum yields. It allows us to trace the influence of substituents, located in the diterpenoid skeleton and anthranilic fragment, on processes in both moieties of LC. Summarizing the data obtained, an inverse dependence of fluorescence and photodegradation quantum yields has been observed. This correlation established for LCs, in particular, allows one to propose a way to evaluate the photostability of potential drugs based on fluorescence analysis. This would be appropriate for compounds in which the reactivity depends on intersystem crossing, i.e. in the cases where the initial and reacting excited states differ in multiplicity.