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.

Time-resolved fluorescence study of exciplex formation in diastereomeric naproxen-pyrrolidine dyads.

The influence of chirality on the elementary processes triggered by excitation of the (S,S)- and (R,S)- diastereoisomers of naproxen-pyrrolidine (NPX-Pyr) dyads has been studied by time-resolved fluorescence in acetonitrile-benzene mixtures. In these systems, the quenching of the (1)NPX*-Pyr singlet excited state occurs through electron transfer and exciplex formation. Fluorescence lifetimes and quantum yields revealed a significant difference (around 20%) between the (S,S)- and (R,S)- diastereomers. In addition, the quantum yields of exciplexes differed by a factor of 2 regardless of solvent polarity. This allows us to suggest a similar influence of the chiral centers on the local charge transfer resulting in exciplex and full charge separation that leads to ion-biradicals. A simplified scheme is proposed to estimate a set of rate constant values (k1-k5) for the elementary stages in each solvent system.

CIDNP and EPR study of phototransformation of lappaconitine derivatives in solution.

Chemically induced dynamic nuclear polarization (CIDNP) and electron paramagnetic resonance (EPR) techniques have been used to study the paramagnetic species formed during the photolysis of the alkaloid lappaconitine and its synthetic analogues in solution. Lappaconitine is a photosensitive antiarrhythmic and hypertension drug, whose major photoproduct (N-acetyl anthranilic acid) is also a potent photosensitizer. Both these compounds are lipophilic and might bind efficiently to cell membranes thereby causing phototoxic damage. Photolysis of natural lappaconitine (I) as well as its N(20) des-ethyl derivatives (N-Bz (II), N-Me (III), N-H (IV), and N(O)-Et (V)) results in cleavage of the ester bond with the formation of N-acetyl anthranilic acid (VIII) and corresponding enamine. The lappaconitine derivative V shows maximum photostability which correlates with reference data about its low toxicity. It was shown that the primary reaction step is electron transfer from the amino group to the anthranilic fragment of lappaconitine resulting in an intermediate biradical. The final products are formed via fragmentation of the neutral lappaconitine radicals.

Enhancement of the photocatalytic activity of TiO2 nanoparticles by water-soluble complexes of carotenoids.

Photoirradiation of TiO(2) nanoparticles by visible light in the presence of the water-soluble natural polysaccharide arabinogalactan complexes of the hydrocarbon carotenoid ß-carotene leads to enhanced yield of the reactive hydroxyl (OH) radicals. The electron paramagnetic resonance (EPR) spin-trapping technique using α-phenyl-N-tert-butyl nitrone (PBN) as the spin-trap has been applied to detect this intermediate by trapping the methyl and methoxy radicals generated upon reaction of the hydroxyl radical with dimethylsulfoxide (DMSO). The free radicals formed in this system proceed via oxygen reduction and not via the reaction of holes on the TiO(2) surface. As compared with pure carotenoids, carotenoid-arabinogalactan complexes exhibit an enhanced quantum yield of free radicals and stability toward photodegradation. The observed enhancement of the photocatalytic efficiency for carotenoid complexes, as measured by the quantum yield of the desired spin adducts, arises specifically from the decrease in the rate constant for the back electron transfer to the carotenoid radical cation. These results are important for a variety of TiO(2) applications, namely, in photodynamic therapy, and in the design of artificial light-harvesting, photoredox, and catalytic devices.

Water soluble complexes of carotenoids with arabinogalactan.

We present the first example of water soluble complexes of carotenoids. The stability and reactivity of carotenoids in the complexes with natural polysaccharide arabinogalactan were investigated by different physicochemical techniques: optical absorption, HPLC, and pulsed EPR spectroscopy. Compared to pure carotenoids, polysaccharide complexes of carotenoids showed enhanced photostability by a factor of 10 in water solutions. A significant decrease by a factor of 20 in the reactivity toward metal ions (Fe(3+)) and reactive oxygen species in solution was detected. On the other hand, the yield and stability of carotenoid radical cations photoproduced on titanium dioxide (TiO(2)) were greatly increased. EPR measurements demonstrated efficient charge separation on complex-modified TiO(2) nanoparticles (7 nm). Canthaxanthin radical cations are stable for approximately 10 days at room temperature in this system. The results are important for a variety of carotenoid applications, in the design of artificial light-harvesting, photoredox, and catalytic devices.

Complex of calcium receptor blocker nifedipine with glycyrrhizic acid.

Physicochemical methods were used to explore the regularities of complexing between the calcium channel blocker nifedipine (NF) and pharmaceutically acceptable complex-forming glycyrrhizic acid (GA) in view of the discovered influence of GA on the therapeutic activity of NF. 1H NMR (including relaxation measurements) and UV-vis spectra have produced illustrative evidence that NF forms stable complexes with GA within a wide concentration range, from 0.05 to 5 mM. At low GA concentrations, below 0.5 mM, NF forms an inclusion complex where each NF molecule is bound by two molecules of GA. Computer simulations of the NMR experimental data have shown that, in aqueous solution, the stability constant of this complex, K, is about 10(5) M(-1). At higher concentrations, GA forms large micelle-like aggregates which increase the water solubility of NF. Quenching of chemically induced dynamic nuclear polarization effects in the photoinduced interaction of the NF-GA complex with tyrosine suggests that complex formation with GA completely blocks the single electron-transfer step between NF and the amino acid. This, arguably, could explain the increased therapeutic activity of GA complexes, since GA might protect the drug molecule from the reaction with amino acid residues of the receptor binding site.

Effect of glycyrrhizic acid on lappaconitine phototransformation.

1H NMR and CIDNP methods were used to demonstrate that triterpene glycoside (glycyrrhizic acid, GA) can substantially change the efficiency and direction of phototransformation of alkaloid lappaconitine (LA) due to both its solubilization in GA micelles and protonation of LA amine nitrogen in water-alcohol solutions. The LA solubilization in the GA micelle suppresses the process of deacylation.

Fast processes and intermediates in photochemistry of 7-dimethyl-germanorbornadiene.

Laser pulse photolysis experiments have shown that the triplet excited-state of 1,2,3,4-tetraphenylnaphthalene (TPN) is one of the primary intermediates of the photochemical transformation of 7,7'-dimethylgerma-1,4,5,6-tetraphenyl-2,3-benzo-norbornadiene (GNB) in hexane solution. The molar absorption of T-T absorption and the quantum yield of the intersystem crossing of TPN were determined from the triplet-triplet energy transfer. The scheme of GNB photocleavage has been suggested where the triplet excited TPN originated from the triplet state of biradical through cleavage of the second C-Ge bond, the latter being generated from the excited singlet state of the initial GNB after the cleavage of the first C-Ge bond and the intersystem crossing. Other channels of GNB's chemical transformation have been discussed.

Elementary steps of enzymatic oxidation of nifedipine catalyzed by horseradish peroxidase.

The elementary steps of the enzymatic oxidation of nifedipine (NF) catalyzed by horseradish peroxidase (HRP) have been described based on analysis of kinetic magnetic field effects (MFEs). It has been shown that the first step of the catalytic cycle is single electron transfer resulting in formation of NF*(+) radical cation and ferroperoxidase (Per(2+)). As a result, comparison with an earlier studied oxidation reaction of NADH catalyzed by HRP evidenced that the enzymatic oxidations of two substrates-native, NADH, and its synthetic analogue, NF-catalyzed by HRP in the absence of H(2)O(2) follow identical mechanisms.

Magnetic spin effects in enzymatic reactions: radical oxidation of NADH by horseradish peroxidase.

A description of the elementary steps of the horseradish peroxidase (HRP)-catalyzed oxidation of NADH is presented, along with a quantitative analysis of the magnetic-field dependence of the enzymatic reaction. In the absence of H(2)O(2), the catalytic cycle begins with single-electron transfer from NADH to native HRP to form the NADH(.+) radical cation and the ferroperoxidase intermediate (Per(2+)). The theoretical framework for the magnetic-field dependent recombination of radical pairs has been extended to describe the magnetic-field dependence of reaction rate constants for multi-spin paramagnetic pairs, including the NADH(.+) radical cation and Per(2+) that exist in a correlated quartet electronic spin state. Good agreement between the experimentally observed and the theoretically calculated magnetic-field dependences of the effective rate constants underlines the importance of the initial single-electron-transfer step and supports a model in which the catalytic cycle begins with the one-electron reduction of HRP by NADH.

Host-guest complexes of carotenoids with beta-glycyrrhizic acid.

The structure, stability, and reactivity of the host-guest complexes between a set of carotenoids and the triterpene glycoside, beta-glycyrrhizic acid (GA), were investigated by different physicochemical techniques: high-performance liquid chromatography, optical absorption, and fluorescence spectroscopy. It has been demonstrated recently that the molecular complexes of GA with a number of drugs are characterized by reduced toxicity and increased therapeutic activity of these drugs. In the present work it was found that carotenoids form 1:2 complexes with GA in aqueous solutions as well as in polar organic solvents, methanol, acetonitrile, and dimethylsulfoxide. We assume that the structure of the complex is a cycliclike dimer of GA encapsulating a carotenoid molecule. The stability constants in all solvents are near 10(4) M(-1). In addition, GA forms inclusion complexes with carotenoid radical cations, which results in their stabilization. Complex formation (a) decreases the rate of electron transfer from carotenoids to electron acceptors (Fe3+ or quinone) and (b) considerably increases the lifetime of the carotenoid-quinone charge-transfer complex and the yield of the major product (a carotenoid-quinone adduct). A thermodynamic study shows that hydrophobic interactions are the main driving force of the carotenoid-GA complex formation. These results are important for understanding both the nature of GA complexes and the influence of GA on the therapeutic activity of some drugs. Furthermore, carotenoid-GA complexes could be used for the design of artificial light-harvesting, photoredox, and catalytic systems.