Phenolic Ring Research Articles

The Sn(IV)-tetra(4-sulfonatophenyl) porphyrin complexes with antioxidants: Synthesis, structure, properties

Complexes of Sn(IV)-tetra(4-sulfophenyl)porphyrin with antioxidants (methoxydol and ionol) and their precursors (para-cresol and 3-hydroxypyridine) were synthesized. All four complexes were obtained by boiling in aqueous solutions of the p-sulfo substituted Sn(IV) dihydroxytetraphenylporphyrin with the corresponding phenols. The structure of the obtained compounds was confirmed by NMR spectroscopy and mass spectrometry methods and quantum chemical calculations. Fluorescent properties of the diphenol complexes of Sn(IV) porphyrins and their photochemical stability in the presence of hydrogen peroxide in buffer media were investigated. It was shown that complexes with antioxidant ligands (ionol and methoxydol) have higher quantum yields and are more resistant to macrocycle destruction than complexes with other phenols and Sn(IV) dihydroxytetraphenylporphyrinate complexes. The main reasons for higher stability and weak quenching of fluorescence intensity are the presence of alkyl groups in the ortho-positions of the phenolic rings in the ionol and methoxydol molecules.

Microbial fuel cell‐mediated lignin depolymerization: a sustainable approach

AbstractBackgroundA microbial electrochemical cell was designed for lignin depolymerization. Alkali‐extracted wheat straw lignin was used as catholyte in a microbial fuel cell and operated for six days. At the cathode, lignin was depolymerized by H2O2, produced during microbial fuel cell operation.ResultsThe power density reached its maximum over two to three days (0.58 µW cm−2), and declined thereafter. Fourier transform infrared analysis of the residual lignin indicated the cleavage of C–O–C (β‐O‐4) bonds without disturbing the phenolic ring structure and high‐power liquid chromatography analysis confirmed the presence of vanillin in the depolymerized sample.ConclusionThe proposed strategy involves a self‐sustainable microbial electrochemical process to convert complex lignin into low molecular weight value‐added aromatic chemicals such as vanillin. © 2018 Society of Chemical Industry

Protonation and Sequential Microsolvation of 5-Hydroxyindole: Infrared Photodissociation Spectra of 5HIH+–Ln with L = Ar and N2 (n ≤ 3)

Protonation and solvation of functionalized heterocyclic aromatic molecules, which often occur as biomolecular building blocks, are important processes in (bio-)organic biochemistry. Herein, we study the protonation and microsolvation mechanisms of 5-hydroxyindole (5HI, 1 H-indol-5-ol, C8H7NO), the chromophore of serotonin, produced by electron and and chemical ionization using infrared photodissociation (IRPD) spectroscopy of mass-selected cold 5HIH+-L n clusters (L = Ar/N2, n ≤ 3) and dispersion-corrected density functional theory calculations (B3LYP-D3/aug-cc-pVTZ). Isomer-selective OH and NH stretch frequencies in the spectral range 3000-3800 cm-1 reveal the coexistence of at least four protonated species: the most stable syn (cis) isomer protonated at the C3 position of indole, both syn- and anti-rotamers protonated at C4 of the phenol ring, and the drastically less stable O-protonated isomer (Δ E0 = 117.1 kJ/mol) stabilized by kinetic trapping. Manipulation of the IRPD conditions (fragmentation channels) facilitates the spectroscopic isolation of O-protonated species. Upon protonation, the acidity of the OH group increases in the order 5HIH+(C3), 5HIH+(C4), and 5HIH+(O), while the acidity of the NH group decreases along this series, strongly affecting the microsolvation motifs of the individual isomers. Comparison of 5HIH+-L to the corresponding neutral and radical cation clusters reveals the impact of both protonation and ionization on the interaction with nonpolar ligands. Furthermore, our results are compared to protonated phenol, for which similar gas-phase protonation mechanisms have been found. Comparison of 5HIH+-L with the corresponding clusters of protonated phenol illustrates the effects of functional substitution and addition of aromatic rings on intermolecular potential.

Quantum-chemical modeling of the electronic structure of quercetin and inhibition by quercetin and quercetin–hydroxypropyl-β-cyclodextrin complex of lipid peroxidation in mitochondria and red blood cells of rats

Quercetin (3,3ʹ,4ʹ,5,7-pentahydroxyflavon), one of the most common and studied flavonoids, possesses the antioxidant activity and demonstrates the pronounced therapeutic potential under a number of pathological conditions. The purpose of this work is to estimate the electronic structure of the quercetin and its semi-quinone radical molecules and to compare the antioxidant activities of quercetin and its inclusion complex with hydroxypropyl-β-cyclodextrin. Generation of maps of the electron density distribution in quercetin and quercetin semi-quinone radical molecules showed that the active electron orbitals (HOMO and LUMO) are delocalized over all phenolic rings providing the radical stabilization. We have showed that quercetin prevents the tert-butyl hydroperoxide-induced lipid peroxidation of erythrocytes (IC50= 25 ± 3 μM) and mitochondrial membranes (IC50= 31 ± 4 μM). The efficiency of quercetin inhibition the reduced glutathione oxidation in erythrocytes and mitochondria is much lower reflecting the lipophilicity of polyphenol. Quercetin also prevented the hypochlorite-induced lysis of red blood cells (IC50= 3 ± 0.5 μM). Our data revealed that the quercetin-hydroxypropyl-β-cyclodex-trin complex is more effective inhibitor of the membrane lipids peroxidation and glutathione oxidation processes.

Jet-Cooled Spectroscopy of ortho-Hydroxycyclohexadienyl Radicals.

The electronic spectra of the ortho-hydroxycyclohexadienyl radical have been observed following the supersonic expansion of the electric discharge products of phenol and water. Hydrogen atoms, split from water, add to the phenol ring at the ortho position, generating syn and anti rotamers with respect to the hydroxyl group. The D1 ← D0 transitions were recorded by resonance-enhanced multiphoton ionization spectroscopy. The spectrum of each isomer was isolated through hole-burning spectroscopy. The assignment and symmetry of the excited state are evaluated through ab initio calculations and are employed to assign each spectrum. Both rotamers are calculated to have a puckered ring in the excited state, leading to C1 symmetry. The spectrum of the anti isomer is assigned well using this symmetry; however, the syn isomer is assigned better in the C s symmetry of the ground state. We use Duschinsky matrices as a tool for the spectroscopist to determine which point group to use when ab initio calculations are ambiguous.

Biodegradation of lignin by Pseudomonas sp. Q18 and the characterization of a novel bacterial DyP-type peroxidase.

Lignin valorization can be obtained through cleavage of selected bonds by microbial enzymes, in which lignin is segregated from cellulose and hemicellulose and abundant phenolic compounds can be provided. In this study, Pseudomonas sp. Q18, previously isolated from rotten wood in China, was used to degrade alkali lignin and raw lignocellulosic material. Gel-permeation chromatography, field-emission scanning electron microscope, and GC-MS were combined to investigate the degradation process. The GC-MS results revealed that the quantities of aromatic compounds with phenol ring from lignin increased significantly after incubation with Pseudomonas sp. Q18, which indicated the degradation of lignin. According to the lignin-derived metabolite analysis, it was proposed that a DyP-type peroxidase (PmDyP) might exist in strain Q18. Thereafter, the gene of PmDyP was cloned and expressed, after which the recombinant PmDyP was purified and the enzymatic kinetics of PmDyP were assayed. According to results, PmDyP showed promising characteristics for lignocellulosic biodegradation in biorefinery.

Structure, electronic properties, and NBO and TD-DFT analyses of nickel(II), zinc(II), and palladium(II) complexes based on Schiff-base ligands

In this work we studied the structural and electronic properties of the metal-Schiff base complexes Ni[Formula: see text] (1), Pd[Formula: see text] (2), Zn[Formula: see text] (3), and Ni[Formula: see text](4), where L1 and L2 are Schiff bases synthesized from salicylaldehyde and 2-hydroxy-5-methylbenzaldehyde, respectively. Natural bond analysis showed that in complexes 1 and 2, the metal ion coordinates to the ligands through electron donation from lone pairs on ligand nitrogen and oxygen atoms to s and d orbitals on the metal ion. In complex 3, metal-N and metal-O bonds are formed through charge transfer from the lone pairs on nitrogen and oxygen atoms to an s orbital of Zn. Dimethylation of the phenolate rings in the ligands decreases the energy gap and redshifts the spectrum of the nickel complex. The main absorptions observed were assigned on the basis of singlet-state transitions. The simulated spectra of the two complexes 1 and 2 are characterized by excited states with ligand-to-ligand charge-transfer (LLCT), metal-to-ligand charge-transfer (MLCT), ligand-to-metal charge-transfer (LMCT), and metal-centered (MC) character. Graphical abstract Geometric structure of the palladium complex.

Protein Tyrosine Nitration in Lung Cancer: Current Research Status and Future Perspectives.

Oxidative/nitrative damage is a crucial element among the complex factors that contribute to lung carcinogenesis. Nitric oxide (NO) free radicals, through chemical modifications such as tyrosine nitration, are significantly involved in lung carcinogenesis and metastasis. NO-mediated protein nitration, which is the addition of the nitro group (-NO2) to position 3 of the phenolic ring of a tyrosine residue, is an important molecular event in lung cancer, and has been studied with mass spectrometry. Nitration is involved in multiple biological processes, including signal transduction, protein degradation, energy metabolism, mitochondrial dysfunction, enzyme inactivation, immunogenic response, apoptosis, and cell death. This article reviews the relationship of NO and its derivates and lung cancer, formation and roles of tyrosine nitration in lung cancer, differences of protein nitration between lung cancer and other inflammatory pulmonary diseases, current status of protein nitration and nitroproteomics in lung cancer, and future perspectives to achieve a better understanding of lung carcinogenesis, for biomarker discovery; and for new diagnostic and prognostic monitoring, and therapeutic targets.

Resveratrol: A Double-Edged Sword in Health Benefits.

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) belongs to polyphenols’ stilbenoids group, possessing two phenol rings linked to each other by an ethylene bridge. This natural polyphenol has been detected in more than 70 plant species, especially in grapes’ skin and seeds, and was found in discrete amounts in red wines and various human foods. It is a phytoalexin that acts against pathogens, including bacteria and fungi. As a natural food ingredient, numerous studies have demonstrated that resveratrol possesses a very high antioxidant potential. Resveratrol also exhibit antitumor activity, and is considered a potential candidate for prevention and treatment of several types of cancer. Indeed, resveratrol anticancer properties have been confirmed by many in vitro and in vivo studies, which shows that resveratrol is able to inhibit all carcinogenesis stages (e.g., initiation, promotion and progression). Even more, other bioactive effects, namely as anti-inflammatory, anticarcinogenic, cardioprotective, vasorelaxant, phytoestrogenic and neuroprotective have also been reported. Nonetheless, resveratrol application is still being a major challenge for pharmaceutical industry, due to its poor solubility and bioavailability, as well as adverse effects. In this sense, this review summarized current data on resveratrol pharmacological effects.

Layer-by-Layer Preparation of Microcapsules and Nanocapsules of Mixed Polyphenols with High Antioxidant and UV-Shielding Properties.

Microcapsules and nanocapsules based on the contemporary presence of sulfonate lignin and tannic acid have been prepared by the layer-by-layer procedure, using MnCO3 or organosolv lignin as core templates, and polydiallyldimethylammonium chloride or chitosan as positive charged supporting layers. Nanocapsules and microcapsules of mixed polyphenols showed antioxidant activity, UV-shielding properties, and electrochemical responsiveness, higher than that in homopolymer nanocapsule counterparts and of the native polyphenols, suggesting the presence of synergistic effects between the two components. The presence of UV-visible bathochromic shift suggested the formation of J-aggregates characterized by an orientation of the adjacent phenolic rings parallel to the longitudinal direction of the layer, with a head-to-tail like arrangement. Moreover, nanocapsules of mixed polyphenols showed an aggregation state higher than that observed in references, the specific morphology of their surface being dependent on the structural arrangement of the different components.

Two New Fluorinated Phenol Derivatives Pyridine Schiff Bases: Synthesis, Spectral, Theoretical Characterization, Inclusion in Epichlorohydrin-β-Cyclodextrin Polymer, and Antifungal Effect.

It has been reported that the structure of the Schiff bases is fundamental for their function in biomedical applications. Pyridine Schiff bases are characterized by the presence of a pyridine and a phenolic ring, connected by an azomethine group. In this case, the nitrogen present in the pyridine is responsible for antifungal effects, where the phenolic ring may be also participating in this bioactivity. In this study, we synthesized two new pyridine Schiff Bases: (E)-2-[(3-Amino-pyridin-4-ylimino)-methyl]-4,6-difluoro-phenol (F1) and (E)- 2-[(3-Amino-pyridin-4-ylimino)-methyl]-6-fluoro-phenol (F2), which only differ in the fluorine substitutions in the phenolic ring. We fully characterized both F1 and F2 by FTIR, UV-vis, 1H; 13C; 19F-NMR, DEPT, HHCOSY, TOCSY, and cyclic voltammetry, as well as by computational studies (DFT), and NBO analysis. In addition, we assessed the antifungal activity of both F1 (two fluorine substitution at positions 4 and 6 in the phenolic ring) and F2 (one fluorine substitution at position 6 in the phenolic ring) against yeasts. We found that only F1 exerted a clear antifungal activity, showing that, for these kind of Schiff bases, the phenolic ring substitutions can modulate biological properties. In addition, we included F1 and F2 into in epichlorohydrin-β-cyclodextrin polymer (βCD), where the Schiff bases remained inside the βCD as determined by the ki, TGA, DSC, and SBET. We found that the inclusion in βCD improved the solubility in aqueous media and the antifungal activity of both F1 and F2, revealing antimicrobial effects normally hidden by the presence of common solvents (e.g., DMSO) with some cellular inhibitory activity. The study of structural prerequisites for antimicrobial activity, and the inclusion in polymers to improve solubility, is important for the design of new drugs.

Mechanistic processes of resveratrol in inhibiting the oxidative damage of guanine, as evidenced by UHPLC-MS2

Resveratrol, as one of the stilbenoids, is present in abundance in wine grapes and has been shown to selectively quench 1O2. DNA is oxidized by 1O2 causing irreparable functional damage, and of the nucleic acids, guanine is the most susceptible. An agarose gel electrophoresis assay demonstrated that DNA was damaged by 1O2 with less than 5 min of UVA irradiation, and also that 5 mM resveratrol dissolved in MeOH could relieve the observed oxidation stress. Ultra-high performance liquid chromatography coupled with mass spectrometry was performed to reveal the mechanism. Four guanine oxidation products at m/z 140.0334 [M-H]−(1), DGh, 8-oxoG, Sp and two conjugates at m/z 377.1104 [M-H]− and 391.0907 [M-H]− were identified and quantified. Thus, we propose the mechanism that the phenol ring of resveratrol links with the free amino groups (NH) of guanine at the beginning of 1O2 attack to form m/z 377.1104 [M-H]−, however, as 1O2 is able to attack the amino groups continuously, resveratrol can efficiently react with 1O2 prior to damage, and form m/z 391.0907 [M-H]− thereby protecting guanine.

Strategies, Setbacks, and Successes in the Synthesis of (-)-Spiroleucettadine.

Various strategies toward the synthesis of the marine natural product (-)-spiroleucettadine are described. In the original strategy, a biomimetic inspired oxidation of a 2-imidazoline scaffold uncovered unexpected reactivity, where benzylic oxidation followed by a Baeyer-Villiger reaction was observed. The second generation approach examined oxidative dearomatization of the phenol ring system first, where a competing spirocyclization process was uncovered. Efforts to forge the scaffold via a carbocation mediated benzyl migration were unsuccessful. Highlights of the successful synthesis include two consecutive hypervalent iodine reactions: the first formed the spirocyclic center and the second facilitated installation of an acetate group at the C-5 position to allow for subsequent introduction of the methyl amine side chain.

Abstract 2379: PTPRT pseudo-phosphatase domain is a denitrase that contributes to its tumor suppressor function

Abstract Department of Genetics & Genome Sciences and Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA. In addition to phosphorylation, tyrosine residues in proteins can have nitration at the 3-carbon position on the phenol ring (Y-NO2). Protein tyrosine nitration occurs under both physiological and pathologic conditions. However, enzymes that add or remove this protein modification remain to be identified. Protein tyrosine phosphatase receptor T (PTPRT) is one of the twelve receptor protein tyrosine phosphatases (RPTPs) that have two catalytic PTP domains in their intracellular parts. While the membrane proximal PTP domains (D1) are protein tyrosine phosphatases, it has been thought that the C-terminal PTP domains (D2) are pseudo-phosphatase that lack enzymatic activity. Here we report that the pseudo-phosphatase domain (D2) of PTPRT is a denitrase that removes nitro-groups from tyrosine residues in paxillin. PTPRT normally functions as a tumor suppressor and is frequently mutated in a variety of human cancers including colorectal cancer. Interestingly, a fifth of tumor-derived mutations of PTPRT are located in the D2 pseudo-PTP domain. We demonstrate that some of the tumor-derived mutations located in the pseudo-phosphatase domain impair the denitrase activity. Moreover, PTPRT mutant mice that inactivate the denitrase activity are susceptible to carcinogen-induced colon tumor formation. Our study uncovers a novel enzyme that functions as a tumor suppressor. Citation Format: Yiqing Zhao, Zhenghe Wang. PTPRT pseudo-phosphatase domain is a denitrase that contributes to its tumor suppressor function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2379.

Asymmetric Total Syntheses of Insulicolide A, 14- O-Acetylinsulicolide A, 6β,9α-Dihydroxy-14- p-nitrobenzoylcinnamolide, and 7α,14-Dihydroxy-6β- p-nitrobenzoylconfertifolin.

Asymmetric total syntheses of insulicolide A, 14- O-acetylinsulicolide A, 6β,9α-dihydroxy-14- p-nitrobenzoyl cinnamolide, and 7α,14-dihydroxy-6β- p-nitrobenzoylconfertifolin have been achieved for the first time. The key steps in the synthesis include: (1) an iridium-catalyzed enantioselective polyene cyclization to construct the drimane core bearing two all-carbon quaternary chiral centers at C4 and C10 and (2) a cascade ozonolysis of the phenol ring to form the lactone fragment of the target molecules.

Coordination chemistry of a redox non-innocent NHC bis(phenolate) pincer ligand with nickel(II)

The electrochemical properties of the neutral nickel(II) complexes of two NHC bis(di-tert-butylphenolate) pincer ligands, namely 1 and 2, are reported. Complex 1 shows a reversible redox wave at 0.10 V vs Fc+/Fc, which corresponds to the oxidation of the phenolate moiety. The complex 1+ SbF6− was prepared and structurally characterized. The nickel ion lies in a square planar geometry identical to that observed for 1, with contracted NiO bond distances. Complex 1+ exhibits a remarkable absorption band in the NIR region, 6370 cm−1 (13,450 M−1 cm−1), assigned to a charge transfer transition associated with the radical moiety. A band shape analysis supports its classification as a mixed-valent (Class II/III) compound. Complex 1+ exhibits a resonance in the EPR spectrum at giso = 2.056, as expected for a paramagnetic (S = ½) system. The shift from the free electron value suggests the participation of a nickel d-orbital in the SOMO. DFT calculations support the mainly radical character of 1+, but show that the spin density is shared between the metal center, which harbours a spin of 0.28, and both phenolic rings of the ligand. The carbene linker does not demonstrate any significant spin population.

Leu169Trp substitution in MnSOD from Staphylococcus equorum created an active new form of similar resistance to UVC irradiation

Manganese superoxide dismutase from Staphylococcus equorum (MnSODSeq) maintains its activity after up to 45 minutes of UVC radiation. The enzyme occurs in a dimeric form that likely contributes to its activity and stability. Therefore, maintaining the dimeric form could be a way to improve the enzyme’s stability. One of the main interactions for dimer formation occurs between Tyr168 and His31, of which the latter is also involved in the enzymatic reaction. UVC radiation may cause alterations in the electronic structure of the phenolic ring in the Tyr168 side chain: this may disrupt the Tyr168-His31 pairing and lead to enzyme instability and/or activity loss. In this report, a Leu169Trp substitution was carried out to protect the Tyr168 residue by introducing an amino acid with an aromatic side chain for better photon absorption of the UV light. Interestingly, although the substitution appeared to have a minor effect on enzyme stability and activity upon UVC irradiation, the melting temperature (TM) of the Leu169Trp mutant was different. Unlike the native protein, the TM of the mutant had not changed after UV irradiation. Thus, our effort to extend the resistance to UVC radiation was not successful, but we have discovered a biologically active new form. The present finding provides evidence that MnSODSeq maintains most of its activity and resistance to UVC irradiation as long as the dimer and its glutamate-bridge are intact, despite an alteration that destabilizes its monomeric structure. The present finding further unravels the relationship between the structure of the enzyme and its activity. Furthermore, the results may provide further insight in how to modify the enzyme to improve its characteristics for application in medicine or cosmetics.

Suspect and untargeted screening of bisphenol S metabolites produced by in vitro human liver metabolism

Bisphenol S (BPS) is increasingly used as substitute for bisphenol A, resulting in higher potential of human exposure to this compound. Yet, information on the human metabolism of BPS is limited. Hence, current biomonitoring studies rely only on the measurement of BPS itself, leading to a potential underestimation of assessing human exposure to this emerging contaminant. The aims of this study were to investigate the in vitro metabolic pathways of BPS using human liver microsomes and cytosol fractions and propose in vitro metabolites for evaluation in pharmacokinetics studies. Liquid chromatography coupled to quadrupole time-of-flight high-resolution mass spectrometry was used for the screening, identification, and structural elucidation of Phase I and II metabolites of BPS for the first time. Metabolite identification was performed using two complementary workflows: suspect and untargeted screening. Two Phase I metabolites were formed through hydroxylation of the phenolic rings. Four Phase II metabolites were formed through conjugation with glucuronic acid or sulfate. Three of these metabolites, namely dihydroxy-BPS, hydroxy-BPS-glucuronide and hydroxy-BPS-sulfate were identified and structurally elucidated for the first time. As such, we provide an expanded set of in vitro biotransformation products of BPS, which can potentially support a reliable assessment of BPS exposure in future biomonitoring studies.

Sugarcane Bagasse Fibers Treated and Untreated: Performance as Reinforcement in Phenolic-Type Matrices Based on Lignosulfonates

In this study, fragile thermoset phenolic-type polymers were chosen as composite matrices that were reinforced with sugarcane bagasse fibers, an agro-residue widely available across the world, which has motivated the search for new applications for this fiber. Lignosulfonate (SL), a macromolecule obtained from lignocellulosic biomass and having phenolic rings in its chemical structure, was used as a substitute for phenol in the synthesis of phenolic-type polymers, yielding lignophenolic polymers. To our knowledge, composites based on lignosulfonates and sugarcane bagasse have not yet been reported in the literature. Composites were also prepared from phenol for a comparison of the properties. SL was also used for the first time to modify the surface of sugarcane bagasse fibers via adsorption, aiming to intensify the interactions at the interface between fibers and matrix, which influences the properties of composites. Untreated and treated (with SL) fibers were characterized for composition and crystallinity, and analyzed using scanning electron microscopy, thermogravimetric analysis, and inverse gas chromatography (IGC). These fibers were used as reinforcements (50 and 70 wt%) in phenolic and lignophenolic matrices. The impact strength of the composites was determined, and the fractured surfaces (after impact) were characterized using SEM. The IGC results showed that the treatment of the fibers increased the number of acidic groups (mainly owing to the increase in the –OH groups, derived from SL) and electron donors (mainly SO3− groups present in the structure of SL) on the surface of the fibers. Similar results were observed in a previous study on the lignophenolic thermoset, which exhibited a greater amount of both acidic and donor groups compared to the phenolic thermoset. The impact strength of all the composites (phenol- and lignophenolic-based matrices) was considerably higher than that of the unreinforced thermoset. The best results were observed for the lignophenolic matrices reinforced with treated fibers (50 and 70 wt%). The high amount of acidic and donor groups on the surface of these fibers and in the lignophenolic polymer favored the interactions between the donor sites of the treated fibers and the lignophenolic matrix acceptors and vice versa, leading to a strong adhesion at the interface of the fibers and matrix. This study showed that surface modification of sugarcane bagasse fibers through adsorption could be a promising alternative to modifications using chemical reactions, besides increasing the possibilities of the use of sugarcane bagasse and SL. To our knowledge, the approach of this study is unprecedented.

Theoretical analysis of orientations and tautomerization of genistein in β-cyclodextrin

Genistein is an isoflavone with promising pharmaceutical applications. However, its low water solubility interferes with its potency, and therefore cyclodextrins (CDs) have been considered as possible drug delivery system (DDS). To investigate the complexation mechanism of genistein in cyclodextrin, we employed molecular dynamics (MD) simulations based on classical potentials and the density-functional tight-binding (DFTB) quantum chemical potential. Both classical and quantum chemical MD simulations predict that the phenol ring of genistein is preferentially complexed in the cavity of CD. The complexation process reduces the water-accessible solvation shell, and it is found that a hydrogen bond is formed between genistein and CD. The DFTB-based MD simulations reveal that spontaneous keto-enol tautomerization occurs even within a hundred picoseconds, which suggests that the encapsulated genistein is complexed in the ordinary enol form of the drug molecule. Analyses of the molecular charge distributions suggest that electrostatic interactions partially induce the complex formation, rather than extensive formation of hydrogen bonds.