Exocyclic Group Research Articles

A comprehensive review of structure-activity relationships and effect mechanisms of polyphenols on heterocyclic aromatic amines formation in thermal-processed food.

Heterocyclic aromatic amines (HAAs) are potent carcinogenic substances mainly generated in thermal-processed food. Natural polyphenols have been widely used for inhibiting the formation of HAAs, whereas the effect of natural polyphenols on HAAs formation is complex and the mechanisms are far from being clearly elucidated. In order to clarify the comprehensive effect of polyphenols on HAAs, this review focused on the structure-activity relationships and effect mechanisms of polyphenols on the formation of HAAs. In addition, the effects of polyphenols on HAAs toxicity were also first reviewed from cell, gene, protein, and animal aspects. An overview of the effect of polyphenol structures such as parent ring and exocyclic group on the mitigation of HAAs was emphasized, aiming to provide some valuable information for understanding their effect mechanism. The HAAs formation is inhibited by natural polyphenols in a dose-dependent manner largely through eliminating free radicals and binding precursors and intermediates. The inhibitory effect was probably affected by the quantity and position of hydroxyl groups in the aromatic rings, and polyphenols with m-hydroxyl group in the aromatic ring had the stronger inhibitory effect. However, the presence of other substituents and excessive hydroxyl groups in natural polyphenols might mitigate the inhibitory effect and even promote the formation of HAAs. This review can provide theoretical reference for effectively controlling the formation of HAAs in thermal-processed food by natural polyphenols and reducing their harm to human health.

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles.

In this work, we report an efficient approach to 2-oxoazetidine-3-carboxylic acid derivatives based on a thermally promoted Wolff rearrangement of diazotetramic acids in the presence of nucleophiles. The method allows easy variation of the substituent in the exocyclic acyl group by introducing different N-, O-, and S-nucleophilic reagents into the reaction. The reaction of chiral diazotetramic acids leads exclusively to trans-diastereomeric β-lactams. The use of variously substituted diazotetramic acids, including spirocyclic derivatives, as well as a wide range of nucleophiles provides access to a structural diversity of medically relevant 2-oxoazetidine-3-carboxylic acid amides and esters.

Improving Zonisamide Manufacturing: Insights into Stereochemistry and Mechanisms for Continuous Optimization

Zonisamide is a heterocyclic sulfonamide widely employed as anticonvulsant. In this work, we report an efficient process for the preparation of zonisamide, obtained in a six‐step synthesis from phenyl salicylate with an overall 31% yield. The key step is represented by a base‐promoted intramolecular rearrangement of a β‐ketosultone oxime, leading to the concomitant formation of the benzisoxazole ring and of the exocyclic sulfonic group. This intriguing transformation is investigated with a combination of analytical techniques (NMR, HRMS, PXRD), leading to a preliminary mechanistic proposal.

Conformational disorder in the crystal structure of methyl 2-acetamido-2-deoxy-β-D-glucopyranosyl-(1→4)-2-acetamido-2-deoxy-β-D-glucopyranoside (methyl β-chitobioside) methanol monosolvate.

Methyl 2-acetamido-2-deoxy-β-D-glucopyranosyl-(1→4)-2-acetamido-2-deoxy-β-D-glucopyranoside (methyl β-chitobioside), (IV), crystallizes from aqueous methanol at room temperature to give a structure (C17H30N2O22·CH3OH) containing conformational disorder in the exocyclic hydroxymethyl group of one of its βGlcNAc residues. As observed in other X-ray structures of disaccharides containing β-(1→4) O-glycosidic linkages, inter-residue hydrogen bonding between O3H of the βGlcNAc bearing the OCH3 aglycone and O5 of the adjacent βGlcNAc is observed based on the 2.79 Å internuclear distance between the O atoms. The structure of (IV) was compared to that determined previously for 2-acetamido-2-deoxy-β-D-glucopyranosyl-(1→4)-2-acetamido-2-deoxy-β-D-glucopyranose (β-chitobiose), (III). The O-glycosidic linkage torsion angles, phi (φ) and psi (ψ), in (III) and (IV) differ by 6-8°. The N-acetyl side chain conformation in (III) and (IV) shows some context dependence, with the C1-C2-N-Ccar torsion angle 10-15° smaller for the βGlcNAc residue involved in the internal O-glycosidic linkage. In (IV), conformational disorder is observed in the exocyclic hydroxymethyl (-CH2OH) group in the βGlcNAc residue bearing the OCH3 aglycone, and a fitting of the electron density indicates an approximate 50:50 distribution of the gauche-gauche (gg) and gauche-trans (gt) conformers in the lattice. Similar behavior is not observed in (III), presumably due to the different packing structure in the vicinity of the -CH2OH substituent that affects its ability to hydrogen bond to proximal donors/acceptors. Unlike (IV), a re-examination of the previously reported electron density of (III) revealed conformational disorder in the N-acetyl side chain attached to the reducing-end βGlcNAc residue caused by rotation about the C2-N bond.

Acceptor molecules with Carbon–Carbon singly bonded central and terminal units for efficient P3HT-based organic solar cells

Herein, we synthesized two small molecules named as 4TBTCN and 6TBTCN with strongly electron-rich 4,4,9,9-tetrakis(4-hexylphenyl)-4,9-dihydrothieno[3′,2′:4,5]cyclopenta[1,2-b]thieno[2″,3′′:3′,4′]cyclopenta[1′,2′:4,5]thieno[2,3-d]thiophene or 6,6,12,12-tetrakis(4-hexylphenyl)-6,12-dihydrothieno[2″,3′′:4′,5′]thieno[3′,2′:4,5]cyclopenta[1,2-b]thieno[2‴,3‴:4″,5′′]thieno[2″,3′′:3′,4′]cyclopenta[1′,2′:4,5]thieno[2,3-d]thiophene as central unit and weak electron-withdrawing benzo[c] [1,2,5] thiadiazole-4-carbonitrile as termini, which were connected by C–C single bond. Both molecules exhibited medium optical bandgap and high-lying frontier molecular orbital energy levels, which were matched with those of the representative low-cost polymer donor P3HT. Moreover, 4TBTCN and 6TBTCN showed high stability under continuous illumination and base condition, owing to a lack of exocyclic vinyl group between the central unit and end group. Compared to P3HT:6TBTCN, P3HT:4TBTCN blend system displayed lower miscibility and thus more distinct phase separation, leading to more efficient charge transport and collection. Although the LUMO energy level of 4TBTCN was 0.15 eV deeper than that of 6TBTCN, the energy loss for P3HT:4TBTCN based device was similar to that of P3HT:6TBTCN based device. As a result, P3HT:4TBTCN based device displayed a similar open-circuit voltage but higher fill factor and short-circuit current density, yielding a superior power conversion efficiency, in comparison to P3HT:6TBTCN based device. This work provides a new strategy for design of efficient and stable acceptor molecules.

Stable Interstrand Cross-Links Generated from the Repair of 1,N6-Ethenoadenine in DNA by α-Ketoglutarate/Fe(II)-Dependent Dioxygenase ALKBH2.

DNA cross-links severely challenge replication and transcription in cells, promoting senescence and cell death. In this paper, we report a novel type of DNA interstrand cross-link (ICL) produced as a side product during the attempted repair of 1,N6-ethenoadenine (εA) by human α-ketoglutarate/Fe(II)-dependent enzyme ALKBH2. This stable/nonreversible ICL was characterized by denaturing polyacrylamide gel electrophoresis analysis and quantified by high-resolution LC-MS in well-matched and mismatched DNA duplexes, yielding 5.7% as the highest level for cross-link formation. The binary lesion is proposed to be generated through covalent bond formation between the epoxide intermediate of εA repair and the exocyclic N6-amino group of adenine or the N4-amino group of cytosine residues in the complementary strand under physiological conditions. The cross-links occur in diverse sequence contexts, and molecular dynamics simulations rationalize the context specificity of cross-link formation. In addition, the cross-link generated from attempted εA repair was detected in cells by highly sensitive LC-MS techniques, giving biological relevance to the cross-link adducts. Overall, a combination of biochemical, computational, and mass spectrometric methods was used to discover and characterize this new type of stable cross-link both in vitro and in human cells, thereby uniquely demonstrating the existence of a potentially harmful ICL during DNA repair by human ALKBH2.

Photopolymerization of Limonene Dioxide and Vegetable Oils as Biobased 3D-Printing Stereolithographic Formulation.

Epoxidized vegetable oils and limonene dioxide, a bis-epoxide derived from the terpene limonene, are photo-copolymerized to yield highly crosslinked networks with high conversion of all epoxide groups at ambient temperature. However, the slow polymerization of such biobased formulation polymerizes is not compatible for a use in a commercial SLA 3D printer. Adding an acrylated epoxidized vegetable oil to the bis-epoxide leads to a decrease of curing time and an increase in LDO conversion to polymer. For example, in a 60:40 wt:wt mixture of LDO and epoxidized soybean oil, the conversions of both exocyclic and endocyclic epoxide groups of LDO are ≥95%. These formulations were successfully used in SLA 3D printers, leading to generation of hard and dry complex objects using biobased formulations.

MA'AT Analysis: Unbiased Multi-State Conformational Modeling of Exocyclic Hydroxymethyl Group Conformation in Methyl Aldohexopyranosides.

MA'AT analysis (J. Chem. Inf. Model. 2022, 62, 3135-3141) has been applied to model exocyclic hydroxymethyl group conformation in methyl β-D-glucopyranoside (βGlcOMe), methyl β-D-galactopyranoside (βGalOMe), and methyl β-D-mannopyranoside (βManOMe) in an unbiased manner. Using up to eight NMR J-couplings sensitive to rotation about the C5-C6 bond (torsion angle ω), two-state models of ω were obtained that are qualitatively consistent with the relative populations of the gg, gt, and tg rotamers reported previously. MA'AT analysis gave consistent unbiased gt ⇌ tg models of ω in βGalOMe, with gt more populated than tg and mean values of ω for each population similar to those obtained from aqueous 1-μs MD simulation. Using different combinations of J-couplings had little effect on the βGalOMe model in terms of the mean values of ω and circular standard deviations (CSDs). In contrast, MA'AT analysis of ω in βGlcOMe and βManOMe produced more than one two-state model independent of the ensemble of J-values used in the analyses. These models were characterized by gg ⇌ gt conformer exchange as expected, but the mean values of ω in both conformers varied significantly in the different fits, especially for the gg rotamer. Constrained (biased) MA'AT analyses in which only staggered geometries about ω were allowed gave RMSDs slightly larger than those obtained from the unbiased fits, precluding an assignment of an unbiased model. It is unclear why MA'AT analysis gives consistent and predictable unbiased models of ω in βGalOMe but not in βGlcOMe and βManOMe. One possibility is that the distribution of ω in one or both of the gg and gt conformers in the latter does not conform to a von Mises function (i.e., is not Gaussian-like), but rather to a broad and/or flat distribution that cannot be fit by the current version of MA'AT. Nevertheless, the results of this study provide new evidence of the ability of MA'AT analysis to treat multi-state conformational exchange using only experimental NMR data, extending recent MA'AT applications to furanosyl ring pseudorotation (Biochemistry 2022, 61, 239-251).

Ein N‐Heterozyklisches Chinodimethan: Eine starke organische Lewis‐Base mit Diradikal‐Charakter

AbstractWir berichten über die Darstellung eines neuen organischen σ‐Donors mit einem C6H4‐Linker zwischen einem N‐heterozyklischen Carben (NHC) und einer exozyklischen Methylidengruppe, den wir als N‐heterozyklisches Chinodimethan (NHQ) bezeichnen. Die Aromatisierung des C6H4‐Linkers liefert eine entscheidende Triebkraft für die Reaktion des NHQs mit einem Elektrophil und macht das NHQ deutlich basischer als analoge NHCs oder N‐heterozyklische Olefine (NHOs), wie DFT‐Berechnungen und Konkurrenzexperimente zeigen. In Lösung findet beim NHQ eine unerwartete Kopf‐Kopf‐Dimerisierung unter formaler Wasserstofffreisetzung durch C−C‐Kopplung der Methylidengruppen statt. DFT‐Berechnungen zeigen, dass diese Reaktion über einen offenschaligen Singulettpfad verläuft, was auf einen diradikalischen Charakter des NHQs hinweist. Das Produkt dieser Dimerisierung kann als konjugiertes N‐heterozyklisches Bis‐Chinodimethan beschrieben werden, das laut zyklischer Voltammetrie ein starkes organisches Reduktionsmittel ist (E1/2=−1.71 V vs. Fc/Fc+) und eine bemerkenswert kleine Singulett–Triplett‐Lücke von ΔES→T=4.4 kcal mol−1 aufweist.

An N-Heterocyclic Quinodimethane: A Strong Organic Lewis Base Exhibiting Diradical Reactivity.

We report the preparation of a new organic σ-donor with a C6H4-linker between an N-heterocyclic carbene (NHC) and an exocyclic methylidene group, which we term N-heterocyclic quinodimethane (NHQ). The aromatization of the C6H4-linker provides a decisive driving force for the reaction of the NHQ with an electrophile and renders the NHQ significantly more basic than analogous NHCs or N-heterocyclic olefins (NHOs), as shown by DFT computations and competition experiments. In solution, the NHQ undergoes an unprecedented dehydrogenative head-to-head dimerization by C-C coupling of the methylidene groups. DFT computations indicate that this reaction proceeds via an open-shell singlet pathway revealing the diradical character of the NHQ. The product of this dimerization can be described as conjugated N-heterocyclic bis-quinodimethane, which according to cyclic voltammetry is a strong organic reducing agent (E1/2=-1.71 V vs. Fc/Fc+) and exhibits a remarkable small singlet-triplet gap of ΔES→T=4.4 kcal mol-1.

Control of Substrate Conformation by Hydrogen Bonding in a Retaining β-Endoglycosidase.

Bacterial β-glycosidases are hydrolytic enzymes that depolymerize polysaccharides such as β-cellulose, β-glucans and β-xylans from different sources, offering diverse biomedical and industrial uses. It has been shown that a conformational change of the substrate, from a relaxed 4 C1 conformation to a distorted 1 S3 /1,4 B conformation of the reactive sugar, is necessary for catalysis. However, the molecular determinants that stabilize the substrate's distortion are poorly understood. Here we use quantum mechanics/molecular mechanics (QM/MM)-based molecular dynamics methods to assess the impact of the interaction between the reactive sugar, i. e. the one at subsite -1, and the catalytic nucleophile (a glutamate) on substrate conformation. We show that the hydrogen bond involving the C2 exocyclic group and the nucleophile controls substrate conformation: its presence preserves sugar distortion, whereas its absence (e.g. in an enzyme mutant) knocks it out. We also show that 2-deoxy-2-fluoro derivatives, widely used to trap the reaction intermediates by X-ray crystallography, reproduce the conformation of the hydrolysable substrate at the experimental conditions. These results highlight the importance of the 2-OH⋅⋅⋅nucleophile interaction in substrate recognition and catalysis in endo-glycosidases and can inform mutational campaigns aimed to search for more efficient enzymes.

Ag Electrode Anticorrosion in Inverted Perovskite Solar Cells

AbstractAg electrode is widely used in inverted perovskite solar cells (PSCs), but its easy reaction and corrosive nature with perovskite always induces severe stability issue. Here, from typical theory of metal anticorrosion, a chemical anticorrosion approach for Ag electrode in inverted PSCs through introducing 2‐mercaptobenzothiazole (MBT) as a corrosion inhibitor is reported. MBT can strongly bond to Ag and form a compact [MBT‐Ag] chain on Ag surface owing to its N atom in thiazolyl ring and exocyclic thiol groups. As a result, Ag anticorrosion ability is greatly enhanced by increasing the corrosion potential and decreasing the corrosion current, thus effectively inhibiting possible chemical reaction and corrosion between perovskite and Ag electrodes. PSCs containing MBT/Ag exhibit high efficiency of over 23% with good stability, retaining 95 ± 4.1% of initial efficiency after storage for 3800 h in glovebox. Importantly, resulting PSCs also show excellent thermal stability, maintaining 90 ± 1.8% of initial efficiency after aging for 900 h at 85 °C.

Molecule Design of Novel Electron Acceptor with Superior Chemical Stability for Photovoltaic Applications

AbstractThe stability of organic photovoltaic (OPV) cells is significantly affected by the decomposition of acceptor–donor–acceptor type non‐fullerene acceptors (NFAs), bringing a significant challenge for the manufacture and applications. Herein, a novel acceptor with superior chemical stability named GS‐22 is designed and synthesized and the relationship between molecular structure and chemical stability is investigated. Based on structure analysis, the exocyclic vinyl groups are proven to exhibit inferior chemical stability and can be easily destructed under an alkaline environment and illumination. Owing to the single‐bonded end groups and the completely non‐fused core, GS‐22 shows remarkably high chemical stability, contributing to obviously improved device stability. Impressively, the fitting T80 (the lifetime when power conversion efficiency retains 80% of the initial value) of the encapsulated OPV cell reaches 3770 h. This work provides an effective molecular design strategy for NFAs with superior chemical stability.

Synthesis of Highly Functionalized Bismacycles via Post-Transmetallation Modification of Arylboronic Acids.

Bismacycles featuring a sulfone-bridged scaffold have recently been developed as versatile and convenient electrophilic arylating agents. Here, we report that the exocyclic aryl group, which is ultimately transferred to a nucleophilic coupling partner, can be functionalized through cross-coupling, heteroatom substitutions, oxidations and reductions, and protecting group manipulations. This "postsynthetic modification" approach provides concise and divergent access to complex aryl bismacycles. The utility of the functionalized bismacycles in electrophilic arylation of C-H and O-H bonds is demonstrated.

Synthesis of Gamma-Butyrolactone Hormones Enables Understanding of Natural Product Induction.

Bacteria produce natural products (NPs) via biosynthetic gene clusters. Unfortunately, many biosynthetic gene clusters are silent under traditional laboratory conditions. To access novel NPs, a better understanding of their regulation is needed. γ-Butyrolactones, including the A-factor and Streptomyces coelicolor butanolides, SCBs, are a major class of Streptomyces' hormones. Study of these hormones has been limited due to challenges in accessing them in stereochemically pure forms. Herein, we describe an efficient route to (R)-paraconyl alcohol, a key intermediate for these molecules, as well as a biocatalytic method to access the exocyclic hydroxyl group that differentiates A-factor-type from SCB-type hormones. Utilizing these methods, a library of hormones have been synthesized and tested in a green fluorescent protein reporter assay for their ability to relieve repression by the repressor ScbR. This allowed the most quantitative structure-activity relationship of γ-butyrolactones and a cognate repressor to date. Bioinformatics analysis strongly suggests that many other repressors of NP biosynthesis likely bind similar molecules. This efficient, diversifiable synthesis will enable further investigation of the regulation of NP biosynthesis.

New Uracil Analog with Exocyclic Methylidene Group Can Reverse Resistance to Taxol in MCF-7 Cancer Cells.

Taxol (Tx), a microtubule-stabilizing drug, has been widely used as a chemotherapeutic in several types of cancer. However, the development of resistance limited its application. One of the strategies used to prevent the emergence of drug resistance is combination treatment, involving at least two drugs. The aim of the current study was to assess if a new uracil analog, 3-p-bromophenyl-1-ethyl-5-methylidenedihydrouracil (U-359) can prevent the development of Tx resistance in breast cancer cells. The cytotoxicity of the new drug was tested in MCF-7 (hormone receptor (ER, PR) positive cell-line) and MCF-10A cell lines using MTT method. For the detection of apoptosis and necrosis, the Wright and Giemsa staining was used. Gene expression was measured by real-time PCR, and changes in the protein levels were evaluated by ELISA and bioluminescent method. We investigated the effect of Tx and U-359 on cancer MCF-7 and normal MCF-10A cells alone and in combination. Tx co-administered with U-359 inhibited proliferation of MCF-7 cells to 7% while the level of ATPase drastically decreased to 14%, compared with effects produced by Tx alone. The apoptosis process was induced through the mitochondrial pathway. These effects were not seen in MCF-10A cells, showing the wide safety margin. The obtained results have shown that U-359 produced a synergistic effect with Tx probably by reducing Tx resistance in MCF-7 cells. To elucidate the possible mechanism of resistance, expression of tubulin III (TUBIII), responsible for microtubule stabilization and tau and Nlp proteins, responsible for microtubule dynamics, was assessed. Combination of Tx with U-359 reduced overexpression of TUBIII and Nlp. Thus, U-359 may stand for a potential reversal agent for the treatment of MDR in cancer cells.

Sydnone Methides: Intermediates between Mesoionic Compounds and Mesoionic N‐Heterocyclic Olefins

AbstractSydnone methides represent an almost unknown class of mesoionic compounds which possess exocyclic carbon substituents instead of oxygen (sydnones) or nitrogen (sydnone imines) in the 5‐position of a 1,2,3‐oxadiazolium ring. Unsubstituted 4‐positions give rise to the generation of anionic N‐heterocyclic carbenes by deprotonation. Preparations of new sydnone methides are described here. They can be represented by mesomeric structures with either exocyclic carbanionic groups like −C(CN)2−, −C(CN)(COOMe)−, −C(CN)(CONH2)−, and −C(CN)(SO2Me)−, or with the corresponding exocyclic C=C double bonds as a common feature with mesoionic N‐heterocyclic olefins. An X‐ray single structure analysis revealed a length of 140.7(3) pm of the exocyclic bond in the solid state. From the coalescence temperature (55 °C) determined by a series of 13C NMR experiments (150 MHz) at various temperatures, an energy of rotation of 18.5 Kcal/mol was calculated for this bond. The 13C NMR signals of the anionic N‐heterocyclic carbenes, from which the 2‐mesityl‐substituted anionic NHC proved to be stable up to 10 °C, are highly shifted upfield (δcarbene=157.9 ppm−160.5 ppm). The carbenes can be reacted in situ with elemental selenium and chlorophosphanes to yield sydnone methide selenoethers after methylation and 4‐phosphanylsydnone methides in good to excellent yields, respectively.

Nutlin-3a-aa: Improving the Bioactivity of a p53/MDM2 Interaction Inhibitor by Introducing a Solvent-Exposed Methylene Group.

Nutlin-3a is a reversible inhibitor of the p53/MDM2 interaction. We have synthesized the derivative Nutlin-3a-aa bearing an additional exocyclic methylene group in the piperazinone moiety. Nutlin-3a-aa is more active than Nutlin-3a against purified wild-type MDM2, and is more effective at increasing p53 levels and releasing transcription of p53 target genes from MDM2-induced repression. X-ray analysis of wild-type MDM2-bound Nutlin-3a-aa indicated that the orientation of its modified piperazinone ring was altered in comparison to the piperazinone ring of MDM2-bound Nutlin-3a, with the exocyclic methylene group of Nutlin-3a-aa pointing away from the protein surface. Our data point to the introduction of exocyclic methylene groups as a useful approach by which to tailor the conformation of bioactive molecules for improved biological activity.

2-Guanidinobenzazoles as Building Blocks to Afford Biologically Active Derivatives

Abstract: 1,3-Benzazoles (BZs) are interesting compounds in medicinal chemistry. For instance, compounds with the BZ nucleus exhibit diverse biological activities and some of them are broadly utilized in clinical applications. In this sense, medicinal chemists aim at the development of new procedures to synthesize these kinds of molecules. The 2-aminobenzimidazole 2ABI derivatives, such as Enviradine (antiviral), Astemizole (antihistaminic), and Albendazole (antimicrobial), which contain the intra-cyclic guanidine nucleus, are used in medicinal chemistry. The guanidine group, considered a super base, when bonded to a benzazole ring, results in the 2-guanidinobenzazoles (2GBZs), modifying the biological activity of these heterocycles. The structure of 2GBZs is of significance as the 10-π electron system of the aromatic benzazole ring is conjugated with the exocyclic guanidine group to acquire a planar delocalized structure. This class of molecules has at least four nitrogen atoms with free lone pairs and four labile hydrogen atoms, resulting in these compounds having amphoteric character. On the other hand, synthetic chemists have used 2GBZs as a building block to produce derivatives as medicinally important molecules. On these bases, in this work, we prepared a bibliographic review of the methodologies reported in the literature used in the synthesis of 2GBZ derivatives of pharmacological interest. We focused the investigation on 2-guanidinebenzoxazol (2GBO), 2-guanidinebenzothiazol (2GBT) and 2-guanidinebenzimidazole (2GBI) as building blocks. We found that compounds derivatives were N-substituted-2GBZs, 2-(pyrimidyl)-ABZs and 1,3,5-triazino[1,2-a]-BZs, which are described chronologically. This work will help searchers related to bioorganic chemistry, inorganic chemistry, medicinal chemistry and pharmaceutical industry in the recent methodologies to synthetize 2-guanidinobenzazole derivatives to be proposed as materials in the different areas. This topic will provide information on the utility for medicinal chemists dedicated to the design and synthesis of this class of compounds to be tested with respect to their biological activities and be proposed as new pharmacophores.

Conformational flexibility of the disaccharide β-L-Fucp-(1→4)-α-D-Glcp-OMe as deduced from NMR spectroscopy experiments and computer simulations.

Carbohydrates in biological systems are referred to as glycans and modification of their structures is a hallmark indicator of disease. Analysis of the three-dimensional structure forms the basis for further insight into how they function and comparison of crystal structure with solution-state conformation(s) is particularly relevant, which has been performed for the disaccharide β-L-Fucp-(1→4)-α-D-Glcp-OMe. In water solution the conformational space at the glycosidic linkage between the two sugar residues is identified from molecular dynamics (MD) simulations as having a low-energy exo-syn conformation, deviating somewhat from the solid-state conformation, and two anti-conformational states, i.e., anti-ϕ and anti-ψ, indicating flexibility at the glycosidic linkage. NMR data were obtained from 1D 1H,1H-NOESY and STEP-NOESY experiments, measurement of transglycosidic 3JCH coupling constants and NMR spin-simulation. The free energy profile of the ω torsion angle computed from MD simulation was in excellent agreement with the rotamer distribution from NMR experiment being for gt:gg:tg 38 : 53 : 9, respectively, with a proposed inter-residue O5'⋯HO6 hydrogen bond being predominant in the gg rotamer. Quantum mechanics methodology was used to calculate transglycosidic NMR 3JCH coupling constants, averaged over a conformational ensemble of structures representing various rotamers of exocyclic groups, in good to excellent agreement with Karplus-type relationships previously developed. Furthermore, 1H and 13C NMR chemical shifts were calculated using the same methodology and were found to be in excellent agreement with experimental data.