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Isochromans and aryl- C -glycosides are important structural motifs in many natural products and drug candidates with diverse therapeutic potentials. Here we present the first application of pyranosyl aldehydes in the oxa-Pictet–Spengler cyclization to conjugate the two pharmacophore motifs. Enantiomeric pairs of aryl-2-propanols were reacted with pyranosyl dialdoses and 1-formyl sugars in a BF 3 ·Et 2 O-mediated oxa-Pictet–Spengler reaction. The effects of the substitution pattern, configuration, and protecting groups of the reactants on the efficiency and stereochemical outcome of the reactions were studied, and the reaction conditions were optimized. A series of 1,3- cis -substituted 1-( C -glycosyl)isochromans was prepared in high yields with good to complete stereoselectivity from glucosyldialdoses and 1-formyl glucopyranosides. The reaction efficiency dropped significantly with galacto -dialdose derivatives due to steric hindrance, leading to lower yields and anomerization, which slightly limits the universality of the method. ROESY-NMR, X-ray diffraction, and VCD methods were used to determine the structure and the absolute configuration of the compounds. The method developed represents a straightforward and stereocontrolled route to a new chemotype of isochroman C -glycosides.

Results of the high-level computational study of 12 bisindole alkaloids of the Strychnos-Strychnos type are reported in addition of that of five retuline-like monomers frequently encountered in moieties constituting dimeric alkaloids. Based on the comparison of theoretical and experimental NMR chemical shifts, a detailed conformational survey of these stereochemically rich natural products containing multiple asymmetric centers was performed. Our original methodology is based on searching multiple conformational states, geometry optimization, and high-level NMR calculations at the DFT level. Taking into account all known experimental chemical shifts together with their calculated values in the natural products under study, a correlation estimate of NMR chemical shifts was performed by using statistical descriptors. In general, a good agreement of the performed calculations with experiment was achieved, which is manifested by the Corrected Mean Absolute Error of about 0.2 ppm for 1H and 1.9 ppm for 13C NMR chemical shifts in this series.

The human complement system comprises proteolytic cascades that drive protective inflammatory and cytolytic responses, making it a crucial part of innate immunity. Complement component C5 links the upstream activation pathways to the terminal pathway, and its cleavage by classical and alternative pathway C5 convertases generates potent effectors implicated in autoimmune and inflammatory diseases. Several inhibitors targeting diverse sites on C5 are in clinical use or development. However, the structural basis by which binding at distinct sites achieves comparable functional outcomes remains poorly understood. We systematically compare twelve C5-modulator complexes using domain superposition, interface quantification, C5a scissile loop conformational analysis, and rigid cluster decomposition. We demonstrate that modulators propagate conformational and dynamic changes well beyond their binding sites, identifying the MG3 domain as a conformational relay that transmits perturbations across the C5 scaffold and MG8 as a domain whose rigidity correlates with global constraint redistribution. Structurally unrelated inhibitors converge on α-helical restructuring of the normally disordered C5a scissile loop, although this feature is neither necessary nor sufficient for complete pathway blockade. Benchmarking against the cobra venom factor (CVF)-bound structure as a proxy for C5 convertase engagement, we show that complete inhibitors, notably eculizumab and the tick-derived OmCI-RaCI complexes, achieve efficacy through distinct structural rearrangements rather than a single shared mechanism, whereas partial inhibitors each lack a different subset of these properties. These findings establish that C5 inhibition is governed by the nature and extent of conformational perturbation rather than by simple steric hindrance of convertases alone, providing a structural framework for rational design of next-generation complement therapeutics.

trans-3,4-Dihydroxyselenolane (DHS), a water-soluble cyclic selenide, exhibits selenoenzyme-like unique redox activities through reversible oxidation to the corresponding selenoxide. Previously, we demonstrated that DHS can be applied as an antioxidant against lipid peroxidation and a radioprotector by means of adequate modifications of the two hydroxy (OH) groups. Herein, we synthesized new DHS derivatives with a crown-ether ring fused to the OH groups (DHS-crown-n (n = 4 to 7), 1–4) and investigated their behaviors of complex formation with various alkali metal salts. According to the X-ray structure analysis, it was found that the two oxygen atoms of DHS change the directions from diaxial to diequatorial by complexation. The similar conformational transition was also observed in solution NMR experiments. The 1H NMR titration in CD3OD further confirmed that DHS-crown-6 (3) forms stable 1:1 complexes with KI, RbCl and CsCl, while it forms a 2:1 complex with KBPh4. The results suggested that the 1:1 complex (3·MX) exchanges the metal ion with metal-free 3 through the formation of the 2:1 complex. The redox catalytic activity of 3 was evaluated using a selenoenzyme model reaction between H2O2 and dithiothreitol. The activity was significantly reduced in the presence of KCl due to the complex formation. Thus, the redox catalytic activity of DHS could be controlled by the conformational transition induced by coordination to an alkali metal ion.

A recent broadband rotational spectroscopic investigation of the cross-association mechanisms of CO[sub.2] with monoethanolamine (MEA) in molecular beams [F. Xie et al., Angew. Chem. Int. Ed., 2023, 62, e202218539] revealed an intriguing affinity of CO[sub.2] to the hydroxy group. These findings have triggered the present systematic vibrational spectroscopic exploration of weakly bound amine··CO[sub.2] and alcohol··CO[sub.2] van der Waals cluster molecules embedded in inert “quantum” matrices of neon at 4.2 K complemented by high-level quantum chemical conformational analyses. The non-covalent interactions formed between the amino and hydroxy groups and the electron-deficient carbon atom of CO[sub.2] are demonstrated to lift the degeneracy of the doubly degenerate intramolecular CO[sub.2]-bending fundamental significantly with characteristic observed spectral splittings for the amine··CO[sub.2] (≈35–45 cm[sup.−1]) and alcohol··CO[sub.2] (≈20–25 cm[sup.−1]) interactions, respectively, despite the almost identically predicted total association energies (≈12–14 kJ·mol[sup.−1]) for these van der Waals contacts, as revealed by benchmark Domain-based Local Pair Natural Orbital Coupled Cluster DLPNO-CCSD(T) theory. These high-level theoretical predictions reveal significantly higher “geometry preparation energies” for the amine··CO[sub.2] systems leading to a more severe distortion of the CO[sub.2] linearity upon complexation in agreement with the infrared spectroscopic findings. The systematic combined spectroscopic and quantum chemical evidences for cross-association between CO[sub.2] and amines/alcohols in the present work unambiguously confirm an intriguing binding preference of CO[sub.2] to the hydroxy group of the important carbon capture agent MEA, with an accurate vibrational zero-point energy corrected association energy (D [sub.0]) of 13.5 kJ·mol[sup.−1] at the benchmark DLPNO-CCSD(T)/aug-cc-pV5Z level of theory.

Intrinsically disordered protein [alpha]-synuclein ([alpha]S) is implicated in Parkinson's disease due to its aberrant aggregation propensity. In a bid to identify the traits of its aggregation, here we computationally simulate the multi-chain association process of [alpha]S in aqueous as well as under diverse environmental perturbations. In particular, the aggregation of [alpha]S in aqueous and varied environmental condition led to marked concentration differences within protein aggregates, resembling liquid-liquid phase separation (LLPS). Both saline and crowded settings enhanced the LLPS propensity. However, the surface tension of [alpha]S droplet responds differently to crowders (entropy-driven) and salt (enthalpy-driven). Conformational analysis reveals that the IDP chains would adopt extended conformations within aggregates and would maintain mutually perpendicular orientations to minimize inter-chain electrostatic repulsions. The droplet stability is found to stem from a diminished intra-chain interactions in the C-terminal regions of [alpha]S, fostering inter-chain residue-residue interactions. Intriguingly, a graph theory analysis identifies small-world-like networks within droplets across environmental conditions, suggesting the prevalence of a consensus interaction patterns among the chains. Together these findings suggest a delicate balance between molecular grammar and environment-dependent nuanced aggregation behavior of [alpha]S.

This publication reports a facile and convenient preparation of tri-O-acetyl-glucopyranoses, derived from the corresponding 2-deoxyaminosugar, where the vicinal anomeric and C2 positions are decorated by azido and (thio)ureido groups, respectively. This double functionalization leads to an inherently chiral core incorporating the versatile azido and (thio)ureido linkages prone to further manipulation. The latter also provides a structural element for hydrogen-bonded donor-acceptor (HB-DA) sites, which are of immense value in organocatalytic pursuits. A computation-aided conformational analysis unveils the landscape of available conformers and their relative stability. N-aryl (thio)ureas bearing substituents at ortho positions exist as mixtures of M- and P-atropisomeric conformers.

Peptides are an important class of biomolecules that perform many physiological functions and which occupy a significant and increasing share of the pharmaceutical market. Methods to determine the solid-state structures of peptides in different environments are important to help understand their biological functions and to aid the development of drug formulations. Here, a new magic-angle spinning (MAS) solid-state nuclear magnetic resonance (SSNMR) approach is described for the structural analysis of uniformly [sup.13]C-labeled solid peptides. Double-quantum (DQ) coherence between selective pairs of [sup.13]C nuclei in peptide backbone and side-chain CH[sub.3] groups is excited to provide restraints on (i) [sup.13]C–[sup.13]C internuclear distances and (ii) the relative orientations of C–H bonds. DQ coherence is selected by adjusting the MAS frequency to the difference in the resonance frequencies of selected nuclear pairs (the rotational resonance condition), which reintroduces the dipolar coupling between the nuclei. Interatomic distances are then measured using a constant time SSNMR experiment to eliminate uncertainties arising from relaxation effects. Further, the relative orientations of C–H bond vectors are determined using a DQ heteronuclear local field SSNMR experiment, employing [sup.13]C–[sup.1]H coupling amplification to increase sensitivity. These methods are applied to determine the molecular conformation of a uniformly [sup.13]C-labeled peptide, N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF). From just six distance and six angular restraints, two possible molecular conformations are determined, one of which is in excellent agreement with the crystal structure of a closely related peptide. The method is envisaged to a useful addition to the SSNMR repertoire for the solid-state structure determination of peptides in a variety of forms, including amyloid fibrils and pharmaceutical formulations.

The leukocyte receptor complex (LRC) in humans encodes many receptors with immunoglobulin-like (Ig-like) extracellular domains, including the killer Ig-like receptors (KIRs) expressed on natural killer (NK) cells among others, the leukocyte Ig-like receptors (LILRs) expressed on myeloid and B cells, and an Fc receptor (FcR), all of which have important roles in the immune response. These highly-related genes encode activating receptors with positively-charged residues in the transmembrane region, inhibitory receptors with immuno-tyrosine based motifs (ITIMs) in the cytoplasmic tail, and bi-functional receptors with both. The related chicken Ig-like receptors (ChIRs) are almost all found together on a microchromosome, with over 100 activating (A), inhibitory (B), and bi-functional (AB) genes, bearing either one or two extracellular Ig-like domains, interspersed over 500-1,000 kB in the genome of an individual chicken. Sequencing studies have suggested rapid divergence and little overlap between ChIR haplotypes, so we wished to begin to understand their genetics. We chose to use a hybridization technique, reference strand-mediated conformational analysis (RSCA), to examine the ChIR-AB1 family, with a moderate number of genes dispersed across the microchromosome. Using fluorescently-labeled references (FLR), we found that RSCA and sequencing of ChIR-AB1 extracellular exon gave two groups of peaks with mobility correlated with sequence relationship to the FLR. We used this system to examine widely-used and well-characterized experimental chicken lines, finding only one or a few simple ChIR haplotypes for each line, with similar numbers of peaks overall. We found much more complicated patterns from a broiler line from a commercial breeder and a flock of red junglefowl, but trios of parents and offspring from another commercial chicken line show that the complicated patterns are due to heterozygosity, indicating a relatively stable number of peaks within haplotypes of these birds. Some ChIR-AB1 peaks were found in all individuals from the commercial lines, and some of these were shared with red junglefowl and the experimental lines derived originally from egg-laying chickens. Overall, this analysis suggests that there are some simple features underlying the apparent complexity of the ChIR locus.

Three new cycloheximide congeners, 2,3-dehydro-α- epi -isocycloheximide ( 1 ), ( E )- and ( Z )-2,3-dehydroanhydrocycloheximides ( 2 and 3 ), together with three known compounds, anhydroisoheximide ( 4 ), cycloheximide ( 5 ), and isocycloheximide ( 6 ), were obtained from the cultures of Streptomyces sp. SC0581. Their structures were elucidated by extensive spectroscopic analysis in combination with theoretical conformational analysis and ECD computations. The photoinduced interconversion between 2 and 3 was observed and verified and the possible reaction path and mechanism were proposed by theoretical computations. The antifungal and cytotoxic activities of 1 – 6 were evaluated and suggested that 2,3-dehydrogenation results in the loss of the activities and supported that the OH-α is important to the activities of cycloheximide congeners.