Effect of Electronegative Substituents and Angular Dependence on the Heteronuclear Spin−Spin Coupling Constant ³<i>J</i>_C−H: An Empirical Prediction Equation Derived by Density Functional Theory Calculations

A general carbon−proton vicinal coupling constant (3JC−H) prediction equation has been empirically derived by a coupling constant database of 2157 3JC−H calculations (at the hybrid DFT MPW1PW91/6-31G(d,p) level). The equation includes the electronegativity effect of the substituents attached to the 13C−C−C−1H fragment and the dihedral (Φ) dependence of the heteronuclear spin-coupling. A set of butane and pentane models were built, systematically varying both the Φ torsion angle in 30° steps and the substitution pattern with several electronegative substituents (Br, NH2, F, Cl, SH, OH) in order to obtain the coupling constant database. The here reported 3JC−H equation is a quantitative prediction tool, particularly useful as a support in the analysis of NMR data for the structural elucidation of organic compounds characterized by specific substitution patterns. To confirm the accuracy of our equation in the prediction of the experimental 3JC−H couplings, we tested the equation, comparing 114 experimental 3JC−H values obtained from 29 polysubstituded benchmark organic compounds with the predicted data. In addition, a set of 3JC−H coupling bidimensional Karplus-type curves correlating the calculated 3JC−H values to the specific dihedral angle for every substitution pattern considered were built in order to evaluate the magnitude of the electronegativity effect

Inverse Virtual Screening of Antitumor Targets: Pilot Study on a Small Database of Natural Bioactive Compounds

An inverse virtual screening in silico approach has been applied to natural bioactive molecules to screen their efficacy against proteins involved in cancer processes, with the aim of directing future experimental assays. Docking studies were performed on a panel of 126 protein targets extracted from the Protein Data Bank, to analyze their possible interactions with a small library of 43 bioactive compounds. Analysis of the molecular docking results was performed through the use of tables containing energy data organized in a matrix. The application of this approach may facilitate the prediction of the activity of unknown ligands for known targets involved in the development of cancer and could be applied to other models based on different libraries of ligands and different panels of targets

Quantum Mechanical Calculations of NMR <i>J</i> Coupling Values in the Determination of Relative Configuration in Organic Compounds

An approach relying on quantum mechanical calculations of proton−proton and proton−carbon J coupling values is proposed as a tool for assigning the relative configuration on chiral organic compounds. The method is suitable for carbon frameworks containing several adjacent stereogenic centers and may allow significant advances in the extensive use of spin−spin couplings in structural elucidation

Data_Sheet_1_Corylus avellana: A Source of Diarylheptanoids With α-Glucosidase Inhibitory Activity Evaluated by in vitro and in silico Studies.docx

Corylus avellana hard shells, green leafy involucres, leaves, and male flowers have shown to be a source of diarylheptanoids, a class of natural products with promising biological activities. Cyclic diarylheptanoids, named giffonins, were isolated from the Italian cultivar “Tonda di Giffoni.” Even if many efforts have been made to establish the chemistry of these compounds, little is known about their biological properties. Herein, the inhibitory effects of diarylheptanoids isolated from C. avellana byproducts against α-glucosidase enzyme were evaluated. Molecular docking experiments disclosed the establishment of several key interactions between all the screened diarylheptanoids and the protein counterpart, whose model was built through homology modeling procedure, thus rationalizing the detected inhibitory activities. Specifically, the most active compounds giffonin J (10), K (11), and P (16) were able to make both H-bonds and π–π stacking contacts with different residues belonging to the binding site responsible for the catalytic activity of the investigated enzyme. To highlight the occurrence of the bioactive diarylheptanoids in the extracts of C. avellana byproducts obtained by eco-friendly extractions, their LC-MS profiles were analyzed. LC-MS analysis showed how giffonin J (10), K (11), and P (16) occurred in the ethanol extract of the leaves, while in the extracts of shells and green leafy involucres only giffonin P (16) was evident. Moreover, the quantitative analysis of giffonin J (10), K (11), and P (16) in C. avellana byproducts was carried out by an analytical approach based on LC–ESI/QTrap/MS, using the Multiple Reaction Monitoring (MRM) experiment. These results prompt to evaluate C. avellana byproducts, especially the leaves, as a prospective source of bioactive diarylheptanoids for the development of functional ingredients for the treatment of diabetes.</p

Solution Structure of the Complex between the Head-to-Tail Dimer of Calicheamicin γ₁^I Oligosaccharide and a DNA Duplex Containing d(ACCT) and d(TCCT) High-Affinity Binding Sites

The head-to-tail dimer of the calicheamicin oligosaccharide domain exhibits substantially higher DNA binding affinity and sequence selectivity and greater bioactivity than the monomer from which it is derived. To determine the structural basis for these functional properties, the solution structure of the 1:1 complex between the head-to-tail dimer of the calicheamicin oligosaccharide and the oligonucleotide duplex d(GCACCTTCCTGC)·d(GCAGGAAGGTGC) has been solved by restrained molecular dynamics calculations using NMR-derived distance and torsion angle constraints. The final input data consisted of 562 internuclear distance and 114 dihedral angle constraints, an average of 27 constraints per residue. In contrast to observations made for a complex between a DNA duplex and the head-to-head dimer of calicheamicin oligosaccharide, the head-to-tail dimer exhibits a unique binding mode in the DNA minor groove. A comparative analysis of the carbohydrate−DNA interactions at the two different binding sites explains at the atomic level how calicheamicin derivatives are able to effectively recognize both d(ACCT) and d(TCCT) sites. This study brings deeper insight into the factors governing DNA-binding affinity and the sequence preferences of calicheamicin and its derivatives

Chrysophaentins A−H, Antibacterial Bisdiarylbutene Macrocycles That Inhibit the Bacterial Cell Division Protein FtsZ

Eight new antimicrobial natural products named chrysophaentins A−H belonging to a new structural class have been isolated from the marine chrysophyte alga Chrysophaeum taylori. Their structures were determined by extensive 2D NMR and MS techniques and are characterized by the presence of two polyhalogenated, polyoxygenated ω,ω′-diarylbutene units connected by two ether bonds to form the suite of macrocyclic natural products. Chrysophaentin A, the most potent of these antibiotics, inhibited the growth of clinically relevant Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MIC50 1.5 ± 0.7 μg/mL), multidrug-resistant S. aureus (1.3 ± 0.4 μg/mL), and vancomycin-resistant Enterococcus faecium (MIC50 2.9 ± 0.8 μg/mL). In vitro enzyme assays and transmission electron microscopy showed chrysophaentin A to inhibit the GTPase activity of the bacterial cytoskeletal protein FtsZ with an IC50 value of 6.7 ± 1.7 μg/mL, as well as GTP-induced formation of FtsZ protofilaments. Saturation Transfer Difference (STD) NMR experiments further confirmed chrysophaentin A binds to FtsZ, and NMR competition experiments with GTPγS showed chrysophaentin A and GTP to bind competitively to FtsZ. Last, molecular docking simulations provided a low energy model in which chrysophaentin A binds in and occludes a large portion of the GTP binding site of FtsZ in a manner that is consistent with the binding epitope determined by STD NMR

Chrysophaentins A−H, Antibacterial Bisdiarylbutene Macrocycles That Inhibit the Bacterial Cell Division Protein FtsZ

Eight new antimicrobial natural products named chrysophaentins A−H belonging to a new structural class have been isolated from the marine chrysophyte alga Chrysophaeum taylori. Their structures were determined by extensive 2D NMR and MS techniques and are characterized by the presence of two polyhalogenated, polyoxygenated ω,ω′-diarylbutene units connected by two ether bonds to form the suite of macrocyclic natural products. Chrysophaentin A, the most potent of these antibiotics, inhibited the growth of clinically relevant Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MIC50 1.5 ± 0.7 μg/mL), multidrug-resistant S. aureus (1.3 ± 0.4 μg/mL), and vancomycin-resistant Enterococcus faecium (MIC50 2.9 ± 0.8 μg/mL). In vitro enzyme assays and transmission electron microscopy showed chrysophaentin A to inhibit the GTPase activity of the bacterial cytoskeletal protein FtsZ with an IC50 value of 6.7 ± 1.7 μg/mL, as well as GTP-induced formation of FtsZ protofilaments. Saturation Transfer Difference (STD) NMR experiments further confirmed chrysophaentin A binds to FtsZ, and NMR competition experiments with GTPγS showed chrysophaentin A and GTP to bind competitively to FtsZ. Last, molecular docking simulations provided a low energy model in which chrysophaentin A binds in and occludes a large portion of the GTP binding site of FtsZ in a manner that is consistent with the binding epitope determined by STD NMR

Halipeptins A and B: Two Novel Potent Anti-inflammatory Cyclic Depsipeptides from the Vanuatu Marine Sponge <i>Haliclona</i> species

Two new metabolites, named halipeptins A and B, have been isolated from the marine sponge Haliclona sp. Their structures were determined by extensive use of one- and two-dimensional NMR experiments, mass spectrometry, and UV and IR spectroscopy. Halipeptin A is a novel 17-membered cyclic depsipeptide, consisting of five residues including two alanines (with l stereochemistry) and three new residues that appear to be previously undescribed from natural sources:  1,2-oxazetidine-4-methyl-4-carboxylic acid, 3-hydroxy-2,2,4-trimethyl-7-methoxydecanoic acid (HTMMD), and N-methyl-δ-hydroxyisoleucine. The HTMMD residue is substituted with 3-hydroxy-2,2,4-trimethyl-7-hydroxydecanoic acid in halipeptin B. Halipeptin A was found to possess very potent anti-inflammatory activity in vivo, causing about 60% inhibition of edema in mice at the dose of 300 μg/kg (i.p.)

Quantum Chemical Calculations of ¹<i>J</i>_CC Coupling Constants for the Stereochemical Determination of Organic Compounds

Quantum chemical calculations of one-bond carbon–carbon coupling constants are demonstrated as potential probes for the configurational assignment of organic molecules. The stereochemical analysis of strychnine and its possible stereoisomers is presented as proof of concept