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

Hyalachelins A–C, Unusual Siderophores Isolated from the Terrestrial Myxobacterium <i>Hyalangium minutum</i>

Three new siderophores, termed hyalachelins A–C (<b>1</b>–<b>3</b>), were isolated from the terrestrial myxobacterium <i>Hyalangium minutum</i>. Their structures were determined by 2D NMR and HR-MS/MS experiments, and their stereochemical configuration was established by a combination of NMR data, quantum mechanical calculations, and circular dichroism experiments. Hyalachelins are unusual catecholate-type siderophores that bear a 3,7,8-trihydroxy-1-oxo-1,2,3,4-tetra­hydro­isoquinoline-3-carbox­ylic acid. Their iron chelating activities were evaluated in a CAS assay showing EC₅₀ values of ∼30 μM

Discovery and Synthesis of Namalide Reveals a New Anabaenopeptin Scaffold and Peptidase Inhibitor

The discovery, structure elucidation, and solid-phase synthesis of namalide, a marine natural product, are described. Namalide is a cyclic tetrapeptide; its macrocycle is formed by only three amino acids, with an exocyclic ureido phenylalanine moiety at its C-terminus. The absolute configuration of namalide was established, and analogs were generated through Fmoc-based solid phase peptide synthesis. We found that only natural namalide and not its analogs containing l-Lys or l-<i>allo</i>-Ile inhibited carboxypeptidase A at submicromolar concentrations. In parallel, an inverse virtual screening approach aimed at identifying protein targets of namalide selected carboxypeptidase A as the third highest scoring hit. Namalide represents a new anabaenopeptin-type scaffold, and its protease inhibitory activity demonstrates that the 13-membered macrolactam can exhibit similar activity as the more common hexapeptides

Structural Insights for the Optimization of Dihydropyrimidin-2(1<i>H</i>)‑one Based mPGES‑1 Inhibitors

The recently crystallized structure of microsomal prostaglandin E₂ synthase 1 (mPGES-1) in complex with the inhibitor LVJ (PDB code: 4BPM) offered new structural information for the optimization of the previously identified lead compound <b>1</b> (IC₅₀ = 4.16 ± 0.47 μM), which contains the privileged dihydropyrimidin-2-one chemical core. Systematic optimization of <b>1</b>, through accurate structure-based design, provided compound <b>4</b> with a 10-fold improved mPGES-1 inhibitory activity (IC₅₀ = 0.41 ± 0.02 μM). Here we highlight the optimal scaffold decoration pattern of <b>4</b> and propose a three-dimensional model for the interaction with this complex trimeric membrane protein. The reported computational insights, together with the accessible one-pot synthetic procedure, stimulate for the generation of further potent dihydropyrimidine-based mPGES-1 inhibitors

Cyclic Diarylheptanoids from <i>Corylus avellana</i> Green Leafy Covers: Determination of Their Absolute Configurations and Evaluation of Their Antioxidant and Antimicrobial Activities

The methanol extract of the leafy covers of <i>Corylus avellana</i>, source of the Italian PGI (protected geographical indication) product “Nocciola di Giffoni”, afforded two new cyclic diarylheptanoids, giffonins T and U (<b>2</b> and <b>3</b>), along with two known cyclic diarylheptanoids, a quinic acid, flavonoid-, and citric acid derivatives. The structures of giffonins T and U were determined as highly hydroxylated cyclic diarylheptanoids by 1D and 2D NMR experiments. Their relative configurations were assigned by a combined quantum mechanical/NMR approach, comparing the experimental ¹³C/¹H NMR chemical shift data and the related predicted values. The absolute configurations of carpinontriol B (<b>1</b>) and giffonins T and U (<b>2</b> and <b>3</b>) were assigned by comparison of their experimental electronic circular dichroism curves with the TDDFT-predicted curves. The ability of the compounds to inhibit the lipid peroxidation induced by H₂O₂ and H₂O₂/Fe²⁺ was determined by measuring the concentration of thiobarbituric acid reactive substances. Furthermore, the antimicrobial activity of the methanol extract of leafy covers of <i>C. avellana</i> and of the isolated compounds against the Gram-positive strains <i>Bacillus cereus</i> and <i>Staphylococcus aureus</i> and the Gram-negative strains <i>Escherichia coli</i> and <i>Pseudomonas aeruginosa</i> was evaluated. Carpinontriol B (<b>1</b>) and giffonin U (<b>3</b>) at 40 μg/disk caused the formation of zones of inhibition

Tulongicin, an Antibacterial Tri-Indole Alkaloid from a Deep-Water <i>Topsentia</i> sp. Sponge

Antibacterial-guided fractionation of an extract of a deep-water <i>Topsentia</i> sp. marine sponge led to the isolation of two new indole alkaloids, tulongicin A (<b>1</b>) and dihydrospongotine C (<b>2</b>), along with two known analogues, spongotine C (<b>3</b>) and dibromodeoxytopsentin (<b>4</b>). Their planar structures were determined by NMR spectroscopy. Their absolute configurations were determined through a combination of experimental and computational analyses. Tulongicin (<b>1</b>) is the first natural product to contain a di­(6-Br-1<i>H</i>-indol-3-yl)­methyl group linked to an imidazole core. The coexistence of tri-indole <b>1</b> and bis-indole alcohol <b>2</b> suggests a possible route to <b>1</b>. All of the compounds showed strong antimicrobial activity against <i>Staphylococcus aureus</i>

Quantitative NMR-Derived Interproton Distances Combined with Quantum Mechanical Calculations of ¹³C Chemical Shifts in the Stereochemical Determination of Conicasterol F, a Nuclear Receptor Ligand from <i>Theonella swinhoei</i>

Here we report the first application of combined accurate ROE-distance analysis with DFT calculations of NMR chemical shifts to achieve the relative configuration assignment of a marine natural product, conicasterol F, a new polyhydroxylated steroid isolated from the marine sponge <i>Theonella swinhoei</i>. We demonstrate the substantial advantages of this combined approach as a tool for structural studies of natural products, providing a powerful alternative to, or information to underpin, total synthesis when more classical NMR data analysis fails to provide unequivocal results. In this paper, we also describe the isolation and structure elucidation of conicasterol F and its 24-ethyl derivative, theonellasterol I, and their pharmacological evaluation as human nuclear receptor modulators

New Steroids with a Rearranged Skeleton as (h)P300 Inhibitors from the Sponge <i>Theonella swinhoei</i>

Swinhoeisterols A (<b>1</b>) and B (<b>2</b>), two novel sterols with an unprecedented 6/6/5/7 ring system, were isolated from the sponge <i>Theonella swinhoei</i>. The structures and absolute configurations were elucidated by spectroscopic analysis, X-ray single-crystal diffraction, modified Mosher’s method, and TDDFT/ECD calculations. The cytotoxicity of these compounds toward A549 and MG-63 cells encourages studies on their potential target using an inverse virtual screening approach. The predicted inhibitor of h­(p300) was corroborated by an in vitro biological test

Aetheramides A and B, Potent HIV-Inhibitory Depsipeptides from a Myxobacterium of the New Genus “<i>Aetherobacter</i>”

Aetheramides are structurally distinctive cyclic peptides isolated from a novel myxobacterial genus proposed to be termed “<i>Aetherobacter”</i>. The structures were solved by a combination of NMR analyses, quantum mechanical calculations, and chemical derivatizations. Aetheramides which contain a unique polyketide moiety and two amino acid residues potently inhibited HIV-1 infection with IC₅₀ values of ∼0.015 μM. Furthermore aetheramides showed cytostatic activity against human colon carcinoma (HCT-116) cells with IC₅₀ values of 0.11 μM

Structural Evidence of <i>N</i>6‑Isopentenyladenosine As a New Ligand of Farnesyl Pyrophosphate Synthase

<i>N</i>6-isopentenyladenosine (i6A), a modified nucleoside belonging to the cytokinin family, has shown in humans many biological actions, including antitumoral effects through the modulation of the farnesyl pyrophosphate synthase (FPPS) activity. To investigate the relationship between i6A and FPPS, we undertook an inverse virtual screening computational target searching, testing i6A on a large panel of 3D protein structures involved in cancer processes. Experimentally, we performed an NMR investigation of i6A in the presence of FPPS protein. Both inverse virtual screening and saturation transfer difference (STD) NMR outcomes provided evidence of the structural interaction between i6A and FPPS, pointing to i6A as a valuable lead compound in the search of new ligands endowed with antitumoral potential and targeting FPPS protein