Structure Validation of Natural Products by Quantum-Mechanical GIAO Calculations of 13C NMR Chemical Shifts GIAO=gauge including atomic orbitals.
Geometry optimization and GIAO (gauge including atomic orbitals) 1 3 C NMR chemical shift calculations at Hartree-Fock level, using the 6-31G(d) basis set, are proposed as a tool to be applied in the structural characterization of new organic compounds, thus providing useful support in the interpretation of experimental NMR data. Parameters related to linear correlation plots of computed versus experimental 1 3 C NMR chemical shifts for fourteen low-polar natural products, containing 10-20 carbon atoms, were employed to assess the reliability of the proposed structures. A comparison with the hybrid B3LYP method was carried out to evaluate electron correlation contributions to the calculatio…
PLA2-mediated catalytic activation of its inhibitor 25-acetyl-petrosaspongiolide M: serendipitous identification of a new PLA2 suicide inhibitor.
Abstract25-Acetyl-petrosaspongiolide M (PMAc) (1), a mild non-covalent PLA2 inhibitor, unexpectedly recovers, after incubation with bvPLA2, the ability to covalently modify the enzyme target. This study demonstrates the catalytic effect of bvPLA2 in converting 1 in its deacetylated congener petrosaspongiolide M (PM) (2), a strong covalent PLA2 inhibitor whose molecular mechanism of inhibition has already been clarified. Moreover, our findings outline the potential role of PMAc as anti-inflammatory pro-drug, by virtue of its ability of delivering the active PM agent at the site of inflammation, functioning as a suicide inhibitor.
Anti-inflammatory and analgesic activity of a novel inhibitor of microsomal prostaglandin E synthase-1 expression
Abstract In a previous study, we reported a new γ-hydroxybutenolide derivative, 4-benzo[ b ]thiophen-2-yl-3-bromo-5-hydroxy-5 H -furan-2-one (BTH), as inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) expression in lypopolysaccharide (LPS) stimulated RAW 264.7 and TPH-1 cells, without affecting cyclooxygenase-2 (COX-2). In this study, we evaluated the in vivo effect of BTH on some acute and chronic inflammatory animal models in relation to its inhibitory profile on mPGES-1 expression. In the zymosan-induced mouse air pouch model, BTH produced a dose-dependent inhibition of prostaglandin E 2 (PGE 2 ) production and mPGES-1 protein expression in pouch exudates without any effect on…
Determination of the Relative Stereochemistry of Flexible Organic Compounds by Ab Initio Methods: Conformational Analysis and Boltzmann-Averaged GIAO 13C NMR Chemical Shifts GIAO=gauge including atomic orbitals.
Ab initio calculations at the Hartree-Fock level with full-geometry optimization using the 6-31G(d) basis set, and GIAO (gauge including atomic orbitals) 1 3 C NMR chemical shifts, are presented here as a support in the study of the stereochemistry of low-polar organic compounds having an openchain structure. Four linear stereoisomers, fragments of a natural product previously characterized by experimental 1 3 C NMR spectra, which possesses three stereogenic centers, 11 carbon atoms, and 38 atoms in total, were considered. Conformational searches, by empirical force-field molecular dynamics, pointed out the existence of 8-13 relevant conformers per stereoisomer. Thermochemical calculations …
Comparison of different theory models and basis sets in the calculation of 13C NMR chemical shifts of natural products.
The influence of the calculation method in mimicking experimental 13C NMR chemical shifts of 15 low-polarity natural products singularly containing 10–20 carbon atoms was investigated by employing different quantum chemistry approaches and basis sets, both in the preliminary geometry optimizations and in the following single-point 13C GIAO calculations of the NMR chemical shifts. The geometries of the involved species were optimized at the PM3, HF, B3LYP and mPW1PW91 levels whereas the 13C NMR parameters were determined at the HF, B3LYP and mPW1PW91 levels. Different combinations of basis sets were also tested. The consistency and efficiency of the considered combinations of geometry optimi…
2,3-Dihydrobenzofuran privileged structures as new bioinspired lead compounds for the design of mPGES-1 inhibitors
International audience; 2,3-Dihydrobenzofurans are proposed as privileged structures and used as chemical platform to design small compound libraries. By combining molecular docking calculations and experimental verification of biochemical interference, we selected some potential inhibitors of microsomal prostaglandin E2 synthase (mPGES)-1. Starting from low affinity natural product 1, by our combined approach we identified the compounds 19 and 20 with biological activity in the low micromolar range. Our data suggest that the 2,3-dihydrobenzofuran derivatives might be suitable bioinspired lead compounds for development of new generation mPGES-1 inhibitors with increased affinity.
Synthesis, structural aspects and bioactivity of the marine cyclopeptide hymenamide C
Abstract Head-to-tail proline containing cyclopeptide hymenamide C [cyclo(Leu-Trp-Pro 3 -Phe-Gly-Pro 6 -Glu); 1 ], isolated from a marine sponge and for which a preliminary immunomodulating activity was reported, was efficiently synthesized by a three-dimensional orthogonal solid-phase strategy (Fmoc/tBu/Allyl) via anchoring the ω -carboxyl function of the glutamic acid to the solid support (PAC–PEG–PS). The linear precursor was entirely assembled and subsequently cyclized on resin, yielding a major product identical to the natural hymenamide C and a minor one, a geometric isomer of hymenamide C ( 2 ), differing for the geometry of peptide linkages at Pro residues. Both the ‘proline-rich’ c…
Synthesis and biological properties of the seven alanine-modified analogues of the marine cyclopeptide hymenamide C
The synthesis and biological activity of the marine cyclopeptide hymenamide C(1), showing an inhibitory effect on human neutrophil elastase degranulation release, were recently described. Based on this result, it was decided to undertake a systematic structure-activity relationship study of this cyclopeptide, based on the Ala-scan technique, in order to obtain useful information for the rational design of additional analogues. The synthesis and characterization of the seven Ala modified analogues are reported and their biological and pharmacological properties are described.
Toward the Discovery of New Agents Able to Inhibit the Expression of Microsomal Prostaglandin E Synthase-1 Enzyme as Promising Tools in Drug Development
In our recent studies, we focused our attention on the synthesis of several γ-hydroxybutenolides designed on the basis of petrosaspongiolide M 1 (PM) structure that has been recognized to potently inhibit the inflammatory process through the selective PLA2 enzyme inhibition. By means of a combination of computational methods and efficient synthetic strategies, we generated small collections of PM modified analogs to identify new potent PLA2 inhibitors, suitable for clinical development. In the course of the biological screening of our compounds, we discovered a potent and selective inhibitor of mPGES-1 expression, the benzothiophene γ-hydroxybutenolide 2, which so far represents the only pr…
Development of a second generation of inhibitors of microsomal prostaglandin E synthase 1 expression bearing the γ-hydroxybutenolide scaffold
Petrosaspongiolide M (PM), a marine sesterterpene metabolite bearing the gamma-hydroxybutenolide scaffold and displaying a potent inhibitory activity toward PLA(2) enzyme, was selected by us as an attractive target in order to explore its mechanism of action at molecular level. In the course of our investigations we decided to synthetically modify the parent compound to clarify the structural determinants responsible for the activity; in fact, very recently, our research group reported the synthesis and the pharmacological properties of a first collection of PM analogues generated by Ludi approach. The synthesized compounds showed a poor or moderate activity toward PLA(2) enzymes, neverthel…
Chemical Proteomics-Guided Identification of a Novel Biological Target of the Bioactive Neolignan Magnolol
Understanding the recognition process between bioactive natural products and their specific cellular receptors is of key importance in the drug discovery process. In this outline, some potential targets of Magnolol, a natural bioactive compound, have been identified by proteomic approaches. Among them, Importin-β1 has been considered as the most relevant one. A direct binding between Magnolol and this nuclear chaperone has been confirmed by DARTS and molecular docking, while its influence on Importin-β1 translocation has been evaluated by in vitro assays.
Structural basis for the potential antitumour activity of DNA-interacting benzo[kl]xanthene lignans
The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans, rare among natural products and synthetic compounds, are almost unexplored. In the present contribution, the possible interaction of six synthetic benzo[kl]xanthene lignans and the natural metabolite rufescidride with DNA has been investigated through a combined STD-NMR and molecular docking approach, paralleled by in vitro biological assays on their antiproliferative activity towards two different cancer cell lines: SW 480 and HepG2. Our data suggest that the benzo[kl]xanthene lignans are suitable lead compounds for the design of DNA selective ligands with potential antitumour properties.