Jean-François Gallard

Terengganensines A and B, dihydroeburnane alkaloids from Kopsia terengganensis

Five known indole alkaloids, (+)-quebrachamine, (−)-eburnamine, (+)-isoeburnamine, (−)-eburnaminol and (+)-larutensine, and two new alkaloids, terengganensines A 1 and B 2, possessing a unique dihydroeburnane skeleton were isolated from the bark of Kopsia terengganensis. The structures of the new compounds were elucidated by spectral methods.

Piliostigmin, A 2-phenoxychromone, and C-methylflavonols from Piliostigma thonningii

Abstract Piliostigmin, a 2-phenoxychromone, and three C -methylflavonols, 6,8-di- C -methylquercetin 3-methyl ether, 6- C -methylquercetin 3,7-dimethyl ether and 6,8-di- C -methylquercetin 3,7-dimethyl ether, were isolated from the leaves of Piliostigma thonningii , together with the known compounds quercetin, quercitrin, 6- C -methylquercetin 3-methyl ether, 6- C -methylquercetin 3,7,3′-trimethyl ether, 6,8-di- C -methylkaempferol 3-methyl ether and 6,8-di- C -methylkaempferol 3,7-dimethyl ether. The structures of the new compounds were established by spectral methods, especially 2D NMR. Complete 13 C assignments using HMBC experiments are reported for the four latter C -methylflavonols.

Bivalent sequential binding of docetaxel to methyl-β-cyclodextrin.

New docetaxel (Dtx) and cyclodextrin (CD) inclusion complexes having improved apparent water solubility (up to 9.98mgmL(-1)) were obtained from phase solubility diagrams. γ-CD and SBE-β-CD offered only poor solubility enhancements while considerable increases in apparent solubility were obtained with Me-β-CD (20%, w/w) and HP-β-CD (40%, w/w) (9.98mgmL(-1) and 7.43mgmL(-1), respectively). The complexation mechanism between Dtx and Me-β-CD was investigated by circular dichroism spectrometry, two-dimensional (1)H NMR (NOESY) in D(2)O, isothermal titration calorimetry (ITC) and molecular docking calculations. Circular dichroism and NOESY confirmed the existence of non-covalent interactions between Dtx and Me-β-CD and suggested that the tert-butyl group (C(6)-C(9)) and two aromatic groups (C(24)-C(29) and C(30)-C(35)) of Dtx interacted with the Me-β-CD molecules. The combination of ITC results to molecular docking calculations led to the identification of an unconventional sequential binding mechanism between Me-β-CD and Dtx. In this sequential binding, a Me-β-CD molecule first interacted with both tert-butyl and C(30)-C(35) aromatic groups (K(1): 744M(-1)). Then a second Me-β-CD molecule interacted with the C(24)-C(29) aromatic group (K(2): 202M(-1)). The entropy of the first interaction was positive, whereas a negative value of entropy was found for the second interaction. The opposite behavior observed for these two sites was explained by differences in the hydrophobic contact surface and functional group flexibility.

Unprecedented Stylissazoles A–C from Stylissa carteri: Another Dimension for Marine Pyrrole‐2‐aminoimidazole Metabolite Diversity

Theirintriguingdimeric polycyclic ring systems that were isolated during thelast years revealed their elaborate structures and moleculardiversity which arise from a variety of modes of dimerizationand polycyclization. Structurally, it is assumed that thesemetabolites arise from the crucial intermediates clathrodin,

Investigation of the complexation of albendazole with cyclodextrins for the design of new antiparasitic formulations.

Albendazole (ABZ) exhibits a potent antiparasitic activity against a broad spectrum of parasites. Unfortunately, the very low water solubility of ABZ (0.2 μg mL(-1), 0.7 μM) impairs considerably its formulation. Phase solubility diagrams showed that α-cyclodextrin (10% w/w), hydroxypropyl-β-cyclodextrin (40% w/w) and sulfobutylether-β-cyclodextrin (40% w/w) allowed an increase of apparent solubility with enhancement factors of 570, 3970, and 5880, respectively. The apparent aqueous solubility of ABZ was markedly increased from 0.2 μg mL(-1) (0.7 μM) without cyclodextrins to 1.52 mg mL(-1) (5.69 mM) with random methyl-β-cyclodextrin (Me-β-CD) (40% w/w). This corresponds to an apparent solubility enhancement factor of 7600 which is the maximal enhancement factor of ABZ apparent aqueous solubility ever reported in the literature using conventional cyclodextrins. The complexation mechanism between ABZ and cyclodextrins has been investigated using phase solubility diagrams, nuclear magnetic resonance ((1)H NMR) coupled with two-dimensional nuclear Overhauser effect (NOESY) experiments and molecular docking calculations. The results showed that the central bicyclic fragment from ABZ interacts with Me-β-CD according to 1:1 stoichiometry.

The unexpected increase of clotrimazole apparent solubility using randomly methylated β-cyclodextrin.

Clotrimazole (CTZ) and cyclodextrin (CD) inclusion complexes having improved apparent water solubility were obtained from phase solubility diagrams. β‐CD (1.5% w/w) and hydroxypropyl‐β‐CD (40% w/w) offered poor CTZ solubility enhancements (12 and 384 times, respectively). Unexpectedly, the apparent solubility of CTZ was 9980 times increased from 0.4 µg.mL−1 (1.42 μM) without CD to 4.89 mg.mL−1 (14.9 mM) using randomly‐methylated β‐CD (Me‐β‐CD) (40% w/w). This is the highest apparent CTZ solubility improvement ever reported in the literature using conventional CDs. Quantitative nuclear magnetic resonance (1H‐NMR) coupled with two‐dimensional nuclear Overhauser effect (NOESY) experiments and molecular docking calculations showed that the highest interactions with Me‐β‐CD were reported for CTZ two phenyl groups. A lower interaction was reported for chlorophenyl, while imidazole had the weakest interaction with Me‐β‐CD. Copyright

Unified biomimetic assembly of voacalgine A and bipleiophylline via divergent oxidative couplings

Bipleiophylline is a highly complex monoterpene indole alkaloid composed of two pleiocarpamine units anchored on an aromatic spacer platform. The synthesis of bipleiophylline is considered as a mountain to climb by the organic chemistry community. Here, a unified oxidative coupling protocol between indole derivatives and 2,3-dihydroxybenzoic acid, mediated by silver oxide, has been developed to produce the core of bipleiophylline. This method also allows the independent preparation of benzofuro[2,3-b]indolenine and isochromano[3,4-b]indolenine scaffolds, depending only on the nature of the aromatic platform used. The procedure has been applied to simple indole derivatives and to more challenging monoterpene indole alkaloids, thereby furnishing natural-product-like structures. The use of scarce pleiocarpamine as the starting indole allows the first syntheses of bipleiophylline and of its biosynthetic precursor, voacalgine A. The structure of the latter has been reassigned in the course of our investigations by 2D NMR and displays an isochromano[3,4-b]indolenine motif instead of a benzofuro[2,3-b]indolenine.

Advanced Structural Determination of Diterpene Esters Using Molecular Modeling and NMR Spectroscopy.

Three new jatrophane esters (1-3) were isolated from Euphorbia amygdaloides ssp. semiperfoliata, including an unprecedented macrocyclic jatrophane ester bearing a hemiketal substructure, named jatrohemiketal (3). The chemical structures of compounds 1-3 and their relative configurations were determined by spectroscopic analysis. The absolute configuration of compound 3 was determined unambiguously through an original strategy combining NMR spectroscopy and molecular modeling. Conformational search calculations were performed for the four possible diastereomers 3a-3d differing in their C-6 and C-9 stereocenters, and the lowest energy conformer was used as input structure for geometry optimization. The prediction of NMR parameters ((1)H and (13)C chemical shifts and (1)H-(1)H coupling constants) by density functional theory (DFT) calculations allowed identifying the most plausible diastereomer. Finally, the stereostructure of 3 was solved by comparison of the structural features obtained by molecular modeling for 3a-3d with NMR-derived data (the values of dihedral angles deduced from the vicinal proton-proton coupling constants ((3)JHH) and interproton distances determined by ROESY). The methodology described herein provides an efficient way to solve or confirm structural elucidation of new macrocyclic diterpene esters, in particular when no crystal structure is available.

Synthesis of New Phosphonate Derivatives of Naphtho[2,1-b[Pyran]3,2-e][1,2,4]Triazolo [1,5-c]Pyrimidines

Abstract The synthesis of new naphthopyranotriazolopyrimidines phosphonates 4a–i in good yields (74%–93%) has been accomplished via Michaelis–Arbusov rearrangement by the reaction of trialkyl phosphite with naphthopyranotriazolopyrimidines chloride 3a–e, which were obtained from α-functionalized iminoethers 1 in two steps. The synthesized compounds 4a–i were completely characterized by IR, 1H, 13C, and 31P NMR and HRMS. Supplemental materials are available for this article. Go to the publishers online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. GRAPHICAL ABSTRACT

Environmentally Friendly Procedure Based on Supercritical Fluid Chromatography and Tandem Mass Spectrometry Molecular Networking for the Discovery of Potent Antiviral Compounds from Euphorbia semiperfoliata

A supercritical fluid chromatography-based targeted purification procedure using tandem mass spectrometry and molecular networking was developed to analyze, annotate, and isolate secondary metabolites from complex plant extract mixture. This approach was applied for the targeted isolation of new antiviral diterpene esters from Euphorbia semiperfoliata whole plant extract. The analysis of bioactive fractions revealed that unknown diterpene esters, including jatrophane esters and phorbol esters, were present in the samples. The purification procedure using semipreparative supercritical fluid chromatography led to the isolation and identification of two new jatrophane esters (13 and 14) and one known (15) and three new 4-deoxyphorbol esters (16-18). The structure and absolute configuration of compound 16 were confirmed by X-ray crystallography. This compound was found to display antiviral activity against Chikungunya virus (EC50 = 0.45 μM), while compound 15 proved to be a potent and selective inhibitor of HIV-1 replication in a recombinant virus assay (EC50 = 13 nM). This study showed that a supercritical fluid chromatography-based protocol and molecular networking can facilitate and accelerate the discovery of bioactive small molecules by targeting molecules of interest, while minimizing the use of toxic solvents.