Germacrane-type sesquiterpenes from Pilea cavaleriei Levl. subsp. cavaleriei.

The first systematic investigation of germacrane-type sesquiterpenes from Pilea cavaleriei Levl. subsp. cavaleriei was conducted. Eleven undescribed germacrane analogues named cavalinols A-K were identified. Their planar structures were determined by extensive analysis of 1D and 2D NMR spectroscopic data, and the absolute configurations were further determined by X-ray single crystal diffraction, Mosher method, and time dependent density functional theory (TDDFT) electron circular dichroism (ECD) calculation, with the aid from DFT NMR calculation and NOESY experiment. Except for the common 10-memebered ring, ten new compounds contained a p-coumaroyl sidechain connected to C-8 of the nucleus skeleton. All the isolated compounds were screened for anti-inflammatory activity in LPS stimulated RAW 264.7 cells, and compounds 5 and 6 showed moderate activity.

Limonoids and alkaloids from Tetradium austrosinense (Hand.-Mazz.) T.G.Hartley.

A pair of new enantiomeric indolopyridoquinazoline-type alkaloids, (+)-1,7S,8R- and (-)-1,7R,8S-trihydroxyrutaecarpine (3a and 3b), and a new limonoid-tyrosamine hybrid, austrosinin (8), along with six known alkaloids and limonoids, were isolated from the stems with leaves of Tetradium austrosinense. Their structures were elucidated on the basis of analysis of MS, NMR, ECD and time-dependent density functional theory-based electronic circular dichroism (TDDFT-ECD) calculations, as well as proposed biosynthetic pathway. An anti-inflammatory bioassay in vitro showed 8 had significant immunosuppressive effect against the production of pro-inflammatory cytokine TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 cells.

Isolation and characterization of three pairs of verrucosidin epimers from the marine sediment-derived fungus Penicillium cyclopium and configuration revision of penicyrone A and related analogues.

Verrucosidins, a methylated α-pyrone class of polyketides rarely reported upon, have been implicated in one or more neurological diseases. Despite the significance of verrucosidins as neurotoxins, the absolute configurations of most of the derivatives have not been accurately characterized yet. In this study, three pairs of C-9 epimeric verrucosidin derivatives, including the known compounds penicyrones A and B (1a/1b) and 9-O-methylpenicyrones A and B (2a/2b), the new compounds 9-O-ethylpenicyrones A and B (3a/3b), together with the related known derivative verrucosidin (4), were isolated and identified from the culture extract of Penicillium cyclopium SD-413, which was obtained from the marine sediment collected from the East China sea. Their structures were established based on an in-depth analysis of nuclear magnetic resonances (NMR) and mass spectroscopic data. Determination of the absolute configurations of these compounds was accomplished by Mosher's method and time-dependent density functional theory (TDDFT) calculations of electronic circular dichroism (ECD) and optical rotation (OR). The configurational assignment of penicyrone A demonstrated that the previously reported C-6 absolute configuration of verrucosidin derivatives needs to be revised from (6S) to (6R). The 9R/9S epimers of compounds 1-3 were found to exhibit growth inhibition against some pathogenic bacteria, indicating that they have potential as lead compounds for the creation of antimicrobial agents. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00173-2.

Sesquiterpene lactones from Artemisia verlotorum and their anti-inflammatory activities.

Seven new sesquiterpenoids (1-7) and 19 known analogues were isolated from the whole plant of Artemisia verlotorum. Their structures were determined by extensive analysis of 1D and 2D NMR and HRESIMS data, electronic circular dichroism (ECD) spectra, density functional theory (DFT) NMR calculations, and time dependent density functional theory (TDDFT) ECD calculations. The absolute configurations of 1, 3, 5 and 7 were confirmed by single crystal X-ray diffraction experiments. Compounds 1 and 2 possess a rarely reported 5/8-bicyclic skeleton, while both compounds 3 and 4 were uncommon iphionane-type sesquiterpenoids. Eudesmane sesquiterpenoids (5-17) reported in this study are all 7,8-cis-lactones, of which, compound 7 represents the first eudesmane sesquiterpene with an oxygen bridge connecting C-5 and C-11. All the compounds were tested in vitro for their anti-inflammatory activities in LPS-stimulated RAW 264.7 murine macrophages. Compound 18 showed a potent inhibitory effect on NO production, with IC50 values of 3.08 ± 0.61 µM.

Anti-inflammatory sesquiterpenoid dimers from Artemisia atrovirens.

Eight new sesquiterpenoid dimers, artatrovirenolides A-H (1-8), along with three known analogues (9-11), were isolated from Artemisia atrovirens by using the LC-MS guided isolation. Compound 1 was a compound dimerized from a guaianolide and a 1,10-seco-guaianolide unit while others were from two guaianolide units. Their structures were established by comprehensive analysis of spectroscopic data, and their absolute configurations were determined by the aid of time-dependent density functional theory electronic circular dichroism (TDDFT ECD) calculation. Compound 8 showed anti-inflammatory effect in LPS-stimulated BV-2 microglial cells at 1 µM, while compounds 1, 2, 5, and 6 inhibited microglial inflammation at 10 µM.

Ten undescribed cadinane-type sesquiterpenoids from Eupatorium chinense.

Ten undescribed cadinane-type sesquiterpenes (1-10) were isolated from the whole plant of Eupatorium chinense. Their planar structures were mainly elucidated by extensive analysis of spectroscopic data and DFT NMR calculations. The absolute configurations of 1, 2, and 3 were determined by TDDFT ECD calculations while those of compounds 4-7 and 9 were confirmed by single crystal X-ray diffraction experiments. Compounds 2 and 3 are a pair of C-10 epimers, compounds 4 and 5 a pair of C-1 epimers, and compounds 9 and 10 a pair of compounds isomerized at both C-1 and C-10. A possible biosynthetic pathway for these new sesquiterpenes was proposed.

3, 4-seco-Isopimarane and 3, 4-seco-pimarane diterpenoids from Callicarpa nudiflora.

A phytochemical investigation was carried out on the extract of a medicinal plant Callicarpa nudiflora, resulting in the characterization of five new 3, 4-seco-isopimarane (1-5) and one new 3, 4-seco-pimarane diterpenoid (6), together with four known compounds. The structures of the new compounds were fully elucidated by extensive analysis of MS, 1D and 2D NMR spectroscopic data, and time-dependent density functional theory (TDDFT) calculation of electronic circular dichroism (ECD) spectra, and DFT calculations for NMR chemical shifts and optical rotations.

Cytotoxic guaianolides and seco-guaianolides from Artemisia atrovirens.

A phytochemical investigation of a medicinal plant Artemisia atrovirens was carried out, resulting in the characterization of a novel bis-nor seco-guaianolide, seco-atrovirenolide A (1), a new 1,10-seco-guaianolide derivative, seco-atrovirenoic acid A (2), and a new artifact 10-methanoyloxy-seco-atrovirenoic acid A (3), together with eight known guaianolide and seco-guaianolide derivatives (4-11). The structures of new compounds were fully established by extensive analysis of MS, 1D and 2D NMR spectroscopic data. The absolute configurations of the isolated compounds were confirmed by TDDFT ECD calculation, Mosher's method, and X-ray crystal diffraction experiment. All the compounds were tested in vitro for their cytotoxicity against HL-60 and A549 cell lines. Some of them showed moderate inhibitory activity against HL-60 cell lines with IC50 values ranging from 5.99 to 11.74 µM.

Zizaane-Type Sesquiterpenoids and Their Rearranged Derivatives from Agarwood of an Aquilaria Plant.

Nine new sesquiterpenoids (1-9) were isolated from ethyl ether extract of agarwood originated from Aquilaria sp., including three novel sesquiterpenoids (1-3) derived from zizaane, together with six zizaane-type sesquiterpenoids (4-9). All structures were unambiguously elucidated based on 1D and 2D NMR spectra as well as by HRESIMS data. The absolute configuration of sesquiterpenoids was determined by comparison of the experimental and computed ECD spectra. In vitro anti-inflammatory assessment showed that compound 9 exhibited inhibition of NO production in LPS-stimulated RAW264.7 cells with an IC50 value of 62.22 ± 1.27 µM.

The chemical and chemo-ecological studies on Weizhou nudibranch Glossodoris atromarginata.

A detailed chemical investigation of the nudibranch Glossodoris atromarginata collected from Weizhou Island, South China Sea, yielded a new spongian-type diterpene 1, together with the four known-related compounds 2-5. The structure of the new compound 1 was elucidated by the detailed spectroscopic analysis, the comparison of the spectroscopic data with the known diterpene isoagatholactone, and the 13 C chemical shift calculation. In addition, evidence for the absolute stereochemistry of the known compound 2 was, for the first time, provided by the application of time-dependent density functional theory electronic circular dichroism calculation.

Induction of New Lactam Derivatives From the Endophytic Fungus Aplosporella javeedii Through an OSMAC Approach.

Fermentation of the endophytic fungus Aplosporella javeedii on solid rice medium in presence of either 3.5% NaNO3 or 3.5% monosodium glutamate caused a significant change of the fungal metabolite pattern compared to fungal controls grown only on rice. Chemical investigation of the former fungal extracts yielded 11 new lactam derivatives, aplosporellins A-K (2-12), in addition to the known compound, pramanicin A (1). All of these compounds were not detected when the fungus was grown on rice medium without these activators thereby indicating the power of this OSMAC approach. The structures of the new compounds were elucidated by one- and two- dimensional NMR spectroscopy, DFT-NMR calculations and by mass spectrometry as well as by comparison with the literature whereas the absolute configuration of the lactam core was determined by TDDFT-ECD and OR calculations. Pramanicin A (1) showed strong cytotoxicity against human lymphoma (Ramos) and leukemia (Jurkat J16) cells with IC50 values of 4.7 and 4.4 µM, respectively. Mechanistic studies indicated that 1 activates caspase-3 and induces apoptotic cell death.

Synthesis and HPLC-ECD Study of Cytostatic Condensed O,N-Heterocycles Obtained from 3-Aminoflavanones.

Racemic chiral O,N-heterocycles containing 2-arylchroman or 2-aryl-2H-chromene subunit condensed with morpholine, thiazole, or pyrrole moieties at the C-3-C-4 bond were synthesized with various substitution patterns of the aryl group by the cyclization of cis- or trans-3-aminoflavanone analogues. The 3-aminoflavanone precursors were obtained in a Neber rearrangement of oxime tosylates of flavanones, which provided the trans diastereomer as the major product and enabled the isolation of both the cis- and trans-diastereomers. The cis- and trans-aminoflavanones were utilized to prepare three diastereomers of 5-aryl-chromeno[4,3-b][1,4]oxazines. Antiproliferative activity of the condensed heterocycles and precursors was evaluated against A2780 and WM35 cancer cell lines. For a 3-(N-chloroacetylamino)-flavan-4-ol derivative, showing structural analogy with acyclic acid ceramidase inhibitors, 0.15 µM, 3.50 µM, and 6.06 µM IC50 values were measured against A2780, WM35, and HaCat cell lines, and apoptotic mechanism was confirmed. Low micromolar IC50 values down to 2.14 µM were identified for the thiazole- and pyrrole-condensed 2H-chromene derivatives. Enantiomers of the condensed heterocycles were separated by HPLC using chiral stationary phase, HPLC-ECD spectra were recorded and TDDFT-ECD calculations were performed to determine the absolute configuration and solution conformation. Characteristic ECD transitions of the separated enantiomers were correlated with the absolute configuration and effect of substitution pattern on the HPLC elution order was determined.

Furoic acid derivatives from the endophytic fungus Coniothyrium sp.

The endophytic fungus Coniothyrium sp. was isolated from leaves of Quercus robur. Fermentation of this fungus on solid rice medium yielded two new furoic acid derivatives (1 and 2) and two additional known compounds. The structures of the new compounds were determined by extensive analysis of 1D and 2D nuclear magnetic resonance spectra as well as high-resolution mass spectrometry data. Compound 1, containing three aromatic chromophores attached by rotatable sigma bonds and a chirality center in benzylic position, was found to be a scalemic mixture with an excess of the (S) enantiomer, the absolute configuration of which was elucidated as by the solution time-dependent density functional theory-electronic circular dichroism approach. The ωB97X/TZVP PCM/MeCN and SOGGA11-X/TZVP SMD/MeCN methods were used for geometry reoptimization to reproduce the solution conformational ensemble. All isolated compounds were tested for their cytotoxicity but proved to be inactive.

[1,5]-Hydride Shift-Cyclization versus C(sp2)-H Functionalization in the Knoevenagel-Cyclization Domino Reactions of 1,4- and 1,5-Benzoxazepines.

Domino cyclization reactions of N-aryl-1,4- and 1,5-benzoxazepine derivatives involving [1,5]-hydride shift or C(sp2)-H functionalization were investigated. Neuroprotective and acetylcholinesterase activities of the products were studied. Domino Knoevenagel-[1,5]-hydride shift-cyclization reaction of N-aryl-1,4-benzoxazepine derivatives with 1,3-dicarbonyl reagents having active methylene group afforded the 1,2,8,9-tetrahydro-7bH-quinolino [1,2-d][1,4]benzoxazepine scaffold with different substitution pattern. The C(sp3)-H activation step of the tertiary amine moiety occurred with complete regioselectivity and the 6-endo cyclization took place in a complete diastereoselective manner. In two cases, the enantiomers of the chiral condensed new 1,4-benzoxazepine systems were separated by chiral HPLC, HPLC-ECD spectra were recorded, and absolute configurations were determined by time-dependent density functional theory- electronic circular dichroism (TDDFT-ECD) calculations. In contrast, the analogue reaction of the regioisomeric N-aryl-1,5-benzoxazepine derivative did not follow the above mechanism but instead the Knoevenagel intermediate reacted in an SEAr reaction [C(sp2)-H functionalization] resulting in a condensed acridane derivative. The AChE inhibitory assays of the new derivatives revealed that the acridane derivative had a 6.98 µM IC50 value.

Trigonostemons G and H, dinorditerpenoid dimers with axially chiral biaryl linkage from Trigonostemon chinensis.

Trigonostemons G and H, two novel dimeric dinorditerpenoids, were isolated from the stem barks of Trigonostemon chinensis. Their planar structures and relative configurations were established by extensive analysis of spectroscopic data. Trigonostemons G and H possess a homodimeric biaryl skeleton obtained from two rearranged chiral nonracemic abietane-type dinorditerpenes through an axially chiral biaryl 11,11'-linkage. Torsional scan and computation of the transition states were carried out to estimate the rotational energy barrier, and the axial chirality (aS) was determined by time-dependent density functional theory (TDDFT) electronic circular dichroism (ECD) calculations. The positive n-π* ECD transitions of the isolated carbonyl chromophore above 300 nm could be used to determine the central chirality of trigonostemon G independently by ECD calculations of the diastereomers.

New tricyclic prezizaane sesquiterpenoids from agarwood.

Ten new tricyclic prezizaane types sesquiterpenoids (1-10) were isolated from ethyl ether extract of agarwood originated from Aquilaria sp. Their structures were unambiguously elucidated on the basis of 1D and 2D NMR spectra as well as by HRESIMS data. The absolute configuration of the new prezizaenes 1, 2 and 4 was determined by single-crystal X-ray diffraction, while TDDFT-ECD method was applied for 6. Compounds 4 and 5 displayed significant inhibitory activities toward α-glucosidase with IC50 values of 0.22 and 1.99 mM, respectively.

Five new epoxy-5,6,7,8-tetrahydro-2-(2-phenylethyl)chromones from Chinese agarwood by artificial holing.

Five optically active epoxy-5,6,7,8-tetrahydro-2-(2-phenylethyl)chromone derivatives (1-5) with four chirality centers in the condensed cyclohexene ring were isolated from artificial holing agarwood originating from Aquilaria sinensis (Lour.) Gilg. Their structures were elucidated by spectroscopic techniques (UV, IR, 1D and 2D NMR) and MS analyses. The absolute configuration of 2 was elucidated by TDDFT-ECD calculations and ECD spectra of 1, 3-5 allowed their configurational assignment as well. All of the new compounds contained a condensed oxirane ring, and compound 1 was the only 6,7-epoxy-2-(2-phenylethyl)-5,6,7,8-tetrahydrochromone derivative that has ever been found in agarwood. AChE inhibitory activity was tested for the first time of these new compounds by using modified Ellman's colorimetric method. Compounds 3 and 5 exhibited inhibitory activity against AChE with IC50 value of 441.6, and 155.6 µM, respectively.

Flueggenoids A - E, new dinorditerpenoids from Flueggea virosa.

A phytochemical investigation on the twigs and leaves of Flueggea virosa (Euphorbiaceae) led to the isolation of flueggenoids A - E (1-5), five new 13-methyl-ent-podocarpanes, together with eleven known compounds (6-16). Their structures and absolute configurations were elucidated on the basis of extensive MS and NMR data analysis, and/or single-crystal X-ray diffraction, time-dependent density functional theory (TDDFT)-based electronic circular dichroism (ECD) calculations, and chemical transformation. All isolates were evaluated for anti-HCV activity, the results showed that terpenoids of F. virosa had nonnegligible contribution for the anti-HCV activity.

Correction: Varioloid A, a new indolyl-6,10b-dihydro-5aH-[1]benzofuro[2,3-b]indole derivative from the marine alga-derived endophytic fungus Paecilomyces variotii EN-291.

[This corrects the article DOI: 10.3762/bjoc.12.188.].

Phytotoxic Metabolites Produced by Diaporthella cryptica, the Causal Agent of Hazelnut Branch Canker.

From the culture filtrates of Diaporthella cryptica, an emerging hazelnut pathogen, 2-hydroxy-3-phenylpropanoate methyl ester and its 3-(4-hydroxyphenyl) and 3-(1 H-indol-3-yl) analogues, named crypticins A-C, were isolated together with the well-known tyrosol. Crypticins A-C were identified by spectroscopic (essentially nuclear magnetic resonance and high-resolution electrospray ionization mass spectrometry) methods. The R absolute configuration (AC) of crypticin A was determined by comparing its optical rotation and electronic circular dichroism (ECD) spectrum with those of papuline, the methyl ester of (-)( S)-phenyllactic acid isolated as the main phytotoxin of Pseudomonas syringae pv.  papulans, responsible for apple blister spot. The ACs of crypticins B and C were determined by time-dependent density functional theory calculations of their ECD spectra. Papuline and the new metabolites herein isolated, except tyrosol, were tested at 1 mg/mL on cork oak, grapevine, hazelnut, and holm oak leaves using the leaf puncture assay. They were also tested on tomato cuttings at 0.5 and 0.05 mg/mL. In the leaf puncture assay, none of the compounds was found to be active. Crypticin C and papuline were active in the tomato cutting assay. Additionally, crypticin C displayed moderate inhibitory effect against Phytophthora cambivora.