Tetrahydrofuran Ring Research Articles

Unravelling nicotinic receptor and ligand features underlying neonicotinoid knockdown actions on the malaria vectormosquito Anopheles gambiae.

With the spread of resistance to long-established insecticides targeting Anopheles malaria vectors, understanding the actions of compounds newly identified for vector control is essential. With new commercial vector-control products containing neonicotinoids under development, we investigate the actions of 6 neonicotinoids (imidacloprid, thiacloprid, clothianidin, dinotefuran, nitenpyram and acetamiprid) on 13 Anopheles gambiae nicotinic acetylcholine receptor (nAChR) subtypes produced by expression of combinations of the Agα1, Agα2, Agα3, Agα8 and Agβ1 subunits in Xenopus laevis oocytes, the Drosophila melanogaster orthologues of which we have previously shown to be important in neonicotinoid actions. The presence of the Agα2 subunit reduces neonicotinoid affinity for the mosquito nAChRs, whereas the Agα3 subunit increases it. Crystal structures of the acetylcholine binding protein (AChBP), an established surrogate for the ligand-binding domain, with dinotefuran bound, shows a unique target site interaction through hydrogen bond formation and CH-N interaction at the tetrahydrofuran ring. This is of interest as dinotefuran is also under trial as the toxic element in baited traps. Multiple regression analyses show a correlation between the efficacy of neonicotinoids for the Agα1/Agα2/Agα8/Agβ1 nAChR, their hydrophobicity and their rate of knockdown of adult female An. gambiae, providing new insights into neonicotinoid features important for malaria vector control.

Disentangling the Conformational Space and Structural Preferences of Tetrahydrofurfuryl Alcohol Using Rotational Spectroscopy and Computational Chemistry.

The influence of the hydroxymethyl (CH2OH) group on the tetrahydrofuran (THF) ring structure was investigated by disentangling the gas phase conformational landscape of the sugar analogue tetrahydrofurfuryl alcohol (THFA). By combining rotational spectroscopy (6-20 GHz) and quantum chemical calculations, transitions corresponding to two stable conformers of THFA and their 13C isotopologues were observed and assigned in the rotational spectrum. The positions of the C atoms were precisely determined to unambiguously distinguish between nearly isoenergetic pairs of conformers that differ in their ring configurations: envelope (E) versus twist (T). The rotational spectrum confirms that the E ring geometry is favoured when the CH2OH fragment lies gauche (-) to the THF backbone (OCCO ~-60°) whereas the T form is more stable for the gauche (+) alignment of the substituent (OCCO ~+60°). The observed spectral intensities suggest that conformational relaxation of the THF geometry (E↔T) to the more stable form readily occurs within the pairs of g- and g+ conformers which is consistent with the low barriers (1.5-1.7 kJ mol-1) for conversion determined via transition state calculations. Insights into the intramolecular hydrogen bonding and other weak interactions stabilizing the lowest energy structures of THFA were derived and rationalized using non-covalent interaction analyses.

Ring–Opening Mechanism of O‐heterocycles into α,ω‐Diols over Ni−La(OH)3: C−O Bond Hydrogenolysis of THFA to 1,5‐Pentanediol as a Case Study

AbstractThe elucidation of the ring–opening reaction mechanism is a critical step towards improving the catalytic performance for the conversion of biomass into value–added chemicals. Herein, we focused on the stepwise C−O bond hydrogenolysis mechanism of oxygen–containing heterocycles (O‐heterocycles) into α,ω‐diols, in particular THFA to 1,5‐PeD, over selective Ni−La(OH)3 in hydrogen–donor isopropanol. A mechanistic study was carried out on a structurally well–defined Ni−La(OH)3, where the mechanism was elucidated using a combination of kinetic and 13C NMR isotope labeling experiments. It was suggested that both Ni nanoparticles and La(OH)3 support play a critical role in the reaction mechanism, where basic hydroxide species of the support initially deprotonate the CH2OH and −OH modified furan, tetrahydrofuran and tetrahydropyran rings, adsorbing them chemically on the catalyst surface. This step is followed by a direct hydride attack on the second carbon atom of these rings, which is proposed to be the key step for ring cleavage, as indicated by the increased deuteration at this position. In addition to the direct hydrogenolysis using gaseous H2, it is assumed that a catalytic transfer hydrogenolysis reaction (CTH) reaction of THFA is proposed to proceed via the dehydrogenation of isopropanol over isolated Ni species, forming hydrogen species that can be adsorbed on the Ni surface or desorb as H2 molecules.

The chromosome-scale assembly of the Notopterygium incisum genome provides insight into the structural diversity of coumarins

Coumarins, derived from the phenylpropanoid pathway, represent one of the primary metabolites found in angiosperms. The alignment of the tetrahydropyran (THP) and tetrahydrofuran (THF) rings with the lactone structure results in the formation of at least four types of complex coumarins. However, the mechanisms underlying the structural diversity of coumarin remain poorly understood. Here, we report the chromosome-level genome assembly of Notopterygium incisum, spanning 1.64 Gb, with a contig N50 value of 22.7 Mb and 60,021 annotated protein-coding genes. Additionally, we identified the key enzymes responsible for shaping the structural diversity of coumarins, including two p-coumaroyl CoA 2′-hydroxylases crucial for simple coumarins basic skeleton architecture, two UbiA prenyltransferases responsible for angular or linear coumarins biosynthesis, and five CYP736 cyclases involved in THP and THF ring formation. Notably, two bifunctional enzymes capable of catalyzing both demethylsuberosin and osthenol were identified for the first time. Evolutionary analysis implies that tandem and ectopic duplications of the CYP736 subfamily, specifically arising in the Apiaceae, contributed to the structural diversity of coumarins in N. incisum. Conclusively, this study proposes a parallel evolution scenario for the complex coumarin biosynthetic pathway among different angiosperms and provides essential synthetic biology elements for the heterologous industrial production of coumarins.

Development of novel pyrimidine nucleoside analogs as potential anticancer agents: Synthesis, characterization, and In-vitro evaluation against pancreatic cancer

The present study proposed modification of 5-FU by conjugation with an acyl chloride and a 5-membered heterocyclic ring to improve its in-vitro cytotoxicity and metabolic stability. XYZ-I-71 and XYZ-I-73 were synthesized by introducing a tetrahydrofuran ring on 5-fluorocytosine (a precursor of 5-FU) and conjugation with octanoyl chloride and lauroyl chloride, respectively. The structure of the synthesized compounds was validated using NMR and micro-elemental analysis. The antiproliferative activity of the analogs was determined against MiaPaCa-2, PANC-1, and BxPC-3 pancreatic cancer cells. The analog's stability in human liver microsomes was quantified by HPLC. We found that the XYZ-I-73 (IC50 3.6 ± 0.4 μM) analog was most effective against MiaPaCa-2 cells compared to XYZ-I-71(IC50 12.3 ± 1.7 μM), GemHCl (IC50 24.2 ± 1.3 μM), Irinotecan (IC50 10.1 ± 1.5 μM) and 5-FU (IC50 13.2 ± 1.1 μM). The antiproliferative effects of this analog in Miapaca-2 cells is evident based on it having a 7-fold,3-fold, and 4-fold increased cytotoxic effect over Gem-HCl, Irinotecan, and 5-FU, respectively. On the other hand, XYZ-I-71 exhibited a 2-fold increased cytotoxic effect over Gem-HCl but a comparable cytotoxic effect to 5-FU and Irinotecan in MiaPaCa-2 cells. A similar trend of higher XYZ-I-73 inhibition was observed in PANC-1 and BxPC-3 cultures. For 48-h MiaPaCa-2 cell migration studies, XYZ-I-73 (5 μM) significantly reduced migration (# of migrated cells, 168 ± 2.9), followed by XYZ-I-71(315±2.1), Gem-HCl (762±3.1) and 5-FU (710 ± 3.2). PARP absorbance studies demonstrated significant inhibition of PARP expression of XYZ-I-73 treated cells compared to 5-FU, GemHCl, and XYZ-I-71. Further, BAX and p53 expressions were significantly increased in cells treated with XYZ-I-73 compared to 5-FU, GemHCl, and XYZ-I-71. In-vitro, metabolic stability studies showed that 80 ± 5.9% of XYZ-I-71 and XYZ-I-73 remained intact after 2 h exposure in liver microsomal solution compared to 5-FU. The XYZ-I-73 analog demonstrated a remarkable cytotoxic effect and improved in-vitro metabolic stability over the selected standard drugs and may have potential anticancer activity against pancreatic cancer.

Sesquiterpenoids and steroids from Eupatorium fortunei and their inhibitory effects on NO production

Two heterodimers including a clovane-phenylpropanoid hybrid (1) and a clovane-menthane hybrid (2), five linear sesquiterpenoids incorporating a tetrahydrofuran ring (3–6 & 8), and four steroids (7 & 9–11), were separated from the ethanolic extract of a well-known aromatic and medicinal herb Eupatorium fortunei. Their structures were characterised by detailed analyses of spectroscopic data and comparison with known analogues, with seven (1–7) of them being described for the first time. The hybrids 1 and 2 represent the first examples of clovane type sesquiterpenoids hybridising with other class of natural products, and compounds 3–6 and 8 are first linear sesquiterpenyl constituents reported from the title species. All the isolates were evaluated for their inhibitory effect on the NO production induced by LPS in murine RAW264.7 macrophage cells, and 1, 7, 10 and 11 exhibited moderate activity with IC50 values in the range of 24.4–43.5 µM.

Abstract 1825: Synthesis and biological evaluation of novel 5-FU analogs against pancreatic cancer

Abstract Purpose: 5-Fluorouracil (5-FU) is one of the standard chemotherapy drugs used to treat pancreatic cancer. However, treatment only extends survival modestly, and disease recurrence is typical due to systemic instability, drug resistance, severe adverse effects, and limited benefits in patients with locally advanced tumors. These shortcomings have necessitated new strategies to develop safer and more effective anticancer agents. The study’s objective was to synthesize, characterize, and evaluate the cytotoxic effects of novel 5-FU analogs in pancreatic cancer cells. Methods: The analogs, XYZ-I-71 and XYZ-I-73, were synthesized by introducing a tetrahydrofuran ring on 5-fluorocytosine (a precursor of 5-FU) and conjugation with octanoyl chloride and lauroyl chloride, respectively. They were characterized by NMR, HPLC, micro-elemental analysis, and mass spectrometry. Cytotoxicity and cell migration studies were performed to determine the effectiveness of the analogs against MiaPaCa-2, PANC-1, and BxPC-3 pancreatic cancer cells. PARP apoptosis study was conducted in MiaPaca-2 cells using the analogs and 5-FU. The metabolic stability of analogs was determined by using human liver microsomes and quantified by HPLC. Results: Analysis of the 1H-NMR spectra displayed amide bonds at 7.80 ppm and 7.73 ppm, confirming the conjugation of octanoyl and lauroyl chloride to 5-fluorocutosine, respectively. The purity of both analogs was 99.6%. We found that the XYZ-I-73 (IC50 3.6 ± 0.4μM) analog was most effective against MiaPaCa-2 cells compared to XYZ-I-71(IC50 12.3±1.7μM), GemHCl (IC50 24.2 ± 1.3 μM), Irinotecan (IC50 10.1 ± 1.5 μM) and 5-FU (IC50 13.2 ± 1.1 μM). For PANC-1 cell growth inhibition, XYZ-I-73 (IC50 3.9 ± 0.5) was again observed as the most effective agent compared to XYZ-I-71(IC50 8.7±0.9 μM), GemHCl (IC50 10.07±0.9), 5-FU (IC50 20.43±1.2) and Irinotecan (IC50 11.6 ±1.1). A similar pattern of XYZ-I-73 (IC50 5.9±0.7) anticancer activity against BxPC-3 cells was found to be higher than XYZ-I-71(IC50 7.7 ± 0.8), GemHCl (IC50 10.95±0.9), 5-FU (IC50 14±1.1) and Irinotecan (IC50 9.5±1.0). For 24-hour MiaPaCa-2 cell migration studies, XYZ-I-73 (5µM) analog significantly reduced migration (# of migrated cells, 168±2.9) followed by XYZ-I-71(315±2.1), Gem-HCl (762±3.1) and 5-FU (710±3.2). PARP studies demonstrated significant inhibition of PARP expression of XYZ-I-73 treated cells compared to 5-FU and XYZ-I-71. Further, BAX and p53 expressions were significantly increased in cells treated with XYZ-I-73 compared to 5-FU and XYZ-I-71. Metabolic stability studies showed that 80 ± 5.9 % of XYZ-I-71 and XYZ-I-73 remained intact after 2-hour exposure in liver microsomal solution compared to 5-FU. Conclusion: XYZ-I-73 demonstrated a remarkable cytotoxic effect and improved in vitro metabolic stability over the selected standard drugs and may have potential anticancer activity against pancreatic cancer. Citation Format: Esther Frimpong, Raviteja Bulusu, Joy Okoro, Andriana Inkoom, Nkafu Ndemazie, Sherise Rogers, Xue Zhu, Bo Han, Edward Agyare. Synthesis and biological evaluation of novel 5-FU analogs against pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1825.

Anti-inflammatory Polyketides from an Endophytic Fungus Chaetomium sp. UJN-EF006 of Vaccinium bracteatum.

Seven new polyketides including three chromone derivatives (1-3) and four linear ones incorporating a tetrahydrofuran ring (4-7), along with three known compounds (8-10), were obtained from the fermentation of an endophytic fungus (Chaetomium sp. UJN-EF006) isolated from the leaves of Vaccinium bracteatum. The structures of these fungal metabolites have been elucidated by spectroscopic means including MS, NMR and electronic circular dichroism. A preliminary anti-inflammatory screening with the lipopolysaccharide (LPS) induced RAW264.7 cell model revealed moderate NO production inhibitory activity for compounds 1 and 4. In addition, the expression of three LPS-induced inflammatory factors IL-6, iNOS and COX-2 was also blocked by 1 and 4.

Undescribed α-pyrone-containing mycotoxins and an eremophilane-type sesquiterpenoid isolated from Aspergillus aureoterreus and their cytotoxicity

Four previously undescribed and highly oxygenated α-pyrone-containing mycotoxins designated citreoviridins (E‒H), and an unreported eremophilane-type sesquiterpenoid namely aureoterrolide N, were isolated from the culture broth of Aspergillus aureoterreus. Those isolates were inferred from extensive spectroscopic methods and theoretical computation, where their absolute configurations were unambiguously determined by coupling constants following an empirical rule for the acyclic vicinal diol, theoretical ECD calculation, and NMR computation using the GIAO method and DP4+ analysis. Among them, citreoviridins E‒H are four stereoisomers of a citreoviridin derivative, featuring a methylated α-pyrone, an oxidized polyene linker, and a tetrahydrofuran ring. Cytotoxicity assay of all isolates demonstrated that aureoterrolide N exhibited weak inhibitory effect against human cancer cell line HL-60 with an inhibition rate of 55.2% at 40.0 μM.

Crystal structure and Hirshfeld surface analysis of dieth-yl (3aS,3a1R,4S,5S,6R,6aS,7R,9aS)-3a1,5,6,6a-tetra-hydro-1H,3H,4H,7H-3a,6:7,9a-di-epoxy-benzo[de]isochromene-4,5-di-carboxyl-ate.

In the title compound, C18H22O7, two hexane rings and an oxane ring are fused together. The two hexane rings tend toward a distorted boat conformation, while the tetra-hydro-furan and di-hydro-furan rings adopt envelope conformations. The oxane ring is puckered. The crystal structure features C-H⋯O hydrogen bonds, which link the mol-ecules into a three-dimensional network. According to a Hirshfeld surface study, H⋯H (60.3%) and O⋯H/H⋯O (35.3%) inter-actions are the most significant contributors to the crystal packing.

Asymmetric Synthesis of Arboduridine

AbstractThe first asymmetric total synthesis of the monoterpenoid indole alkaloid arboduridine has been accomplished. The tricyclic A/B/D ring system was constructed by an enantioselective Michael reaction followed by intramolecular nucleophilic addition. Intramolecular α‐amination of a ketone forged the piperidine ring, while a Horner–Wadsworth–Emmons (HWE) reaction was used to form the pyrrolidine ring. A reduction cyclization cascade led to formation of the tetrahydrofuran ring.

Asymmetric Synthesis of Arboduridine.

The first asymmetric total synthesis of the monoterpenoid indole alkaloid arboduridine has been accomplished. The tricyclic A/B/D ring system was constructed by an enantioselective Michael reaction followed by intramolecular nucleophilic addition. Intramolecular α-amination of a ketone forged the piperidine ring, while a Horner-Wadsworth-Emmons (HWE) reaction was used to form the pyrrolidine ring. A reduction cyclization cascade led to formation of the tetrahydrofuran ring.

Total Synthesis of Taxol Enabled by Intermolecular Radical Coupling and Pd-Catalyzed Cyclization.

Taxol (1) is a clinically used antineoplastic diterpenoid. The tetracyclic ring system comprises a 6/8/6-membered carbocycle (ABC-ring) and a fused oxetane ring (D-ring) embedded with a bridgehead double bond and decorated with multiple oxygen functionalities. Here, we report a convergent total synthesis of this exceedingly complex natural product. The C-ring fragment was designed to possess a bromocyclohexenone and an extra tetrahydrofuran ring to control the reactivity and selectivity, as well as to minimize functional group manipulations en route to 1. The α-alkoxyacyl telluride of the A-ring served as a radical precursor, and intermolecular radical coupling with the C-ring realized the installation of the C2- and C3-stereocenters and reductive removal of the bromide. After the C8-quaternary stereocenter was constructed by exploiting the three-dimensional shape of the intermediate, the C11-vinyl triflate of A-ring and the C8-methyl ketone of C-ring were utilized for Pd(0)-catalyzed cyclization of the central eight-membered B-ring with the bridgehead olefin. Adjustment of the oxidation level and attachment of the oxetane D-ring completed the total synthesis of 1 (28 steps, as the longest linear sequence). The fragment design principle and implementation of the powerful radical coupling reaction described in the present synthesis provide valuable information for planning and executing syntheses of diverse densely oxygenated terpenoids.

Bioinspired synthesis of cochlearol B and ganocin A

Described here is a divergent, biosynthetically inspired synthesis of cochlearol B and ganocin A. Key steps of the synthesis include the chromene unit construction through a biomimetic acid-catalyzed [4 + 2] ring cyclization. A photochemical [2 + 2] cycloaddition was featured to construct the cyclobutane core of cochlearol B. Different skeletal rearrangements of cochlearol B afforded ganocin A, that one of them was Lewis acid mediated epoxide rearrangement and another was DDQ induced cyclobutane formed tetrahydrofuran ring. The described syntheses not only achieved these natural products in an efficient manner, but also provided insight into the biosynthetic relationship between the two different skeletons.

Two types of coumarins-specific enzymes complete the last missing steps in pyran- and furanocoumarins biosynthesis

Pyran- and furanocoumarins are key representatives of tetrahydropyrans and tetrahydrofurans, respectively, exhibiting diverse physiological and medical bioactivities. However, the biosynthetic mechanisms for their core structures remain poorly understood. Here we combined multiomics analyses of biosynthetic enzymes in Peucedanum praeruptorum and in vitro functional verification and identified two types of key enzymes critical for pyran and furan ring biosynthesis in plants. These included three distinct P. praeruptorum prenyltransferases (PpPT1–3) responsible for the prenylation of the simple coumarin skeleton 7 into linear or angular precursors, and two novel CYP450 cyclases (PpDC and PpOC) crucial for the cyclization of the linear/angular precursors into either tetrahydropyran or tetrahydrofuran scaffolds. Biochemical analyses of cyclases indicated that acid/base-assisted epoxide ring opening contributed to the enzyme-catalyzed tetrahydropyran and tetrahydrofuran ring refactoring. The possible acid/base-assisted catalytic mechanisms of the identified cyclases were theoretically investigated and assessed using site-specific mutagenesis. We identified two possible acidic amino acids Glu303 in PpDC and Asp301 in PpOC as vital in the catalytic process. This study provides new enzymatic tools in the epoxide formation/epoxide-opening mediated cascade reaction and exemplifies how plants become chemically diverse in terms of enzyme function and catalytic process.

Anthriscus sylvestris Deoxypodophyllotoxin Synthase Involved inthe Podophyllotoxin Biosynthesis.

Tetrahydrofuran ring formation from dibenzylbutyrolactone lignans is a key step in the biosynthesis of aryltetralin lignans including deoxypodophyllotoxin and podophyllotoxin. Previously, Fe(II)- and 2-oxoglutarate-dependent dioxygenase (2-ODD) from Podophyllum hexandrum (Himalayan mayapple, Berberidaceae) was found to catalyze the cyclization of a dibenzylbutyrolactone lignan, yatein, to give deoxypodophyllotoxin and designated as deoxypodophyllotoxin synthase (DPS). Recently, we reported that the biosynthesis of deoxypodophyllotoxin and podophyllotoxin evolved in a lineage-specific manner in phylogenetically unrelated plant species such as P. hexandrum and Anthriscus sylvestris (cow parsley, Apiaceae). Therefore, a comprehensive understanding of the characteristics of DPSs that catalyze the cyclization of yatein to deoxypodophyllotoxin in various plant species is important. However, for plant species other than P. hexandrum, the isolation of the DPS enzyme gene and the type of the enzyme, e.g.whether it is 2-ODD or another type of enzyme such as cytochrome P-450, have not been reported. In this study, we report the identification and characterization of A. sylvestris DPS (AsDPS). Phylogenetic analysis showed that AsDPS belonged to the 2-ODD superfamily and shared moderate amino acid sequence identity (40.8%) with P. hexandrum deoxypodophyllotoxin synthase (PhDPS). Recombinant protein assay indicated that AsDPS and PhDPS differ in terms of the selectivity of substrate enantiomers. Protein modeling using AlphaFold2 and site-directed mutagenesis indicated that the Tyr305 residue of AsDPS probably contributes to substrate recognition. This study advances our understanding of the podophyllotoxin biosynthetic pathway in A. sylvestris and provides new insight into 2-ODD involved in plant secondary (specialized) metabolism.

Mechanism of tetrahydrofuran separation from water by stearic acid

Stearic acid separates tetrahydrofuran (THF) and water into either bulk phase or emulsions, above 30 % THF (relative to water, v/v). The oxygen on the THF ring interacts with either water or stearic acid through hydrogen (H) bonding, as probed using attenuated total reflectance – Fourier transform infrared spectroscopy. Upon mixing with water, the COC band of THF splits into four peaks (at 1020 cm−1, 1040 cm−1, 1050 cm−1 and 1070 cm−1). These correspond to different THF species, i.e., THF molecules which coordinate in different ways with water. In THF-water mixtures containing >30 % THF (v/v), the dominant THF species yields a peak at 1050 cm−1·THF also interacts with stearic acid through H bonds, splitting the ν(COC) vibration into three peaks, at 1030 cm−1, 1050 cm−1 and 1065 cm−1. Similar to THF-water mixtures, the peak at 1050 cm−1 is dominant in THF-stearic acid mixtures. Therefore, we propose that stearic acid induces separation by competing against water for interactions with the same THF species. Synchrotron X Ray diffraction in the small angle X ray scattering region shows that stearic acid self assembles into reverse micelles. Water likely partitions inside them, yielding either kinetically stable emulsions or rapidly separating into bulk layers. Upon separation, stearic acid resides in the THF-rich phase. This is because its hydrophobic tail prevents it from mixing with water, thereby rendering THF-stearic acid interactions more favorable. Acetic acid resembles the head of stearic acid and H bonds THF, without yielding separation. This demonstrates the importance of the stearic acid tail.

Towards a dearomative oxidation strategy for dihydro-β-agarofuran natural products

Herein, we describe an attempted dearomative oxidation strategy toward the core carbocyclic structure of the dihydro-β-agarofuran natural products. Beginning with a commercially available tetralone, this oxidation strategy transformed an sp2-framework to an sp3-system containing the characteristic tetrahydrofuran ring within the dihydro-β-agarofuran skeleton. Further elaboration of this intermediate, with an emphasis on the C-14 methyl group stereochemistry and the unsuccessful installation of the C-15 methyl group is detailed.

Total Synthesis of (+)-Muricatetrocin B via a Late-Stage Co-Catalyzed Hartung-Mukaiyama Cyclization.

Convergent total synthesis of (+)-muricatetrocin B, a tetrahydrofuran-containing acetogenin with potent and selective cytotoxicity against the HT-29 human colon adenocarcinoma cell line, was achieved in 13 steps. Our synthesis is highlighted by a late-stage sequential olefin cross-metathesis/Hartung-Mukaiyama cyclization for convergent assembly of the 2,5-trans-substituted tetrahydrofuran ring.

Bisabolane-Type Sesquiterpenoids with a Tetrahydrofuran or Tetrahydropyran Ring from Vernonia solanifolia.

Phytochemical investigation of the aerial parts of Vernonia solanifolia resulted in the isolation of 23 new highly oxidized bisabolane-type sesquiterpenoids (1-23). Structures were determined by interpretation of spectroscopic data, single-crystal X-ray diffraction analysis, and time-dependent density functional theory electronic circular dichroism calculations. Most compounds possess a rare tetrahydrofuran (1-17) or tetrahydropyran ring (18-21). Compounds 1/2 and 11/12 are pairs of epimers isomerized at C-10, while compounds 9/10 and 15/16 are isomerized at C-11 and C-2, respectively. The anti-inflammatory effect in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages was evaluated for pure compounds. Compound 9 inhibited LPS-stimulated NO production at the concentration of 80 μM. It showed an anti-inflammatory effect by suppressing the activation of the NF-κB signaling pathway.