Tetrahydrofuran Moiety Research Articles

Combining the Elicitor Up-Regulated Production of Unusual Linear Diterpene-Derived Variants for an In-Depth Assessment of the Application Value and Risk of the Medicinal and Edible Basidiomycete Schizophyllum commune.

To better assess the practical value and avoid potential risks of the traditionally medicinal and edible basidiomycete Schizophyllum commune, which may arise from undescribed metabolites, a combination of elicitors was introduced for the first time to discover products from cryptic and low-expressed gene clusters under laboratory cultivation. Treating S. commune NJFU21 with the combination of five elicitors led to the upregulated production of a class of unusual linear diterpene-derived variants, including eleven new ones (1-11), along with three known ones (12-14). The structures and stereochemistry were determined by 1D and 2D NMR, HRESIMS, ECD, OR and VCD calculations. Notably, the elongation terminus of all the diterpenes was decorated by an unusual butenedioic acid moiety. Compound 1 was a rare monocyclic diterpene, while 2-6 possessed a tetrahydrofuran moiety. The truncated metabolites 4, 5 and 13 belong to the trinorditerpenes. All the diterpenes displayed approximately 70% scavenging of hydroxyl radicals at 50 μM and null cytotoxic activity at 10 μM. In addition, compound 1 exhibited potent antifungal activity against the plant pathogenic fungi Colletotrichum camelliae, with MIC values of 8 μg/mL. Our findings indicated that this class of diterpenes could provide valuable protectants for cosmetic ingredients and the lead compounds for agricultural fungicide development.

Albifimbrins A and B, a pair of epimeric tetrahydrofuran-containing linear polyketide derivatives from the marine-derived fungus Albifimbria verrucaria CD1-4

A pair of new epimeric polyketides, named albifimbrins A and B (1 and 2), were isolated from the cultures of the shellfish-derived fungus Albifimbria verrucaria CD1–4. Their structures were determined by extensive spectroscopic analysis including HR-MS, 1D and 2D NMR data, together with the CD exciton chirality method. Compounds 1 and 2 possess unusual tetrahydrofuran moiety in their linear molecule structures. The antimicroalgal assay indicated that compounds 1 and 2 shown moderate inhibitory activities against marine harmful microalgae, Prorocentrum donghaiense, Amphidinium carterae and Heterocapsa circulariaquama.

Acremosides A-G, Sugar Alcohol-Conjugated Acyclic Sesquiterpenes from a Sponge-Derived Acremonium Species.

Seven new sugar alcohol-conjugated acyclic sesquiterpenes, acremosides A-G (1-7), were isolated from the cultures of the sponge-associated fungus Acremonium sp. IMB18-086 cultivated with heat-killed Pseudomonas aeruginosa. The structures were determined by comprehensive analyses of 1D and 2D NMR spectroscopic data. The relative configurations were established by J-based configuration analysis and acetonide derivatization. The absolute configurations were elucidated by the Mosher ester method and ECD calculations. The structures of acremosides E-G (5-7) featured the linear sesquiterpene skeleton with a tetrahydrofuran moiety attached to a sugar alcohol. Acremosides A (1) and C-E (3-5) showed significant inhibitory activities against hepatitis C virus (EC50 values of 4.8-8.8 μM) with no cytotoxicity (CC50 of >200 μM).

Two Undescribed Protostane Triterpenoids from the Rhizome of Alisma plantago-aquatica.

Two undescribed protostane triterpenoids, 11-deoxy-13(17),15-dehydro-alisol B 23-acetate (2) and alisol S (3), together with 21 known ones (1, 4-23), were isolated from the dried rhizome of Alisma plantago-aquatica. Of these compounds, 13(17),15-Dehydro-alisol B 23-acetate (1) and 11-deoxy-13(17),15-dehydro-alisol B 23-acetate (2) are two protostane triterpenoids containing conjugated double bonds in the five-membered ring D that are rarely found from nature resource, while alisol S (3) is a protostane triterpenoid with undescribed tetrahydrofuran moiety linked via C20 -O-C24 at the side chain. Additionally, compound 18 is a new natural product, and cycloartenol triterpenoid 23 is a non protostane triterpenoid firstly isolated from genus Alisma. Their structures were elucidated by extensive spectral analysis of the UV, IR, MS, 1D and 2D NMR, and comparison of the experimental and calculated CD curves.

Structure‐Unit‐Based Total Synthesis of (−)‐Sinulochmodin C

AbstractHerein we report a structure‐unit‐based asymmetric total synthesis of sinulochmodin C, a norcembranoid diterpenoid bearing a transannular strained ether bridge β‐keto tetrahydrofuran moiety. Our synthetic route features an intramolecular double Michael addition to construct stereospecifically the [7,6,5,5] tetracyclic skeleton, a vinylogous hydroxylation/oxidation procedure or a stereospecific epoxide opening/oxidation sequence to establish the γ‐keto enone intermediate, a Lewis acid/Brønsted acid mediated transannular oxa‐Michael addition to fuse the β‐keto tetrahydrofuran moiety, a Mukaiyama hydration/Pd−C hydrogenation to reverse the C1‐configuration of the isopropenyl unit, and a bioinspired transformation of sinulochmodin C into scabrolide A.

Structure-Unit-Based Total Synthesis of (-)-Sinulochmodin C.

Herein we report a structure-unit-based asymmetric total synthesis of sinulochmodin C, a norcembranoid diterpenoid bearing a transannular strained ether bridge β-keto tetrahydrofuran moiety. Our synthetic route features an intramolecular double Michael addition to construct stereospecifically the [7,6,5,5] tetracyclic skeleton, a vinylogous hydroxylation/oxidation procedure or a stereospecific epoxide opening/oxidation sequence to establish the γ-keto enone intermediate, a Lewis acid/Brønsted acid mediated transannular oxa-Michael addition to fuse the β-keto tetrahydrofuran moiety, a Mukaiyama hydration/Pd-C hydrogenation to reverse the C1-configuration of the isopropenyl unit, and a bioinspired transformation of sinulochmodin C into scabrolide A.

Interaction of mitoxantrone with abasic sites - DNA strand cleavage and inhibition of apurinic/apyrimidinic endonuclease 1, APE1

Mitoxantrone (1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]-anthracene-9,10-dione) is a clinically-relevant synthetic anthracenedione that functions as a topoisomerase II poison by trapping DNA double-strand break intermediates. Mitoxantrone binds to DNA via both stacking interactions with DNA bases and hydrogen bonding with the sugar-phosphate backbone. It has been shown that mitoxantrone inhibits apurinic/apyrimidinic (AP) endonuclease 1 (APE1)-catalyzed incision of DNA containing a tetrahydrofuran (THF) moiety and more recently, that mitoxantrone forms Schiff base conjugates at AP sites in DNA. In this study, mitoxantrone-mediated inhibition of APE1 at THF sites was shown to be consistent with preferential binding to, and thermal stabilization of DNA containing a THF site as compared to non-damaged DNA. Investigations into the properties of mitoxantrone at AP and 3′ α,β-unsaturated aldehyde sites demonstrated that in addition to being a potent inhibitor of APE1 at these biologically-relevant substrates (∼ 0.5 μM IC50 on AP site-containing DNA), mitoxantrone also incised AP site-containing DNA by catalyzing β- and β/δ-elimination reactions. The efficiency of these reactions to generate the 3′ α,β-unsaturated aldehyde and 3′ phosphate products was modulated by DNA structure. Although these cell-free reactions revealed that mitoxantrone can generate 3′ phosphates, cells lacking polynucleotide kinase phosphatase did not show increased sensitivity to mitoxantrone treatment. Consistent with its ability to inhibit APE1 activity on DNAs containing either an AP site or a 3′ α,β-unsaturated aldehyde, combined exposures to clinically-relevant concentrations of mitoxantrone and a small molecule APE1 inhibitor revealed additive cytotoxicity. These data suggest that in a cellular context, mitoxantrone may interfere with APE1 DNA repair functions.

New secondary metabolites with cytotoxicity from fungus Penicillium roqueforti

Two novel compounds including a cyclohelminthol type polyketide (namely oxaleimide K, 1) and a maleimide derivative (namely peniroquefortine A, 2), and a new natural product (namely 2-(acetylamino)-N-[(1E)-2-phenylethenyl]-acetamide, 3), together with four known compounds (4–7), were isolated and identified from fungus Penicillium roqueforti, which was separated from the root soil of Hypericum beanii N. Robson collected from the Shennongjia Forestry District, Hubei Province. Their structures including absolute configurations were mainly established by the NMR spectroscopy analyses and single-crystal X-ray diffraction experiment. Compound 1 represents the second example of a cyclohelminthol type polyketide, which features a rare 6/6/5/5 tetracyclic system and a branched aliphatic chain containing a terminal olefin (oct-1-en-3-yl) moiety, and compound 2 possesses an unprecedented carbon skeleton that is uniquely defined by a maleimide moiety linked to the respective 4-methylene-2-(3-methylbut-2-en-1-yl)-phenol and para-substituted aromatic moieties via the carbon-carbon bonds. Remarkably, the absolute configuration of a cyclohelminthol type polyketide as exemplified by compound 1 is determined by the single-crystal diffraction analysis for the first time, highlighting an E-configuration for the linkage of a succinimide moiety and a tetrahydrofuran moiety for 1 rather than a Z-configuration as previously reported in the biosynthesis study, which gives a new insight into the structural elucidation of this category of polyketides. Additionally, compound 1 exhibited significant cytotoxic activity against multiple tumor cells, especially against the Farage and SU-DHL-2 cells (IC50 < 20 µM, 48 h). Further mechanism study revealed that compound 1 significantly induced cell cycle arrest in Farage and SU-DHL-2 cells by causing abnormal ROS level and triggering oxidative stress.Graphical

Thiophene Carboxamide Analogs with Long Alkyl Chains Comprising Ethylene Glycol Units Inhibit Glioblastoma Cell Proliferation by Activating AMPK.

Glioblastoma is a refractory malignant tumor that requires novel therapeutic strategies for effective treatment. We have previously reported that JCI-20679 (1), an analog of annonaceous acetogenins, shows potent antitumor activity against glioblastomas. However, the synthesis of 1 requires 23 steps, including 16 steps for the preparation of a tetrahydrofuran (THF) moiety. This study reports the design and synthesis of 11 analogs with a triethylene glycol moiety in place of the THF moiety in 1. Among these, the analog 2k with an n-decyl chain exhibited potent inhibitory activity against the growth of glioblastoma stem cells by inhibiting mitochondrial function and synergistically enhancing the effect of temozolomide (TMZ). Furthermore, 2k significantly suppressed tumor growth without critical toxicity in vivo. Hence, this study presents novel potential anticancer agents and a strategy for the development of these agents that can be produced easily.

Hydroaminomethylation of Natural Allylic and Homoallylic Alcohols: A Ligand‐Controlled Route to New Amines

AbstractHydroaminomethylation (HAM) is a tandem catalytic process that allows accessing amines from olefin scaffolds and is perfectly aligned with green chemistry precepts. In this work, HAM was applied to the natural hydroxyolefins: isoprenol, linalool, nerolidol, and isopulegol. Employing 4‐methylpiperidine, morpholine, and 1,2,3,4‐tetrahydroisoquinoline as counterparts, several new, structurally complex amines were prepared from biorenewable, low‐cost substrates, opening a path to exploit this structure diversity in biological activity. By the appropriate choice of rhodium‐based catalytic systems, as well as the reaction conditions, the necessary fine tuning for each counterpart was achieved. The unpromoted rhodium system leaded mostly to aminoalcohols, while certain phosphorus(III)‐promoted rhodium systems afforded amines containing a tetrahydropyran or a tetrahydrofuran moiety in moderate to high yields.

Diterpenoids with anti-inflammatory activity from Euphorbia wallichii

The Euphorbia plants are the focus of natural product drug discovery because of their fascinating structural diversity and broad biological activities. Here we reported the discovery of eight undescribed diterpenoids, including two ent-trachylobanes, five ent-atisanes, and one ent-abietane, together with 15 known ones from the whole plant of Euphorbia wallichii. Their chemical structures were elucidated by detailed spectrometry data analysis and X-ray crystallography. Among them, wallichane G represents a rare ent-atisane type pentacyclic diterpenoid featuring a tetrahydrofuran moiety. Furthermore, bioassays indicated that jolkinolide B exhibited potent inhibitory activities on the production of NO, with an IC50 value of 3.84 ± 0.25 μM. Meanwhile, the mechanistic study revealed that jolkinolide B could obviously downregulate the expression of iNOS, COX-2, NF-κB, and phosphorylated IκBα in a dose-dependent manner and strongly upregulate the expression of Nrf2 and HO-1 protein, thereby suppressing the inflammatory process in macrophage cells induced by LPS.

Diterpenoids from the whole plant of Euphorbia wallichii and their protective effects on H2O2-induced BV-2 microglial cells injury

Thirteen undescribed diterpenoids, including an ent-isopimarane (1), ten ent-atisanes (2–8 and 15–17), and two ingenanes (20 and 21) and ten known compounds, were separated from the whole plant of E. wallichii. The structures and absolute stereochemistry of these compounds were delineated by 1D and 2D NMR, mass spectrometry, pyridine-induced solvent shifts, and X-ray diffraction analyses. Euphwanoid A (1) is elucidated as an ent-16‑norisopimarane type diterpenoid featuring a C-8-O-C-15 lactone fragment. And euphwanoid B (2) represents a rare ent-atisane type tetranorditerpene possessing a tetrahydrofuran moiety. In addition, all these isolated compounds were assayed for their protective effects on H2O2-induced BV-2 microglial cells damage. And representative compound 1 could protect BV-2 cells against oxidative damage via the NRF2/HO-1 signaling pathway.

Teuchamaedol A, a new neo-clerodane diterpenoid from the aerial parts of Teucrium chamaedrys

A new neo-clerodane diterpenoid, teuchamaedol A (1) was isolated from the EtOAc-soluble materials of the aerial parts of Teucrium chamaedrys. The structure of 1 was elucidated on the basis of spectral data. The absolute configuration of 1 was determined by modified Mosher’s method. Teuchamaedol A (1) is the first neo-clerodane diterpenoid possessing a tetrahydrofuran moiety without additional oxygen function.

Neopestolides A-D, Diphenyl Ether Derivatives from the Plant Endophytic Fungus Neopestalotiopsis sp.

Four new diphenyl ether derivatives, neopestolides A-D (2-5), were isolated from cultures of the plant endophytic fungus Neopestalotiopsis sp., along with the known metabolite pestalotiollide A (1); their structures were elucidated primarily by NMR experiments. The absolute configurations of 2 and 3-5 were deduced by electronic circular dichroism calculations and via Snatzke's method, respectively. Compounds 2-4 incorporate tetrahydrofuran moieties attached to the dibenzo[b,g][1,5]dioxocin-5(7H)-one skeleton via C-C linkages. Compounds 1 and 2 showed modest cytotoxicity against HepG2 cells.

Structure-antitumor activity relationship of hybrid acetogenins focusing on connecting groups between heterocycles and the linker moiety.

We studied hybrid molecules of annonaceous acetogenins and mitochondrial complex I-inhibiting insecticides to develop a novel anticancer agent. A structure–antitumor activity relationship study focusing on the connecting groups between the heterocycles and the linker moiety bearing the tetrahydrofuran moiety was conducted. Eleven hybrid acetogenins with 1-methylpyrazole instead of γ-lactone were synthesized and their growth inhibitory activities against 39 human cancer cell lines were evaluated. The nitrogen atom at the 2′-position of the linker moiety was essential for inhibiting cancer growth. The 1-methylpyrazole-5-sulfonamide analog showed potent growth inhibition of NCI-H23, a human lung cancer cell line, in a xenograft mouse assay without critical toxicity. Hence, the results of this study may pave the way for the development of novel anticancer agents, with both selective and broad anticancer activities.

Clays catalyzed cascade Prins and Prins-Friedel-Crafts reactions for synthesis of terpenoid-derived polycyclic compounds

The Prins/Friedel-Crafts cascade reactions of the terpenoid trans-4-hydroxymethyl-2-carene (synthesized from 3-carene) with aromatic aldehydes were systematically studied for the first time on acidic mesoporous clays (halloysite, illite, montmorillonites). Both the reaction rate and selectivity to the desired polycyclic product with tetrahydrofuran moiety increased with an increase in the catalyst acidity and their drying temperature, indicating that relatively strong Brønsted and Lewis acid sites favored their formation. The best activity and selectivity (up to 97%) was demonstrated over commercial montmorillonite K-10 with acidity of ca. 100 μmol/g. In contrast, on strongest acids (resin Amberlyst-15), dehydration/aromatization of the substrate was observed. It was shown, that mesoporosity of the catalyst is one of the key factors governing catalytic behavior. The presence of at least one an electron-donor substituent at the meta-position of benzaldehyde is critical for the Prins-Friedel-Crafts reaction. Overall, available montmorillonites are an effective replacement for homogeneous catalysts for the Prins/Friedel-Crafts cascade reactions.

Nucleophilic substitution at the anomeric position of furanose carbohydrates. The case of the C-allylations

Taking advantage of the locked conformation of cyclic furanose form, carbohydrate derivatives have been transformed into relevant tetrahydrofuran moieties through a chemical operation commonly known as C-glycosylation reaction. Consequently, a large number of total synthesis of naturally occurring products containing this heterocycle have been accomplished by applying this reaction. In this regard, the C-allylation reaction of furanose carbohydrates provides flexible routes for stereoselective anomeric functionalization by incorporating an allyl group, which is eventually re-functionalized into advanced natural product intermediates. Therefore, this mini review deals with the description of the origin of the stereoselectivity and synthetic applications of this type of glycosylation reaction, which can be also called as: “Nucleophilic Substitution at the Anomeric Position”, conducted by various research groups including our own group.

Cobalt-Catalyzed Hartung-Mukaiyama Cyclization of γ-Hydroxy Olefins: Stereocontrolled Synthesis of the Tetrahydrofuran Moiety of Amphidinolide N.

Cobalt-catalyzed Mukaiyama-type cyclization of γ-hydroxy olefins is known as an atom- and step-economical means for stereoselective synthesis of 2,5-trans-substituted tetrahydrofuran derivatives. In this study, we investigated the synthesis of a series of 2,5-substituted tetrahydrofuran derivatives by means of a cobalt-catalyzed Hartung-Mukaiyama cyclization. The stereochemical consequence of the reaction was found to be largely dependent on the substitution pattern and relative configuration of γ-hydroxy olefins. 2,5-cis-Substituted tetrahydrofuran derivatives could be obtained diastereoselectively from appropriately substituted γ-hydroxy olefins. Additionally, relatively bulky olefin substituents and unprotected hydroxy groups at non-interfering positions (e.g., α and δ) were well tolerated in the reaction. Finally, the synthetic versatility of the Hartung-Mukaiyama cyclization was demonstrated through a stereocontrolled synthesis of the tetrahydrofuran moiety of amphidinolide N, a potent cytotoxic macrolide of marine origin. This study expands the capacity of Mukaiyama-type cyclization in that it can be used in convergent assembly of complex tetrahydrofuran motifs from internal olefins.

Discovery of andrastones from the deep-sea-derived Penicillium allii-sativi MCCC 3A00580 by OSMAC strategy

Andrastones are unusual 6,6,6,5-tetracyclic meroterpenoids that are rarely found in nature. Previously, three andrastones were obtained from the rice static fermentation extract of the deep-sea-derived fungus Penicillium allii-sativi MCCC 3A00580. Inspired by one strain many compounds (OSMAC) approach, the oat static fermentation on P. allii-sativi was conducted. As a result, 14 andrastones were isolated by UV-guided isolation. The chemical structures of the nine new compounds (1–9) was established by comprehensive analysis of the NMR, MS, ECD, and X-ray crystallography and the five known ones (10–14) were assigned by comparing their NMR, MS, and OR data with those reported in literature. Compound 1 bears a novel hemiketal moiety while 2 is the first example to possess a novel tetrahydrofuran moiety via C-7 and C-15. All isolates were tested for anti-allergic bioactivity. Compound 10, 3-deacetylcitreohybridonol, significantly decreased degranulation with the IC50 value of 14.8 μM, compared to that of 92.5 μM for the positive control, loratadine. Mechanism study indicated 10 could decrease the generation of histamine and TNF-α by reducing the accumulation of Ca2+ in RBL-2H3 cells. These findings indicate andrastones could be potential to discover new anti-allergic candidate drugs.

Spirocyclizations Involving Oxonium Ylides Derived from Cyclic α-Diazocarbonyl Compounds: An Entry into 6-Oxa-2-azaspiro[4.5]decane Scaffold.

New types of cyclic diazo compounds capable of Rh(II)-catalyzed spirocyclizations with tetrahydrofuran have been discovered. The formation of the spirocyclic framework is thought to proceed via the formation of Rh(II) carbene species followed by interaction with the Lewis basic oxygen atom of tetrahydrofuran to give oxonium ylide species. The latter evolves predominantly via the Stevens type rearrangement leading to an [n + 1] ring expansion of the tetrahydrofuran moiety, which results in the formation of a medicinally relevant 6-oxa-2-azaspiro[4.5]decane scaffold. The spirocyclization process was often observed in competition with mechanistically distinct C-H insertion into a tetrahydrofuran molecule. This competing process gave compounds based on the 3-(tetrahydrofur-2-yl)pyrrolidine scaffold, which are also relevant from the medicinal chemistry standpoint. These findings enrich the available arsenal of metal-catalyzed spirocyclization methods based on the use of cyclic diazo compounds.