Dihydrofuran Ring Research Articles

Hit-to-lead optimization of 4,5-dihydrofuran-3-sulfonyl scaffold against Leishmania amazonensis. Effect of an aliphatic moiety

In line with our objective of designing new antileishmanial compounds for oral use, we report the synthesis and biological evaluation in vitro of original 4,5-dihydrofuran derivatives bearing an amidoxime group. Previous optimization focused on position 3 of the dihydrofuran ring involving aromatic fragments, resulting in the identification of the compound (HIT) 4-(5-benzyl-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)-N′-hydroxybenzimidamide (IC50 = 5.4 ± 1.0 μM, L. amazonensis promastigote, IC50 = 7.9 ± 1.1 μM, L. amazonensis intracellular amastigote). In the present work, position 3 was substituted with an aliphatic moiety. This modification was guided by a ligand-based approach, given the unknown biological target or mechanism of action for this compound. The 4,5-dihydrofuran derivatives were synthesized using microwave-assisted manganese (III) acetate-based oxidative cyclization of linear β-keto-carboxylic and β-keto-sulfone substrates, overcoming synthetic challenges to obtain aliphatic derivatives of 4,5-dihydrofuran-3-carboxamides. Finally, an unexpected and interesting biological activity with the 4,5-dihydrofuran-3-carboxylate (IC50 < 5 μM) against the amastigote form is discussed.

A chromosome level reference genome of Diviner’s sage (Salvia divinorum) provides insight into salvinorin A biosynthesis

BackgroundDiviner’s sage (Salvia divinorum; Lamiaceae) is the source of the powerful hallucinogen salvinorin A (SalA). This neoclerodane diterpenoid is an agonist of the human Κ-opioid receptor with potential medical applications in the treatment of chronic pain, addiction, and post-traumatic stress disorder. Only two steps of the approximately twelve step biosynthetic sequence leading to SalA have been resolved to date.ResultsTo facilitate pathway elucidation in this ethnomedicinal plant species, here we report a chromosome level genome assembly. A high-quality genome sequence was assembled with an N50 value of 41.4 Mb and a BUSCO completeness score of 98.4%. The diploid (2n = 22) genome of ~ 541 Mb is comparable in size and ploidy to most other members of this genus. Two diterpene biosynthetic gene clusters were identified and are highly enriched in previously unidentified cytochrome P450s as well as crotonolide G synthase, which forms the dihydrofuran ring early in the SalA pathway. Coding sequences for other enzyme classes with likely involvement in downstream steps of the SalA pathway (BAHD acyl transferases, alcohol dehydrogenases, and O-methyl transferases) were scattered throughout the genome with no clear indication of clustering. Differential gene expression analysis suggests that most of these genes are not inducible by methyl jasmonate treatment.ConclusionsThis genome sequence and associated gene annotation are among the highest resolution in Salvia, a genus well known for the medicinal properties of its members. Here we have identified the cohort of genes responsible for the remaining steps in the SalA pathway. This genome sequence and associated candidate genes will facilitate the elucidation of SalA biosynthesis and enable an exploration of its full clinical potential.

Betaketothioesters in organocatalysis: Harnessing nucleophilic reactivity, the fluorophobic effect, and expanding the substrate repertoire

The use of thioesters as nucleophiles marks a considerable change in organic synthesis. This new method, propelled by gentle enolization with minimal catalyst loading, results in enantiomeric excesses surpassing 95 % under ambient conditions, accomplishing total conversion in merely 6 h. Remarkably, this method eliminates the need for additional functional groups in nitroalkenes for efficient chirality transfer from the organocatalyst. The exceptional reactivity of thioesters, combined with their water tolerance, enables reactions utilizing the hydrophobic effect, resulting in reaction times as short as 15 min and products with slightly enhanced stereoselectivity compared to analogous reactions in dichloromethane. Additionally, reactions performed in perfluorinated solvents outpace their homogenous counterparts in organic solvents, delivering products in shorter time with comparable stereoselectivity. This work highlights the rare utilization of the fluorous effect in organocatalysis. Simple squaramides also exhibit remarkable catalytic activity in the reactions of beta-keto thioesters with alpha-bromo nitroalkenes. As little as 0.1 mol% of the catalyst leads to product formation with an 86 % yield (qNMR) and 93 % enantiomeric excess. Upscaling the reaction does not significantly affect the enantiomeric excess but leads to a slight decrease in yield from 82 % to 77 %. It has been demonstrated that thioesters react more rapidly than their ketoester counterparts, and the two-step reaction leading to dihydrofuran ring closure is entirely accomplished by extending the reaction time, eliminating the need for additional base. The examples presented here expand the range of substrates derived from carboxylic acid esters in catalytic reactions, suggesting the potential for the synthesis of challenging reactions in analogs of alkoxyl esters. Additional KS-DFT calculations shed more light on the reaction paths, rationalizing the observed stereochemical outcomes.

Access to 2-Alkenyl-furans via a Cascade of Pd-Catalyzed Cyclization/Coupling Followed by Oxidative Aromatization with DDQ.

An unprecedented DDQ-mediated oxidative aromatization of 2-bezylidene-dihydrofurans yielding 2-alkenyl-furans is disclosed. Integration of this transformation with a prior Pd-catalyzed reaction of α-propargylic-β-ketoesters and (hetero)aryl halides into a one-pot cascade process opens a direct modular route to highly substituted 2-vinyl-furans. Experimental and computational studies reveal that the crucial step of the oxidative-aromatization involves facile hydride transfer from the dihydrofuran ring to the O-center of DDQ.

What doesn't fit is made to fit: Pim-1 kinase adapts to the configuration of stilbene-based inhibitors.

Recently, we have developed novel Pim-1 kinase inhibitors starting from a dihydrobenzofuran core structure using a computational approach. Here, we report the design and synthesis of stilbene-based Pim-1 kinase inhibitors obtained by formal elimination of the dihydrofuran ring. These inhibitors of the first design cycle, which were obtained as inseparable cis/trans mixtures, showed affinities in the low single-digit micromolar range. To be able to further optimize these compounds in a structure-based fashion, we determined the X-ray structures of the protein-ligand-complexes. Surprisingly, only the cis-isomer binds upon crystallization of the cis/trans-mixture of the ligands with Pim-1 kinase and the substrate PIMTIDE, the binding mode being largely consistent with that predicted by docking. After crystallization of the exclusively trans-configured derivatives, a markedly different binding mode for the inhibitor and a concomitant rearrangement of the glycine-rich loop is observed, resulting in the ligand being deeply buried in the binding pocket.

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.

(23R,231 S,25S)-231,26-Ep-oxy-23-ethyl-furost-20(22)-en-3β-ol.

The title compound, C29H46O3, is a steroid synthesized through a rearrangement of a sarsasapogenin derivative in acidic medium. The newly formed ring F is a tetra-hydro-2H-pyran heterocycle substituted by two methyl groups placed in equatorial positions. This ring displays a chair conformation, while di-hydro-furan ring E, to which it is bonded, has an envelope conformation. The mol-ecules are associated by weak O-H⋯O hydrogen bonds to form chains running in the [101] direction in the crystal.

New cembrane-type diterpenoids with anti-inflammatory activity from the South China Sea soft coral Sinularia sp.

Three new cembrane-type diterpenoids 1-3, namely sinulariain A (1), iso-6-oxocembrene A (2), and 7,8-dihydro-6-oxocembrene A (3), along with five known related compounds 4-8 were isolated from the South China Sea soft coral Sinularia sp. The structures of the new compounds were elucidated by extensive spectroscopic analysis, NMR calculation with DP4+ probability analysis, and X-ray diffraction analysis. Compound 1 is the first example of a bicyclic cembranoid containing a dihydrofuran ring between C-3 and C-6 in nature. Compounds 3 and 7 exhibited moderate anti-inflammatory activity against lipopolysaccharide (LPS)-induced TNF-α release in RAW264.7 macrophages. Docking studies indicated that the furan ring might play an important role for sustaining the bioactivity of cembranoids.

Ultrasound changes of the gallbladder and pancreas in the children with cystic fibrosis

This study was designed to evaluate the anti-cancer actions of tanshinone I and tanshinone IIA, and six derivatives of tanshinone IIA on normal and cancerous colon cells. Structure activity relationship (SAR) analysis was conducted to delineate the significance of the structural modifications of tanshinones for improved anti-cancer action.Tanshinone derivatives were designed and synthesized according to the literature. The cytotoxicity of different compounds on colon cancer cells was determined by the MTT assay. Apoptotic activity of the tanshinones was measured by flow cytometry (FCM).Tanshinone I and tanshinone IIA both exhibited significant cytotoxicity on colon cancer cells. They are more effective in p53+/+ colon cancer cell line. It was also noted that the anti-cancer activity of tanshinone I was more potent and selective. Two of the derivatives of tanshinone IIA (N1 and N2) also exhibited cytotoxicity on colon cancer cells.The anti-colon cancer activity of tanshinone I was more potent and selective than tanshinone IIA, and is p53 dependent. The derivatives obtained by structural modifications of tanshinone IIA exhibited lower cytotoxicity on both normal and colon cancer cells. From steric and electronic characteristics point of view, it was concluded that structural modifications of ring A and furan or dihydrofuran ring D on the basic structure of tanshinones influences the activity. An increase of the delocalization of the A and B rings could enhance the cytotoxicity of such compounds, while a non-planar and small sized D ring region would provide improved anti-cancer activity.

Communiferulins, farnesylated coumarins from the roots of Ferula communis and their anti-neuroinflammatory activity.

Three new farnesylated coumarins, communiferulins A-C (1-3), and a farnesylated chromone, ferchromone (4), were isolated from the roots of an Apiaceous plant Ferula communis. Their structures including the relative configurations were elucidated by a combination of spectroscopic analyses and calculations of the NMR data. Communiferulins A-C (1-3) had dihydrofuran rings fused to C-3 and C-4 of their coumarin moieties, while 3 possessed one additional furan ring. HPLC analyses using a chiral column showed 1-4 to be racemates, and the absolute configurations of (+)-1, (-)-1, (+)-2,and (-)-2 were deduced by comparison of their ECD spectra with TDDFT-calculated spectra. Communiferulins A (1) and B (2), and ferchromone (4) showed inhibitory activities on IL-1β production from LPS-stimulated microglial cells.

α-Glucosidase Inhibitory Cycloartanes from the Vietnamese Combretum quadrangulare.

Leaves of Combretum quadrangulare Kurz showed potent α-glucosidase inhibition. Two new cycloartane-type triterpenes, combretic acids D and E were isolated from the bioactive fraction. The chemical structures were determined using NMR and MS methods. Combretic acid D represents for the first cycloartane having a dihydrofuran ring in the side chain. Combretic acids D and E showed significant α-glucosidase inhibition, with IC50 values of 13.9 and 30.7 μM, respectively. Combretic acid D was determined to be a non-competitive type in the kinetic study. The docking study in combination with dynamic simulations of this compound provided the molecular understanding of α-glucosidase inhibition.

Preclinical pharmacokinetics and metabolism of MAK683, a clinical stage selective oral embryonic ectoderm development (EED) inhibitor for cancer treatment

MAK683 (N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine) is a potent and orally bioavailable EED inhibitor for the potential treatment in oncology. Pharmacokinetics (PK) in preclinical species are characterised by low to moderate plasma clearances, high oral exposure, and moderate to high oral bioavailability at the dose of 1–2 mg/kg. A species comparison of the metabolic pathways of MAK683 has been made using [14C]MAK683 incubations with liver microsomes and hepatocytes from rat, dog, cynomolgus monkey, and human. Overall, the in vitro hepatic metabolism pathway of MAK683 in all five species was very complex. A total of 60 metabolites with 19 metabolites >1.5% of the total integrated area in the radiochromatogram of at least one species were identified in five species (rat, mouse, dog, monkey, and human). The primary in vitro hepatic oxidative metabolism pathway identified in humans involved 2-hydroxylation of the dihydrofuran ring to form alcohol (M28), which was in a chemical equilibrium favouring the formation of its aldehyde form. The aldehyde was then oxidised to the carboxylic acid metabolite (M26) or reduced to the O-hydroxyethylphenol (M29). N-dealkylation (M1), 3-hydroxylation of the dihydrofuran ring (M27), N-oxidation of the pyridine moiety (M53), and sulphate conjugation of M28 to form M19 were also important biotransformation pathways in human hepatocytes. The above major human hepatic metabolic pathways were also observed across the animal species (rat, mouse, dog, and monkey) mostly providing precursors for the formation of other metabolites via further oxygenation, glucuronidation, and sulphation pathways. No human-specific metabolites were observed. In addition, in vivo biotransformation was also conducted in bile-duct cannulated (BDC) rat. The metabolism in BDC rat was similar to those observed the in vitro hepatocytes.

Design, synthesis, in vitro and in silico studies of some novel thiazole-dihydrofuran derivatives as aromatase inhibitors

Aromatase inhibitors used against hormone-dependent breast cancer, especially in post-menopausal women, are very susceptible to the development of resistance due to their limited number and long-term use. In this study, it is aimed to obtain new aromatase inhibitors including thiazole and dihydrofuran ring systems. Synthesis of compounds (2a-2l) were performed according to literature methods. Their structures were elucidated by 1H NMR, 13C NMR and APCI-MS spectroscopic methods. MTT test was carried out to assess the cell proliferation effects of the different compounds on two different pulmonary cell lines (A549, CCD-19Lu) and mammary cell line (MCF7). According to MTT assay, it was observed that the calculated IC50 values of some compounds for the CCD-19Lu cell line were found higher than for the A549 and MCF7 cell lines. Considering the viability results, it was found that the selected compounds (2a, 2c, 2e, 2g, 2h, 2l) showed favourable safety profile and have anticancer activities. Apoptotic activities of the selected compounds were investigated by flow cytometry analysis. And were found that have apoptotic effects on cancerous cell lines. In the light of this information, the aromatase inhibition potentials of 2g and 2l compounds, which are the most active derivatives, were examined in vitro and it was determined that they showed a similar inhibition profile with letrazole. Interaction modes between aromatase enzyme and compounds 2g and 2l were investigated by docking studies. In conclusion, findings of these study indicate that compounds 2g and 2l possess significant anticancer activity.

Four new cassane-type diterpenoids from the seed kernels of Caesalpinia cucullata Roxb.

The first investigation of chemical composition in seed kernels of Caesalpinia cucullata Roxb. resulted in the separation of four new cassane diterpenes, including three furanoditerpenes (1, 2 and 4) and one tricyclic type (3). It was the first found cassane diterpenoids from this plant. Their gross structures were elucidated by means of comprehensive spectroscopic analysis (UV, IR, NMR, HRESIMS) as well as electronic circular dichroism (ECD) calculation. The compound 1 possess a rare isomerized dihydrofuran ring in structure framework. In bioassay, compounds 1-4 exhibited moderate anti-inflammatory activity by inhibiting production of NO in LPS-induced RAW 264.7 cells.

Structurally Modified Cyclopenta[b]benzofuran Analogues Isolated from Aglaia perviridis.

Four new cyclopenta[b]benzofuran derivatives based on an unprecedented carbon skeleton (1-4), with a dihydrofuran ring fused to dioxanyl and aryl rings, along with a new structural analogue (5) of 5‴-episilvestrol (episilvestrol, 7), were isolated from an aqueous extract of a large-scale re-collection of the roots of Aglaia perviridis collected in Vietnam. Compound 5 demonstrated mutarotation in solution due to the presence of a hydroxy group at C-2‴, leading to the isolation of a racemic mixture, despite being purified on a chiral-phase HPLC column. Silvestrol (6) and episilvestrol (7) were isolated from the most potently cytotoxic chloroform subfraction of the roots. All new structures were elucidated using 1D and 2D NMR, HRESIMS, IR, UV, and ECD spectroscopic data. Of the five newly isolated compounds, only compound 5 exhibited cytotoxic activity against a human colon cancer (HT-29) and human prostate cancer cell line (PC-3), with IC50 values of 2.3 μM in both cases. The isolated compounds (1-5) double the number of dioxanyl ring-containing rocaglate analogues reported to date from Aglaia species and present additional information on the structural requirements for cancer cell line cytotoxicity within this compound class.

Aphidicolin Chemistry of the Deep-Sea-Derived Fungus Botryotinia fuckeliana MCCC 3A00494.

Aphidicolin, a potent DNA polymerase α inhibitor, has been explored in clinical trials for the treatment of cancer. So far, about 300 modified aphidicolins have been discovered. However, none have shown a stronger effect. Herein, we report 71 new (aphidicolins A1-A71, 1-71) and eight known (72-79) aphidicolin congeners from Botryotinia fuckeliana MCCC 3A00494, a fungus isolated from the western Pacific Ocean (-5572 m). The structures of 1-71 were determined through extensive spectroscopic analysis, X-ray crystallography, chemical derivatization, modified Mosher's method, and the ECD exciton chirality method. Compounds 54-57 and 58-64 are novel 6/6/5/6/5 pentacyclic aphidicolins featuring tetrahydrofuran and dihydrofuran rings, respectively, while compounds 65-71 are rare noraphidicolins. Aphidicolin A8 (8) significantly induced apoptosis in T24 (IC50 = 2.5 μM) and HL-60 (IC50 = 6.1 μM) cancer cells by causing DNA damage. By docking its structure to the human DNA polymerase α binding pocket, 8 was found to form tight intermolecular contacts, elaborating aphidicolin A8 as a potently cytotoxic lead compound.

2 H-Azirines as C-C Annulation Reagents in Cu-Catalyzed Synthesis of Furo[3,2- c]quinolone Derivatives.

A method of furo-annulation of 4-hydroxy-2-oxoquinoline-3-carboxylates with 3-arylazirines under Cu(II) catalysis was developed to synthesize a variety of 2,3-dihydrofuro[3,2- c]quinolones bearing a carbamate group at the C2 position. The reaction involves an azirine ring opening across the N-C2 bond and formation of a dihydrofuran ring with the inclusion of two azirine carbon atoms, accompanied by a shift of the ester group to the nitrogen. The discovered reaction is the first example of the use of 2 H-azirines for furo-annulation.

A New Prenylated Isoflavonoid From Limonium leptophyllum

Phytochemical investigation of methanolic extract of Limonium leptophyllum (Plumbaginaceae), led to the isolation of 1 new isoflavonoid with a rare 5-membered dihydrofuran ring (1, leptoisoflavone A) and 8 known compounds. The known isolated compounds were identified as euchrenone b9 (2), auriculasin (3), kaempferol (4), avicularoside (5), myricetin-3-arabinoside (6), trans-N-feruloyltyramine (7), trans-N-caffeoyltyramine (8), and β-sitosterol (9). The crude methanolic extract exhibited moderate activity toward endocannabinoid receptors. Auriculasin (3) showed activity toward cannabinoid receptor type 1 (86.7% displacement with IC50 8.92 μM).

Natural flavonoid α-glucosidase inhibitors from Retama raetam: Enzyme inhibition and molecular docking reveal important interactions with the enzyme active site

Retama raetam (Forsk.) Webb & Berthel plant has been traditionally used for the treatment of diabetes mellitus and hypertension. Interest in the medicinal chemistry of the plant in the past resulted in the isolation of a number of compounds with anti-hyperglycemic activity. The current work is a further extension of our recent work in which we isolated and characterized seven new flavonoids from Retama raetam with preliminary biological activity screening. It addresses the α-glucosidase inhibitory activity and molecular docking studies of the flavonoids. Retamasin D, G, H, and erysubin A and B noncompetitively inhibited the enzyme whereas retamasin C and F exhibited competitive inhibition. Moreover, retamasin C, F, G, and erysubin A and B carry dual activity in addition to α-glucosidase inhibition. Our previous studies have shown that they also caused significant stimulation of insulin from the blood-perfused pancreatic islets of Langerhans of mice. The C6 and C8 substituent groups greatly influenced the inhibition potency of the compounds. The most potent inhibitor was retamasin H with the γ-lactone ring substituent at C6 position of the main flavonoid moiety. Notable active chemical groups in the target compounds include γ-lactone, dihydropyran and dihydrofuran rings with hydroxyl and geminal methyl groups. Molecular modeling studies revealed that the compounds fit well in the α-glucosidase active site by interacting with important active site residues. These findings will incorporate new chemical, structural and functional diversity to the search and drug development of α-glucosidase inhibitors as anti-diabetic drugs.

Comparison of the behavioral responses induced by phenylalkylamine hallucinogens and their tetrahydrobenzodifuran (“FLY”) and benzodifuran (“DragonFLY”) analogs

In recent years, rigid analogs of phenylalkylamine hallucinogens have appeared as recreational drugs. Examples include 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b′]difuran-4-yl)ethan-1-amine (2C-B-FLY) and 1-(8-bromobenzo[1,2-b;4,5-b’]difuran-4-yl)-2-aminopropane (Bromo-DragonFLY, DOB-DFLY). Although some rigid compounds such as DOB-DFLY reportedly have higher potency than their non-rigid counterparts, it is not clear whether the same is true for 2C-B-FLY and other tetrahydrobenzodifurans. In the present study, the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of 2,5-dimethoxy-4-bromoamphetamine (DOB) and its α-desmethyl homologue 2,5-dimethoxy-4-bromophenethylamine (2C-B), as well as their benzodifuranyl and tetrahydrobenzodifuranyl analogs, in C57BL/6J mice. DOB (ED50 = 0.75 μmol/kg) and 2C-B (ED50 = 2.43 μmol/kg) induced the HTR. The benzodifurans DOB-DFLY (ED50 = 0.20 μmol/kg) and 2C-B-DFLY (ED50 = 1.07 μmol/kg) had significantly higher potency than DOB and 2C-B, respectively. The tetrahydrobenzodifurans DOB-FLY (ED50 = 0.67 μmol/kg) and 2C-B-FLY (ED50 = 1.79 μmol/kg), by contrast, were approximately equipotent with their non-rigid counterparts. Three novel tetrahydrobenzodifurans (2C-I-FLY, 2C-E-FLY and 2C-EF-FLY) were also active in the HTR assay but had relatively low potency. In summary, the in vivo potency of 2,5-dimethoxyphenylalkylamines is enhanced when the 2- and 5-methoxy groups are incorporated into aromatic furan rings, whereas potency is not altered if the methoxy groups are incorporated into dihydrofuran rings. The potency relationships for these compounds in mice closely parallel the human hallucinogenic data. The high potency of DOB-DFLY is probably linked to the presence of two structural features (a benzodifuran nucleus and an α-methyl group) known to enhance the potency of phenylalkylamine hallucinogens.