An antibiotic preorganized for ribosomal binding overcomes antimicrobial resistance.

We report the design conception, chemical synthesis, and microbiological evaluation of the bridged macrobicyclic antibiotic cresomycin (CRM), which overcomes evolutionarily diverse forms of antimicrobial resistance that render modern antibiotics ineffective. CRM exhibits in vitro and in vivo efficacy against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We show that CRM is highly preorganized for ribosomal binding by determining its density functional theory-calculated, solution-state, solid-state, and (wild-type) ribosome-bound structures, which all align identically within the macrobicyclic subunits. Lastly, we report two additional x-ray crystal structures of CRM in complex with bacterial ribosomes separately modified by the ribosomal RNA methylases, chloramphenicol-florfenicol resistance (Cfr) and erythromycin-resistance ribosomal RNA methylase (Erm), revealing concessive adjustments by the target and antibiotic that permit CRM to maintain binding where other antibiotics fail.

Biosynthesis of Chryseno[2,1,c]oxepin-12-Carboxylic Acid from Glycyrrhizic Acid in Aspergillus terreus TMZ05-2, and Analysis of Its Anti-inflammatory Activity.

Glycyrrhizic acid, glycyrrhetinic acid, and their oxo, ester, lactone, and other derivatives, are known for their anti-inflammatory, anti-oxidant, and hypoglycemic pharmacological activities. In this study, chryseno[2,1-c]oxepin-12-carboxylic acid (MG) was first biosynthesized from glycyrrhizic acid through sequential hydrolysis, oxidation, and esterification using Aspergillus terreus TMZ05-2, providing a novel in vitro biosynthetic pathway for glycyrrhizic acid derivatives. Assessing the influence of fermentation conditions and variation of strains during culture under stress-induction strategies enhanced the final molar yield to 88.3% (5 g/L glycyrrhizic acid). CCK8 assays showed no cytotoxicity and good cell proliferation, and anti-inflammatory experiments demonstrated strong inhibition of NO release (36.3%, low-dose MG vs. model), transcriptional downregulation of classical effective cellular factors tumor necrosis factor-α (TNF-α; 72.2%, low-dose MG vs. model), interleukin-6 (IL-6; 58.3%, low-dose MG vs. model) and interleukin-1ß (IL-1ß; 76.4%, low-dose MG vs. model), and decreased abundance of P-IKK-α, P-IKB-α, and P-P65 proteins, thereby alleviating inflammatory responses through the NF-κB pathway in LPS-induced RAW264.7 cells. The findings provide a reference for the biosynthesis of lactone compounds from medicinal plants.

Dibenzo[b,f]oxepine Molecules Used in Biological Systems and Medicine.

In this short review, including 113 references, issues related to dibenzo[b,f]oxepine derivatives are presented. Dibenzo[b,f]oxepine scaffold is an important framework in medicinal chemistry, and its derivatives occur in several medicinally relevant plants. At the same time, the structure, production, and therapeutic effects of dibenzo[b,f]oxepines have not been extensively discussed thus far and are presented in this review. This manuscript addresses the following issues: extracting dibenzo[b,f]oxepines from plants and its significance in medicine, the biosynthesis of dibenzo[b,f]oxepines, the active synthetic dibenzo[b,f]oxepine derivatives, the potential of dibenzo[b,f]oxepines as microtubule inhibitors, and perspective for applications of dibenzo[b,f]oxepine derivatives. In conclusion, this review describes studies on various structural features and pharmacological actions of dibenzo[b,f]oxepine derivatives.

Synthesis of Curved Polycyclic Arenes Embedded with Oxepine and Thiepine Using Ring Expansion Strategy.

A tandem oxidative ring expansion of a six- to seven-membered ring was developed to construct a new class of negatively curved polycyclic arenes embedded with oxepine and thiepine, namely, dibenzo[b,f]phenanthro[9,10-d]oxepine (DBPO) and dibenzo[b,f]phenanthro[9,10-d]thiepine (DBPT), respectively. Mechanistic studies disclosed that an unexpected [4 + 2] cycloadduct formed between the alkene moiety of o-biphenyl-linked methylenexanthenes and o-chloranil serves as a radical cation or a dication equivalent that facilitates the FeCl3-mediated tandem ring expansion process.

Oxepine-containing pyrazinopyrimidine alkaloids and quinolinone derivatives produced by Aspergillus versicolor AS-212, a deep-sea-derived endozoic fungus.

Four new oxepine-containing pyrazinopyrimidine alkaloids, versicoxepines A - D (1-4), two quinolinone alkaloid analogs including 3-hydroxy-6-methoxy-4-phenylquinolin-2(1H)-one (5) and 3-methoxy-6-hydroxy-4-phenylquinolin-2(1H)-one (6) which were new naturally occurring compounds, together with two known compounds (7 and 8) were isolated from Aspergillus versicolor AS-212, an endozoic fungus isolated from the deep-sea coral Hemicorallium cf. imperiale, which was collected from the Magellan Seamounts in the Western Pacific Ocean. Their structures were determined by extensive analysis of the spectroscopic and X-ray crystallographic data as well as by chiral HPLC analysis, ECD calculation, and DP4+ probability prediction. Structurally, versicoxepines B and C (2 and 3) represent the first example of a new oxepine-containing pyrazinopyrimidine alkaloid whose cyclic dipeptide moiety is composed of the same type of amino acid (Val or Ile). Compound 5 displayed antibacterial activity against aquatic pathogens, Vibrio harveyi and V. alginolyticus, with MICs of 8 µg/mL.

Systematic Studies on Anti-Cancer Evaluation of Stilbene and Dibenzo[b,f]oxepine Derivatives.

Cancer is one of the most common causes of human death worldwide; thus, numerous therapies, including chemotherapy, have been and are being continuously developed. In cancer cells, an aberrant mitotic spindle-a microtubule-based structure necessary for the equal splitting of genetic material between daughter cells-leads to genetic instability, one of the hallmarks of cancer. Thus, the building block of microtubules, tubulin, which is a heterodimer formed from α- and ß-tubulin proteins, is a useful target in anti-cancer research. The surface of tubulin forms several pockets, i.e., sites that can bind factors that affect microtubules' stability. Colchicine pockets accommodate agents that induce microtubule depolymerization and, in contrast to factors that bind to other tubulin pockets, overcome multi-drug resistance. Therefore, colchicine-pocket-binding agents are of interest as anti-cancer drugs. Among the various colchicine-site-binding compounds, stilbenoids and their derivatives have been extensively studied. Herein, we report systematic studies on the antiproliferative activity of selected stilbenes and oxepine derivatives against two cancer cell lines-HCT116 and MCF-7-and two normal cell lines-HEK293 and HDF-A. The results of molecular modeling, antiproliferative activity, and immunofluorescence analyses revealed that compounds 1a, 1c, 1d, 1i, 2i, 2j, and 3h were the most cytotoxic and acted by interacting with tubulin heterodimers, leading to the disruption of the microtubular cytoskeleton.

Design and synthesis of hetero-steroids via ring-closing metathesis: Biological studies towards in vitro anticancer activity.

Here, we report a synthetic approach to hetero-steroids and also studied their biological activities as anticancer agents. A novel class of oxacycles containing estrone moiety were synthesized in this report. Allyl ether derived from estrone underwent Claisen rearrangement (CR) and again O-allylation and subsequent ring-closure gave A-ring-furan and oxepine fused derivatives in high yields. We used double bond isomerization and ring-closing metathesis (RCM) as key steps to assemble hetero steroids containing a mixture of regio isomers like benzofurans and benzoxepine moieties. The novel benzofuran and benzoxepine-based hybrid steroid derivatives were subjected to in vitro cytotoxicity analysis and were found to exert cancer cell-specific activity.

Rhodium-Catalyzed Annulation of Vinylated Tyrosines with Internal Alkynes to Access Oxepine-Mounted Unnatural Tyrosines and Its Peptide Late Stage Functionalization.

A Rh(III)-catalyzed [5+2] annulation of vinyl tyrosines with symmetrical and unsymmetrical internal alkynes was achieved, furnishing a series of oxepine-mounted tyrosine-based unnatural amino acids. In addition, the chemical applicability of the developed strategy was exemplified by stapling amino acid/peptide-appended alkynes with vinyl tyrosines and late stage functionalization of tyrosine-containing dipeptides and tripeptide with internal alkynes.

Synthesis and Study of Dibenzo[b, f]oxepine Combined with Fluoroazobenzenes-New Photoswitches for Application in Biological Systems.

Dibenzo[b, f]oxepine derivatives are an important scaffold in natural, medicinal chemistry, and these derivatives occur in several medicinally relevant plants. Two dibenzo[b, f]oxepines were selected and connected with appropriate fluorine azobenzenes. In the next step, the geometry of E/Z isomers was analyzed using density functional theory (DFT) calculations. Then the energies of the HOMO and LUMO orbitals were calculated for the E/Z isomers to determine the HOMO-LUMO gap. Next, modeling of the interaction between the obtained isomers of the compounds and the colchicine α and ß-tubulin binding site was performed. The investigated isomers interact with the colchicine binding site in tubulin with a part of the dibenzo[b, f]oxepine or in a part of the azo switch, or both at the same time. Based on the UV-VIS spectra, it was found that in the case of compounds with an azo bond in the meta position, the absorption bands n→π* for both geometric isomers and their separation from π→π* are visible. These derivatives therefore have the potential to be used in photopharmacology.

Diversification of (E,E)-1,6-Dioxo-2,4-Dienes for the Synthesis of (+)-Aspicillin, Isolaurepan, and ß-Parinaric Acid.

A divergent formal synthesis of polyhydroxylated macrocyclic lactone (+)-aspicillin and polyene bioactive natural product ß-parinaric acid and the total synthesis of non-terpenoid metabolite isolaurepan have been achieved using a ruthenium-catalyzed stereo- and chemoselective oxidative coupling reaction of easily accessible vinyl ketones and acrylates. The crucial transformation involves the efficient synthesis and functionalization of stereodefined (E,E)-1,6-dioxo-2,4-dienes using simple reaction protocols, which enabled straightforward access to a diverse range of bioactive natural products.

Polyketides with anti-inflammatory activity from Rhodiola tibetica endophytic fungus Alternaria sp. HJT-Y7.

Seven undescribed polyketides with particular ortho-trisubstituted benzo[c]furan and benzo[c]oxepin spiro structures were isolated from Rhodiola tibetica endophytic fungus Alternaria sp. HJT-Y7. Structural elucidations of these compounds were determined mainly by NMR and HR-ESI-MS analysis. An assumed polyketide biosynthetic pathway of these isolates was proposed. Two undescribed compounds and four known compounds showed significant inhibitory effects on LPS-induced NO production in RAW 264.7 cells without cytotoxicity at their effective concentrations.

Total synthesis and antibacterial evaluation of Empetroxepins A and B and related analogs.

Empetroxepins A and B, which are 10,11-dihydrodibenz[b,f]oxepins produced by the Black Crowberry (Empetrum nigrum), displayed weak anti-tubercular activity upon isolation, but have not been explored for antibiotic activity despite their molecular similarity to other phenolic antibacterial natural products. Herein we detail the first total synthesis of Empetroxepins A and B via a selective demethylation strategy and antibacterial structure activity relationship (SAR) study of the natural products and related analogs. Empetroxepin A was found to be weakly active against susceptible strains of Staphylococcus aureus (SA) and Bacillus subtilis (BS) with a minimum inhibitory concentration (MIC) of 256 µg/mL against both bacteria, whereas Empetroxepin B was found to be weakly active against only BS (MIC = 256 µg/mL). Neither natural product was active against Escherichia coli (EC). Antibiotic activity was improved through derivatization of the 10,11-dihydrodibenz[b,f]oxepin core with the best compound of the SAR series, 9-chloro-10,11-dihydrodibenzo[b,f]oxepine-2,3,4-triol, having MICs of 8 µg/mL, 16 µg/mL, and 256 µg/mL against SA, BS, and EC respectively.

An Updated Review on Biologically Promising Natural Oxepines.

Benzo-oxepines and dibenzo-oxepines, a unique class of naturally occurring secondary metabolites, are distributed mainly in plants and fungi and have received much attention from phytochemists and biologists based on their fascinating structural features and health-promoting functions. This review summarizes 100 oxepine derivatives comprising three categories: benzo-oxepine, dibenzo-oxepine, and pyrano-oxepine. Studies on various structural features and pharmacological activities of oxepine derivatives promote further in-depth research on these potent natural products. This review portrays the natural occurrence, bioactivity and biosynthesis of oxepines reported from 1984 to 2021.

Shortest Enantioselective Total Syntheses of (+)-Isolaurepinnacin and (+)-Neoisoprelaurefucin.

The shortest enantioselective total syntheses of (+)-isolaurepinnacin and (+)-neoisoprelaurefucin have been accomplished. These syntheses were based on a common parallel synthetic strategy using Prins-Peterson cyclization in their core construction. In only one step, a seven-membered ring oxacycle with the correct cis-stereochemistry ring closure and the Δ4 position of the endocyclic double bond in (+)-isolaurepinnacin was obtained. This unsaturation was also necessary to accede to the bromodioxabicycle on (+)-neoisoprelaurefucin.

Synthesis of a Diacetonide-Protected, Mannose-Based Oxepine: Configurational Control of Anomeric Acetate Activation.

Carbohydrate-based oxepines are seven-membered-ring oxacycles containing an enol ether moiety. These compounds have been used as intermediates in the preparation of septanose carbohydrates by functionalization through their double bond. Reported here is a new synthesis of a carbohydrate based oxepine that uses 2,3;4,6-di-O-acetonide mannose as a key starting material. The oxepine is an important precursor used in the synthesis of septanose glycomimetics of mannopyranosides. The central feature of the synthesis is a two-step sequence that converts a septanose 1,2-di-O-acetate to the septanosyl bromide and onward to the oxepine via a reductive elimination.

Propargyl Chalcones' Radical Annulation/Sulfonation Reaction: Efficient Synthesis of Benzo[b]oxepin-5(2H)-one and Chromane Derivatives.

A novel and facile methodology for the synthesis of sulfonated benzo[b]oxepinone and chromane derivatives was reported by the reaction of propargyl chalcones with arylsulfonyl chloride via radical cascade annulation/sulfonation under laboratory conditions. Readily available propargyl chalcones, commercialized arylsulfonyl chloride, and simple reaction conditions make this six(seven)-membered oxygen-containing heterocycles' synthetic strategy more attractive and with significant application values.

Concise Synthesis of 7-Deoxypsammaplysins K and O and 7-Deoxyceratinamide A by 1,3-Dipole Cycloaddition.

A spiro-oxepin isoxazoline skeleton was constructed via 1,3-dipole cycloaddition as a key step, which enabled the total syntheses of 7-deoxyceratinamide A and 7-deoxypsammaplysins K and O. The developed chemistry could be applied to total synthesis of structurally diverse spiro-oxepin isoxazoline-based marine natural products.

Phosphine-Mediated [4 + 3] Annulation of Diynoates and 2-Arylidene Indane-1,3-diones: Access of Indeno[1,2-b]oxepin-4-ylidenes and Beyond.

A novel unprecedented triphenylphosphine-mediated [4 + 3] annulation reaction of 2-benzylidene indane-1,3-diones and -diynoates through initial phosphine α-addition was discovered and found to result in biologically interesting indeno[1,2-b]oxepin-4-ylidenes in up to 75% yield. The seven-membered separable Z and E isomeric oxepins were confirmed using single-crystal X-ray diffraction.

The Roles Played by FP/EP3 Receptors During Pressure-lowering in Mouse Eyes Mediated by a Dual FP/EP3 Receptor Agonist.

Purpose: We investigated the intraocular pressure (IOP)-lowering effect of topical sepetaprost (SPT), a dual agonist of the FP and EP3 receptors. We explored whether certain receptors mediated the hypotensive effect of SPT and outflow facility changes in C57BL/6 mice (wild-type [WT]) and FP and EP3 receptor-deficient mice (FPKO and EP3KO mice, respectively). Methods: IOP was measured using a microneedle. Outflow facility was measured using a two-level, constant-pressure perfusion method. Results: SPT significantly reduced IOP for 8 hours after administration to WT mice. The 2-hour IOP reductions afforded by latanoprost were 15.3 ± 2.5, 1.8 ± 2.0, and 12.3 ± 2.4% in WT, FPKO, and EP3KO mice, respectively; the SPT figures were 13.6 ± 2.1, 5.9 ± 2.7, and 6.6 ± 2.6%, respectively. Latanoprost-mediated IOP reduction was significantly decreased in FPKO mice, and SPT-mediated IOP reduction was reduced in both FPKO and EP3KO mice. At 6 hours after administration, latanoprost did not significantly reduce the IOP in any tested mouse strain. SPT-mediated IOP reduction was reduced in both FPKO and EP3KO mice. IOP reduction at 6 hours was significantly higher after simultaneous administration of selective FP and EP3 receptor agonists, but IOP did not fall on administration of (only) a selective EP3 receptor agonist. SPT significantly increased outflow facility in WT mice, but less so in FPKO and EP3KO mice. Conclusions: The IOP-lowering effect of SPT lasted longer than that of latanoprost. Our data imply that this may be attributable to augmented outflow facility mediated by the FP and EP3 receptors.