An Enantioselective Aminocatalytic Cascade Reaction Affording Bioactive Hexahydroazulene Scaffolds.

A novel cascade reaction initiated by an enantioselective aminocatalysed 1,3-dipolar [6+4] cycloaddition between catalytically generated trienamines and 3-oxidopyridinium betaines is presented. The [6+4] cycloadduct spontaneously undergoes an intramolecular enamine-mediated aldol, hydrolysis, and E1cb sequence, which ultimately affords a chiral hexahydroazulene framework. In this process, three new C-C bonds and three new stereocenters are formed, enabled by a formal unfolding of the pyridine moiety from the dipolar reagent. The hexahydroazulenes are formed with excellent diastereo-, regio- and periselectivity (>20 : 1), up to 96 % ee, and yields up to 52 %. Synthetic elaborations of this scaffold were performed, providing access to a variety of functionalised hydroazulene compounds, of which some were found to display biological activity in U-2OS osteosarcoma cells in cell painting assays.

Photochemical and Oxidative Degradation of Chamazulene Contained in Artemisia, Matricaria and Achillea Essential Oils and Setup of Protection Strategies.

Chamazulene (CA) is an intensely blue molecule with a wealth of biological properties. In cosmetics, chamazulene is exploited as a natural coloring and soothing agent. CA is unstable and tends to spontaneously degrade, accelerated by light. We studied the photodegradation of CA upon controlled exposure to UVB-UVA irradiation by multiple techniques, including GC-MS, UHPLC-PDA-ESI-MS/MS and by direct infusion in ESI-MSn, which were matched to in silico mass spectral simulations to identify degradation products. Seven byproducts formed upon UVA exposure for 3 h at 70 mW/cm2 (blue-to-green color change) were identified, including CA dimers and CA benzenoid, which were not found on extended 6 h irradiation (green-to-yellow fading). Photostability tests with reduced irradiance conducted in various solvents in the presence/absence of air indicated highest degradation in acetonitrile in the presence of oxygen, suggesting a photo-oxidative mechanism. Testing in the presence of antioxidants (tocopherol, ascorbyl palmitate, hydroxytyrosol, bakuchiol, γ-terpinene, TEMPO and their combinations) indicated the highest protection by tocopherol and TEMPO. Sunscreens ethylhexyl methoxycinnamate and particularly Tinosorb® S (but not octocrylene) showed good CA photoprotection. Thermal stability tests indicated no degradation of CA in acetonitrile at 50 °C in the dark for 50 days; however, accelerated degradation occurred in the presence of ascorbyl palmitate.

Azulene and Its Derivatives as Potential Compounds in the Therapy of Dermatological and Anticancer Diseases: New Perspectives against the Backdrop of Current Research.

The scientific article focuses on the role of azulene and its derivatives in the therapy of dermatological diseases, presenting the latest laboratory and clinical research as well as prospects for further studies. In a synthetic literature review, various databases such as PubMed, Scopus, Web of Science, and the Database of Polish Scientific Journals were queried to select relevant articles concerning azulene. The conclusions drawn from the thematic analysis of the studies emphasize the multifaceted pharmacological actions of azulene and its derivatives including their anti-inflammatory properties, potential anticancer effects, photoprotective abilities, alleviation of itching, management of atopic dermatitis, and treatment of erectile dysfunction. However, there are certain limitations associated with the application of unmodified azulene on the skin, particularly related to photodecomposition and the generation of reactive oxygen species under UV radiation. These effects, in turn, necessitate further research on the safety of azulene and azulene-derived substances, especially regarding their long-term use and potential application in phototherapy. The authors of this work emphasize the necessity of conducting further preclinical and clinical studies to fully understand the mechanisms of action. Incorporating azulene and its derivatives into the therapy of dermatological disorders may represent an innovative approach, thereby opening new treatment avenues for patients.

Synthesis and Properties of Benzo[h]imidazo[1,2-a]quinolines and 1,2a-Diazadibenzo[cd,f]azulenes.

Benzo[h]imidazo[1,2-a]quinolines and 1,2a-diazadibenzo[cd,f]azulenes were prepared from a common intermediate by regioselective cycloisomerization reactions. The selectivity was controlled by the choice of Brønsted acid and solvent. The optical and electrochemical properties of the products were studied by UV/vis, fluorescence, and cyclovoltammetric measurements. The experimental results were complemented by density functional theory calculations.

Azulene as a biphenyl mimetic in orexin/hypocretin receptor agonists.

Azulene is a rare ring structure in drugs, and we investigated whether it could be used as a biphenyl mimetic in known orexin receptor agonist Nag 26, which is binding to both orexin receptors OX1 and OX2 with preference towards OX2. The most potent azulene-based compound was identified as an OX1 orexin receptor agonist (pEC50 = 5.79 ± 0.07, maximum response = 81 ± 8% (s.e.m. of five independent experiments) of the maximum response to orexin-A in Ca2+ elevation assay). However, the azulene ring and the biphenyl scaffold are not identical in their spatial shape and electron distribution, and their derivatives may adopt different binding modes in the binding site.

Synthesis, Reactivity, and Properties of Benz[a]azulenes via the [8 + 2] Cycloaddition of 2H-Cyclohepta[b]furan-2-ones with an Enamine.

Starting with the reaction of 2H-cyclohepta[b]furan-2-ones with an enamine, which was prepared from 4-tert-butylcyclohexanone and pyrrolidine, benz[a]azulenes having both formyl and tert-butyl groups were obtained in the three-step sequence. Subsequently, both the formyl and tert-butyl groups were eliminated by heating the benz[a]azulene derivatives in 100% H3PO4 to give benz[a]azulenes without these substituents in high yields. In terms of product yield, this method is the best one ever reported for the synthesis of the parent benz[a]azulene so far. The conversion of the benz[a]azulene derivatives with a formyl group into cyclohept[a]acenaphthylen-3-one derivatives was also investigated via Knoevenagel condensation with dimethyl malonate, followed by Brønsted acid-mediated intramolecular cyclization. The structural features including the bond alternation in the benz[a]azulene derivatives were revealed by NMR studies, NICS calculations, and a single-crystal X-ray structural analysis. The optical and electrochemical properties of a series of benz[a]azulene derivatives were evaluated by UV/Vis, fluorescence spectroscopy, and voltammetry experiments. As a result, we found that some benz[a]azulene derivatives showed remarkable luminescence in acidic media. In addition, the benz[a]azulene derivatives with the electron-withdrawing group and cyclohept[a]acenaphthylen-3-one derivative displayed good reversibility in the spectral changes under the electrochemical redox conditions.

Photoswitchable inhibitors of human ß-glucocerebrosidase.

Light-switchable inhibitors of the enzyme ß-glucocerebrosidase (GCase) have been developed by anchoring a specific azasugar to a dihydroazulene or an azobenzene responsive moiety. Their inhibitory effect towards human GCase, before and after irradiation are reported, and the effect on thermal denaturation of recombinant GCase and cytotoxicity were studied on selected candidates.

Strong second order nonlinear optical properties of azulene-based porphyrin derivatives.

The high stability, feasible modification, and good π-conjugation of porphyrin derivatives render these porphyrin-based nanomaterials suitable as potential third order nonlinear optical (NLO) materials. Introducing an azulene in pristine porphyrins can significantly improve the second order NLO properties of the system, and this is studied in the present work using density functional theory based methods and the sum-over-states model. The relative orientation of azulene plays a determinant role in the enhancement of the static first hyperpolarizability (〈ß0〉), e.g., the 〈ß0〉 per heavy atom increases from 0.31 × 10-30 esu to 9.78 × 10-30 esu. Further addition of metals (Mg and Zn) in these azulene-fused porphyrin systems leads to an even larger 〈ß0〉 per heavy atom of 41.59 × 10-30 esu, much larger than that of a recently reported porphyrin derivative (26.47 × 10-30 esu). A novel strategy to stabilize the electronic structures as well as maintain good second order NLO responses by introducing appropriate metals into the azulene-fused porphyrins is extendable to other similar systems. Strong sum frequency generation and different frequency generations of those azulene-fused porphyrins in visible and near-infrared regions may inspire experimental exploration and related applications of azulene-based porphyrins particularly in biological nonlinear optics.

Challenging Approach to the Development of Novel Estrogen Receptor Modulators Based on the Chemical Properties of Guaiazulene.

Tamoxifen, a therapeutic agent for breast cancer, has been associated with genetic polymorphisms in the metabolism of N,N-dialkylaminoethyl substituent, which plays an important role in the expression of selective estrogen receptor modulator (SERM) activity. To solve this problem, we developed a novel estrogen receptor (ER) modulator, Az-01, on the basis of the aromaticity, dipole moment, and isopropyl group of guaiazulene. Az-01 showed four-fold lower binding affinity for ER than E2 but had similar ER-binding affinity to that of 4-hydroxytamoxifen (4-HOtam). Unlike tamoxifen, Az-01 acted as a partial agonist with very weak estrogenic activity at high concentrations when used alone, and it showed potent anti-estrogenic activity in the presence of E2. The cell proliferation and inhibition activities of Az-01 were specific to ER-expressing MCF-7 cells, and no effect of Az-01 on other cell proliferation signals was observed. These findings are important for the development of new types of SERMs without the N,N-dialkylaminoethyl substituent as a privileged functional group for SERMs.

The Effect of Benzannulation on the Structures, Reactivity and Molecular Dynamics of Indenes, Pentalenes, Azulenes and Related Molecules.

The stabilising effect of benzannulation on isoindenes formed in the course of sigmatropic shifts of (C5H5)Fe(CO)2 or of organo-silyl groups, and on exocyclic allyl intermediates in the course of haptotropic shifts of organometallic fragments over polycyclic skeletons (fluorene, cyclopenta[def]phenanthrene, syn and anti dibenzpentalenes) is exemplified. This approach led to the development of the first organometallic molecular brake. Benzyne cycloadditions to anthracenes to form triptycenes also led to unexpected or multiple adducts that were characterised by X-ray crystallography. Synthetic routes to the previously elusive benz[cd]azulene system are presented. Finally, the complete mechanism of the stepwise assembly of dispiro- and diindenyltetracenes from fluorenylallenes is presented, whereby every intermediate has been unambiguously structurally characterised.

Room temperature stable multitalent: highly reactive and versatile copper guanidine complexes in oxygenation reactions.

Inspired by the efficiency of natural enzymes in organic transformation reactions, the development of synthetic catalysts for oxygenation and oxidation reactions under mild conditions still remains challenging. Tyrosinases serve as archetype when it comes to hydroxylation reactions involving molecular oxygen. We herein present new copper(I) guanidine halide complexes, capable of the activation of molecular oxygen at room temperature. The formation of the reactive bis(µ-oxido) dicopper(III) species and the influence of the anion are investigated by UV/Vis spectroscopy, mass spectrometry, and density functional theory. We highlight the catalytic hydroxylation activity towards diverse polycyclic aromatic alcohols under mild reaction conditions. The selective formation of reactive quinones provides a promising tool to design phenazine derivatives for medical applications.

Synthesis of Azulene Derivatives from 2H-Cyclohepta[b]furan-2-ones as Starting Materials: Their Reactivity and Properties.

A variety of synthetic methods have been developed for azulene derivatives due to their potential applications in pharmaceuticals and organic materials. Particularly, 2H-cyclohepta[b]furan-2-one and its derivatives have been frequently used as promising precursors for the synthesis of azulenes. In this review, we describe the development of the synthesis of azulenes by the reaction of 2H-cyclohepta[b]furan-2-ones with olefins, active methylenes, enamines, and silyl enol ethers as well as their reactivity and properties.

Azulene-A Bright Core for Sensing and Imaging.

Azulene is a hydrocarbon isomer of naphthalene known for its unusual colour and fluorescence properties. Through the harnessing of these properties, the literature has been enriched with a series of chemical sensors and dosimeters with distinct colorimetric and fluorescence responses. This review focuses specifically on the latter of these phenomena. The review is subdivided into two sections. Section one discusses turn-on fluorescent sensors employing azulene, for which the literature is dominated by examples of the unusual phenomenon of azulene protonation-dependent fluorescence. Section two focuses on fluorescent azulenes that have been used in the context of biological sensing and imaging. To aid the reader, the azulene skeleton is highlighted in blue in each compound.

Tuning π-Acceptor/σ-Donor Ratio of the 2-Isocyanoazulene Ligand: Non-Fluorinated Rival of Pentafluorophenyl Isocyanide and Trifluorovinyl Isocyanide Discovered.

Isocyanoazulenes (CNAz) constitute a relatively new class of isocyanoarenes that offers rich structural and electronic diversification of the organic isocyanide ligand platform. This article considers a series of 2-isocyano-1,3-X2-azulene ligands (X = H, Me, CO2Et, Br, and CN) and the corresponding zero-valent complexes thereof, [(OC)5Cr(2-isocyano-1,3-X2-azulene)]. Air- and thermally stable, X-ray structurally characterized 2-isocyano-1,3-dimethylazulene may be viewed as a non-benzenoid aromatic congener of 2,6-dimethyphenyl isocyanide (2,6-xylyl isocyanide), a longtime "workhorse" aryl isocyanide ligand in coordination chemistry. Single crystal X-ray crystallographic {Cr-CNAz bond distances}, cyclic voltametric {E1/2(Cr0/1+)}, 13C NMR {δ(13CN), δ(13CO)}, UV-vis {dπ(Cr) → pπ*(CNAz) Metal-to-Ligand Charge Transfer}, and FTIR {νN≡C, νC≡O, kC≡O} analyses of the [(OC)5Cr(2-isocyano-1,3-X2-azulene)] complexes provided a multifaceted, quantitative assessment of the π-acceptor/σ-donor characteristics of the above five 2-isocyanoazulenes. In particular, the following inverse linear relationships were documented: δ(13COtrans) vs. δ(13CN), δ(13COcis) vs. δ(13CN), and δ(13COtrans) vs. kC≡O,trans force constant. Remarkably, the net electron withdrawing capability of the 2-isocyano-1,3-dicyanoazulene ligand rivals those of perfluorinated isocyanides CNC6F5 and CNC2F3.

Helical Nanographenes Embedded with Contiguous Azulene Units.

The azulene moiety, composed of contiguous pentagonal and heptagonal rings, is a structural defect that alters the electronic, magnetic, and structural properties of graphenes and graphene nanoribbons. However, nanographenes embedded with an azulene cluster have not been widely investigated because these compounds are difficult to synthesize in their pure form. Herein, azulene-embedded nanographenes bearing a unique cove-type edge were synthesized by a novel synthetic protocol. Experimental and theoretical investigations revealed that this cove edge imparts stable helical chirality, unlike normal cove edges. The in-solution self-association behavior and the structural, electronic, and electrochemical properties were also described in detail.

Development of Heterocycle-Substituted and Fused Azulenes in the Last Decade (2010-2020).

Azulene derivatives with heterocyclic moieties in the molecule have been synthesized for applications in materials science by taking advantage of their unique properties. These derivatives have been prepared by various methods, involving electrophilic substitution, condensation, cyclization, and transition metal-catalyzed cross-coupling reactions. Herein, we present the development of the synthetic methods, reactivities, and physical properties for the heterocycle-substituted and heterocycle-fused azulenes reported in the last decade.

Azulene-Derived Fluorescent Probe for Bioimaging: Detection of Reactive Oxygen and Nitrogen Species by Two-Photon Microscopy.

Two-photon fluorescence microscopy has become an indispensable technique for cellular imaging. Whereas most two-photon fluorescent probes rely on well-known fluorophores, here we report a new fluorophore for bioimaging, namely azulene. A chemodosimeter, comprising a boronate ester receptor motif conjugated to an appropriately substituted azulene, is shown to be an effective two-photon fluorescent probe for reactive oxygen species, showing good cell penetration, high selectivity for peroxynitrite, no cytotoxicity, and excellent photostability.

Novel amides modified rupestonic acid derivatives as anti-influenza virus reagents.

In spired by the important role of amide groups of anti-influenza drugs oseltamivir, zanamivir and peramivir in bioactivity, a series of novel amides modified rupestonic acid derivatives were designed and synthesized. The absolute configuration of critical intermediate bearing chloride with newly formed stereocenter was confirmed by X-ray crystallographic analysis. And all new compounds were evaluated for their in vitro inhibitory activities against influenza A (H1N1 and H3N2) and influenza B viruses. The bioassay results showed that 5h with 4-fluorbenzylsulfonyl modified to 2 position of methyl rupestonate displayed the highest activity against influenza A (H1N1 and H3N2) viruses, even stronger than reference drugs oseltamivir and ribavirin (RVB), and might be recommended as a lead compound to further develop the new anti-influenza reagent.

Structural modification on rupestonic acid leads to highly potent inhibitors against influenza virus.

Influenza viruses are responsible for seasonal epidemics and occasional pandemics, which cause significant morbidity and mortality. Although several drugs (adamantanes and neuraminidase inhibitors) are available in the market, the worldwide spread of drug-resistant influenza strains poses an urgent need for novel antiviral drugs. Artemisia rupestris L. is a folk medicine used to treat cold. In this paper, we structurally modified rupestonic acid, a bioactive component of A. rupestris, to synthesize a series of 2-substituted rupestonic acid methyl esters (3a-3o). Their structures were fully characterized by 1H NMR, 13C NMR, HRMS spectra. Among them, compounds 3b and 3c exhibited potent activities against influenza H1N1 with micromolar IC50 values and might serve as new lead compounds for the treatment of influenza.

Painting argyrins blue: Negishi cross-coupling for synthesis of deep-blue tryptophan analogue ß-(1-azulenyl)-l alanine and its incorporation into argyrin C.

The argyrins are a family of non-ribosomal peptides that exhibits different biological activities through only small structural changes. Ideally, a biologically active molecule can be tracked and observed in a variety of biological and clinical settings in a non-invasive manner. As a step towards this goal, we report here a chemical synthesis of unnatural deep blue amino acid ß-(1-azulenyl)-l alanine with different fluorescence and photophysical properties, which allows a spectral separation from the native tryptophan signal. This might be especially useful for cell localization studies and visualizing the targeted proteins. In particular, the synthesis of ß-(1-azulenyl)-l alanine was achieved through a Negishi coupling which proved to be a powerful tool for the synthesis of unnatural tryptophan analogs. Upon ß-(1-azulenyl)-l alanine incorporation into argyrin C, deep blue octapeptide variant was spectrally and structurally characterized.