ABSTRACT
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.
Subject(s)
Azulenes , Oils, Volatile , Oxidation-Reduction , Azulenes/chemistry , Oils, Volatile/chemistry , Photolysis , Ultraviolet Rays , Antioxidants/chemistry , Achillea/chemistry , Artemisia/chemistry , Tandem Mass Spectrometry , Gas Chromatography-Mass SpectrometryABSTRACT
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.
Subject(s)
Antineoplastic Agents , Azulenes , Skin Diseases , Azulenes/chemistry , Azulenes/therapeutic use , Humans , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Skin Diseases/drug therapy , Neoplasms/drug therapy , AnimalsABSTRACT
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.
Subject(s)
Azulenes , Cycloaddition Reaction , Stereoisomerism , Catalysis , Azulenes/chemistry , Humans , Cell Line, Tumor , Molecular StructureABSTRACT
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.
Subject(s)
Azulenes , Quinolines , Azulenes/chemistry , Quinolines/chemistry , FluorescenceABSTRACT
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.
Subject(s)
Azulenes , Orexins , Orexin Receptors/metabolism , Azulenes/chemistryABSTRACT
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.
Subject(s)
Azulenes , Indenes , Azulenes/chemistry , Crystallography, X-Ray , Indenes/chemistry , Molecular Dynamics SimulationABSTRACT
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 (ãß0ã), e.g., the ãß0ã 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 ãß0ã 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.
Subject(s)
Porphyrins , Azulenes/chemistry , Porphyrins/chemistryABSTRACT
Azulene is a bicyclic scaffold rarely applied in medicinal chemistry. Here we report physicochemical and in vitro parameters relevant for drug discovery for a series of diversely substituted azulenes. We synthesized and characterized several scaffold hopping series of analogously substituted azulenes, indoles and naphthalenes. This enabled a comparison of azulene with the more common scaffolds indole and naphthalene. Our data indicates that undesirably low photostability of azulenes is restricted to certain substitution patterns. Generally, we conclude that azulene is an underused lipophilic bicycle and should be considered as a valuable complement to the collection of medicinal chemistry scaffolds.
Subject(s)
Azulenes , Drug Discovery , Azulenes/chemistry , Azulenes/pharmacology , Chemistry, PharmaceuticalABSTRACT
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.
Subject(s)
Azulenes , Furans , Azulenes/chemistry , Cyclization , Cycloaddition Reaction , Magnetic Resonance SpectroscopyABSTRACT
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.
Subject(s)
Azulenes/chemical synthesis , Breast Neoplasms/metabolism , Estradiol/pharmacology , Estrogen Receptor Modulators/chemical synthesis , Receptors, Estrogen/metabolism , Sesquiterpenes, Guaiane/chemistry , Azulenes/chemistry , Azulenes/pharmacology , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Development , Drug Synergism , Estrogen Receptor Modulators/chemistry , Estrogen Receptor Modulators/pharmacology , Female , Humans , MCF-7 Cells , Models, Molecular , Molecular Structure , Protein Binding , Protein Conformation , Receptors, Estrogen/chemistry , Tamoxifen/analogs & derivatives , Tamoxifen/chemistry , Tamoxifen/pharmacologyABSTRACT
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.
Subject(s)
Azo Compounds/pharmacology , Azulenes/pharmacology , Enzyme Inhibitors/pharmacology , Glucosylceramidase/antagonists & inhibitors , Azo Compounds/chemical synthesis , Azo Compounds/chemistry , Azulenes/chemical synthesis , Azulenes/chemistry , Cell Line , Cell Survival/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Glucosylceramidase/metabolism , Humans , Light , Molecular Structure , Photochemical ProcessesABSTRACT
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.
Subject(s)
Azulenes/chemical synthesis , Furans/chemistry , Azulenes/chemistry , Chemistry Techniques, Synthetic , Cycloaddition Reaction , Ethers , Molecular Structure , Spectrum Analysis , StereoisomerismABSTRACT
AzuFluor® 435-DPA-Zn, an azulene fluorophore bearing two zinc(II)-dipicolylamine receptor motifs, exhibits fluorescence enhancement in the presence of adenosine diphosphate. Selectivity for ADP over ATP, AMP and PPi results from appropriate positioning of the receptor motifs, since an isomeric sensor cannot discriminate between ADP and ATP.
Subject(s)
Adenosine Diphosphate/analysis , Azulenes/chemistry , Fluorescent Dyes/chemistry , Humans , Molecular Structure , Spectrometry, FluorescenceABSTRACT
The major obstacle in applying peptides to intracellular targets is their low inherent cell permeability. Standard approaches to attach a fluorophore (e. g. FITC, TAMRA) can change the physicochemical properties of the parent peptide and influence their ability to penetrate and localize in cells. We report a label-free strategy for evaluating the cell permeability of cyclic peptide leads. Fluorescent tryptophan analogues 4-cyanotryptophan (4CNW) and ß-(1-azulenyl)-L-alanine (AzAla) were incorporated into inâ vitro translated macrocyclic peptides by initiator reprogramming. We then demonstrate these efficient blue fluorescent emitters are good tools for monitoring peptide penetration into cells.
Subject(s)
Alanine/analogs & derivatives , Fluorescent Dyes/chemistry , Optical Imaging , Peptides, Cyclic/chemistry , Sesquiterpenes/chemistry , Tryptophan/analogs & derivatives , Alanine/chemistry , Azulenes/chemistry , Cell Line, Tumor , Humans , Molecular Structure , Permeability , Tryptophan/chemistryABSTRACT
Vibrational energy transfer (VET) is essential for protein function. It is responsible for efficient energy dissipation in reaction sites, and has been linked to pathways of allosteric communication. While it is understood that VET occurs via backbone as well as via non-covalent contacts, little is known about the competition of these two transport channels, which determines the VET pathways. To tackle this problem, we equipped the ß-hairpin fold of a tryptophan zipper with pairs of non-canonical amino acids, one serving as a VET injector and one as a VET sensor in a femtosecond pump probe experiment. Accompanying extensive non-equilibrium molecular dynamics simulations combined with a master equation analysis unravel the VET pathways. Our joint experimental/computational endeavor reveals the efficiency of backbone vs. contact transport, showing that even if cutting short backbone stretches of only 3 to 4 amino acids in a protein, hydrogen bonds are the dominant VET pathway.
Subject(s)
Alanine/analogs & derivatives , Proteins/chemistry , Tryptophan/chemistry , Allosteric Regulation , Azulenes/chemistry , Energy Transfer , Hydrogen Bonding , Molecular Dynamics Simulation , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Quantum Theory , Solutions , Thermodynamics , VibrationABSTRACT
Antimicrobial peptides (AMPs) present a promising scaffold for the development of potent antimicrobial agents. Substitution of tryptophan by non-natural amino acid Azulenyl-Alanine (AzAla) would allow studying the mechanism of action of AMPs by using unique properties of this amino acid, such as ability to be excited separately from tryptophan in a multi-Trp AMPs and environmental insensitivity. In this work, we investigate the effect of TrpâAzAla substitution in antimicrobial peptide buCATHL4B (contains three Trp side chains). We found that antimicrobial and bactericidal activity of the original peptide was preserved, while cytocompatibility with human cells and proteolytic stability was improved. We envision that AzAla will find applications as a tool for studies of the mechanism of action of AMPs. In addition, incorporation of this non-natural amino acid into AMP sequences could enhance their application properties.
Subject(s)
Azulenes/metabolism , Pore Forming Cytotoxic Proteins/metabolism , Tryptophan/metabolism , 3T3 Cells , Animals , Azulenes/chemistry , Bacteria/drug effects , Cell Membrane Permeability/drug effects , Circular Dichroism , Erythrocytes/drug effects , Erythrocytes/metabolism , Fibroblasts/drug effects , Fibroblasts/metabolism , Hemolysis/drug effects , Mice , Microbial Sensitivity Tests , Peptide Hydrolases/metabolism , Pore Forming Cytotoxic Proteins/chemistry , Sheep , Spectrometry, Fluorescence , Tryptophan/chemistryABSTRACT
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) â 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.
Subject(s)
Cyanides/chemistry , Electrons , Heterocyclic Compounds/chemistry , Isothiocyanates/chemistry , Azulenes/chemistry , Crystallography, X-Ray , Ligands , Magnetic Resonance Spectroscopy , Metals/chemistry , Models, Molecular , Molecular StructureABSTRACT
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.
Subject(s)
Azulenes/chemistry , Coordination Complexes/chemistry , Copper/chemistry , Oxygen/chemistry , Sesquiterpenes, Guaiane/chemistry , Temperature , Density Functional Theory , Models, Molecular , Molecular ConformationABSTRACT
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.
Subject(s)
Azulenes/chemistry , Biosensing Techniques , Imaging, Three-Dimensional , Fluorescence , Models, Molecular , Polymers/chemical synthesis , Polymers/chemistryABSTRACT
Azulene samples in ethanol/distilled water (1, 10 and 100 µm) were irradiated with a 638 nm red laser (0.5 watts, light-to-target distance 2 cm, energy density 4 or 40 J cm-2 ) by either continuous, fractionation or pulse mode. Singlet oxygen in the samples was measured using 10 µm 9,10-dimethyl anthracene (positive control 10 µm erythrosine) and relative fluorescence intensities were measured at 375/436 nm excitation/emission. Peripheral blood mononuclear cells (PBMCs, 1 × 105 cells/well) preincubated with 0.01 µg mL-1 rhTNF-α for 6 h were cultured with irradiated azulene samples in RPMI-1640 under standard conditions. PGE2 was quantified by rhPGE2 ELISA kit using a Varioscan® microplate reader at an excitation wavelength of 420 nm. Kruskal Wallis with Dunn`s test was performed at a significance level of P < 0.05. The highest singlet oxygen amount was found in 10 µm azulene samples irradiated at 40 J cm-2 under continuous mode (P = 0.001 when compared with 10 µm erythrosine). PGE2 expression in rhTNF-α-induced PBMCs was reduced to 45% of control by 1 µm azulene irradiated at 40 J cm-2 under fractionation mode. Fractionation mode with intermediate laser energy density in the presence of low concentration of azulene could increase singlet oxygen and tend to reduce PGE2 .