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Objective: To evaluate the effectiveness and feasibility of combined treatment with compound fluocinolone acetonide cream and guaiazulene in patients with neurodermatitis. Methods: A prospective study was conducted on 92 outpatient patients diagnosed with neurodermatitis at our dermatology department from January 2022 to December 2023. Using a random number table, these patients were evenly divided into a control group and an experimental group, with 46 individuals in each group. The control group received treatment with compound fluocinolone acetonide alone, while the experimental group additionally received oral guaiazulene tablets. Clinical symptom and sign scores, Visual Analog Scale (VAS) scores, skin lesion itching scores, comprehensive efficacy, treatment onset time, adverse reactions, and quality of life were monitored, recorded, and compared. Results: In the 2-week treatment period, patients in the experimental group showed significant improvement in skin symptoms and signs, with scores significantly lower than those in the control group (P < 0.05). After treatment, VAS and skin lesion itching scores in the experimental group were significantly reduced (P < 0.05), demonstrating a more pronounced therapeutic advantage compared to the control group (P < 0.05). Although the effective rate in the experimental group was as high as 86.96%, there was no significant advantage compared to the control group, and the difference in treatment efficacy was not significant (P > 0.05). The treatment onset time in the experimental group was significantly shorter than that in the control group (P < 0.05), and the incidence of adverse reactions was lower (P < 0.05). The quality of life in the experimental group improved significantly after treatment, with DLQI scores lower than those in the control group (P < 0.05). Conclusion: Combined treatment with compound fluocinolone acetonide cream and guaiazulene demonstrates excellent efficacy and feasibility in the management of neurodermatitis. Compared to standard treatment alone, it yields superior clinical outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The impact of organometallic chemistry on the terpene field only really blossomed in the 1960s and 1970s with the realisation that carbon–carbon bond formation under mild conditions could be achieved by using nickel or iron carbonyls as synthetic reagents. Concomitantly, the development of palladium derivatives capable of the controlled coupling of isoprene units attracted the attention of numerous highly talented researchers, including future Nobel laureates. We discuss briefly how early work on the syntheses of simple monoterpenes soon progressed to sesquiterpenes and diterpenes of increasing complexity, such as humulene, flexibilene, vitamin A, or pheromones of commercial value, in particular those used in perfumery (muscone, lavandulol), or grandisol and red scale pheromone as replacements for harmful pesticides. As the field progressed, there has been more emphasis on developing organometallic routes to enantiopure rather than racemic products, as well as gaining precise mechanistic data on the transformations, notably the course of metal-promoted molecular rearrangements that have long been a feature of terpene chemistry. We note the impact of the enormously enhanced analytical techniques, high-field NMR spectroscopy and X-ray crystallography, and their use to re-examine the originally proposed structures of terpenes and their organometallic derivatives. Finally, we highlight the very recent ground-breaking use of the crystalline sponge method to acquire structural data on low-melting or volatile terpenes. The literature cited herein covers the period 1959 to 2023. [ABSTRACT FROM AUTHOR]

We present an in‐depth study of the sterically demanding Cp‐synthon (8‐H‐GuaH)Li isolated from natural product guaiazulene (Gua) as a ligand transfer reagent towards late transition metal complex precursors. The synthesis and full characterization of selected, essentially unexplored homo‐ and heteroleptic 8‐H‐guaiazulenide complexes of iron, ruthenium, cobalt, rhodium, platinum, copper and zinc are discussed in detail. In order to demonstrate their potential in catalytic applications, [(GuaH)PtMe3] was selected. The latter proved an even higher catalytic activity in light induced olefin hydrosilylation at catalyst loads as low as 5 ppm than classical [CpPtMe3] in a typical test reaction of silicone elastomer fabrication. Our results demonstrate that traditional petrochemical based Cp metal chemistry and catalysis can be replaced, sometimes even outmatched by superior catalysts based on cheap building blocks from renewable feedstock. [ABSTRACT FROM AUTHOR]

We present an in‐depth study of hydride transfer or proton abstraction at natural product guaiazulene to form guaiazulenide salts (8‐H‐GuaH)Li 1 a and (Gua")Na(OEt2) 2. Both carbanions were correctly proposed by Hafner et al. but could never be isolated in isomerically, spectroscopically and analytically pure form so far. Therefore, their use as cyclopentadienyl synthons in organometallic chemistry remained essentially unexplored. Here, we present their synthesis and full characterisation including 2D NMR spectroscopy and two XRD structural analyses. 1 a is isolated in isomerically and chemically pure form via a catalytic variant of olefin hydrolithiation, the addition of LiH to an activated hydrocarbon C=C double bond catalysed by LiAlH4. This atom economic synthesis of a pure organolithium compound from an olefin, LiH or lithium and dihydrogen, respectively, is without precedence. In a follow up report we will demonstrate that these valuable ligand salts can be used as cheap sterically demanding renewable feedstock‐based cyclopentadienyl synthons in the synthesis of homo‐ and heteroleptic late transition metal complexes and catalysts. [ABSTRACT FROM AUTHOR]

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.

Guaiazulene is a crystalline bicyclic sesquiterpene. Today, besides being used in herbal treatment, it is also used in skin - body care products, toothpaste, hair dyes, eye solutions and also in the treatment of nipple irritation in nursing mothers. In the study, it was aimed to evaluate the effects of Guaiazulen and its solvent dimethyl sulfoxide on the level of malondialdehyde, which is a lipid peroxidation marker, and superoxide dismutase and catalase enzyme activities, which belong to antioxidant defense systems, in Drosophila melanogaster. it was determined that dimethyl sulfoxide caused lipid peroxidation by increasing the level of malondialdehyde at all hour and dose concentrations. At the same time, it was determined that dimethyl sulfoxide caused an increase in catalase enzyme activity by increasing the radical formation, but did not affect superoxide dismutase enzyme activity. In addition, it was observed that increasing in the dose of guaiazulene or the exposure time to it decreased superoxide dismutase enzyme activity, and catalase enzyme activity at all doses and hours. It was concluded that these data support the fact that guaiazulene shows antioxidant properties. Malondialdehyde amount increased upon increasing in the exposure time to guaiazulene. And it was concluded that it caused lipid peroxidation. [ABSTRACT FROM AUTHOR]

In present study, seventeen α -nitrile substituted guaiazulene-based chalcone derivatives including twelve new were designed, synthesized, and assayed for antiviral, cytotoxicity and signal pathway activities. All derivatives showed potential antiviral activity towards influenza virus or herpes simplex virus (HSV), 7 g with the substitution of nitro group showed strong effects towards H1N1 virus at 30 μM with inhibitory rate of 66.0%, 7o with thiophene exhibited potent anti HSV-1 activities with inhibitory rate of 65.8%. Moreover, several compounds exhibited inhibitory effects on tumor cells and hypoxia-inducible factor-1 (HIF1) signaling pathways. These results showed that α -nitrile substituted guaiazulene-based chalcones offered a promising framework for the further development of new highly efficient drugs. [Display omitted] • Seventeen α -nitrile substituted guaiazulene-based chalcone derivatives together with five know were designed and synthesized. • All compounds showed potential antiviral activity towards H1N1 and HSV-1. • 7 g disclosed strong effects towards H1N1 virus with inhibitory rate of 66.0% at 30 μM. • 7o exhibited potent anti HSV-1 activities with inhibitory rate of 65.8% at 30 μM. • 7e showed moderate cytotoxicity and 7 k exhibited suitable inhibitory ability towards HIF1 signal. [ABSTRACT FROM AUTHOR]

In nanoparticle-based drug delivery systems, dispersion stability is one of the most significant factors controlling drug efficacy and side effects. Herein, we synthesized guaiazulene derivatives-conjugated podophyllotoxin prodrugs and fabricated their nanoparticles (GA-CN-PPT nano-prodrugs). GA-CN-PPT nano-prodrugs were obtained with a size of about 100 nm and possessed high dispersion stability. The cytotoxicity was tunable by changing the length of the carbon chain linker. Notably, the release rate of PPT was the key factor for the anticancer activity of GA-CN-PPT nano-prodrugs. The nano-prodrugs could serve as a promising template for developing a novel delivery system using nano-prodrugs. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is one of the most frequent cancers worldwide, yet effective treatment remains a clinical challenge. Guaiazulene (GYZ), a cosmetic color additive, has previously been characterized as a potential antitumor agent due to observed anticancer effects. However, the efficacy of GYZ in the treatment of NSCLC and the involved molecular mechanisms remain largely unknown. Here, we indicated a role for GYZ in the suppression of NSCLC both in vitro and in vivo via triggering reactive oxygen species (ROS)-induced apoptosis. Concomitantly, GYZ induced complete autophagic flux in NSCLC cells via inhibiting the Akt/mTOR signaling pathway, which displayed cytoprotective effect against GYZ-induced growth suppression. Accompanied with autophagy inhibition obviously enhanced the effects of GYZ. Notably, GYZ acts synergistically with paclitaxel in the suppression of NSCLC in vitro. Together, our results for the first time reported that GYZ suppressed the proliferation of NSCLC and suggested a potential strategy for inhibiting NSCLC growth by combinational use of GYZ and autophagy inhibitors.

Guaiazulene, 1,4-dimethyl-7-isopropylazulene, is one of the non-benzenoid aromatic compounds consisting of fused of the seven- and the five-membered ring. Guaiazulene is an important natural product and having great potential due to its unique optical and electronic properties. In this study, a method for propargyl insertion into the C-4 methyl group of the guaiazulene is developed. A one-pot reaction of the guaiazulene, LDA, and propargyl bromide in THF affords the corresponding a new propargyl-azulene hybrid derivative. Additionally, Diels-Alder cycloaddition reaction between the propargyl-GA and tetraphenylcyclopentadienone was performed, and the cycloadduct was obtained with excellent yield. The structures of new compounds were elucidated on the basis of extensive spectroscopic (IR, NMR, and UV-vis) data analysis. This approach may be potentially useful for the development of the new azulene derivatives. [ABSTRACT FROM AUTHOR]

Abstract A natural essential oil component, guaiazulene (1,4-dimethyl-7-isopropylazulene, GAZ) has a low melting point of 30–33 °C, is oily at room temperature, is poorly soluble in water (0.663 μg/mL: 25 °C), and is difficult to handle. Therefore, the current study prepared a solid dispersion using β-cyclodextrin (βCD) and γ-cyclodextrin (γCD), and the physicochemical properties, solubility, and diffusibility of those dispersions were investigated. A physical mixture (PM) and a ground mixture (GM) were prepared using GAZ, βCD, and γCD. Physicochemical properties were evaluated using differential scanning calorimetry (DSC), X-ray diffraction (PXRD), near-infrared (NIR) absorption spectroscopy, and 1H-1H NOESY NMR (D 2 O) spectroscopy. In addition, solubility testing was conducted and DOSY NMR spectroscopy was performed. Evaluation of the solid state of the dispersions indicated that a GM of GAZ and βCD and a GM of GAZ and γCD formed a complex at a molar ratio of 1/1, suggesting intermolecular interaction between GAZ and CD. In addition, the GM of GAZ and βCD and the GM of GAZ and γCD had improved solubility compared to that of GAZ alone. Differences in solubility were thought to be affected by the physicochemical properties of CD, stability constants, and diffusibility. Inclusion complexes of GAZ and βCD and γCD resulted in improved thermal stability and solubility. Graphical abstract Image 1 Highlights • GAZ/CD inclusion complexes can be produced by combining GAZ, βCD and γCD at a molar ratio of 1/1 via co-grinding. • Differences in solubility were thought to be affected by the physicochemical properties of CD, stability constants, and diffusibility by DOSY NMR spectroscopy. • The form of CD used resulted in different physicochemical properties, and inclusion complexes of GAZ/βCD and GAZ/γCD resulted in improved thermal stability and solubility. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate for the cytotoxicity, genotoxicity and antioxidant/oxidant activity of GYZ on human peripheral blood lymphocytes (PBLs). Guaiazulene (GYZ) was added into culture tubes at various concentrations (0-400 µg/mL-1). Cytotoxicity against the human lymphocytes cultures was examined by lactate dehydrogenase (LDH) release assay. The proliferative response was estimated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Antioxidant/oxidant activity was evaluated by measuring the total oxidant status (TOS) and total antioxidant capacity (TAC) levels. Micronucleus (MN) and chromosomal aberration (CA) tests were used in genotoxicity studies. The results showed that GYZ caused cytotoxicity in the PBLs at high concentrations, but TOS level were not affected, while the level of TAC was significantly increased. GYZ also did not induce chromosomal aberrations when compared to that of the control group. Results this study clearly revealed that GYZ was not genotoxic and also increased the capacity of the antioxidant in the culture of human PBL cells. This report is first report on the impact of GYZ on human PBL cells.

With the scientific community becoming increasingly aware of the need for greener products and methodologies, the optimization of synthetic design is of greater importance. Building on experimental data collected from a synthesized guaiazulene derivative, a series of analogous structures were investigated with time-dependent density functional theory (TD-DFT) methods in an effort to identify a compound with desirable photophysical properties. This in silico analysis may eliminate the need to synthesize numerous materials that, when investigated, do not possess viable characteristics. The synthesis of several computationally investigated structures revealed discrepancies in the calculation results. Further refined computational study of the molecules yielded results closer to those observed experimentally and helps set the stage for computationally guided design of organic photonic materials. Three novel derivatives were synthesized from guaiazulene, a naturally occurring chromophore, exhibiting distinct halochromic behaviour, which may have potential in a switchable optoelectronic system or combined with a photoacid generator for data storage. The protonated forms were readily excitable via two-photon absorption.

Thousands of people worldwide pass away yearly due to neurological disorders, cardiovascular illnesses, cancer, metabolic disorders, and microbial infections. Additionally, a sizable population has also been impacted by hepatotoxicity, ulcers, gastroesophageal reflux disease, and breast fissure. These ailments are likewise steadily increasing along with the increase in life expectancy. Finding innovative therapies to cure and consequently lessen the impact of these ailments is, therefore, a global concern. All provided literature on Guaiazulene (GA) and its related compounds were searched using various electronic databases such as PubMed, Google Scholar, Web of Science, Elsevier, Springer, ACS, CNKI, and books via the keywords Guaiazulene, Matricaria chamomilla, GA-related compounds, and Guaiazulene analogous. The FDA has approved the bicyclic sesquiterpene GA, commonly referred to as azulon or 1,4-dimethyl-7-isopropylazulene, as a component in cosmetic colorants. The pleiotropic health advantages of GA and related substances, especially their antioxidant and anti-inflammatory effects, attracted a lot of research. Numerous studies have found that GA can help to manage various conditions, including bacterial infections, tumors, immunomodulation, expectorants, diuretics, diaphoresis, ulcers, dermatitis, proliferation, and gastritis. These conditions all involve lipid peroxidation and inflammatory response. In this review, we have covered the biomedical applications of GA. Moreover, we also emphasize the therapeutic potential of guaiazulene derivatives in pre-clinical and clinical settings, along with their underlying mechanism(s). GA and its related compounds exhibit therapeutic potential in several diseases. Still, it is necessary to investigate their potential in animal models for various other ailments and establish their safety profile. They might be a good candidate to advance to clinical trials. [Display omitted] [ABSTRACT FROM AUTHOR]

Background & Aims: Gastroesophageal reflux disease (GERD) therapy is challenging and suppression of acid secretion or prokinetics do not cure all cases. Some drugs with protective action on the esophageal mucosa have been used alternatively or in association with proton pump inhibitors (PPIs) and/or prokinetics. The Romanian Society of Neurogastroenterology undertook an Evidence-Based analysis, from which this position paper evolved. Methods: We performed a systematic literature search in PubMed until October 2015, using the terms: sucralfate, guaiazulene, gaiazulene, dimethicone, alginate, antacids and gastroesophageal reflux. Forty-seven papers were included and analyzed. Several statements were elaborated regarding the use of these drugs in GERD. The evidence and recommendations were discussed between the authors. Results: There is evidence in the medical literature suggesting the benefit of these drugs in GERD. In patients with persistent or mild reflux symptoms antacids rapidly relieve heartburn. Alginate-antacid combination is superior both over placebo and antacids to treat mild reflux symptoms, and can be used to treat persistent reflux symptoms despite acid suppressant therapy. Sucralfate is superior over placebo in alleviating GERD symptoms and can be used as maintenance therapy. Guaiazulene-dimethicone improves the quality of life in patients with GERD. Conclusions: Drugs used to protect the esophageal mucosa against acid are useful in alleviating chronic heartburn, especially in patients with mild reflux symptoms. [ABSTRACT FROM AUTHOR]

Recent studies showed that Guaiazulene (GA) and Sodium guaiazulene sulfonate (GAS-Na) have good anti-gastric ulcer effect. Here, two series of GA derivatives were synthesized and evaluated for their anti-gastric ulcer activity. The data obtained from in vivo testing of these compounds in a rodent ethanol-induced stomach injury model are discussed. Among the tested compounds, A1, A4, and A9 (ulcer index: 1.125 ± 1.246**, 1.714 ± 0.756*, 1.875 ± 1.126*) exhibited better anti-gastric ulcer activity than the positive control Omeprazole (2.005 ± 1.011*). The information got from these studies and the results of 3D-SAR investigation may be useful in the design of novel anti-gastric ulcer agents. [ABSTRACT FROM AUTHOR]

Guaiazulene and related derivatives were famous for diverse biological activities. In an effort to discover new highly efficient candidate drugs derived from guaiazulene, four series of guaiazulene derivatives were designed, synthesized, and evaluated for antiproliferation, antiviral, anti-inflammatory and peroxisome proliferators-activated receptor γ (PPARγ) signalling pathway agonist activities. Among them, two guaiazulene condensation derivatives showed selective cytotoxic activities towards K562 cell with IC 50 values 5.21 μM and 5.14 μM, respectively, accompanied by slight effects on normal cell viability. For the first time, one guaiazulene derivative from series I exhibited potent antiviral activity towards influenza A virus with IC 50 of 17.5 μM. A guaiazulene-based chalcone showed higher anti-inflammatory activity than positive drug indomethacin with an inhibitory rate of 34.29 % in zebrafish model in vivo. One guaiazulene-based flavonoid could strongly agitate PPARγ pathway at 20 μM, indicating the potential of guaiazulene derivatives to reduce obesity development and ameliorate hepatic steatosis. Preliminary in silico ADME studies predicted the excellent drug-likeness properties of bioactive guaiazulene derivatives., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Abstract: Wittig reaction of (E)-3-(3-guaiazulenyl)propenal (11) with (3-guaiazulenylmethyl)triphenylphosphonium bromide (9) in ethanol containing NaOEt at 25 °C for 24 h under argon gives the title new (2E,4E)-1,3-butadiene derivative 4, in 33% isolated yield, which upon treatment with hexafluorophosphoric acid (i.e., 65% HPF6 aqueous solution) in tetrahydrofuran (=THF) at 25 °C for 1 h under aerobic conditions affords a new air (two-electron) oxidation product (E)-ethylene-1,2-bis(3-guaiazulenylmethylium) bis(hexafluorophosphate) (14), quantitatively, and further, zinc-reduction of 14 in trifluoroacetic acid (=CF3COOH) at 0 °C for 1 h under argon reverts 4, quantitatively. Along with the above interesting results, our discovered another preparation method, spectroscopic properties, crystal structure, and electrochemical behavior of 4, which serves as a strong two-electron donor and acceptor, compared with those of the previously reported (E)-1,2-di(3-guaiazulenyl)ethylene (3) are documented in detail. [Copyright &y& Elsevier]

Abstract: Wittig reactions of 2-furaldehyde (20) [and thiophene-2-carbaldehyde (21)] with (3-guaiazulenylmethyl)triphenylphosphonium bromide (19) in ethanol containing NaOEt at 25 °C for 24 h under argon give (E)-1-(2-furyl)-2-(3-guaiazulenyl)ethylene (22E) and (E)-1-(2-thienyl)-2-(3-guaiazulenyl)ethylene (23E) in 53 and 36% yields. Similarly, Wittig reactions of 3-furaldehyde (29) [and thiophene-3-carbaldehyde (30)] with 19 under the same reaction conditions as for 20 and 21 afford (E)-1-(3-furyl)-2-(3-guaiazulenyl)ethylene (31E) and (E)-1-(3-thienyl)-2-(3-guaiazulenyl)ethylene (32E) in 32 and 46% yields. Molecular structures and characteristic properties as well as preparation of the title E (i.e., one of the geometrical isomers) forms, with a view to comparative study, are reported. Moreover, reactions of those conjugated π-electron systems with TCNE (=tetracyanoethylene) in benzene [and in DMF (=N,N-dimethylformamide)] at 25 °C for 24 h under argon yield unique products, possessing interesting molecular structures, respectively, whose characteristic properties and crystal structures are documented, also. [Copyright &y& Elsevier]

Abstract: Reaction of guaiazulene (8) with 2,3-dihydroxybenzaldehyde (9) in methanol in the presence of hexafluorophosphoric acid (i.e., 65% aqueous solution) at 25°C for 2 h gives (3-guaiazulenyl)(2,3-dihydroxyphenyl)methylium hexafluorophosphate (13) in 86% yield. Similarly, reaction of 8 with 2-hydroxy-3-methoxybenzaldehyde (10) [or 3,4-dihydroxybenzaldehyde (11) or 4-hydroxy-3-methoxybenzaldehyde (12)] under the same reaction conditions as for 9 affords the corresponding monocarbenium ion compound 14 (63% yield) [or 15 (43% yield) or 16 (77% yield)], respectively, each product of which is stabilized by 3-guaiazulenyl and dihydroxyphenyl (or hydroxymethoxyphenyl) groups. A facile preparation and crystal structures as well as spectroscopic, chemical, and electrochemical properties of 13–16, possessing two interesting resonance structures, respectively, i.e., a protonated o- (or p-) benzoquinonemethide form and a 3-guaiazulenylium ion form, in a solution of acetonitrile and further, in a single crystal, are reported. [Copyright &y& Elsevier]

Abstract: 5-Isoproyl-3,8-dimethylazulene derivatives were synthesized and evaluated for antigastric ulcer activity in vivo. Some of them possess the best activity against gastric ulcer with ulcer index values lower than the drug reference (omeprazole). The structure–activity relationship (SAR) shows that the lipophilic flat structure contributes to quite potent antigastric ulcer activity. [Copyright &y& Elsevier]

Abstract: Reaction of azulene (1) with 1,2-bis[4-(dimethylamino)phenyl]-1,2-ethanediol (2) in a mixed solvent of methanol and acetonitrile in the presence of 36% hydrochloric acid at 60 °C for 3 h gives 2-(azulen-1-yl)-1,1-bis[4-(dimethylamino)phenyl]ethylene (3) (8% yield), 1-(azulen-1-yl)-(E)-1,2-bis[4-(dimethylamino)phenyl]ethylene (4) (28% yield), and 1,3-bis{2,2-bis[4-(dimethylamino)phenyl]ethenyl}azulene (5) (9% yield). Besides the above products, this reaction affords 1,1-di(azulen-1-yl)-2,2-bis[4-(dimethylamino)phenyl]ethane (6) (15% yield), a meso form (1R,2S)-1,2-di(azulen-1-yl)-1,2-bis[4-(dimethylamino)phenyl]ethane (7) (6% yield), and the two enantiomeric forms (1R,2R)- and (1S,2S)-1,2-di(azulen-1-yl)-1,2-bis[4-(dimethylamino)phenyl]ethanes (8) (6% yield). Furthermore, addition reaction of 3 with 1 under the same reaction conditions as the above provides 6, in 46% yield, which upon oxidation with DDQ (=2,3-dichloro-5,6-dicyano-1,4-benzoquinone) in dichloromethane at 25 °C for 24 h yields 1,1-di(azulen-1-yl)-2,2-bis[4-(dimethylamino)phenyl]ethylene (9) in 48% yield. Interestingly, reaction of 1,1-bis[4-(dimethylamino)phenyl]-2-(3-guaiazulenyl)ethylene (11) with 1 in a mixed solvent of methanol and acetonitrile in the presence of 36% hydrochloric acid at 60 °C for 3 h gives guaiazulene (10) and 3, owing to the replacement of a guaiazulen-3-yl group by an azulen-1-yl group, in 91 and 46% yields together with 5 (19% yield) and 6 (13% yield). Similarly, reactions of 2-(3-guaiazulenyl)-1,1-bis(4-methoxyphenyl)ethylene (12) and 1,1-bis{4-[2-(dimethylamino)ethoxy]phenyl}-2-(3-guaiazulenyl)ethylene (13) with 1 under the same reaction conditions as the above provide 10, 2-(azulen-1-yl)-1,1-bis(4-methoxyphenyl)ethylene (16), and 1,3-bis[2,2-bis(4-methoxyphenyl)ethenyl]azulene (17) (93, 34, and 19% yields) from 12 and 10 and 2-(azulen-1-yl)-1,1-bis{4-[2-(dimethylamino)ethoxy]phenyl}ethylene (18) (97 and 58% yields) from 13. [Copyright &y& Elsevier]

Abstract: Guaiazulene (GA) is widely used as a natural ingredient in many health care products and solutions. Although it has been reported to have interesting biological effects, GA and azulene derivatives have been proven to be cytotoxic against normal human cells and human tumor cells; moreover, guaiazulene has shown photomutagenic properties on bacterial strains. Therefore, we evaluated and compared the cytotoxicity of GA at different concentrations on human gingival fibroblast (HGF) cell cultures under normal conditions and under UV irradiation (UV-A dose: 6.4J/cm2). The compound tested was found to significantly reduce cell viability (dose-dependent trend, IC50 72.1μM), decrease protein procollagen α1 type I synthesis, a marker for HGF protein, and COL1A1 mRNA expression. The cytotoxic effects were accompanied by activation of an intrinsic apoptotic pathway, studied using transmission electron microscopy (TEM) and caspase-3 activation. The light exposure of the cell culture treated decreased GA-induced cell death (IC50 128.9μM), suggesting a photoprotective effect due to the photodegradation of the toxic agent, guaiazulene. Furthermore, the products of the photodegradation reaction of GA proved not to be toxic against HGFs. [ABSTRACT FROM AUTHOR]

Abstract: Wittig reaction of 3-[4-(dimethylamino)phenyl]propanal (5) with (3-guaiazulenylmethyl)triphenylphosphonium bromide (4) in ethanol containing NaOEt at 25°C for 24h under argon gives the title (2E,4E)-1,3-butadiene derivative 6E in 19% isolated yield. Spectroscopic properties, crystal structure, and electrochemical behavior of the obtained new extended π-electron system 6E, compared with those of the previously reported (E)-2-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)ethylene (12), are documented. Furthermore, reaction of 6E with 1,1,2,2-tetracyanoethylene (TCNE) in benzene at 25°C for 24h under argon affords a new Diels–Alder adduct 8 in 59% isolated yield. Along with spectroscopic properties of the [π4+π2] cycloaddition product 8, the crystal structure, possessing a cis-3,6-substituted 1,1,2,2-tetracyano-4-cyclohexene unit, is shown. Moreover, reaction of 6E with (E)-1,2-dicyanoethylene (DCNE) under the same reaction conditions as the above gives no product; however, this reaction in p-xylene at reflux temperature (138°C) for four days under argon affords a new Diels–Alder adduct 9 in 54% isolated yield. Although reaction of 6E with DCNE in toluene at reflux temperature (110°C) for four days under argon provides 9 very slightly, reaction of 6E with dimethyl acetylenedicarboxylate (DMAD) in toluene at reflux temperature for two days under argon yields a new Diels–Alder adduct 10, in 58% isolated yield, which upon oxidation with MnO2 in CH2Cl2 at 25°C for 1h gives 11, converting a (CH3)2N-4″ into CH3NH-4″ group, in 37% isolated yield. The crystal structure of 11 supports the molecular structure 10 possessing a partial structure cis-3,6-substituted 1,2-dimethoxycarbonyl-1,4-cyclohexadiene. The title basic studies on the above are reported in detail. [Copyright &y& Elsevier]

Abstract: Azulene and guaiazulene are popular ingredients in beauty, cosmetic, skin, and body care products. We previously determined that these chemicals are photomutagenic in Salmonella and phototoxic, causing DNA damage in human Jurkat T-cells. In this study we report that photoirradiation of azulene and guaiazulene, respectively, by UVA light at 0–70J/cm2 in the presence of a lipid, methyl linoleate, resulted in lipid peroxidation in a light dose–responsive manner. When irradiated in the presence of sodium azide or superoxide dismutase, the level of lipid peroxidation decreased, indicating that lipid peroxidation is mediated by free radical and superoxide in particular. In contrast, lipid peroxidation was not enhanced when deuterated methanol was incorporated to the system, which suggests that singlet oxygen is not a predominant photo-induced product. Electron spin resonance (ESR) spin trapping study confirmed that photoirradiation of azulene predominantly generated superoxide and none or very low quantity of singlet oxygen was produced. These results indicate that photoirradiation of azulene and guaiazulene by UVA light generates reactive oxygen species (ROS), and induces lipid peroxidation when irradiation in the presence of a lipid. These results implicate that azulene and guaiazulene are phototoxic when exposed to sunlight. [Copyright &y& Elsevier]

Coloring carbohydrate derivatives by a chromophore tag greatly facilitates all purification steps during a synthetic sequence, according to a methodology called “chromophore-supported purification” (CSP). Herein an Fmoc-analogous blue protective group for CSP is introduced, based on guaiazulene. Following a mechanistic rational, the synthesis and introduction of this new protecting group is shown, together with its removal under variable conditions and its application for the synthesis of glycoclusters of a glycopeptide and glycopeptoid type. [ABSTRACT FROM AUTHOR]

Abstract: A liquid chromatographic method with UV detection (HPLC-DAD) and a gas chromatographic method coupled with mass spectrometry (GC–MS) have been developed for the determination of guaiazulene (GA) in complex matrices such as creams and toothpastes. A solid phase extraction (SPE) sample pre-treatment on a polymeric sorbent (Strata-X polymer) was applied before the HPLC analyses, which were performed on a XTerra™ C8 stationary phase, using a mobile phase consisting of acetonitrile–water 50:50 (v/v). For GC–MS analyses, solid–liquid extraction (creams) and SPE (toothpastes) were applied. The proposed methods, based on techniques with different selectivity, were validated and both proved to be suitable to obtain an unambiguous identification and reliable determination of GA in commercial health care products (creams and toothpastes), giving concordant results. Moreover, the described methods can offer a useful analytical support for photostability studies of GA, a photolabile natural compound, in creams. [Copyright &y& Elsevier]

The molecular and crystal structure of dimethyl-(1,4-dimethyl-7-ethylazulyl)-sulfonium perchlorate and dimethyl-(1,4-dimethyl-7-isopropylazulyl)-sulfonium perchlorate was determined by X-ray diffraction analysis. Their crystal structure is mainly determined by C-H...π intermolecular interactions. [ABSTRACT FROM AUTHOR]

Abstract: Reaction of guaiazulene (1) with 2-methoxybenzaldehyde (2) in methanol in the presence of hexafluorophosphoric acid at 25°C for 2h gives (3-guaiazulenyl)(2-methoxyphenyl)methylium hexafluorophosphate (5a) in 93% yield. Similarly, reaction of 1 with 3-methoxybenzaldehyde (3) or 4-methoxybenzaldehyde (4) under the same reaction conditions as for 2 affords (3-guaiazulenyl)(3-methoxyphenyl)methylium hexafluorophosphate (6) (91% yield) or (3-guaiazulenyl)(4-methoxyphenyl)methylium hexafluorophosphate (7) (97% yield). The crystal structures as well as the spectroscopic, electrochemical, and chemical properties of these monocarbenium-ion compounds, possessing interesting resonance forms, stabilized by the 3-guaiazulenyl and anisyl (i.e., 2-, 3-, or 4-methoxyphenyl) groups are reported. [Copyright &y& Elsevier]

Abstract: Reaction of azulene (1) with all-trans-retinal in diethyl ether in the presence of hexafluorophosphoric acid at −10°C for 1h in a dark room gives the corresponding monocarbenium-ion compound, (2E,4E,6E,8E)-1-azulenyl-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraen-1-ylium hexafluorophosphate (3), in 74% isolated yield. The spectroscopic, chemical, and electrochemical properties of 3 compared with those of the previously-documented (2E,4E,6E,8E)-1-(3-guaiazulenyl)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraen-1-ylium hexafluorophosphate (4) are reported. Along with the above delocalized monocarbenium-ion compounds 3 and 4, stabilized by the expanded π-electron systems possessing an azulenyl (or 3-guaiazulenyl) group, an efficient preparation as well as the spectroscopic, chemical, and electrochemical properties of (2E)-1-azulenyl-3-phenyl-2-propen-1-ylium and (2E)-1-(3-guaiazulenyl)-3-phenyl-2-propen-1-ylium hexafluorophosphates (5 and 6) (90 and 96% isolated yields), having a similar partial structure [i.e., the (2E)-1-azulenyl-2-propen-1-ylium-ion or (2E)-1-(3-guaiazulenyl)-2-propen-1-ylium-ion part] to those of 3 and 4, is documented. Moreover, the crystal structure of 6, whose carbenium-ion framework is planar, is shown. [Copyright &y& Elsevier]

Abstract: Reaction of guaiazulene (1) with thiophene-2,5-dicarbaldehyde (2) in methanol in the presence of hexafluorophosphoric acid at 25°C for 3h gives as high as 90% isolated yield of the delocalized dicarbenium-ion compound, 2,5-thienylenebis(3-guaiazulenylmethylium) bis(hexafluorophosphate) (3). Similarly, reaction of 1 with furan-2,5-dicarbaldehyde (4) under the same conditions as the above reaction affords the corresponding dicarbenium-ion compound, 2,5-furylenebis(3-guaiazulenylmethylium) bis(hexafluorophosphate) (5), in 84% isolated yield. Along with a facile preparation and the spectroscopic and electrochemical properties of 3 and 5, comparative studies on the 1H and 13C NMR spectral and chemical properties of 3 and 5 with those of the delocalized mono- and dicarbenium-ion compounds [i.e., (3-guaiazulenyl)(2-thienyl)methylium hexafluorophosphate (7), (2-furyl)(3-guaiazulenyl)methylium hexafluorophosphate (9), α,α′-bis(3-guaiazulenylmethylium) bis(tetrafluoroborate) (10), 1,2-phenylenebis(3-guaiazulenylmethylium) bis(hexafluorophosphate) (11), and 1,4-phenylenebis(3-guaiazulenylmethylium) bis(tetrafluoroborate) (12)] are reported. Moreover, referring to the results of the X-ray crystallographic analyses of 7, 9, 11, and 12, the optimized 2,5-thienylenebis(3-guaiazulenylmethylium)- and 2,5-furylenebis(3-guaiazulenylmethylium)-ion structures for 3 and 5, calculated by a WinMOPAC (version 3.0) program using PM3 as a semiempirical Hamiltonian, are described. [Copyright &y& Elsevier]

Abstract: Reaction of guaiazulene (1) with o-formylbenzoic acid (2) in diethyl ether in the presence of hexafluorophosphoric acid at 25°C for 90min gives the corresponding monocarbenium-ion compound, [2-(carboxy)phenyl](3-guaiazulenyl)methylium hexafluorophosphate (3), quantitatively, which upon treatment with aq NaHCO3 leads to 3-(3-guaiazulenyl)-2-benzofuran-1(3H)-one (5) in 96% isolated yield. Similarly, reaction of 1 with 2 in methanol under the same conditions as the above reaction affords two kinds of inseparable monocarbenium-ion compounds, 3 and (3-guaiazulenyl)[2-(methoxycarbonyl)phenyl]methylium hexafluorophosphate (4) with an equilibrium between them, which upon reaction with a solution of NaBH4 in ethanol at 25°C for 30min leads to 5 in 46% isolated yield and (3-guaiazulenyl)[2-(methoxycarbonyl)phenyl]methane (6) in 37% isolated yield. Along with the 1H and 13C NMR spectral properties of a solution of 5 in trifluoroacetic acid-d 1 at 25°C, whose molecular structure is converted to a ca. 1:1 equilibrium mixture of 7 possessing a partial structure of the 3-guaiazulenylmethylium-ion and 8 possessing a partial structure of the 3-guaiazulenium-ion, comparative studies on the 1H and 13C NMR spectral properties of 7 and 8 with those of the monocarbenium-ion compound, (3-guaiazulenyl)[4-(methoxycarbonyl)phenyl]methylium hexafluorophosphate (A), 5, and 6 are reported. From these NMR studies, it can be inferred that the positive charge of the 3-guaiazulenylmethylium-ion part of 7 apparently is transferred to the seven-membered ring, generating a resonance form of the 3-guaiazulenylium-ion structure η′, and the same result can be inferred for the previously documented monocarbenium-ion compounds A–I. Moreover, referring to a comparative study on the C–C bond lengths of A observed by the X-ray crystallographic analysis with those of the optimized (3-guaiazulenyl)[4-(methoxycarbonyl)phenyl]methylium-ion structure for A calculated by a WinMOPAC (Ver. 3.0) program using PM3, AM1, or MNDOD as a semiempirical Hamiltonian, the optimized [2-(carboxy)phenyl](3-guaiazulenyl)methylium-ion structure for 3 calculated using PM3 is described. [Copyright &y& Elsevier]

Abstract: Reactions of the title meso forms, (1R,2S)-1,2-di(2-furyl)-1,2-di(3-guaiazulenyl)ethane ( 1 ) and (1R,2S)-1,2-di(3-guaiazulenyl)-1,2-di(2-thienyl)ethane ( 2 ), with a two molar amount of TCNE in benzene at 25°C for 5h (for 1 ) and 48h (for 2 ) under oxygen give new compounds, 2,2,3,3-tetracyano-4-(2-furyl)-8-isopropyl-6-methyl-1,4-dihydrocyclohepta[c,d]azulene ( 3 ) and 2,2,3,3-tetracyano-8-isopropyl-6-methyl-4-(2-thienyl)-1,4-dihydrocyclohepta[c,d]azulene ( 4 ), respectively, in 74 and 21% isolated yields. Comparative studies on the above reactions as well as the spectroscopic properties of the unique products 3 and 4 , possessing interesting molecular structures, are reported and, further, a plausible reaction pathway for the formation of these products is described. [Copyright &y& Elsevier]