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1.
Molecules ; 29(11)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38893479

RESUMO

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.


Assuntos
Azulenos , Óleos Voláteis , Oxirredução , Azulenos/química , Óleos Voláteis/química , Fotólise , Raios Ultravioleta , Antioxidantes/química , Achillea/química , Artemisia/química , Espectrometria de Massas em Tandem , Cromatografia Gasosa-Espectrometria de Massas
2.
Molecules ; 29(9)2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38731510

RESUMO

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.


Assuntos
Antineoplásicos , Azulenos , Dermatopatias , Azulenos/química , Azulenos/uso terapêutico , Humanos , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Dermatopatias/tratamento farmacológico , Neoplasias/tratamento farmacológico , Animais
3.
Chemistry ; 30(32): e202401156, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38564298

RESUMO

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.


Assuntos
Azulenos , Reação de Cicloadição , Estereoisomerismo , Catálise , Azulenos/química , Humanos , Linhagem Celular Tumoral , Estrutura Molecular
4.
ScientificWorldJournal ; 2024: 9844242, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38390436

RESUMO

Indonesia is an important essential oil-exporting country globally, where 40 types of essential oils have been traded on the international market and are products of Indonesia. However, the quality and quantity of patchouli oil produced in Indonesia are still low. Most essential oil processing units use simple or traditional technology and generally have limited production capacity. This study aimed to obtain the optimum water flow rate in a condenser system for patchouli oil production in Maluku, Indonesia. Patchouli oil extraction from fresh patchouli leaves and twigs was carried out by increasing the condenser water discharge rate. Patchouli oil extraction with a condenser cooling water discharge treatment of 1.74 L/min and drying time for 5 days produced the highest patchouli oil yield of 1.4%. The greater the condenser water discharge rate, the better the yield and accumulation of patchouli oil recovery obtained. In addition, based on the results of the analysis of the composition of patchouli oil compounds with GCMS, it can be seen that 13 compounds can be detected in patchouli oil. The three main components of patchouli oil in all condenser cooling water treatments were alpha-guaiene, delta-guaiene, and patchouli alcohol. Considering the results of all parameters mentioned above, the treatment of the condenser cooling water discharge of 1.74 L/min and drying time for 5 days increases the quality and quantity of patchouli oil.


Assuntos
Azulenos , Óleos Voláteis , Pogostemon , Sesquiterpenos de Guaiano , Destilação , Cromatografia Gasosa-Espectrometria de Massas , Óleos Voláteis/análise
5.
Cancer Biol Med ; 21(2)2024 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-38172525

RESUMO

OBJECTIVE: Neutrophils are one of the most predominant infiltrating leukocytes in lung cancer tissues and are associated with lung cancer progression. How neutrophils promote lung cancer progression, however, has not been established. METHODS: Kaplan-Meier plotter online analysis and tissue immunohistochemistry were used to determine the relationship between neutrophils and overall survival in lung cancer patients. The effect of neutrophils on lung cancer was determined using the Transwell migration assay, a proliferation assay, and a murine tumor model. Gene knockdown was used to determine poly ADP-ribose polymerase (PARP)-1 function in lung cancer-educated neutrophils. Western blot analysis and gelatin zymography were used to demonstrate the correlation between PARP-1 and matrix metallopeptidase 9 (MMP-9). Immunoprecipitation coupled to mass spectrometry (IP/MS) was used to identify the proteins interacting with PARP-1. Co-immunoprecipitation (Co-IP) was used to confirm that PARP-1 interacts with arachidonate 5-lipooxygenase (ALOX5). Neutrophil PARP-1 blockage by AG14361 rescued neutrophil-promoted lung cancer progression. RESULTS: An increased number of infiltrating neutrophils was negatively associated with overall survival in lung cancer patients (P < 0.001). Neutrophil activation promoted lung cancer cell invasion, migration, and proliferation in vitro, and murine lung cancer growth in vivo. Mechanistically, PARP-1 was shown to be involved in lung cancer cell-induced neutrophil activation to increase MMP-9 expression through interacting and stabilizing ALOX5 by post-translational protein modification (PARylation). Blocking PARP-1 by gene knockdown or AG14361 significantly decreased ALOX5 expression and MMP-9 production, and eliminated neutrophil-mediated lung cancer cell invasion and in vivo tumor growth. CONCLUSIONS: We identified a novel mechanism by which PARP-1 mediates lung cancer cell-induced neutrophil activation and PARylates ALOX5 to regulate MMP-9 expression, which exacerbates lung cancer progression.


Assuntos
Benzodiazepinas , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Araquidonato 5-Lipoxigenase/uso terapêutico , Azulenos , Linhagem Celular Tumoral , Pulmão , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/uso terapêutico , Invasividade Neoplásica , Processos Neoplásicos , Neutrófilos/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases
6.
Cell Death Dis ; 15(1): 85, 2024 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-38267463

RESUMO

The global burden of colorectal cancer (CRC) has rapidly increased in recent years. Dysregulated cholesterol homeostasis facilitated by extracellular matrix (ECM) remodeling transforms the tumor microenvironment. Collagen I, a major with ECM component is highly expressed in colorectal tumors with infiltrative growth. Although oxysterol binding protein (OSBP)-related proteins accommodate tumorigenesis, OSBPL2, which is usually involved in deafness, is not associated with CRC progression. Therefore, we aimed to investigate the pathological function of OSBPL2 and identify the molecular link between ECM-Collagen I and OSBPL2 in CRC to facilitate the development of new treatments for CRC. OSBPL2 predicted a favorable prognosis in stage IV CRC and substantially repressed Collagen I-induced focal adhesion, migration, and invasion. The reduction of OSBPL2 activated ERK signaling through the VCAN/AREG/EREG axis during CRC growth, while relying on PARP1 via ZEB1 in CRC metastasis. OSBPL2 defect supported colorectal tumor growth and metastasis, which were suppressed by the ERK and PARP1 inhibitors SCH772984 and AG14361, respectively. Overall, our findings revealed that the Collagen I-induced loss of OSBPL2 aggravates CRC progression through VCAN-mediated ERK signaling and the PARP1/ZEB1 axis. This demonstrates that SCH772984 and AG14361 are reciprocally connective therapies for OSBPL2Low CRC, which could contribute to further development of targeted CRC treatment.


Assuntos
Neoplasias Colorretais , Receptores de Esteroides , Humanos , Benzodiazepinas , Azulenos , Colágeno Tipo I , Neoplasias Colorretais/genética , Microambiente Tumoral , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Versicanas , Poli(ADP-Ribose) Polimerase-1
7.
J Agric Food Chem ; 71(30): 11607-11614, 2023 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-37437259

RESUMO

Safety concerns in the food industry have increased the demand for natural food colorants. However, the application ranges of natural blue colorants are insufficient because they are scarce in nature, and the currently available natural blue dyes are limited to water-soluble products. In this study, we investigated a fat-soluble azulene derivative isolated from the mushroom Lactarius indigo as a potential candidate for a natural blue colorant. We developed its first total synthesis, where the azulene skeleton was constructed from a pyridine derivative and an ethynyl group was converted into an isopropenyl group using zirconium complexes. Moreover, nanoparticles of the azulene derivative were prepared via reprecipitation method, and their colorant ability was investigated in aqueous solutions. The new candidate food colorant exhibited a deep-blue color in an organic solvent and aqueous dispersion.


Assuntos
Azulenos , Corantes de Alimentos , Corantes de Alimentos/análise , Corantes , Água
8.
J Org Chem ; 88(13): 7929-7939, 2023 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-37341723

RESUMO

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.


Assuntos
Azulenos , Quinolinas , Azulenos/química , Quinolinas/química , Fluorescência
9.
Sci Rep ; 13(1): 10260, 2023 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-37355719

RESUMO

Herein, we investigated the thermodynamic stability and opto-electronic properties of a newly BN-doped azulene. The gas-phase formation enthalpies of 11 BN-doped azulene were calculated by the atomization energy method using three computational models (CBS-APNO, CBS-QB3, and G3MP2). The results suggest that AZ-1N9B exhibits the highest stability among the studied isomers. On the other hand, AZ-1B9N and AZ-9B10N display nearly equal stability with relative energies of 19.36 and 19.82 kcal/mol at CBS-QB3, respectively. These two isomers are considered the least stable among the investigated compounds. The frontier molecular orbitals (FMO), ionization energies (IE), and electron affinities (EA) of these isomers were discussed. Additionally, the electronic absorption spectra of the BN-doped azulenes were computed using the TD-B3LYP/6-31 + G(d,p) and TD-CAM-B3LYP level of theories, which using a long-range corrected hybrid functional in acetone. The computational results obtained in this research are align closely with the existing literature, thereby reinforcing the credibility and reliability of our findings.


Assuntos
Azulenos , Reprodutibilidade dos Testes , Termodinâmica , Isomerismo
10.
Bioorg Med Chem ; 88-89: 117325, 2023 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-37209639

RESUMO

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.


Assuntos
Azulenos , Orexinas , Receptores de Orexina/metabolismo , Azulenos/química
11.
Angew Chem Int Ed Engl ; 62(25): e202218839, 2023 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-36897123

RESUMO

We report here the one-pot synthesis of benzo[1,2-a : 3,4-a' : 5,6-a'']triazulene (BTA), wherein three azulene units are embedded through a tandem reaction comprising two steps, Suzuki coupling and Knoevenagel condensation, between a readily available triborylated truxene precursor and 8-bromo-1-naphthaldehyde. Its nitration leads to a regioselective trinitrated product, namely, BTA-NO2 . Single-crystal X-ray crystallography revealed that the superstructure of BTA consists of a dimer stacked by two enantiomeric helicene conformers, while that of BTA-NO2 consists of an unprecedented π-tetramer stacked from two enantiomeric dimers, that is, four distinct helicene conformers. Both compounds show excellent stability and fluorescence with large Stokes shifts of up to 5100 cm-1 . In addition, BTA-NO2 exhibits a unique solvatochromic effect in different solvents and hydrogen-bonding-induced emission transfer in different ratios of THF/H2 O solutions.


Assuntos
Azulenos , Dióxido de Nitrogênio , Cristalografia por Raios X , Solventes/química
12.
J Vet Dent ; 40(2): 154-163, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36721365

RESUMO

This study evaluated the efficacy of photodynamic therapy using the photosensitizer azulene and low-intensity laser associated with standard root chemical-surgical preparation (performed with 0.5% sodium hypochlorite) in dogs. Twenty animals from the Veterinary Hospital of the School of Veterinary Medicine and Animal Science, University of São Paulo (HOVET-FMVZ/USP) and treated at the Compared Dentistry Laboratory (Laboratório de Odontologia Veterinária [LOC]-FMVZ/USP) were included. Each subject possessed one single rooted tooth with complete root formation, pulp necrosis, complicated crown fracture and periapical bone rarefaction at the time of the radiographic examination. The endodontic treatment was performed in all dogs, which were divided into two equal groups. For group one, the standard chemical-surgical preparation was followed by the photodynamic therapy to evaluate the role of azulene after instrumentation. For group two, the photodynamic therapy was followed by the standard chemical-surgical preparation to evaluate the antimicrobial action of azulene before instrumentation. The results show that intracanal photodynamic therapy is efficient in eliminating unspecified bacterial and Enterococcus organism loads. In addition, this therapeutic modality reduces yeast contamination. The photodynamic therapy showed similar efficacy compared to standard chemical-surgical preparation. The application order of therapeutic modalities does not influence intracanal disinfection in both cases. This study shows that photodynamic therapy with low-intensity laser and azulene as a photosensitizer is a feasible alternative for improving treatment outcomes in routine practice of veterinary dentistry.


Assuntos
Azulenos , Fármacos Fotossensibilizantes , Cães , Animais , Fármacos Fotossensibilizantes/uso terapêutico , Cavidade Pulpar , Preparo de Canal Radicular/métodos , Preparo de Canal Radicular/veterinária , Lasers
13.
Life Sci ; 316: 121389, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36646376

RESUMO

BACKGROUND: 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. METHODS AND MATERIALS: 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. RESULTS: 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). CONCLUSION: 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.


Assuntos
Neoplasias , Úlcera , Animais , Úlcera/tratamento farmacológico , Azulenos/farmacologia , Azulenos/uso terapêutico , Sesquiterpenos de Guaiano/farmacologia , Sesquiterpenos de Guaiano/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos , Extratos Vegetais/uso terapêutico
14.
Int J Biol Macromol ; 232: 123441, 2023 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-36708902

RESUMO

Coenzyme A acts as a necessary cofactor for many enzymes and is a part of many biochemical processes. One of the critical enzymes involved in Coenzyme A synthesis is Dephospho-coenzyme A-kinase (DPCK). In this study, we have used integrated computational and experimental approaches for promising inhibitors of DPCK using the natural products available in the ZINC database for anti-leishmanial drug development. The top hit compounds chosen after molecular docking were Veratramine, Azulene, Hupehenine, and Hederagenin. The free binding energy of Veratramine, Azulene, Hupehenine, and Hederagenin was estimated. Besides the favourable binding point, the ligands also showed good hydrogen bonding and other interactions with key residues of the enzyme's active site. The natural compounds were also experimentally investigated for their effect on the L. donovani promastigotes and murine macrophage (J774A.1). A good antileishmanial activity by the compounds on the promastigotes was observed as estimated by the MTT assay. The in-vitro experiments revealed that Hupehenine (IC50 = 7.34 ± 0.37 µM) and Veratramine (IC50 = 12.46 ± 2.28 µM) exhibited better inhibition than Hederagenin (IC50 = 23.36 ± 0.54 µM) and Azulene (IC50 = 24.42 ± 3.28 µM). This work has identified novel anti-leishmanial molecules possibly acting through the inhibition of DPCK.


Assuntos
Antiprotozoários , Leishmania donovani , Leishmania , Animais , Camundongos , Azulenos/farmacologia , Simulação de Acoplamento Molecular , Leishmania/metabolismo , Antiprotozoários/farmacologia , Antiprotozoários/química , Coenzima A/metabolismo
15.
Chem Biodivers ; 20(2): e202201174, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36573597

RESUMO

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 IC50 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 IC50 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.


Assuntos
Antineoplásicos , PPAR gama , Animais , Peixe-Zebra , Azulenos/farmacologia , Antineoplásicos/farmacologia , Antivirais/farmacologia , Relação Estrutura-Atividade , Estrutura Molecular , Desenho de Fármacos
16.
Chemphyschem ; 24(2): e202200474, 2023 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-36125423

RESUMO

Structural rearrangements in ions are essential for understanding the composition and evolution of energetic and chemically active environments. This study explores the interconversion routes for simple polycyclic aromatic hydrocarbons, namely naphthalene and azulene radical cations (C10 H8 + ), by combining mass spectrometry and vacuum ultraviolet tunable synchrotron radiation through the chemical monitoring technique. Products of ion-molecule reactions are used to probe C10 H8 + structures that are formed as a function of their internal energies. Isomerisation from azulene radical cation towards naphthalene radical cation in a timescale faster than 80 µs was monitored, whereas no reverse isomerisation was observed in the same time window. When energising C10 H8 + with more than 6 eV, the reactivity of C10 H8 + unveils the formation of a new isomeric group with a contrasted reactivity compared with naphthalene and azulene cations. We tentatively assigned these structures to phenylvinylacetylene cations.


Assuntos
Hidrocarbonetos Policíclicos Aromáticos , Hidrocarbonetos Policíclicos Aromáticos/química , Azulenos , Naftalenos/química , Cátions/química
17.
Int J Mol Sci ; 25(1)2023 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-38203554

RESUMO

The centrosome is involved in cytoplasmic microtubule organization during interphase and in mitotic spindle assembly during cell division. Centrosome amplification (abnormal proliferation of centrosome number) has been observed in several types of cancer and in precancerous conditions. Therefore, it is important to elucidate the mechanism of centrosome amplification in order to understand the early stage of carcinogenesis. Primary cells could be used to better understand the early stage of carcinogenesis rather than immortalized cells, which tend to have various genetic and epigenetic changes. Previously, we demonstrated that a poly(ADP-ribose) polymerase (PARP) inhibitor, 3-aminobenzamide (3AB), which is known to be nontoxic and nonmutagenic, could induce centrosome amplification and chromosomal aneuploidy in CHO-K1 cells. In this study, we compared primary mouse embryonic fibroblasts (MEF) and immortalized MEF using 3AB. Although centrosome amplification was induced with 3AB treatment in immortalized MEF, a more potent PARP inhibitor, AG14361, was required for primary MEF. However, after centrosome amplification, neither 3AB in immortalized MEF nor AG14361 in primary MEF caused chromosomal aneuploidy, suggesting that further genetic and/or epigenetic change(s) are required to exhibit aneuploidy. The DNA-damaging agents doxorubicin and γ-irradiation can cause cancer and centrosome amplification in experimental animals. Although doxorubicin and γ-irradiation induced centrosome amplification and led to decreased p27Kip protein levels in immortalized MEF and primary MEF, the phosphorylation ratio of nucleophosmin (Thr199) increased in immortalized MEF, whereas it decreased in primary MEF. These results suggest that there exists a yet unidentified pathway, different from the nucleophosmin phosphorylation pathway, which can cause centrosome amplification in primary MEF.


Assuntos
Benzodiazepinas , Fibroblastos , Nucleofosmina , Animais , Camundongos , Cricetinae , Centrossomo , Células CHO , Aneuploidia , Carcinogênese , Doxorrubicina/farmacologia , Azulenos
18.
Angew Chem Int Ed Engl ; 61(43): e202212279, 2022 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-36068173

RESUMO

Face-to-face noncovalent arene-fullerene interactions are important in several research fields such as synthetic chemistry, materials chemistry, and medicinal chemistry; however, their nature and strength are still poorly understood. In this study, we prepare a fullerene-based torsion balance containing thioanisole, phenol, naphthalene, azulene, and pyrene moieties as a unimolecular model system. Moreover, we compare the folding free energies between the folded and the unfolded conformers of a series of the molecular torsion balances to quantify noncovalent interactions between arenes and the fullerene surface. This work demonstrates that the contributions of polarizabilities, anionic charges, electronic dipole moments, and the number of arene rings to the interactions can be experimentally measured by analyzing the folding equilibrium of the molecular torsion balances.


Assuntos
Fulerenos , Modelos Moleculares , Azulenos , Naftalenos/química , Pirenos , Fenóis
19.
Acc Chem Res ; 55(18): 2698-2707, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-36048561

RESUMO

According to Kasha's rule, the emission of a photon in a molecular system always comes from the lowest excited state. A corollary of this rule (i.e., the Kasha-Vavilov rule) states that the emission spectra are independent of the excitation wavelength. Although these rules apply for most of the molecular systems, violations of these rules are often reported. The prototypical case of a Kasha's rule violation is the fluorescence observed from S2 in azulene. Thanks to the advances in both theoretical and experimental research, other types of anomalous fluorescence (e.g., excitation energy transfer (EET)-based dual emissions, thermally activated fluorescence, etc.) are more recurrently reported in the literature. Sometimes, these anomalous processes involve higher-lying excited states but are mechanistically different from the azulene-like anomalous fluorescence. However, the underlying mechanisms leading to these anomalous emissions can be numerous and are not yet well understood.In order to shed some light on the above phenomena, this Account provides a comprehensive review of this topic. We herein report quantum chemical investigations in target molecular systems breaking Kasha's rule. The latter molecules were chosen because they were unambiguously reported to display anti-Kasha fluorescence. Our studies highlight three different types of anti-Kasha scenarios. Specifically, (i) the strong electronic, weak vibrational nonadiabatic coupling (NAC) regime (here named the type I case, i.e., azulene-like); (ii) the strong electronic, strong vibrational NAC regime (type II case, i.e., thermally activated S2 fluorescence); and the (iii) very weak electronic NAC regime (type III case, i.e., EET dyads). In addition, by combining state-of-the-art quantum chemical calculations with excited-state decay rate theories and appropriate excited-state kinetic models, we provide semiquantitative estimations of photoluminescence quantum yields for the most rigid molecular entities. Finally, we propose the use of simple theoretical descriptors relying on calculations of the excited-state density difference and the electron-vibrational coupling to classify anomalous emissions according to their coupling scenario.Besides the fundamental interest of the above investigations, the herein developed computational protocols and descriptors will be useful for the tailored design of dyes with tunable and unconventional fluorescence properties and their exploitation in a wide range of areas (i.e., from organic light-emitting diodes (OLEDs) to bioimaging, small-molecule fluorescent probes, and photocatalysis). Finally, our theoretical framework enables the attainment of a holistic understanding of the interconversion processes between excited states, where the electron-vibrational coupling is shown to play a central role in determining the efficacy.


Assuntos
Elétrons , Corantes Fluorescentes , Azulenos , Fluorescência
20.
Biomed Pharmacother ; 155: 113736, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36156366

RESUMO

Dysregulation of iron homeostasis is one of the important processes in the development of many oncological diseases, such as pancreatic cancer. Targeting it with specific agents, such as an iron chelator, are promising therapeutic methods. In this study, we tested the cytotoxicity of novel azulene hydrazide-hydrazone-based chelators against pancreatic cancer cell lines (MIA PaCa-2, PANC-1, AsPC-1). All prepared chelators (compounds 4-6) showed strong cytotoxicity against pancreatic cancer cell lines and high selectivity for cancer cell lines compared to the healthy line. Their cytotoxicity is lower than thiosemicarbazone-based chelators Dp44mT and DpC, but significantly higher than hydroxamic acid-based chelator DFO. The chelator tested showed mitochondrial and lysosomal co-localization and its mechanism of action was based on the induction of hypoxia-inducible factor-1-alpha (HIF-1α), N-myc downstream-regulated gene-1 (NDRG1) and transferrin receptor 1 (TfR1). This strongly implies that the cytotoxic effect of tested chelators could be associated with mitophagy induction. Lipinski's rule of five analyses was performed to determine whether the prepared compounds had properties ensuring their bioavailability. In addition, the drug-likeness and drug-score were calculated and discussed.


Assuntos
Neoplasias Pancreáticas , Tiossemicarbazonas , Humanos , Hidrazonas/farmacologia , Linhagem Celular Tumoral , Azulenos , Hidrazinas , Tiossemicarbazonas/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Quelantes de Ferro/farmacologia , Ferro , Receptores da Transferrina , Ácidos Hidroxâmicos , Neoplasias Pancreáticas
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