The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor integral to various physiological and pathological processes. Among its diverse ligands, indole-based compounds have garnered attention due to their significant biological activity and potential therapeutic applications. This study explores the activation of AhR by structurally diverse halogenated indoles. We evaluated the transcriptional activity of AhR and cell viability in the human LS174T-AhR-luc reporter cell line. Among the tested compounds, 4-FI, 7-FI, 6-BrI, 7-BrI, 6-Cl-2-ox, 5-Br-2-ox, and 6-Br-2-ox activated AhR in a concentration-dependent manner, displaying high efficacy and potency. Molecular docking analysis revealed moderate binding affinities of these compounds to the PAS-B domain of AhR, corroborated by competitive radioligand binding assays. Functional assays showed that halogenated indoles induce the formation of AhR-ARNT heterodimer and enhance the binding of the AhR to the CYP1A1 promoter. Additionally, 4-FI and 7-FI exhibited anti-inflammatory properties in Caco-2 cell models, highlighting their potential for therapeutic applications. This study underscores the significance of the type and position of halogen moiety in indole scaffold, suggesting their potential as candidates for developing therapeutics drugs to treat conditions such as inflammatory bowel disease via AhR activation.
- Klíčová slova
- Aryl hydrocarbon receptor, Halogen, Indole derivatives, Inflammation,
- MeSH
- cytochrom P-450 CYP1A1 metabolismus MeSH
- halogenace MeSH
- indoly * chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- receptory aromatických uhlovodíků * metabolismus chemie MeSH
- simulace molekulového dockingu * MeSH
- transkripční faktory bHLH MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- AHR protein, human MeSH Prohlížeč
- cytochrom P-450 CYP1A1 MeSH
- indoly * MeSH
- receptory aromatických uhlovodíků * MeSH
- transkripční faktory bHLH MeSH
Herein, a series of new 1,1,2-trimethyl-1H-benzo[e]indole dyes was prepared via Knoevenagel condensation reaction between 1,1,2-trimethyl-1H-benzo[e]indole and benzaldehydes, and characterized using various spectroscopic methods. The obtained compounds showed cytotoxic properties in G361 melanoma cell line upon irradiation with 414 nm blue light at submicromolar doses. The mechanism of action of the most potent compound 15 was further investigated. The treatment induced substantial generation of reactive oxygen species, leading to DNA damage followed by cell death depending on the concentration of the photosensitizer compound and the irradiation intensity.
- Klíčová slova
- DNA damage, Knoevenagel condensation, benzo[e]indole, photo-induced activity, reactive oxygen species,
- MeSH
- antitumorózní látky * farmakologie chemická syntéza chemie MeSH
- barvicí látky farmakologie chemie chemická syntéza MeSH
- fotosenzibilizující látky farmakologie chemická syntéza chemie MeSH
- indoly * chemie farmakologie chemická syntéza MeSH
- léky antitumorózní - screeningové testy * MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- poškození DNA účinky léků MeSH
- proliferace buněk účinky léků MeSH
- reaktivní formy kyslíku metabolismus MeSH
- světlo MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antitumorózní látky * MeSH
- barvicí látky MeSH
- fotosenzibilizující látky MeSH
- indoly * MeSH
- reaktivní formy kyslíku MeSH
This work presents results on the efficiency of newly designed zinc phthalocyanine-mediated photodynamic therapy of both tumoral and nontumoral cell models using the MTT assay. Further detailed examinations of mechanistic and cell biological effects were focused on the HELA cervical cancer cell model. Here, ROS production, changes in the mitochondrial membrane potential, the determination of genotoxicity, and protein changes determined by capillary chromatography and tandem mass spectrometry with ESI were analyzed. The results showed that, in vitro, 5 Jcm-2 ZnPc PDT caused a significant increase in reactive oxygen species. Still, except for superoxide dismutase, the levels of proteins involved in cell response to oxidative stress did not increase significantly. Furthermore, this therapy damaged mitochondrial membranes, which was proven by a more than 70% voltage-dependent channel protein 1 level decrease and by a 65% mitochondrial membrane potential change 24 h post-therapy. DNA impairment was assessed by an increased level of DNA fragmentation, which might be related to the decreased level of DDB1 (decrease in levels of more than 20% 24 h post-therapy), a protein responsible for maintaining genomic integrity and triggering the DNA repair pathways. Considering these results and the low effective concentration (LC50 = 30 nM), the therapy used is a potentially very promising antitumoral treatment.
- Klíčová slova
- DNA, liposome, mitochondria, oxidative stress, photodynamic therapy, proteins, reactive oxygen species,
- MeSH
- fotochemoterapie * metody MeSH
- fotosenzibilizující látky * farmakologie chemie MeSH
- HeLa buňky MeSH
- indoly * farmakologie chemie MeSH
- isoindoly * MeSH
- lidé MeSH
- membránový potenciál mitochondrií * účinky léků MeSH
- organokovové sloučeniny * farmakologie chemie MeSH
- oxidační stres účinky léků MeSH
- poškození DNA účinky léků MeSH
- reaktivní formy kyslíku * metabolismus MeSH
- sloučeniny zinku * farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- fotosenzibilizující látky * MeSH
- indoly * MeSH
- isoindoly * MeSH
- organokovové sloučeniny * MeSH
- reaktivní formy kyslíku * MeSH
- sloučeniny zinku * MeSH
- Zn(II)-phthalocyanine MeSH Prohlížeč
A series of new indole-pyrazole hybrids 8a-m were synthesized through the palladium-catalyzed ligandless Heck coupling reaction from easily accessible unsubstituted, methoxy- or fluoro-substituted 4-ethenyl-1H-pyrazoles and 5-bromo-3H-indoles. These compounds exerted cytotoxicity to melanoma G361 cells when irradiated with blue light (414 nm) and no cytotoxicity in the dark at concentrations up to 10 µM, prompting us to explore their photodynamic effects. The photodynamic properties of the example compound 8d were further investigated in breast cancer MCF-7 cells. Evaluation revealed comparable anticancer activities of 8d in both breast and melanoma cancer cell lines within the submicromolar range. The treatment induced a massive generation of reactive oxygen species, leading to different types of cell death depending on the compound concentration and the irradiation intensity.
- Klíčová slova
- cytotoxicity, indole, photodynamic effect, pyrazole, reactive oxygen species,
- MeSH
- antitumorózní látky * farmakologie chemická syntéza chemie MeSH
- fotochemoterapie * MeSH
- fotosenzibilizující látky * farmakologie chemická syntéza chemie MeSH
- indoly * farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- nádory prsu farmakoterapie patologie MeSH
- palladium chemie farmakologie MeSH
- pyrazoly * farmakologie chemická syntéza chemie MeSH
- reaktivní formy kyslíku * metabolismus MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antitumorózní látky * MeSH
- fotosenzibilizující látky * MeSH
- indoly * MeSH
- palladium MeSH
- pyrazoly * MeSH
- reaktivní formy kyslíku * MeSH
Polydopamine (PDA) is a widely used anchoring layer for multiple purposes. While simple to prepare, PDA is characterized by high chemical and topological diversity, which can limit its versatility. Unraveling the formation mechanism and physicochemical properties of continuous confluent layer and adherent nanoparticles on the nanoscale is crucial to further extend the prospective applications of PDA. Utilizing nano-FTIR spectroscopy, we investigate layers of PDA on three different substrates (silicon/silicon dioxide, nitrogen-doped titanium oxide, and gold substrates) at varying times of deposition (ToD). We observed a good correlation between the nano-FTIR and macroscopic FTIR spectra that reflected the changes in the relative abundance of PDA and polymerization intermediates as ToD increased. To gain analytical power, we utilized the principal component analysis (PCA) and extracted additional information from the resulting loadings spectral curves and data distribution in the score plots. We revealed a higher variability of the spectra of ultrathin surface confluent layers compared to the adherent nanoparticles. While the spectra of nanoparticles showed no apparent dependency on either ToD or the substrate material, the spectra of layers were highly affected by the increasing ToD and exhibited a rise in the absorption of PDA. Concomitantly, the spectra of layers grouped according to the substrate material at the lowest ToD point to the fact that the substrate material affects the PDA's initial physicochemical structure. The observed separation gradually diminished with the increasing ToD as the PDA physicochemical structure became less influenced by the substrate material.
- Klíčová slova
- Anchoring layers, Infrared, Nano-FTIR, Polydopamine, Self-assembly, Vibrational nanoscopy,
- MeSH
- indoly chemie MeSH
- nanočástice * chemie MeSH
- oxid dusnatý MeSH
- polymery * chemie MeSH
- spektroskopie infračervená s Fourierovou transformací MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- indoly MeSH
- oxid dusnatý MeSH
- polydopamine MeSH Prohlížeč
- polymery * MeSH
The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) exhibits remarkable anticancer efficacy; however, its therapeutic potential is hindered by its toxicity to gastrointestinal (GI) tissues. We recently reported the discovery of DRP-104, a tumor-targeted DON prodrug with excellent efficacy and tolerability, which is currently in clinical trials. However, DRP-104 exhibits limited aqueous solubility, and the instability of its isopropyl ester promoiety leads to the formation of an inactive M1-metabolite, reducing overall systemic prodrug exposure. Herein, we aimed to synthesize DON prodrugs with various ester and amide promoieties with improved solubility, GI stability, and DON tumor delivery. Twenty-one prodrugs were synthesized and characterized in stability and pharmacokinetics studies. Of these, P11, tert-butyl-(S)-6-diazo-2-((S)-2-(2-(dimethylamino)acetamido)-3-phenylpropanamido)-5-oxo-hexanoate, showed excellent metabolic stability in plasma and intestinal homogenate, high aqueous solubility, and high tumor DON exposures and preserved the ideal tumor-targeting profile of DRP-104. In conclusion, we report a new generation of glutamine antagonist prodrugs with improved physicochemical and pharmacokinetic attributes.
- MeSH
- acetamidy * chemie farmakologie MeSH
- diazooxonorleucin farmakokinetika MeSH
- estery terapeutické užití MeSH
- glutamin MeSH
- indoly * chemie farmakologie MeSH
- lidé MeSH
- nádory * farmakoterapie MeSH
- prekurzory léčiv * chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- acetamidy * MeSH
- diazooxonorleucin MeSH
- estery MeSH
- glutamin MeSH
- indoly * MeSH
- prekurzory léčiv * MeSH
- sirpiglenastat MeSH Prohlížeč
Microbial colonisations of gypsum from Eastern Poland (Badenian, Middle Miocene age) were investigated by Raman microspectrometry with a rarely used excitation 445 nm excitation. Zones of microbial colonisation in selenitic gypsum endolithic outcrops comprise algae and cyanobacteria, which commonly contain the photosynthetic and protective pigments carotenoids, scytonemin and gloeocapsin. Diagnostic bands differing from those of scytonemin have been identified in black colonies in gypsum outcrops at Chotel Czierwony (Poland). Raman spectral signatures of scytonin are reported here for the first time in two endolithic specimens identified by the band wavenumbers predicted from DFT calculations. The strong or medium strong intensity Raman bands observed at 1603, 1585, 1559, 1435, and 1424 cm-1. Other weaker bands were located at 1676 (sh), 1660 (sh), 1649, 1399, 1362, 1342, 1320, 1294, 1272, 1259, and 1052 cm-1. The first observation of the Raman spectrum of scytonin in the cyanobacterial colonisation of gypsum facilitates the inclusion of this new biomolecular signature in the library of unique Raman spectra of biological pigments invaluable for detection of traces of life in frame of the planetary missions.
- Klíčová slova
- Astrobiology, Biomarkers, Raman spectroscopy, Scytonemin, Scytonin,
- MeSH
- exobiologie metody MeSH
- indoly chemie MeSH
- sinice * chemie MeSH
- síran vápenatý * chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- indoly MeSH
- scytonemin MeSH Prohlížeč
- síran vápenatý * MeSH
Polydopamine (PDA) is one of the most commonly used materials for the preparation of protective adhesive layers for biomedical and tribological applications. Despite its widespread use, the way in which the polymer binds to the substrate is yet to be fully understood. At the nanometre level, the spatial arrangement of individual molecules and the initial growth of PDA layers are expected to be influenced by the utilized substrate material and PDA deposition time. To investigate these hypotheses, we have prepared PDA layers with various times of deposition on surfaces of gold and oxygen-terminated materials (silicon/silicon dioxide and nitrogen-doped titanium oxide). The prepared samples were subsequently analysed using a scattering-type scanning near-field optical microscope utilizing four irradiation energies in the mid-infrared region to detect the chemical contrast originating from vibrational modes of selected chemical moieties. It was found that the polymerization process leads to a formation of a surface confluent PDA layer and deposition of PDA nanoaggregates. The differences in the optical contrast observed at irradiation energies corresponding to the vibrations of indole units of PDA and quinoid groups of polymerization intermediates indicated a slightly different composition of the nanoaggregates and the surrounding confluent layer.
- Klíčová slova
- Anchoring layers, Infrared, Nanoimaging, Polydopamine, Self-assembly, s-SNOM,
- MeSH
- adheziva chemie MeSH
- indoly * chemie MeSH
- polymerizace MeSH
- polymery * chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- adheziva MeSH
- indoly * MeSH
- polydopamine MeSH Prohlížeč
- polymery * MeSH
1H-Indole-3-carbaldehyde and related members of the indole family are ideal precursors for the synthesis of active molecules. 1H-Indole-3-carbaldehyde and its derivatives are essential and efficient chemical precursors for generating biologically active structures. Multicomponent reactions (MCRs) offer access to complex molecules. This review highlights the recent applications of 1H-indole-3-carbaldehyde in such inherently sustainable multicomponent reactions from the period, 2014 to 2021 and provides an overview of the field that awaits further exploitation in the assembly of pharmaceutically interesting scaffolds.
- Klíčová slova
- 1H-Indole-3-carbaldehyde, Carbazole derivatives, Heterocycles, Multicomponent reactions, Pyrimidine derivatives, Triazole derivatives,
- MeSH
- indoly * chemie MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- indole-3-carbaldehyde MeSH Prohlížeč
- indoly * MeSH
Prion disorders, or transmissible spongiform encephalophaties (TSE), are fatal neurodegenerative diseases affecting mammals. Prion-infectious particles comprise of misfolded pathological prion proteins (PrPTSE). Different TSEs are associated with distinct PrPTSE folds called prion strains. The high resistance of prions to conventional sterilization increases the risk of prion transmission in medical, veterinary and food industry practices. Recently, we have demonstrated the ability of disulfonated hydroxyaluminum phthalocyanine to photodynamically inactivate mouse RML prions by generated singlet oxygen. Herein, we studied the efficiency of three phthalocyanine derivatives in photodynamic treatment of seven mouse adapted prion strains originating from sheep, human, and cow species. We report the different susceptibilities of the strains to photodynamic oxidative elimination of PrPTSE epitopes: RML, A139, Fu-1 > mBSE, mvCJD > ME7, 22L. The efficiency of the phthalocyanine derivatives in the epitope elimination also differed (AlPcOH(SO3)2 > ZnPc(SO3)1-3 > SiPc(OH)2(SO3)1-3) and was not correlated to the yields of generated singlet oxygen. Our data suggest that the structural properties of both the phthalocyanine and the PrPTSE strain may affect the effectiveness of the photodynamic prion inactivation. Our finding provides a new option for the discrimination of prion strains and highlights the necessity of utilizing range of prion strains when validating the photodynamic prion decontamination procedures.
- Klíčová slova
- PDI, PrP, TSE, photodynamic, phthalocyanine, prion, prion inactivation, protein folding, singlet oxygen, strain,
- MeSH
- fotochemoterapie metody MeSH
- fotosenzibilizující látky farmakologie MeSH
- indoly chemie MeSH
- lidé MeSH
- mozek účinky léků metabolismus účinky záření MeSH
- myši MeSH
- organokovové sloučeniny chemie MeSH
- ovce MeSH
- oxidace-redukce MeSH
- prionová bílkovina metabolismus MeSH
- prionové nemoci farmakoterapie metabolismus patologie MeSH
- sbalování proteinů MeSH
- singletový kyslík MeSH
- skot MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- fotosenzibilizující látky MeSH
- indoly MeSH
- organokovové sloučeniny MeSH
- prionová bílkovina MeSH
- singletový kyslík MeSH
- zinc(II) phthalocyanine trisulfonic acid MeSH Prohlížeč
