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.

• 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

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.

• 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

BACKGROUND: The indole derivatives and the N-phenylpiperazine fragment represent interesting molecular moieties suitable for the research of new potentially biologically active compounds. This study was undertaken to identify if indol-2-carboxylic acid esters containing N-phenylpiperazine moiety possess acetylcholinesterase and butyrylcholinesterase inhibitory activity. MATERIALS AND METHODS: The study dealt with the synthesis of a novel series of analogs of 1H-indole-2- carboxylic acid and 3-methyl-1H-indole-2-carboxylic acid. The structure of the derivatives was represented by the indolylcarbonyloxyaminopropanol skeleton with the attached N-phenylpiperazine or diethylamine moiety, which formed a basic part of the molecule. The final products were synthesized as dihydrochloride salts, fumaric acid salts, and quaternary ammonium salts. The first step of the synthetic pathway led to the preparation of esters of 1H-indole-2-carboxylic acid from the commercially available 1H-indole-2-carboxylic acid. The Fischer indole synthesis was used to synthesize derivatives of 3-methyl-1H-indole-2-carboxylic acid. RESULTS AND DISCUSSION: Final 18 indolylcarbonyloxyaminopropanols in the form of dihydrochlorides, fumarates, and quaternary ammonium salts were prepared using various optimization ways. The very efficient way for the formation of 3-methyl-1H-indole-2-carboxylate (Fischer indole cyclization product) was the one-pot synthesis of phenylhydrazine with methyl 2-oxobutanoate with acetic acid and sulphuric acid as catalysts. CONCLUSION: Most of the derivatives comprised of an attached N-phenylpiperazine group, which formed a basic part of the molecule and in which the phenyl ring was substituted in position C-2 or C-4. The synthesized compounds were subjected to cholinesterase-inhibiting activity evaluation, by modified Ellman method. Quaternary ammonium salt of 1H-indole-2-carboxylic acid which contain N-phenylpiperazine fragment with nitro group in position C-4 (7c) demonstrated the most potent activity against acetylcholinesterase.

• MeSH
• acetylcholinesterasa chemie   MeSH
• butyrylcholinesterasa chemie   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   MeSH
• Electrophorus MeSH
• enzymatické testy MeSH
• estery chemická syntéza   chemie   MeSH
• indoly chemická syntéza   chemie   MeSH
• koně MeSH
• piperaziny chemická syntéza   chemie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The literature reports on cationic and anionic phthalocyanines (Pcs) for photodynamic therapy suggest systematically significant differences in activity. In this work, ten different zinc(II) Pcs with carboxylate functions or quaternary nitrogens (hydrophilic anionic, hydrophilic cationic, amphiphilic anionic, and amphiphilic cationic) were investigated, with the aim of revealing reasons for such differences. In vitro assays on HeLa, MCF-7, and HCT-116 cells confirmed higher photoactivity for cationic Pcs (EC50 ∼ 3-50 nM) than for anionic Pcs (EC50 ∼ 0.3-10 μM), the latter being additionally significantly more active in serum-free medium. The environmental pH, binding to serum proteins, interaction with biomembranes, differences in subcellular localization, and relocalization after irradiation were found to be the main factors contributing to the generally lower photoactivity of anionic Pcs than that of the cationic derivatives. This result is not limited only to the presented derivatives and should be considered in the design of novel photosensitizers.

• MeSH
• antitumorózní látky chemická syntéza   metabolismus   farmakologie   účinky záření   MeSH
• fosfatidylcholiny chemie   metabolismus   MeSH
• fotochemoterapie MeSH
• fotosenzibilizující látky chemická syntéza   metabolismus   farmakologie   účinky záření   MeSH
• indoly chemická syntéza   metabolismus   farmakologie   účinky záření   MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• liposomy chemie   metabolismus   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• sérový albumin hovězí metabolismus   MeSH
• singletový kyslík metabolismus   MeSH
• světlo MeSH
• zinek chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

This minireview is devoted to the complexes of various transition metals, which contain azaindole ring coordinated to the metal centre, and whose cytotoxicity was studied. We decided to overview this interesting group of coordination compounds with the aim to highlight various structural types of complexes depending on the metal centre (i.e., Pt, Pd, Ru, Ir or Au) and type of the used co-ligand(s). The presented complexes are also reviewed in context of their toxicity, selectivity and processes connected with their mechanism of action. Some of complexes were also studied on in vivo models showing promising results comparable with the commonly used anticancer drug cisplatin. It can be deduced from the herein overviewed literature data regarding transition metal complexes containing azaindoles as ligands, that at least a few of them may represent suitable and promising candidates in the field of anticancer therapy. As one of the examples, the cis-[PtI2(2Me4Cl-7aza)2] complex (2Me4Cl-7aza = 2-methyl-4-chloro-7-azaindole) should be mentioned, which showed considerably higher in vitro cytotoxicity than cisplatin, the ability to overcome both the acquired and natural resistance of human cancer cells in comparison with the biological action of cisplatin, different mechanism of action than cisplatin and comparable in vivo anticancer activity with cisplatin.

• MeSH
• antitumorózní látky * chemická syntéza   chemie   terapeutické užití   MeSH
• cytotoxiny * chemická syntéza   chemie   terapeutické užití   MeSH
• indoly * chemická syntéza   chemie   terapeutické užití   MeSH
• komplexní sloučeniny * chemická syntéza   chemie   terapeutické užití   MeSH
• lidé MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• přechodné kovy chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A series of pentamethinium salts with benzothiazolium and indolium side units comprising one or two positive charges were designed and synthesized to determine the relationships among the molecular structure, charge density, affinity to sulfated polysaccharides, and biological activity. Firstly, it was found that the affinity of the pentamethinium salts to sulfated polysaccharides correlated with their biological activity. Secondly, the side heteroaromates displayed a strong effect on the cytotoxicity and selectivity towards cancer cells. Finally, doubly charged pentamethinium salts possessing benzothiazolium side units exhibited remarkably high efficacy against a taxol-resistant cancer cell line.

• MeSH
• antitumorózní látky chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• benzothiazoly chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• estery kyseliny sírové metabolismus   MeSH
• glykosaminoglykany metabolismus   MeSH
• hydrofobní a hydrofilní interakce MeSH
• indoly chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• pyridinové sloučeniny chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• racionální návrh léčiv MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• audiovizuální média MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH

High photodynamic activity was observed for hexadeca-cationic zinc, magnesium, and metal-free phthalocyanines (Pcs) and tetrapyrazinoporphyrazines with EC50 values as low as 5 nM (MCF-7 cells) for the best compound; this activity was several times better than that of clinically established photosensitizers verteporfin, temoporfin, S3AlOHPc, or protoporphyrin IX. This lead compound was characterized by low dark toxicity (TC50 = 369 μM), high efficiency against other cell lines (HCT 116 and HeLa), and possible activation by light above 680 nm. The excellent photodynamic activity resulted from the rigid spatial arrangement of the quaternized triazole moieties above and below the Pc core, as confirmed by X-ray crystallography. The triazole moieties thus formed two "cationic donuts" that protected the hydrophobic core against aggregation in water. The lysosomes were found to be the site of subcellular localization and were consequently the primary targets of photodynamic injury, resulting in predominantly necrotic cell death.

• MeSH
• fotochemoterapie MeSH
• fotosenzibilizující látky chemická syntéza   chemie   farmakologie   MeSH
• indoly chemická syntéza   chemie   farmakologie   MeSH
• krystalografie rentgenová MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• lyzozomy metabolismus   MeSH
• molekulární konformace MeSH
• nádorové buněčné linie MeSH
• nekróza MeSH
• porfyriny chemická syntéza   chemie   farmakologie   MeSH
• pyrazoly chemická syntéza   chemie   farmakologie   MeSH
• triazoly chemická syntéza   chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Plant growth regulating properties of brevicompanines (Brvs), natural products of the fungus Penicillium brevicompactum, have been known for several years, but further investigations into the molecular mechanism of their bioactivity have not been performed. Following chemical synthesis of brevicompanine derivatives, we studied their activity in the model plant Arabidopsis by a combination of plant growth assays, transcriptional profiling, and numerous additional bioassays. These studies demonstrated that brevicompanines cause transcriptional misregulation of core components of the circadian clock, whereas other biological read-outs were not affected. Brevicompanines thus represent promising chemical tools for investigating the regulation of the plant circadian clock. In addition, our study also illustrates the potential of an unbiased -omics-based characterization of bioactive compounds for identifying the often cryptic modes of action of small molecules.

• MeSH
• Arabidopsis účinky léků   fyziologie   MeSH
• biologické přípravky chemická syntéza   farmakologie   MeSH
• cirkadiánní rytmus účinky léků   MeSH
• cyklické peptidy chemická syntéza   farmakologie   MeSH
• fyziologie rostlin účinky léků   MeSH
• genetická transkripce účinky léků   MeSH
• indoly chemická syntéza   farmakologie   MeSH
• kořeny rostlin účinky léků   růst a vývoj   MeSH
• Penicillium chemie   MeSH
• Publikační typ
• časopisecké články MeSH

From four molecules, inspired by the structural features of fascaplysin, with an interesting potential to inhibit cyclin-dependent kinases (CDKs), we designed a new series of tri-heterocyclic derivatives based on 1H-pyrrolo[2,3-b]pyridine (7-azaindole) and triazole heterocycles. Using a Huisgen type [3 + 2] cycloaddition as the convergent key step, 24 derivatives were synthesized and their biological activities were evaluated. Comparative molecular field analysis (CoMFA), based on three-dimensional quantitative structure-activity relationship (3D-QSAR) studies, was conducted on a series of 30 compounds from the literature with high to low known inhibitory activity towards CDK2/cyclin E and was validated by a test set of 5 compounds giving satisfactory predictive r(2) value of 0.92. Remarkably, it also gave a good prediction of pIC50 for our tri-heterocyclic series which reinforce the validation of this model for the pIC50 prediction of external set compounds. The most promising compound, 43, showed a micro-molar range inhibitory activity against CDK2/cyclin E and also an antiproliferative and proapoptotic activity against a panel of cancer cell lines.

• MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• cyklin E antagonisté a inhibitory   metabolismus   MeSH
• cyklin-dependentní kinasa 2 antagonisté a inhibitory   metabolismus   MeSH
• heterocyklické sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• indoly chemická syntéza   chemie   farmakologie   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• kvantitativní vztahy mezi strukturou a aktivitou MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• molekulární modely * MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A series of gold(I) complexes of the general composition [Au(naza)(PPh₃)] (1-8) was prepared and thoroughly characterized (e.g., electrospray ionization (ESI) mass spectrometry and multinuclear nuclear magnetic resonance (NMR) spectroscopy). The N1-deprotonated anions of 7-azaindole or its derivatives (naza) are coordinated to the metal centre through the N1 atom of their pyrrole ring, as proved by a single crystal X-ray analysis of the complexes [Au(3I5Braza)(PPh₃)] (7) and [Au(2Me4Claza)(PPh₃)]·½H₂O (8'). The in vitrocytotoxicity of the complexes 1-8 was studied against both the cisplatin-sensitive and -resistant variants of the A2780 human ovarian carcinoma cell line, as well as against the MRC-5 human normal fibroblast cell line. The complexes 4, 5, and 8, containing deprotonated 3-iodo-7-azaindole, 5-bromo-7-azaindole, and 2-methyl-4-chloro-7-azaindole (2Me4Claza), respectively, showed significantly higher potency (IC50 = 2.8-3.5 µM) than cisplatin (IC50 = 20.3 µM) against the A2780 cells and markedly lower effect towards the MRC-5 non-cancerous cells (IC50 = 26.0-29.2 µM), as compared with the mentioned A2780 cancer cells. The results of the flow cytometric studies of the A2780 cell cycle perturbations revealed a G₂-cell cycle phase arrest of the cells treated by the representative complexes 1 and 5, which is indicative of a different mechanism of action from cisplatin (induced S-cell cycle phase arrest). The stability of the representative complex 8 in the water-containing solution as well as its ability to interact with the reduced glutathione, cysteine and bovine serum albumin was also studied using ¹H and (31)P-NMR spectroscopy (studied in the 50% DMF-d₇/50% D₂O mixture) and ESI+ mass spectrometry (studied in the 50% DMF/50% H₂O mixture); DMF = dimethylformamide. The obtained results are indicative for the release of the N-donor azaindole-based ligand in the presence of the used biomolecules.

• MeSH
• antitumorózní látky farmakologie   MeSH
• buněčná smrt účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• fosfiny chemická syntéza   chemie   farmakologie   MeSH
• indoly chemická syntéza   chemie   farmakologie   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• protonová magnetická rezonanční spektroskopie MeSH
• voda chemie   MeSH
• zlato farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH