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
- barvicí látky farmakologie chemie chemická syntéza MeSH
- fotosenzibilizující látky farmakologie chemická syntéza chemie MeSH
- indoly * chemie farmakologie chemická syntéza MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- poškození DNA účinky léků MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky * farmakologie chemická syntéza chemie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- screeningové testy protinádorových léčiv * 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
- barvicí látky MeSH
- fotosenzibilizující látky MeSH
- indoly * MeSH
- protinádorové látky * MeSH
- reaktivní formy kyslíku 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.
- Klíčová slova
- cytotoxicity, indole, photodynamic effect, pyrazole, reactive oxygen species,
- 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
- protinádorové látky * farmakologie chemická syntéza chemie 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
- fotosenzibilizující látky * MeSH
- indoly * MeSH
- palladium MeSH
- protinádorové látky * MeSH
- pyrazoly * MeSH
- reaktivní formy kyslíku * 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.
- Klíčová slova
- Acetylcholinesterase, Fischer indole synthesis, N-phenylpiperazine, T3P®, butyrylcholinesterase, indoles,
- 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
- Názvy látek
- acetylcholinesterasa MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- estery MeSH
- indoly MeSH
- piperaziny 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
- fosfatidylcholiny chemie metabolismus MeSH
- fotochemoterapie MeSH
- fotosenzibilizující látky chemická syntéza metabolismus farmakologie účinky záření MeSH
- indoly chemická syntéza metabolismus farmakologie účinky záření MeSH
- lidé MeSH
- liposomy chemie metabolismus MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- protinádorové látky chemická syntéza metabolismus farmakologie účinky záření MeSH
- screeningové testy protinádorových léčiv 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
- Názvy látek
- 1,2-oleoylphosphatidylcholine MeSH Prohlížeč
- fosfatidylcholiny MeSH
- fotosenzibilizující látky MeSH
- indoly MeSH
- liposomy MeSH
- protinádorové látky MeSH
- sérový albumin hovězí MeSH
- singletový kyslík MeSH
- zinek MeSH
A major structural retroviral protein, capsid protein (CA), is able to oligomerize into two different hexameric lattices, which makes this protein a key component for both the early and late stages of HIV-1 replication. During the late stage, the CA protein, as part of the Gag polyprotein precursor, facilitates protein-protein interactions that lead to the assembly of immature particles. Following protease activation and Gag polyprotein processing, CA also drives the assembly of the mature viral core. In the early stage of infection, the role of the CA protein is distinct. It controls the disassembly of the mature CA hexameric lattice i.e., uncoating, which is critical for the reverse transcription of the single-stranded RNA genome into double stranded DNA. These properties make CA a very attractive target for small molecule functioning as inhibitors of HIV-1 particle assembly and/or disassembly. Of these, inhibitors containing the PF74 scaffold have been extensively studied. In this study, we reported a series of modifications of the PF74 molecule and its characterization through a combination of biochemical and structural approaches. Our data supported the hypothesis that PF74 stabilizes the mature HIV-1 CA hexameric lattice. We identified derivatives with a higher in vitro stabilization activity in comparison to the original PF74 molecule.
- Klíčová slova
- HIV-1 CA inhibitor, PF74 derivatives, disassembly, uncoating,
- MeSH
- HIV-1 účinky léků MeSH
- indoly chemická syntéza chemie farmakologie MeSH
- látky proti HIV chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- racionální návrh léčiv MeSH
- rekombinantní proteiny MeSH
- sestavení viru účinky léků MeSH
- techniky syntetické chemie MeSH
- virion účinky léků ultrastruktura MeSH
- virové plášťové proteiny antagonisté a inhibitory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- indoly MeSH
- látky proti HIV MeSH
- rekombinantní proteiny MeSH
- virové plášťové proteiny MeSH
A series of fluoroalkylated cyclic λ3 -iodanes and their hydrochloride salts was prepared and used in a combination with sodium ascorbate in buffer or aqueous methanol mixtures for radical fluoroalkylation of a range of substituted indoles, pyrroles, tryptophan or its derivatives, and Trp residues in peptides. As demonstrated on several peptides, the aromatic amino acid residues of Trp, Tyr, Phe, and His are targeted with high selectivity to Trp. The functionalization method is biocompatible, mild, rapid, and transition-metal-free. The proteins myoglobin, ubiquitin, and human carbonic anhydrase I were also successfully functionalized.
- Klíčová slova
- bioconjugation, fluorine, iodine, radicals, tryptophan,
- MeSH
- alkylace MeSH
- aminokyseliny aromatické chemická syntéza chemie MeSH
- halogenace MeSH
- indoly chemická syntéza chemie MeSH
- lidé MeSH
- molekulární modely MeSH
- peptidy chemická syntéza chemie MeSH
- proteiny chemická syntéza chemie MeSH
- pyrroly chemická syntéza chemie MeSH
- volné radikály chemická syntéza chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- aminokyseliny aromatické MeSH
- indoly MeSH
- peptidy MeSH
- proteiny MeSH
- pyrroly MeSH
- volné radikály 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.
- Klíčová slova
- Anticancer activity, Azaindole, Complexes, Cytotoxicity,
- 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
- protinádorové látky * chemická syntéza chemie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cytotoxiny * MeSH
- indoly * MeSH
- komplexní sloučeniny * MeSH
- přechodné kovy MeSH
- protinádorové látky * 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.
- Klíčová slova
- Anticancer activity, Cytotoxicity, Fluorescent cyanine, Pentamethinium salt, Recognition, Sulfated polysaccharides,
- 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
- protinádorové látky chemická syntéza chemie metabolismus farmakologie 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
- Názvy látek
- benzothiazoly MeSH
- estery kyseliny sírové MeSH
- glykosaminoglykany MeSH
- indoly MeSH
- ligandy MeSH
- protinádorové látky MeSH
- pyridinové sloučeniny MeSH
The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg-1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.
- Klíčová slova
- antioxidants, drug design, inhibitors, multitarget drugs, neurological agents,
- MeSH
- antagonisté histaminového receptoru H3 chemická syntéza chemie farmakokinetika terapeutické užití MeSH
- antioxidancia chemická syntéza chemie farmakokinetika terapeutické užití MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakokinetika terapeutické užití MeSH
- hematoencefalická bariéra metabolismus MeSH
- indoly chemická syntéza chemie farmakokinetika terapeutické užití MeSH
- inhibitory MAO chemická syntéza chemie farmakokinetika terapeutické užití MeSH
- kognitivní dysfunkce farmakoterapie metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- myši MeSH
- neurodegenerativní nemoci farmakoterapie metabolismus MeSH
- neuroprotektivní látky chemická syntéza chemie farmakokinetika terapeutické užití MeSH
- piperidiny chemická syntéza chemie farmakokinetika terapeutické užití MeSH
- racionální návrh léčiv MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antagonisté histaminového receptoru H3 MeSH
- antioxidancia MeSH
- cholinesterasové inhibitory MeSH
- indoly MeSH
- inhibitory MAO MeSH
- ligandy MeSH
- N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine MeSH Prohlížeč
- neuroprotektivní látky MeSH
- piperidiny 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
- isoindoly MeSH
- krystalografie rentgenová 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
- screeningové testy protinádorových léčiv MeSH
- triazoly chemická syntéza chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- fotosenzibilizující látky MeSH
- indoly MeSH
- isoindoly MeSH
- phthalocyanine MeSH Prohlížeč
- porfyriny MeSH
- pyrazoly MeSH
- triazoly MeSH
