The formation of a G-quadruplex motif in the promoter region of the c-MYC protooncogene prevents its expression. Accordingly, G-quadruplex stabilization by a suitable ligand may be a viable approach for anticancer therapy. In our study, we used the 4-(4-methylpiperazin-1-yl)aniline molecule, previously identified as a fragment library screen hit, as a template for the SAR-guided design of a new small library of clickable fragments and subjected them to click reactions, including kinetic target-guided synthesis in the presence of a G-quadruplex forming oligonucleotide Pu24. We tested the clickable fragments and products of click reactions for their G-quadruplex stabilizing activity and determined their mode of binding to the c-MYC G-quadruplex by NMR spectroscopy. The enhanced stabilizing potency of click products in biology assays (FRET, Polymerase extension assay) matched the increased yields of in situ click reactions. In conclusion, we identified the newly synthesized click products of bis-amino derivatives of 4-(4-methylpiperazin-1-yl)aniline as potent stabilizers of c-MYC G-quadruplex, and their further evolution may lead to the development of an efficient tool for cancer treatment.

• Klíčová slova
• G-quadruplex, NMR, anticancer therapy, click chemistry, secondary structures,
• MeSH
• aniliny chemická syntéza   chemie   farmakologie   MeSH
• G-kvadruplexy účinky léků   MeSH
• geny myc genetika   MeSH
• kinetika MeSH
• ligandy MeSH
• simulace molekulární dynamiky MeSH
• syntetická chemie okamžité shody MeSH
• techniky syntetické chemie MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aniline MeSH Prohlížeč
• aniliny MeSH
• ligandy MeSH

Alzheimer's disease (AD) is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient's death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs) and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs) strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds' behavior was confirmed in the subsequent molecular modeling studies.

• Klíčová slova
• 7-methoxy-tacrine, Alzheimer’s disease, MTDLs, acetylcholinesterase, butyrylcholinesterase, tacrine,
• MeSH
• acetylcholinesterasa chemie   MeSH
• amyloidní beta-protein antagonisté a inhibitory   chemie   MeSH
• aniliny chemická syntéza   chemie   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   MeSH
• kinetika MeSH
• látky ovlivňující centrální nervový systém chemická syntéza   chemie   MeSH
• lidé MeSH
• rekombinantní proteiny chemie   MeSH
• simulace molekulového dockingu MeSH
• takrin analogy a deriváty   MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• amyloidní beta-protein MeSH
• aniliny MeSH
• cholinesterasové inhibitory MeSH
• látky ovlivňující centrální nervový systém MeSH
• rekombinantní proteiny MeSH
• takrin MeSH

Polyaniline colloids rank among promising application forms of this conducting polymer. Cytotoxicity, antibacterial activity, and neutrophil oxidative burst tests were performed on cells treated with colloidal polyaniline dispersions. The antibacterial effect of colloidal polyaniline against gram-positive and gram-negative bacteria was most pronounced for Bacillus cereus and Escherichia coli, with a minimum inhibitory concentration of 3,500 μg mL(-1). The data recorded on human keratinocyte (HaCaT) and a mouse embryonic fibroblast (NIH/3T3) cell lines using an MTT assay and flow cytometry indicated a concentration-dependent cytotoxicity of colloid, with the absence of cytotoxic effect at around 150 μg mL(-1). The neutrophil oxidative burst test then showed that colloidal polyaniline, in concentrations <150 μg mL(-1), was not able to stimulate the production of reactive oxygen species in neutrophils and whole human blood. However, it worked efficiently as a scavenger of those already formed.

• Klíčová slova
• Antibacterial activity, Apoptosis, Colloidal polyaniline, Cytotoxicity, Necrosis, Oxidative burst,
• MeSH
• aniliny chemická syntéza   chemie   farmakologie   MeSH
• antibakteriální látky chemická syntéza   chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• Bacillus cereus účinky léků   MeSH
• buněčné linie MeSH
• buňky NIH 3T3 MeSH
• Escherichia coli účinky léků   MeSH
• koloidy chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• myši MeSH
• neutrofily účinky léků   metabolismus   MeSH
• povrchové vlastnosti MeSH
• Pseudomonas aeruginosa účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• Staphylococcus aureus účinky léků   MeSH
• velikost částic MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aniliny MeSH
• antibakteriální látky MeSH
• koloidy MeSH
• polyaniline MeSH Prohlížeč
• reaktivní formy kyslíku MeSH

Three heterobifunctional photoaffinity probes, N-(p-azidobenzyl)-N-methyl-p-aminobenzylamine (I), N-(p-azidobenzyl)-N-methyl-p-aminophenethylamine (II), and N-(p-azidophenethyl)-N-methyl-p-aminophenethylamine (III), were synthesized and characterized. These probes, containing a photolabile azido-group and an amino-group on opposite sides of the molecule, were designed for photoaffinty labeling of the cytochrome P450 (CYP) 2B active site cavity differing in distance from the heme iron. Spectroscopic studies proved that probes I and II coordinated with the heme iron via their amino-group in the enzyme active center, whereas probe III did not. This result in conjunction with data from kinetic studies suggests probes I and II are appropriate for photoaffinity labeling of the CYP 2B active center. Thus, probe II was used to identify amino acid residues within a distance of the probe length (about 16.5 A) from the heme. Analysis of a Lys-C digest of the probe II-labeled CYP 2B4 revealed a single labeled hexapeptide corresponding to position 192-197 of the CYP 2B4 sequence. Using postsource decay/matrix-assisted laser desorption ionization-time of flight, Arg197 was identified as a probe II target. The location of the labeled site in three-dimensional structures of bacterial CYPs and in CYP 2B homology models is discussed.

• MeSH
• afinitní značky chemická syntéza   chemie   MeSH
• aniliny chemická syntéza   chemie   MeSH
• aromatické hydroxylasy * MeSH
• azidy chemická syntéza   chemie   MeSH
• Bacteria enzymologie   genetika   MeSH
• druhová specificita MeSH
• jaterní mikrozomy enzymologie   MeSH
• katalytická doména MeSH
• králíci MeSH
• krysa rodu Rattus MeSH
• magnetická rezonanční spektroskopie MeSH
• molekulární sekvence - údaje MeSH
• racionální návrh léčiv MeSH
• sekvence aminokyselin MeSH
• sekvenční homologie aminokyselin MeSH
• spektrofotometrie MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
• steroidhydroxylasy chemie   genetika   MeSH
• systém (enzymů) cytochromů P-450 chemie   genetika   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• afinitní značky MeSH
• aniliny MeSH
• aromatické hydroxylasy * MeSH
• azidy MeSH
• N-(4-azidobenzyl)-N-methyl-4-aminobenzylamine MeSH Prohlížeč
• N-(4-azidobenzyl)-N-methyl-4-aminophenethylamine MeSH Prohlížeč
• N-(4-azidophenethyl)-N-methyl-4-aminophenethylamine MeSH Prohlížeč
• steroid 15-alpha-hydroxylase MeSH Prohlížeč
• steroidhydroxylasy MeSH
• systém (enzymů) cytochromů P-450 MeSH

Reactive isomeric 3- and 4-trifluoromethylanilines (3-,4-TFMA), and control aniline itself, induced the following effects on biosynthesis of DNA in the liver, kidney, thymus and spleen of rats: (a) The administration of 4-TFMA initially suppressed the utilization of labeled thymidine for splenic DNA synthesis during the early prereplicative stage. However, with progressing time the incorporation of the labeled marker began to increase and in 30 h its level exceeded the controls by more than 200%. As expected, aniline administration resulted in mild depression of incorporation during the whole period studied. (b) 4-TFMA caused a significant increase of incorporation of labeled thymidine into DNA thymine also in the thymus. After administration of aniline the utilization of labeled thymidine for the synthesis of DNA thymine in thymus was suppressed during the first 16 h. (c) The dose-response curve showed a linear increase of incorporation in the spleen within the dose range between 0.125 and 0.500 mmol/kg of 4-TFMA. (d) It appears that enhanced incorporation of labeled thymidine into splenic and thymic DNA is a phenomenon specific for compounds bearing the CF3 group on the 4-position of the phenyl ring, such as 4-TFMA and 4-TFMPD. On the contrary, the analogous 3-CF3 substituted derivatives had no effect. Increased incorporation of labeled thymidine into spleen and thymus DNA apparently represents an increased DNA synthesis and cellular proliferation in lymphatic organs. The proliferative response was possibly evoked by the preceding hemolysis or by other toxic effects caused by the drug.

• MeSH
• aniliny chemická syntéza   toxicita   MeSH
• buněčné dělení účinky léků   MeSH
• DNA biosyntéza   MeSH
• játra účinky léků   MeSH
• krysa rodu Rattus MeSH
• potkani Wistar MeSH
• slezina účinky léků   metabolismus   MeSH
• velikost orgánu účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 4-trifluoromethylaniline MeSH Prohlížeč
• aniliny MeSH
• DNA MeSH

• MeSH
• anestetika lokální chemická syntéza   farmakologie   toxicita   MeSH
• aniliny chemická syntéza   MeSH
• estery chemická syntéza   MeSH
• ethery chemická syntéza   MeSH
• ethylaminy chemická syntéza   MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anestetika lokální MeSH
• aniliny MeSH
• estery MeSH
• ethery MeSH
• ethylaminy MeSH