The tri-dentate Schiff base ligand 3-(2-hydroxyethylimino)-1-phenylbut-1-en-1-ol (L) produced the tetra-nuclear Cu(II) distorted cubane complex which contain Cu4O4 core, upon reaction with Cu(II)acetate.H2O. The complex was structurally characterized by X-ray crystallography and found that, in this tetrameric and tetra-nuclear distorted cubane structure, each two-fold deprotonated Schiff base ligand coordinated to a Cu(II) center with their alcoholic oxygens and imine nitrogens and formed six and five-membered chelate rings. At the same time, each ligand bridged to a neighboring Cu(II) atom by its alcoholic oxygen, thus the metal centers became penta-coordinated. The copper(II) complex with μ-ɳ2-hydroxo bridges and Cu….Cu distance about 3 Å was structurally similar to the active site of natural catechol oxidase enzyme and exhibited excellent catecholase activity in aerobic oxidation of 3,5-di-tert-butyl catechol to its o-quinone. The kinetics and mechanism of the oxidation of 3, 5-DTBCH2 catalyzed by [CuL]4 complex, were studied at four different temperatures from 283 to 313K by UV-Vis spectroscopy. Interaction of [CuL]4 complex with FS-DNA was investigated by UV-Vis and fluorescence spectroscopy, viscosity measurements, cyclic voltammetry (CV), circular dichroism (CD) and agarose gel electrophoresis. The main mode of binding of the complexes with DNA was intercalation. The interaction between [CuL]4 complex and bovine serum albumin (BSA) was studied by UV-Vis, fluorescence and synchronous fluorescence spectroscopic techniques. The results indicated a high binding affinity of the complex to BSA. In vitro anticancer activity of the complex was evaluated against A549, Jurkat and Ragi cell lines by MTT assay. The complex was remarkably active against the cell lines and can be a good candidate for an anticancer drug. Theoretical docking studies were performed to further investigate the DNA and BSA binding interactions.

• Klíčová slova
• Anticancer activity, BSA, Catecholase activity, Cu(II) cubane complex, Docking study, FS-DNA,
• MeSH
• DNA metabolismus   MeSH
• interkalátory chemie   farmakologie   MeSH
• katalýza MeSH
• katecholoxidasa chemie   MeSH
• katecholy chemie   MeSH
• komplexní sloučeniny chemie   farmakologie   MeSH
• krystalografie rentgenová MeSH
• měď chemie   farmakologie   MeSH
• molekulární modely MeSH
• oxidace-redukce účinky léků   MeSH
• sérový albumin hovězí metabolismus   MeSH
• skot MeSH
• teplota MeSH
• zvířata MeSH
• Check Tag
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 3,5-di-tert-butylcatechol MeSH Prohlížeč
• DNA MeSH
• interkalátory MeSH
• katecholoxidasa MeSH
• katecholy MeSH
• komplexní sloučeniny MeSH
• měď MeSH
• sérový albumin hovězí MeSH

A series of 116 small-molecule 1-hydroxynaphthalene-2-carboxanilides was designed based on the fragment-based approach and was synthesized according to the microwave-assisted protocol. The biological activity of all of the compounds was tested on human colon carcinoma cell lines including a deleted TP53 tumor suppressor gene. The mechanism of activity was studied according to the p53 status in the cell. Several compounds revealed a good to excellent activity that was similar to or better than the standard anticancer drugs. Some of these appeared to be more active against the p53 null cells than their wild-type counterparts. Intercalating the properties of these compounds could be responsible for their mechanism of action.

• MeSH
• apoptóza účinky léků   MeSH
• DNA metabolismus   MeSH
• doxorubicin farmakologie   MeSH
• HCT116 buňky MeSH
• interkalátory farmakologie   MeSH
• knihovny malých molekul chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• naftoly chemická syntéza   chemie   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• racionální návrh léčiv * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-naphthol MeSH Prohlížeč
• calf thymus DNA MeSH Prohlížeč
• DNA MeSH
• doxorubicin MeSH
• interkalátory MeSH
• knihovny malých molekul MeSH
• nádorový supresorový protein p53 MeSH
• naftoly MeSH
• protinádorové látky MeSH

Nine novel cobalt(III) ternary complexes bearing 4N donor ligands (tris(2-aminoethyl)amine (tren) or tris(2-methylpyridyl)amine (tpa)) and (fluoro)quinolones (quinH) with antibacterial and potential antitumor activity have been synthesized, characterized and screened in various biological assays. The molecular structures of [Co(tpa)(nal)](PF6)2 (3) and [Co(tpa)(nor)(Co(tpa)(norH)](PF6)3(Cl)2∙5MeOH (8) (nal = deprotonated form of nalidixic acid, norH = norfloxacin) with the expected octahedral geometry and (O,O) coordination of the quinolone ligands are also reported. Cyclic voltammetric studies revealed that the 4N donor ligands have much higher effect on the reduction potential of these ternary complexes than the quinolones. Due to the π-back-bonding interaction of the metal ion with the pyridyl-N atoms, the tpa containing compounds demonstrated lower stability and were easier to get reduced in a reversible manner. This character makes them unlikely candidates for development of effective, highly selective hypoxia-activated pro-drug complexes, but this goal might be achieved by substitution of tpa by tren. [Co(tren)(cip)](PF6)2 (4) and [Co(tpa)(cip)](PF6)2 (5) (cip = deprotonated form of ciprofloxacin) showed slightly less antibacterial activity against Escherichia coli than free ciprofloxacin (cipH) and they found to have very low toxicity towards both selected cancer (HeLa, MCF 7, MDA-MB-239) and noncancerous (MRC5 pd30) cells. Interaction of 4 and 5 with calf thymus DNA studied by UV-Vis, flow linear dichroism, viscometry and DNA melting indicated the complexes to bind to DNA as intercalators. DNA electrophoresis revealed that, unlike Co(II) complexes, 4 and 5 are not capable of cleaving DNA, but they can inhibit bacterial DNA gyrase 5 being slightly more active than 4.

• MeSH
• antibakteriální látky chemická syntéza   farmakologie   toxicita   MeSH
• chinolony chemická syntéza   farmakologie   toxicita   MeSH
• ciprofloxacin farmakologie   MeSH
• DNA gyráza metabolismus   MeSH
• DNA metabolismus   MeSH
• inhibitory topoisomerasy II chemická syntéza   farmakologie   toxicita   MeSH
• interkalátory chemická syntéza   farmakologie   toxicita   MeSH
• kobalt chemie   MeSH
• komplexní sloučeniny chemická syntéza   farmakologie   toxicita   MeSH
• lidé MeSH
• ligandy MeSH
• mikrobiální testy citlivosti MeSH
• nádorové buněčné linie MeSH
• skot MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antibakteriální látky MeSH
• calf thymus DNA MeSH Prohlížeč
• chinolony MeSH
• ciprofloxacin MeSH
• DNA gyráza MeSH
• DNA MeSH
• inhibitory topoisomerasy II MeSH
• interkalátory MeSH
• kobalt MeSH
• komplexní sloučeniny MeSH
• ligandy MeSH

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used drugs in the world but some NSAIDs such as diclofenac and tolfenamic acid display levels of cytotoxicity, an effect which has been attributed to the presence of diphenylamine contained in their structures. A novel series of diphenylamine derivatives were synthetised and evaluated for their cytotoxic activities and proliferation inhibition. The most active compounds in the cytotoxicity tests were derivative 6g with an IC50 value of 2.5 ± 1.1 × 10-6 M and derivative 6f with an IC50 value of 6.0 ± 3.0 × 10-6 M (L1210 cell line) after 48 h incubation. The results demonstrate that leukemic L1210 cells were much more sensitive to compounds 6f and 6g than the HEK293T cells (IC50 = 35 × 10-6 M for 6f and IC50 > 50 × 10-6 M for 6g) and NIH-3T3 (IC50 > 50 × 10-6 M for both derivatives). The IC50 values show that these substances may selectively kill leukemic cells over non-cancer cells. Cell cycle analysis revealed that a primary trend of the diphenylamine derivatives was to arrest the cells in the G1-phase of the cell cycle within the first 24 h. UV-visible, fluorescence spectroscopy and circular dichroism were used in order to study the binding mode of the novel compounds with DNA. The binding constants determined by UV-visible spectroscopy were found to be in the range of 2.1-8.7 × 104 M-1. We suggest that the observed trend for binding constant K is likely to be a result of different binding thermodynamics accompanying the formation of the complexes.

• Klíčová slova
• Antiproliferative, DNA binding study, DNA minor groove binder, Diphenylamine,
• MeSH
• benzimidazoly chemie   MeSH
• buňky NIH 3T3 MeSH
• difenylamin analogy a deriváty   chemická syntéza   farmakologie   MeSH
• DNA chemie   účinky léků   MeSH
• fluorescenční barviva chemie   MeSH
• HEK293 buňky MeSH
• interkalátory chemická syntéza   chemie   farmakologie   MeSH
• kontrolní body fáze G1 buněčného cyklu účinky léků   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• termodynamika MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• benzimidazoly MeSH
• bisbenzimide ethoxide trihydrochloride MeSH Prohlížeč
• difenylamin MeSH
• DNA MeSH
• fluorescenční barviva MeSH
• interkalátory MeSH
• protinádorové látky MeSH

Guanine-rich nucleic acid sequences can fold into four-stranded G-quadruplex (G4) structures. Despite growing evidence for their biological significance, considerable work still needs to be done to detail their cellular occurrence and functions. Herein, we describe an optimized core-extended naphthalene diimide (cex-NDI) to be exploited as a G4 light-up sensor. The sensing mechanism relies on the shift of the aggregate-monomer equilibrium towards the bright monomeric state upon G4 binding. In contrast with the majority of other ligands, this novel cex-NDI is able to discriminate among G4s with different topologies, with a remarkable fluorescent response for the parallel ones. We investigate this sensing by means of biophysical methods, comparing the lead compound to a non-selective analogue. We demonstrate that mitigating the affinity of the binding core for G4s results in an increased selectivity and sensitivity of the fluorescent response. This is achieved by replacing positively charged substituents with diethylene glycol (DEG) side chains. Remarkably, the limit of detection values obtained for parallel G4s are more than one order of magnitude lower than those of the parallel-selective ligand N-methyl mesoporphyrin IX (NMM). Interestingly, the classical fluorescent intercalator displacement (FID) assay failed to reveal binding of cex-NDI to G4 because of the presence a ternary complex (G4-TO-cex-NDI) revealed by electrospray-MS. Our study thus provides a rational basis to design or modify existent scaffolds to redirect the binding preference of G4 ligands.

• MeSH
• biosenzitivní techniky metody   MeSH
• fluorescenční barviva chemická syntéza   chemie   farmakologie   MeSH
• G-kvadruplexy * účinky léků   MeSH
• imidy chemická syntéza   chemie   farmakologie   MeSH
• interkalátory chemická syntéza   chemie   farmakologie   MeSH
• ligandy * MeSH
• naftaleny chemická syntéza   chemie   farmakologie   MeSH
• rozpustnost MeSH
• substrátová specifita MeSH
• vazebná místa MeSH
• voda chemie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fluorescenční barviva MeSH
• imidy MeSH
• interkalátory MeSH
• ligandy * MeSH
• naftaleny MeSH
• naphthalenediimide MeSH Prohlížeč
• voda MeSH

Two new 1-acridin-9-yl-3-methylthiourea Au(I) DNA intercalators [Au(ACRTU)2]Cl (2) and [Au(ACRTU) (PPh3)]PF6 (3) have been prepared. Both complexes were highly active in the human ovarian carcinoma cisplatin-sensitive A2780 cell line, exhibiting IC50 values in the submicromolar range. Compounds 2 and 3 are also cytotoxic toward different phenotypes of breast cancer cell lines MDA-MB-231 (triple negative), SK-BR-3 (HER2+, ERα-, and ERβ-), and MCF-7 (ER+). Both complexes induce apoptosis through activation of caspase-3 in vitro. While inhibition of some proteins (thiol-containing enzymes) seems to be the main mechanism of action for cytotoxic gold complexes, 2 and 3 present a DNA-dependent mechanism of action. They locate in the cell nucleus according to confocal microscopy and transmission electronic microscopy. The binding to DNA resulted to be via intercalation as shown by spectroscopic methods and viscometry, exhibiting a dose-dependent response on topoisomerase I mediated DNA unwinding. In addition, 2 and 3 exhibit potent antiangiogenic effects and are also able to inhibit vasculogenic mimicry of highly invasive MDA-MB-231 cells.

• MeSH
• akridiny chemie   MeSH
• buněčné jádro metabolismus   MeSH
• inhibitory angiogeneze chemie   farmakologie   MeSH
• interkalátory chemie   farmakologie   MeSH
• invazivní růst nádoru prevence a kontrola   MeSH
• lidé MeSH
• molekulární mimikry MeSH
• nádorové buněčné linie MeSH
• patologická angiogeneze farmakoterapie   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• thiomočovina chemie   MeSH
• zlato chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akridiny MeSH
• inhibitory angiogeneze MeSH
• interkalátory MeSH
• protinádorové látky MeSH
• thiomočovina MeSH
• zlato MeSH

The DNA interstrand cross-links of the antitumor drug {[cis-Pt(NH3)2Cl]2(4,4'-methylenedianiline)}2+ (1) play a prevalent role in its antitumor effects. Complex 1 forms DNA long-range interstrand cross-links uniquely in the 3'-3' direction. Conformational distortions induced by these interstrand cross-links in DNA represent a potential structural motif for recognition by high-mobility-group proteins.

• MeSH
• adukty DNA chemie   MeSH
• DNA chemie   MeSH
• interkalátory chemie   farmakologie   MeSH
• konformace nukleové kyseliny účinky léků   MeSH
• lidé MeSH
• organoplatinové sloučeniny chemie   farmakologie   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• reagencia zkříženě vázaná chemie   farmakologie   MeSH
• sekvence nukleotidů MeSH
• simulace molekulového dockingu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• DNA MeSH
• interkalátory MeSH
• organoplatinové sloučeniny MeSH
• protinádorové látky MeSH
• reagencia zkříženě vázaná MeSH

This study examines the binding properties of a series of newly synthetized tacrine derivatives 1-4 and their anticancer effects. Spectroscopic techniques (UV-Vis, fluorescence spectroscopy, thermal denaturation, and linear spectropolarimetry) and viscometry were used to study DNA binding properties and to determine the types of DNA interaction with the studied derivatives. The binding constants for the complexes with DNA were obtained using UV-Vis spectroscopic titrations (K = 1.6 × 10(4)-4.0 × 10(5) M(-1)) and electrophoretic methods were used to determine the effect of the derivatives on topoisomerase I and II activity. Monotacrine derivative 1 showed evidence of topoisomerase Irelaxation activity at a concentration of 30 × 10(-6) M, while bistacrine derivatives 2-4 produced a complete inhibition of topoisomerase Iat a concentration of 5 × 10(-6) M. The biological activities of the derivatives were studied using MTT-assay and flow cytometric methods (detection of mitochondrial membrane potential and measurement of cell viability) following incubation of 24 and 48 h with human leukemic cancer cell line HL60. The ability of the derivatives to impair cell proliferation was also tested through the analysis of cell cycle distribution.

• Klíčová slova
• Spectroscopic techniques, Tacrine derivatives, Topoisomerase I and II,
• MeSH
• apoptóza účinky léků   MeSH
• DNA-topoisomerasy metabolismus   MeSH
• DNA metabolismus   MeSH
• HL-60 buňky MeSH
• inhibitory topoisomerasy I chemie   farmakologie   MeSH
• inhibitory topoisomerasy II chemie   farmakologie   MeSH
• interkalátory chemie   farmakologie   MeSH
• leukemie farmakoterapie   metabolismus   MeSH
• lidé MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• takrin chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA-topoisomerasy MeSH
• DNA MeSH
• inhibitory topoisomerasy I MeSH
• inhibitory topoisomerasy II MeSH
• interkalátory MeSH
• protinádorové látky MeSH
• takrin MeSH

A series of lichen secondary metabolites (parietin, atranorin, usnic and gyrophoric acid) and their interactions with calf thymus DNA were investigated using molecular biophysics and biochemical methods. The binding constants K were estimated to range from 4.3×10(5) to 2.4×10(7)M(-1) and the percentage of hypochromism was found to be 16-34% (from spectral titration). The results of spectral measurement indicate that the compounds act as effective DNA-interacting agents. Electrophoretic separation studies prove that from all the metabolites tested in this study, only gyrophoric acid exhibited an inhibitory effect on Topo I (25μM).

• Klíčová slova
• DNA-binding, Lichens, Topoisomerase I, II,
• MeSH
• benzoáty farmakologie   MeSH
• benzofurany farmakologie   MeSH
• cirkulární dichroismus MeSH
• DNA účinky léků   metabolismus   MeSH
• emodin analogy a deriváty   farmakologie   MeSH
• hydroxybenzoáty farmakologie   MeSH
• inhibitory topoisomerasy I farmakologie   MeSH
• inhibitory topoisomerasy II farmakologie   MeSH
• interkalátory farmakologie   MeSH
• kinetika MeSH
• konformace nukleové kyseliny MeSH
• lidé MeSH
• lišejníky chemie   metabolismus   MeSH
• skot MeSH
• spektrofotometrie ultrafialová MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• atranorin MeSH Prohlížeč
• benzoáty MeSH
• benzofurany MeSH
• calf thymus DNA MeSH Prohlížeč
• DNA MeSH
• emodin MeSH
• gyrophoric acid MeSH Prohlížeč
• hydroxybenzoáty MeSH
• inhibitory topoisomerasy I MeSH
• inhibitory topoisomerasy II MeSH
• interkalátory MeSH
• physcione MeSH Prohlížeč
• usnic acid MeSH Prohlížeč

When antitumor platinum drugs react with DNA they form various types of intrastrand and interstrand cross-links (CLs). One class of new antitumor platinum compounds comprises bifunctional Pt(II) compounds based on the dinuclear or trinuclear geometry of leaving ligands. It has been shown that the DNA-binding modes of dinuclear or trinuclear bifunctional Pt(II) agents are distinct from those of mononuclear cisplatin, forming markedly more intramolecular interstrand CLs. However, at least two types of DNA interstrand cross-linking by bifunctional Pt(II) complexes can be envisaged, depending on whether the platinum complex coordinates to the bases in one DNA molecule (intramolecular interstrand CLs) or in two different DNA duplexes (interduplex CLs). We hypothesized that at least some antitumor bifunctional poly(di/tri)nuclear complexes could fulfill the requirements placed on interduplex DNA cross-linkers. To test this hypothesis we studied the interduplex cross-linking capability of a representative of antitumor polynuclear agents, namely, dinuclear Pt(II) complex [{trans-PtCl(NH(3))(2)}(2)-μ-{trans-(H(2)N(CH(2))(6)NH(2)(CH(2))(2)NH(2)(CH(2))(6)NH(2))}](4+) (BBR3535). The investigations were conducted under molecular crowding conditions mimicking environmental conditions in the cellular nucleus, namely, in medium containing ethanol, which is a commonly used crowding agent. We found with the aid of native agarose gel electrophoresis that the DNA interduplex cross-linking efficiency of BBR3535 under molecular crowding conditions was remarkable: the frequency of these CLs was 54%. In contrast, the interduplex cross-linking efficiency of mononuclear cisplatin or transplatin was markedly lower (approximately 40-fold or 18-fold, respectively). We suggest that the production of interduplex CLs in addition to other DNA intramolecular adducts may provide polynuclear Pt(II) compounds with a wider spectrum of cytotoxicity.

• MeSH
• adukty DNA chemie   metabolismus   MeSH
• DNA chemie   metabolismus   MeSH
• interkalátory chemie   farmakologie   MeSH
• lidé MeSH
• nádory farmakoterapie   MeSH
• organoplatinové sloučeniny chemie   farmakologie   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• reagencia zkříženě vázaná chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• DNA MeSH
• interkalátory MeSH
• organoplatinové sloučeniny MeSH
• protinádorové látky MeSH
• reagencia zkříženě vázaná MeSH