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1.
Acta Crystallogr C Struct Chem ; 75(Pt 8): 1091-1101, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31380792

RESUMO

A new set of differently hydrated barium and strontium squarates, namely poly[[triaqua(µ-1,2-dioxocyclobut-3-ene-1,2-diolato)barium] monohydrate], {[Ba(C4O4)(H2O)3]·H2O}n (1), poly[[diaqua(µ-1,2-dioxocyclobut-3-ene-1,2-diolato)strontium] monohydrate], {[Sr(C4O4)(H2O)2]·H2O}n (2), and poly[[triaqua(µ-1,2-dioxocyclobut-3-ene-1,2-diolato)barium/strontium(0.85/0.15)] monohydrate], {[Ba0.85Sr0.15(C4O4)(H2O)3]·H2O}n (3), is reported. The study of their crystal structures indicates that all the complexes crystallize in the triclinic space group P-1. Complexes 1 and 3 have a rare combination of squarate units coordinated through monodentate O atoms to two different metal atoms and through two bidentate O atoms to three different metal atoms. Furthermore, they have three coordinated water molecules to give a coordination number of nine. The squarate ligands in complex 2 exhibit two different coordination modes: (i) monodentate O atoms coordinated to four different Sr atoms and (ii) two monodentate O atoms coordinated to two different metal atoms with the other two O atoms bidentate to four different Sr atoms. All the compounds decompose to give the respective carbonates when heated to 800 °C, as evidenced by thermogravimetry/differential thermal analysis (TG-DTA), which are clusters of nanoparticles. Complexes 1 and 3 show additional endothermic peaks at 811 and 820 °C, respectively, indicating the phase transition of BaCO3 from an orthorhombic (α-Pmcn) to a trigonal phase (ß-R3m). All three complexes have significant DNA-binding constants, ranging from 2.45 × 104 to 9.41 × 104 M-1 against EB-CT (ethidium bromide-calf thymus) DNA and protein binding constants ranging from 1.1 × 105 to 8.6 × 105 with bovine serum albumin. The in vitro cytotoxicity of the complexes is indicated by the IC50 values, which range from 128.8 to 261.3 µg ml-1. Complex 3 shows better BSA binding, antioxidant activity against the DPPH radical and cytotoxicity than complexes 1 and 2.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Ciclobutanos/farmacologia , Depuradores de Radicais Livres/farmacologia , Substâncias Intercalantes/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Bário/química , Bovinos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Cristalografia por Raios X , Ciclobutanos/síntese química , Ciclobutanos/química , Ciclobutanos/metabolismo , DNA/metabolismo , Depuradores de Radicais Livres/síntese química , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/metabolismo , Humanos , Ligações de Hidrogênio , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/metabolismo , Ligantes , Células MCF-7 , Estrutura Molecular , Ligação Proteica , Soroalbumina Bovina/metabolismo , Estrôncio/química , Água/química
2.
Int J Nanomedicine ; 14: 3027-3041, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118620

RESUMO

Background: In the discovery of DNA intercalators, ß-carbolines compose one member of the most interesting alkaloid family and are of clinical importance. In the efforts, N-(3-benzyloxycarbonyl-ß-carboline-1-yl)ethyl-Ser-Ala-OBzl (BCESA) was designed as a nano-scaled DNA intercalator without Dox-like toxicity. Methods: Based on the structural analysis and CDOCKER energy comparison, BCESA was rationally designed as such a nano-scaled intercalator. The anti-tumor activity, the toxicity and the tumor targeting action of BCESA were evaluated on mouse models. Results: The in vitro proliferation of cancer cells, but not non-cancer cells, was effectively inhibited by BCESA. On S180 mouse model BCESA dose-dependently slowed the tumor growth, and 0.01 µmol/kg/day was found as a minimal effective dose. Both BCESA and its moiety were found in the tumor tissue, but not in the organs and the blood, of S180 mice. Conclusion: BCESA should be a nano-scaled intercalator capable of targeting tumor tissue to release anti-tumoral ß-carboline-3-carboxylic acid and its 1-methyl derivative, while Ser-Ala-OBzl is a simple and desirable carrier.


Assuntos
Carbolinas/farmacologia , Nanopartículas/química , Neoplasias/patologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Carbolinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Creatinina/sangue , DNA/metabolismo , Humanos , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Masculino , Camundongos Endogâmicos ICR , Nanopartículas/ultraestrutura
3.
Artigo em Inglês | MEDLINE | ID: mdl-31081456

RESUMO

Three new Ru(II) polypyridyl complexes [Ru(phen)2CIIP]2+ (1) {CIIP = 2-(5-Chloro-3a H-Isoindol-3-yl)-1H-Imidazo[4,5-f][1, 10]phenantholine} (phen = 1, 10 phenanthroline), [Ru(bpy)2CIIP]2+ (2) (bpy = 2, 2' bipyridine) and [Ru(dmb)2CIIP]2+ (3) (dmb = 4, 4'-dimethyl 2, 2' bipyridine) were synthesized and characterized by different spectral methods. The DNA-binding behavior of these complexes was investigated by absorption, emission spectroscopic titration and viscosity measurements, indicating that these three complexes bind to CT-DNA in an intercalative mode, but binding affinities of these complexes were different. The DNA-binding constants Kb of complexes 1, 2 and 3 were calculated in the order of 106. All three complexes cleave pBR322 DNA in photoactivated cleavage studies and exhibit good antimicrobial activity. Anticancer activity of these Ru(II) complexes was evaluated in MCF7 cells. Cytotoxicity by MTT assay showed growth inhibition in a dose dependent manner. Cell cycle analysis by flow cytometry data showed an increase in Sub G1 population. Annexin V FITC/PI staining confirms that these complexes cause cell death by the induction of apoptosis.


Assuntos
Antibacterianos/química , Antineoplásicos/química , Complexos de Coordenação/química , Substâncias Intercalantes/química , Isoindóis/química , Fenantrolinas/química , Piridinas/química , Rutênio/química , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Bacillus subtilis/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , DNA/metabolismo , Clivagem do DNA , Escherichia coli/efeitos dos fármacos , Humanos , Substâncias Intercalantes/farmacologia , Isoindóis/farmacologia , Células MCF-7 , Fenantrolinas/farmacologia , Processos Fotoquímicos , Piridinas/farmacologia , Termodinâmica
4.
Biosens Bioelectron ; 133: 160-168, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30933710

RESUMO

An efficient and new electrochemical biosensor for detection of DNA damage, induced by the interaction of the hybrid anti-cancer compound (7ESTAC01) with DNA, was studied by differential pulse voltammetry (DPV). The biosensor consists of a Stem-Loop DNA (SL-DNA) probe covalently attached to the gold electrode (GE) surface that hybridizes to a complementary DNA strand (cDNA) to form a double-stranded DNA (dsDNA). The interaction and DNA damage induced by 7ESTAC01 was electrochemically studied based on the oxidation signals of the electroactive nucleic acids on the surface of the GE by DPV. As a result, the SL-DNA/GE and dsDNA/GE were tested with the reduced 7ESTAC01, showing the voltammetric signal of guanine and adenine, increase in the presence of 7ESTAC01. Under optimum conditions, the dsDNA/GE biosensor exhibited excellent DPV response in the presence of 7ESTAC01. The bonding interaction between 7ESTAC01 and calf thymus DNA (ctDNA) was confirmed by UV-Vis absorption spectroscopy, dynamic simulations (performed to investigate the DNA structure under physiological conditions), and molecular docking. Theoretical results showed the presence of hydrogen bonding and intercalation in the minor groove of DNA, involving hydrophobic interactions.


Assuntos
Antineoplásicos/química , Técnicas Biossensoriais , DNA/isolamento & purificação , Técnicas Eletroquímicas , Antineoplásicos/farmacologia , DNA/química , DNA/genética , Dano ao DNA/efeitos dos fármacos , DNA Complementar/química , DNA Complementar/genética , Ouro/química , Humanos , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Sequências Repetidas Invertidas/genética , Simulação de Acoplamento Molecular , Oxirredução/efeitos dos fármacos , Raios Ultravioleta
5.
Artigo em Inglês | MEDLINE | ID: mdl-30890029

RESUMO

A novel ligand BOPIP (BOPIP = {2-(4-(benzyloxy)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline}) and its mononuclear Ru(II) polypyridyl complexes [Ru(phen)2 BOPIP]2+(1) (phen = 1,10-Phenanthrolene), [Ru(bpy)2 BOPIP]2+(2) (bpy = 2,2' bipyridyl), [Ru(dmb)2 BOPIP]2+(3) (dmb = 4, 4' -dimethyl 2, 2' -bipyridine), [Ru(Hdpa)2 BOPIP]2+(4) (Hdpa = 2,2'dipyridylamine) have been synthesized successfully and characterized by elemental analysis, UV-vis, IR, 1H, 13 C-NMR, and ESI-MS Spectroscopy. The interaction of these complexes with CT-DNA was studied using absorption, emission techniques, viscosity measurements and molecular docking studies. The docking study also supports the binding ability of complexes obtained through the absorption and emission techniques. These studies reveal that the Four Ru(II) polypyridyl complexes bind to DNA predominantly by intercalation. The Antimicrobial activity and cytotoxicity of these complexes are also reported.


Assuntos
Antibacterianos/síntese química , Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Clivagem do DNA/efeitos dos fármacos , Imidazóis/química , Fenantrolinas/química , Rutênio/química , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , DNA/química , Células HeLa , Humanos , Imidazóis/farmacologia , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Conformação de Ácido Nucleico , Fenantrolinas/farmacologia , Processos Fotoquímicos , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 167: 105-123, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30769240

RESUMO

A series of aminothiazolyl norfloxacin analogues as a new type of potential antimicrobial agents were synthesized and screened for their antimicrobial activities. Most of the prepared compounds exhibited excellent inhibitory efficiencies. Especially, norfloxacin analogue II-c displayed superior antimicrobial activities against K. pneumoniae and C. albicans with MIC values of 0.005 and 0.010 mM to reference drugs, respectively. This compound not only showed broad antimicrobial spectrum, rapid bactericidal efficacy and strong enzymes inhibitory potency including DNA gyrase and chitin synthase (CHS), low toxicity against mammalian cells and no obvious propensity to trigger the development of bacterial resistance, but also exerted efficient membrane permeability, and could effectively intercalate into K. pneumoniae DNA to form a steady supramolecular complex, which might block DNA replication to exhibit their powerful antimicrobial activity. Quantum chemical studies were also performed to explain the high antimicrobial activities. Molecular docking showed that compound II-c could bind with gyrase-DNA and topoisomerase IV-DNA through hydrogen bonds and π-π stacking.


Assuntos
Anti-Infecciosos/química , Norfloxacino/análogos & derivados , Norfloxacino/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Quitina Sintase/antagonistas & inibidores , DNA Girase/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Desenho de Drogas , Fungos/efeitos dos fármacos , Substâncias Intercalantes/farmacologia , Simulação de Acoplamento Molecular , Norfloxacino/síntese química , Teoria Quântica , Relação Estrutura-Atividade , Tiazóis/química
7.
Mar Drugs ; 17(1)2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30654589

RESUMO

The temperate marine sponge, Tsitsikamma favus, produces pyrroloiminoquinone alkaloids with potential as anticancer drug leads. We profiled the secondary metabolite reservoir of T. favus sponges using HR-ESI-LC-MS/MS-based molecular networking analysis followed by preparative purification efforts to map the diversity of new and known pyrroloiminoquinones and related compounds in extracts of seven specimens. Molecular taxonomic identification confirmed all sponges as T. favus and five specimens (chemotype I) were found to produce mainly discorhabdins and tsitsikammamines. Remarkably, however, two specimens (chemotype II) exhibited distinct morphological and chemical characteristics: the absence of discorhabdins, only trace levels of tsitsikammamines and, instead, an abundance of unbranched and halogenated makaluvamines. Targeted chromatographic isolation provided the new makaluvamine Q, the known makaluvamines A and I, tsitsikammamine B, 14-bromo-7,8-dehydro-3-dihydro-discorhabdin C, and the related pyrrolo-ortho-quinones makaluvamine O and makaluvone. Purified compounds displayed different activity profiles in assays for topoisomerase I inhibition, DNA intercalation and antimetabolic activity against human cell lines. This is the first report of makaluvamines from a Tsitsikamma sponge species, and the first description of distinct chemotypes within a species of the Latrunculiidae family. This study sheds new light on the putative pyrroloiminoquinone biosynthetic pathway of latrunculid sponges.


Assuntos
Poríferos/metabolismo , Pirroliminoquinonas/química , Animais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/isolamento & purificação , Antimetabólitos Antineoplásicos/farmacologia , Vias Biossintéticas , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , DNA/química , DNA/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Ensaios Enzimáticos , Células HEK293 , Células HeLa , Humanos , Substâncias Intercalantes/química , Substâncias Intercalantes/isolamento & purificação , Substâncias Intercalantes/farmacologia , Estrutura Molecular , Pirroliminoquinonas/isolamento & purificação , Pirroliminoquinonas/metabolismo , Pirroliminoquinonas/farmacologia , Espectrometria de Massas em Tandem/métodos , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/isolamento & purificação , Inibidores da Topoisomerase I/metabolismo , Inibidores da Topoisomerase I/farmacologia
8.
Bioelectrochemistry ; 127: 12-20, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30623791

RESUMO

This study presents evaluation of the possible interaction mechanism between calf thymus dsDNA and three calcium antagonists; nifedipine, lercanidipine and amlodipine. The interactions between Nifedipine-dsDNA and Lercanidipine-dsDNA were investigated by differential pulse voltammetry using two different interaction methods; at the dsDNA-electrochemical biosensor surface and in bulk incubated solution. Amlodipine was used as model drug in bulk incubated solution. The decrease in the peak current of guanine and adenine were used as an indicator for confirmation of the interaction event in acetate buffer of pH 4.70. In bulk incubated solution, after interaction with Nifedipine and Amlodipine the guanine signal was almost disappeared. At the dsDNA modified glassy carbon electrode surface, the peak currents of guanine and adenine were decreased while Nifedipine and Lercanidipine interacts with DNA. The interactions between Nifedipine-dsDNA and Lercanidipine-dsDNA were further studied by UV-Vis absorption spectroscopy which indicates the intermolecular interaction between these drugs and ds-DNA can be mainly through hydrogen bonding and van der Waals forces. Molecular docking calculations shown that the AMP-1-2, NDP and LDP-1-2-ctDNA having groove binding. Beside spectral data, docking studies elicited that AMP-1-2, NDP and LDP-1-2 complexes have different interaction and conformation trends to target (ctDNA).


Assuntos
Bloqueadores dos Canais de Cálcio/metabolismo , DNA/metabolismo , Di-Hidropiridinas/metabolismo , Substâncias Intercalantes/metabolismo , Nifedipino/metabolismo , Animais , Sítios de Ligação/efeitos dos fármacos , Técnicas Biossensoriais , Bloqueadores dos Canais de Cálcio/farmacologia , Bovinos , DNA/química , Di-Hidropiridinas/farmacologia , Técnicas Eletroquímicas , Substâncias Intercalantes/farmacologia , Simulação de Acoplamento Molecular , Nifedipino/farmacologia , Conformação de Ácido Nucleico/efeitos dos fármacos
9.
Inorg Chem ; 58(1): 307-319, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30565467

RESUMO

Two novel rhodium(III) complexes, namely, [RhIII(X)Cl3] (X = 2 2,6-bis((4 S,7 R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1 H-4,7-methanoindazol-3-yl)pyridine or 2,6-bis((4 S,7 R)-1,7,8,8-tetramethyl-4,5,6,7-tetrahydro-1 H-4,7-methanoindazol-3-yl)pyridine), were synthesized from camphor derivatives of a bis(pyrazolylpyridine), tridentate nitrogen-donor chelate system, giving [RhIII(H2L*)Cl3] (1a) and [RhIII(Me2L*)Cl3] (1b). A rhodium(III) terpyridine (terpy) ligand complex, [RhIII(terpy)Cl3] (1c), was also synthesized. By single-crystal X-ray analysis, 1b crystallizes in an orthorhombic P212121 system, with two molecules in the asymmetric unit. Tridentate coordination by the N,N,N-donor localizes the central nitrogen atom close to the rhodium(III) center. Compounds 1a and 1b were reactive toward l-methionine (l-Met), guanosine-5'-monophosphate (5'-GMP), and glutathione (GSH), with an order of reactivity of 5'-GMP > GSH > l-Met. The order of reactivity of the RhIII complexes was: 1b> 1a > 1c. The RhIII complexes showed affinity for calf thymus DNA and bovine serum albumin by UV-vis and emission spectral studies. Furthermore, 1b showed significant in vitro cytotoxicity against human epithelial colorectal carcinoma cells. Since the RhIII complexes have similar coordination modes, stability differences were evaluated by density functional theory (DFT) calculations (B3LYP(CPCM)/LANL2DZp). With (H2L*) and (terpy) as model ligands, DFT calculations suggest that both tridentate ligand systems have similar stability. In addition, molecular docking suggests that all test compounds have affinity for the minor groove of DNA, while 1b and 1c have potential for DNA intercalation.


Assuntos
Cânfora/análogos & derivados , Cânfora/farmacologia , Complexos de Coordenação/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Ródio/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Cânfora/síntese química , Cânfora/química , Bovinos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , DNA/química , Teoria da Densidade Funcional , Células HCT116 , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Cinética , Ligantes , Modelos Químicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Soroalbumina Bovina/química
10.
Spectrochim Acta A Mol Biomol Spectrosc ; 209: 100-108, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30384015

RESUMO

A new Dichlorotetra(4-hydroxy-N'-(pyridin-4-ylmethylene)benzohydrazone)Ru(II) complex 1 has been synthesized and characterized using spectroscopic techniques. The structure of complex 1 has been optimized through ORCA computational programme package using B3LYP functionals. The complex binds efficiently with calf thymus DNA (CT-DNA) as monitored by UV-visible titrations (Kb = 4.8 × 105), ethidium bromide displacement studies (Ksv = 1.39) as well as Circular Dichroism (CD) titrations. The complex intercalates with DNA base pairs. It shows cleavage of supercoiled (SC) DNA into nicked circular (NC) DNA efficiently via oxidative pathway. Complex 1 also inhibits Topoisomerase I (Topo I) relaxation activity at concentration < 20 µM. The molecular docking studies support that Topo I inhibition occur via blocking religation of G11 hydroxyl group.


Assuntos
Complexos de Coordenação/farmacologia , DNA/química , Desoxirribonucleases/antagonistas & inibidores , Substâncias Intercalantes/farmacologia , Modelos Teóricos , Simulação de Acoplamento Molecular , Rutênio/química , Inibidores da Topoisomerase I/farmacologia , Animais , Bovinos , Dicroísmo Circular , Complexos de Coordenação/química , DNA/metabolismo , Etídio/química , Hidrazonas/química , Substâncias Intercalantes/química , Termodinâmica , Inibidores da Topoisomerase I/química
11.
Eur J Med Chem ; 159: 393-422, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30312931

RESUMO

In this review, we describe a detailed investigation about the structural variations and relative activity of 1,8-naphthalimide based intercalators and anticancer agents. The 1,8-naphthalimides binds to the DNA via intercalation, and exert their antitumor activities through Topoisomerase I/II inhibition, photoinduced DNA damage or related mechanism. Here, our discussion focused on works published over the last ten years (2007-2017) related to therapeutic applications, in the order of cancer treatment followed by other properties of 1,8-naphthalimides. In preparing for this review, we considered that several seminal reviews have appeared over the last fifteen years and focused on closely related subjects, however, none of them is exhaustive.


Assuntos
Antineoplásicos/farmacologia , DNA de Neoplasias/efeitos dos fármacos , Substâncias Intercalantes/farmacologia , Naftalimidas/farmacologia , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/metabolismo , DNA de Neoplasias/química , Humanos , Substâncias Intercalantes/química , Naftalimidas/química , Neoplasias/patologia , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase II/química
12.
Eur J Med Chem ; 156: 148-161, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30006161

RESUMO

Fluorescent 4-ethylthio-1,8-naphthalimides containing rhodium(I) N-heterocyclic carbene (NHC) and ruthenium (II) NHC fragments were synthesised and evaluated for their antiproliferative effects, cellular uptake and DNA-binding activity. Both types of organometallics triggered ligand dependent efficient cytotoxic effects against tumor cells with the rhodium(I) NHC derivatives causing stronger effects than the ruthenium (II) NHC analogues. Antiproliferative effects could also be observed against several pathogenic Gram-positive bacterial strains, whereas the growth of Gram-negative bacteria was not substantially affected. Cellular uptake was confirmed by atomic absorption spectroscopy as well as by fluorescence microscopy indicating a general ligand dependent accumulation in the cells. An in-depth study on the interaction with DNA confirmed insertion of the naphthalimide moiety between the planar bases of B-DNA via an intercalation mechanism, as well as its stacking on top of the quartets of G-quadruplex structures. Furthermore, additional coordinative binding of the organometallic complexes to the model DNA base 9-ethylguanine could be detected. The studied compounds thus represent promising bioorganometallics featuring strong pharmacological effects in combination with excellent cellular imaging properties.


Assuntos
Antibacterianos/química , Antineoplásicos/química , Corantes Fluorescentes/química , Substâncias Intercalantes/química , Naftalimidas/química , Ródio/química , Rutênio/química , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/farmacologia , Quadruplex G/efeitos dos fármacos , Humanos , Substâncias Intercalantes/farmacologia , Ligantes , Naftalimidas/farmacologia , Neoplasias/tratamento farmacológico , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Ródio/farmacologia , Rutênio/farmacologia
13.
Inorg Chem ; 57(7): 4009-4022, 2018 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-29543468

RESUMO

The development of photoactivatable metal complexes with potential anticancer properties is a topical area of current investigation. Photoactivated chemotherapy using coordination compounds is typically based on photochemical processes occurring at the metal center. In the present study, an innovative approach is applied that takes advantage of the remarkable photochemical properties of diarylethenes. Following a proof-of-concept study with two complexes, namely, C1 and C2, a series of additional platinum(II) complexes from dithienylcyclopentene-based ligands was designed and prepared. Like C1 and C2, these new coordination compounds exhibit two thermally stable, interconvertible photoisomers that display distinct properties. The photochemical behavior of ligands L3-L7 has been analyzed by 1H NMR and UV-vis spectroscopies. Subsequently, the corresponding platinum(II) complexes C3-C7 were synthesized and fully characterized, including by single-crystal X-ray diffraction for some of them. Next, the interaction of each photoisomer (i.e., containing the open or closed ligand) of the metal complexes with DNA was examined thoroughly using various techniques, revealing their distinct DNA-binding modes and affinities, as observed for the earlier compounds C1 and C2. The antiproliferative activity of the two forms of the complexes was then assessed with five cancer cell lines and compared with that of C1 and C2, which supported the use of such diarylethene-based systems for the generation of a new class of potential photochemotherapeutic metallodrugs.


Assuntos
Complexos de Coordenação/farmacologia , DNA Super-Helicoidal/química , Compostos Organoplatínicos/farmacologia , Platina/química , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , Ciclização , Fluorescência , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Substâncias Intercalantes/efeitos da radiação , Isomerismo , Ligantes , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Compostos Organoplatínicos/efeitos da radiação
14.
Inorg Chem ; 57(6): 3133-3143, 2018 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-29509011

RESUMO

This article describes the synthesis and characterization of novel cationic five-coordinate Pt(II) complexes containing nitrogen sugar-based ligands. The cytotoxicity of the complexes was evaluated on different cell lines with the expectation that both the coordinative saturation and the sugar moiety cooperate to enhance their biological activity. In fact, the complexes resulted to be more active than cisplatin but still with little selectivity. They activate the apoptosis pathway. Binding of representative compounds with DNA was studied by ethidium bromide displacement assay and circular dichroism. Binding to model proteins was also investigated; the X-ray structure of the adduct formed in the reaction between a representative compound and the model protein bovine pancreatic ribonuclease was obtained. The structure discloses an unprecedented interaction between a five-coordinate Pt(II) moiety and a His side chain.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Glucosídeos/farmacologia , Platina/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Bovinos , Linhagem Celular Tumoral , Galinhas , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , DNA/química , Glucosídeos/síntese química , Glucosídeos/química , Histidina/química , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Ligantes , Estrutura Molecular , Muramidase/química , Ratos , Ribonuclease Pancreático/química
15.
Chem Biol Interact ; 286: 34-44, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29476729

RESUMO

In this work, we report on the synthesis of two new mono-alkylated tetrandrine derivatives with acridine and anthracene units, MAcT and MAnT. The compounds were fully characterized by physicochemical techniques and single-crystal X-ray diffraction analysis. In addition, both derivatives were studied as nucleotide receptors and double-stranded DNA binders in aqueous phosphate buffer at pH = 7.2 using UV-vis and fluorescence spectroscopy. According to the molecular recognition studies, MAcT and MAnT exhibit high affinity (K ∼ 105 M-1) and selectivity for ds-DNA, presumably in an intercalation mode. Finally, the anti-proliferative effects of the tetrandrine derivatives on different cancer cell lines were explored, revealing promising activities. Particularly, the mono-anthracene tetrandrine derivative MAnT showed an IC50 of 2.74 µg/mL on the HeLa cervical cancer cell line, representing a value 3.3 times smaller than that obtained for unsubstituted tetrandrine. Examination of the cytotoxic effects on the HeLa cell line by inverted microscopy suggests that the cell death mechanism consists basically in apoptosis. The molecular modelling of three ds-DNA-MAcT complexes, suggested that the macrocycles may use an intercalation binding mode towards DNA. MAcT is predicted to bind into the major groove of the ds-DNA providing non-covalent interactions such as electrostatic, van der Waals and hydrophobic interactions that lead to selectivity. Overall experimental data supports the mode of action of MAnT and MAcT as cytotoxic compounds against cancer cell lines via a DNA interaction mechanism.


Assuntos
Acridinas/química , Antracenos/química , Benzilisoquinolinas/química , Compostos Macrocíclicos/síntese química , Células A549 , Acridinas/síntese química , Acridinas/farmacologia , Antracenos/síntese química , Antracenos/farmacologia , Apoptose/efeitos dos fármacos , Benzilisoquinolinas/síntese química , Benzilisoquinolinas/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/química , DNA/metabolismo , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Simulação de Acoplamento Molecular , Conformação de Ácido Nucleico , Eletricidade Estática
16.
Eur J Med Chem ; 153: 131-139, 2018 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-28502586

RESUMO

Three novel Zn(II) complexes of NSAID niflumic acid (Hnif) were prepared and studied, namely; [Zn(MeOH)4(nif)2] (1), [Zn(cyclam)(nif)2] (2) and [Zn(nif)2(tmen)] (3), where nif is deprotonated niflumic acid, cyclam is 1,4,8,11-Tetraazacyclotetradecane and tmen is N,N,N',N'-Tetramethylethylenediamine. The complexes have been characterized by infrared spectroscopy, elemental and thermal analysis and single-crystal X-ray structure analysis. All three complexes contain two deprotonated niflumato anions monodentately coordinated via carboxylato groups. Furthermore, fluorescence binding studies of the prepared compounds with human genomic DNA-EB (ethidium bromide) were carried out, which suggest that all complexes are able to bind to DNA via intercalation. Moreover, from the obtained results it followed that complexes 2 and 3 bind to DNA from the tissue with aortic aneurysm (aDNA) and control (cDNA) with a different strength. Additionally, complexes 1-3 exhibit good binding affinity to human serum albumin with high binding constant.


Assuntos
Anti-Inflamatórios não Esteroides/química , Complexos de Coordenação/química , DNA/metabolismo , Substâncias Intercalantes/química , Ácido Niflúmico/análogos & derivados , Albumina Sérica/metabolismo , Zinco/química , Anti-Inflamatórios não Esteroides/farmacologia , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , Humanos , Substâncias Intercalantes/farmacologia , Modelos Moleculares , Ácido Niflúmico/farmacologia , Zinco/farmacologia
17.
Eur J Med Chem ; 143: 583-590, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29207341

RESUMO

((3RS,5SR)- and ((3RS,5RS)-2-(2-methoxybenzyl)-3-(1,10-phenanthrolin-2-yl)isoxazolidin-5-yl)methanol have been synthesized, according to 1,3-dipolar cycloaddition methodology, as DNA intercalating agents and evaluated for their anticancer activity against human cervical carcinoma HeLa and head and neck squamous cells carcinoma cell lines. The synthesized compounds exhibited good cytotoxic activity with IC50 better than cisplatin, used as the main and effective treatment for HNSCC, and a 24.3-72.0-fold selectivity respect to the 184B5 non-cancerous immortalized breast epithelial cell lines. Unwinding assay, circular dichroism data, and Uv-vis melting experiments confirmed that these compounds act as DNA intercalators with a binding constant in the order of 104 M-1. Docking studies showed that both compounds can interact as intercalating agent with both poly-d(AT)2 and poly-d(GC)2, preferring an entrance by the minor groove of the poly-d(AT)2.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/farmacologia , DNA de Neoplasias/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Substâncias Intercalantes/farmacologia , Isoxazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/química , DNA de Neoplasias/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Isoxazóis/síntese química , Isoxazóis/química , Modelos Moleculares , Estrutura Molecular , Carcinoma de Células Escamosas de Cabeça e Pescoço , Relação Estrutura-Atividade
18.
J Biochem Mol Toxicol ; 32(1)2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28972679

RESUMO

A new tetracopper(II) complex bridged both by oxamido and carboxylato groups, namely [Cu4 (dmaepox)2 (bpy)2 ](NO3 )2 ·2H2 O, where H3 dmaepox and bpy represent N-benzoato-N'- (3-methylaminopropyl)oxamide and 2,2'-bipyridine, was synthesized, and its structure reveals the presence of a centrosymmetric cyclic tetracopper(II) cation assembled by a pair of cis-dmaepox3- - bridged dicopper(II) units through the carboxylato groups, in which the endo- and exo-copper(II) ions bridged by the oxamido group have a square-planar and a square-pyramidal coordination geometries, respectively. The aromatic packing interactions assemble the complex molecules to a two-dimensional supramolecular structure. The reactivity toward DNA and protein bovine serum albumin (BSA) indicates that the complex can interact with herring sperm DNA through the intercalation mode and the binding affinity is dominated by the hydrophobicity and chelate ring arrangement around copper(II) ions and quenches the intrinsic fluorescence of BSA via a static process. The cytotoxicity of the complex shows selective cancer cell antiproliferative activity.


Assuntos
Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cobre/farmacologia , Desenho de Drogas , Hepatócitos/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Compostos Organometálicos/farmacologia , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/metabolismo , Sítios de Ligação , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cobre/efeitos adversos , Cobre/química , Cobre/metabolismo , Cristalografia por Raios X , Hepatócitos/patologia , Humanos , Substâncias Intercalantes/efeitos adversos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Cinética , Ligantes , Neoplasias Hepáticas/patologia , Estrutura Molecular , Compostos Organometálicos/efeitos adversos , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Solubilidade
19.
Chem Res Toxicol ; 31(1): 22-36, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29185724

RESUMO

Parabens, phthalates, and perfluorinated compounds are pollutant compounds used in cosmetics, plastics, and fire-fighting foams. All three compounds have been studied over several years for toxicity mechanism; however, a clear view of their ability to bind to DNA has not been supplied empirically. In this work, a simulation study is done to reveal the interaction of three of these pollutants, bis(2-ethylhexyl)-phthalate (DEHP), butylparaben (BPRB), and the protonated form of perfluorooctanesulfonic acid (PFOS(H)), with DNA. The results show that the DEHP, PFOS(H), and BPRB bind with a probability of 1/5 to DNA, with respective bonding energies -23.96 kJ/mol (PFOS(H)), -94.92 kJ/mol (BPRB), and -216.52 kJ/mol (DEHP). The positive control, benzo[a]pyrene diol epoxide (BAP), which is known for its notorious DNA intercalation, binds at a rate of 3/5 simulations, with bonding energies of -6544.52, -7034.66, and -7578.67 kJ/mol. The results are compared to empirical studies and conclusively show that all these pollutants can interfere with transcription and DNA related mechanisms by forming noncovalent interactions with DNA. The results show also that these pollutants are unlikely to undergo strong noncovalent intercalation to DNA, such as BAP, and do not possess the frontier orbital profiles to undergo adduct formation. After many years of research and several unanswered questions on the action of these pollutants on DNA, a calculation on their properties hence to the DNA confirms that there is a low probability for these to undergo a strong intercalation with DNA. Literature shows however that the pollutants are strongly interfering with the protein machinery and receptors on the cell surface and are therefore still priority pollutants for ecotoxicity research.


Assuntos
Ácidos Alcanossulfônicos/química , Benzo(a)pireno/química , DNA/química , Dietilexilftalato/química , Fluorcarbonetos/química , Substâncias Intercalantes/química , Parabenos/química , DNA/efeitos dos fármacos , Substâncias Intercalantes/farmacologia , Simulação de Dinâmica Molecular , Teoria Quântica
20.
Nucleosides Nucleotides Nucleic Acids ; 36(11): 676-689, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29185900

RESUMO

In this study, an attempt has been made to study the interaction of a Zn(II) complex containing an antibiotic drug, ciprofloxacin, with calf thymus DNA using spectroscopic methods. It was found that Zn(II) complex could bind with DNA via intercalation mode as evidenced by: hyperchromism in UV-Vis spectrum; these spectral characteristics suggest that the Zn(II) complex interacts with DNA most likely through a mode that involves a stacking interaction between the aromatic chromophore and the base pairs of DNA. DNA binding constant (Kb = 1.4 × 104 M-1) from spectrophotometric studies of the interaction of Zn(II) complex with DNA is comparable to those of some DNA intercalative polypyridyl Ru(II) complexes 1.0 -4.8 × 104 M-1. CD study showed stabilization of the right-handed B form of DNA in the presence of Zn(II) complex as observed for the classical intercalator methylene blue. Thermodynamic parameters (ΔH < 0 and ΔS < 0) indicated that hydrogen bond and Van der Waals play main roles in this binding prose. Competitive fluorimetric studies with methylene blue (MB) dye have shown that Zn(II) complex exhibits the ability of this complex to displace with DNA-MB, indicating that it binds to DNA in strong competition with MB for the intercalation.


Assuntos
Pareamento de Bases , Ciprofloxacino/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , DNA/química , Zinco/química , Animais , Ligação Competitiva , Bovinos , Complexos de Coordenação/metabolismo , DNA/metabolismo , Substâncias Intercalantes/química , Substâncias Intercalantes/metabolismo , Substâncias Intercalantes/farmacologia , Azul de Metileno/metabolismo , Termodinâmica
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