Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 463
Filtrar
Filtros adicionais











País/Região como assunto
Intervalo de ano
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.
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
3.
Org Biomol Chem ; 17(7): 1827-1833, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30604825

RESUMO

We report a high-affinity photoswitchable DNA binder, which displays different nucleosome-binding capacities upon visible-light irradiation. Both photochemical and DNA-recognition properties were examined by UV-Vis, HPLC, CD spectroscopy, NMR, FID assays, EMSA and DLS. Our probe sets the basis for developing new optoepigenetic tools for conditional modulation of nucleosomal DNA accessibility.


Assuntos
Compostos Azo/química , DNA/química , Substâncias Intercalantes/química , Luz , Nucleossomos/química , Compostos Azo/síntese química , Substâncias Intercalantes/síntese química , Estrutura Molecular , Processos Fotoquímicos
4.
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
5.
Talanta ; 192: 212-219, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30348380

RESUMO

Nucleus imaging is of great importance for understanding cellular processes of genetic expression, proliferation and growth, etc. Although many nucleic-acid selective dyes for nucleus staining are available, few of them meet multiple standards. Herein, we report a cationic fluorescence dye FTI that possesses visible light excitation (436 nm), orange emission (571 nm) and a large Stokes shift (~135 nm) for nucleic-acid staining. FTI displays an obvious and sensitive fluorescent response to DNA in vitro with a 6.4-fold quantum yield increasing. Co-staining and nucleic acid digest experiments in live cells demonstrate that FTI exhibits an unexpected selectivity for the nucleolus of the cells due to the stronger affinity to RNA than DNA. Because of good photostability and low cytotoxicity, FTI can accomplish a promising stain for DNA recognition in vitro and nucleolus-specific imaging in cancer cells.


Assuntos
Nucléolo Celular/metabolismo , DNA/metabolismo , Fluorenos/química , Corantes Fluorescentes/química , Compostos de Piridínio/química , Estabilidade de Medicamentos , Fluorenos/síntese química , Fluorenos/efeitos da radiação , Fluorenos/toxicidade , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Corantes Fluorescentes/toxicidade , Células Hep G2 , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/efeitos da radiação , Substâncias Intercalantes/toxicidade , Luz , Microscopia Confocal , Microscopia de Fluorescência , Compostos de Piridínio/síntese química , Compostos de Piridínio/efeitos da radiação , Compostos de Piridínio/toxicidade
6.
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
7.
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
8.
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
9.
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
10.
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
11.
Inorg Chem ; 56(22): 13679-13696, 2017 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-29099179

RESUMO

The synthesis and characterization of Pt(II) (1 and 2) and Ru(II) arene (3 and 4) or polypyridine (5 and 6) complexes is described. With the aim of having a functional group to form bioconjugates, one uncoordinated carboxyl group has been introduced in all complexes. Some of the complexes were selected for their potential in photodynamic therapy (PDT). The molecular structures of complexes 2 and 5, as well as that of the sodium salt of the 4'-(4-carboxyphenyl)-2,2':6',2″-terpyridine ligand (cptpy), were determined by X-ray diffraction. Different techniques were used to evaluate the binding capacity to model DNA molecules, and MTT cytotoxicity assays were performed against four cell lines. Compounds 3, 4, and 5 showed little tendency to bind to DNA and exhibited poor biological activity. Compound 2 behaves as bonded to DNA probably through a covalent interaction, although its cytotoxicity was very low. Compound 1 and possibly 6, both of which contain a cptpy ligand, were able to intercalate with DNA, but toxicity was not observed for 6. However, compound 1 was active in all cell lines tested. Clonogenic assays and apoptosis induction studies were also performed on the PC-3 line for 1. The photodynamic behavior for complexes 1, 5, and 6 indicated that their nuclease activity was enhanced after irradiation at λ = 447 nm. The cell viability was significantly reduced only in the case of 5. The different behavior in the absence or presence of light makes complex 5 a potential prodrug of interest in PDT. Molecular docking studies followed by molecular dynamics simulations for 1 and the counterpart without the carboxyl group confirmed the experimental data that pointed to an intercalation mechanism. The cytotoxicity of 1 and the potential of 5 in PDT make them good candidates for subsequent conjugation, through the carboxyl group, to "selected peptides" which could facilitate the selective vectorization of the complex toward receptors that are overexpressed in neoplastic cell lines.


Assuntos
Antineoplásicos/farmacologia , Ácidos Carboxílicos/farmacologia , Complexos de Coordenação/farmacologia , Compostos Organoplatínicos/farmacologia , Rutênio/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/efeitos da radiação , Linhagem Celular Tumoral , Cisplatino/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , DNA/química , Dano ao DNA , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Substâncias Intercalantes/efeitos da radiação , Luz , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Compostos Organoplatínicos/efeitos da radiação , Plasmídeos
12.
J Med Chem ; 60(19): 8055-8070, 2017 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-28933851

RESUMO

XPA is a unique and essential protein required for the nucleotide excision DNA repair pathway and represents a therapeutic target in oncology. Herein, we are the first to develop novel inhibitors of the XPA-DNA interaction through structure-guided drug design efforts. Ester derivatives of the compounds 1 (X80), 22, and 24 displayed excellent inhibitory activity (IC50 of 0.82 ± 0.18 µM and 1.3 ± 0.22 µM, respectively) but poor solubility. We have synthesized novel amide derivatives that retain potency and have much improved solubility. Furthermore, compound 1 analogs exhibited good specificity for XPA over RPA (replication protein A), another DNA-binding protein that participates in the nucleotide excision repair (NER) pathway. Importantly, there were no significant interactions observed by the X80 class of compounds directly with DNA. Molecular docking studies revealed a mechanistic model for the interaction, and these studies could serve as the basis for continued analysis of structure-activity relationships and drug development efforts of this novel target.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , DNA/efeitos dos fármacos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/farmacologia , Proteína de Xeroderma Pigmentoso Grupo A/antagonistas & inibidores , Antineoplásicos/química , Simulação por Computador , Reparo do DNA/efeitos dos fármacos , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Substâncias Intercalantes/química , Modelos Moleculares , Simulação de Acoplamento Molecular , Solubilidade , Relação Estrutura-Atividade
13.
Inorg Chem ; 56(20): 12232-12247, 2017 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-28956596

RESUMO

A pyrazole-appended quinoline-based 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (L1, BODIPY) has been synthesized and used as a ligand for the preparation of iridium(III) complexes [Ir(phpy)2(L1)]PF6 (1; phpy = 2-phenylpyridine) and [(η5-C5Me5)Ir(L1)Cl]PF6 (2). The ligand L1 and complexes 1 and 2 have been meticulously characterized by elemental analyses and spectral studies (IR, electrospray ionization mass spectrometry, 1H and 13C NMR, UV/vis, fluorescence) and their structures explicitly authenticated by single-crystal X-ray analyses. UV/vis, fluorescence, and circular dichroism studies showed that complexes strongly bind with calf-thymus DNA and bovine serum albumin. Molecular docking studies clearly illustrated binding through DNA minor grooves via van der Waals forces and their electrostatic interaction and occurrence in the hydrophobic cavity of protein (subdomain IIA). Cytotoxicity, morphological changes, and apoptosis have been explored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst 33342 staining. IC50 values for complexes (1, 30 µM; 2, 50 µM) at 24 h toward the human cervical cancer cell line (HeLa) are as good as that of cisplatin (21.6 µM) under analogous conditions, and their ability to kill cancer cells lies in the order 1 > 2. Because of the inherent emissive nature of the BODIPY moiety, these are apt for intracellular visualization at low concentration and may find potential applications in cellular imaging and behave as a theranostic agent.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Complexos de Coordenação/farmacologia , Irídio/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Compostos de Boro/síntese química , Compostos de Boro/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , DNA/química , Fluorescência , Células HEK293 , Células HeLa , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Ligantes , Modelos Químicos , Simulação de Acoplamento Molecular , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia , Albumina Sérica/química , Viscosidade
14.
J Inorg Biochem ; 177: 127-137, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28961475

RESUMO

Two phosphorescent cyclometalated iridium(III)-triptycenyl-1,10-phenanthroline complexes [Ir(ppy)2(tpt-phen)]+ (1) and [Ir(bhq)2(tpt-phen)]+ (2) {ppy=2-phenylpyridine, bhq=Benzo[h]quinoline, tpt-phen=triptycenyl-1,10-phenanthroline} have been synthesized and structurally characterized. The structure of complex 2 has been studied by single crystal X-ray crystallography. The photophysical properties of complexes in a different solvent have also been investigated. The binding of complexes to the double stranded calf thymus (CT-DNA) has been investigated by spectroscopic techniques. These complexes condense originally circular plasmid DNA into particulate structures. The DNA-condensation induced by these complexes have been investigated by electrophoretic mobilty shift assay, dynamic light scattering, and fluorescence microscopy. Furthermore, the cytotoxicity of these complexes towards HeLa cells have been studied and their cellular localisation properties have been investigated by fluorescence microscopy.


Assuntos
Complexos de Coordenação/farmacologia , DNA/metabolismo , Corantes Fluorescentes/farmacologia , Irídio/química , Núcleo Celular/metabolismo , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , Cristalografia por Raios X , Estabilidade de Medicamentos , Difusão Dinâmica da Luz , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/efeitos da radiação , Células HeLa , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Substâncias Intercalantes/efeitos da radiação , Ligantes , Estrutura Molecular , Plasmídeos/metabolismo
15.
J Inorg Biochem ; 175: 276-283, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28806644

RESUMO

Two new Ru(II) polypyridyl complexes containing fluorine substituents, [Ru(bpy)2(o-fpip)]2+ (Ru1, bpy=2,2'-bipyridine, o-fpip=2-(2-fluorophenyl)imidazo[4,5-f] [1,10]phenanthroline) and [Ru(bpy)2(p-fpip)]2+ (Ru2, p-fpip=2-(4-fluorophenyl)imidazo[4,5-f] [1,10]phenanthroline) have been synthesized as binders for poly(U)•poly(A)∗poly(U) triplex RNA. The binding of the two complexes with the triplex RNA has been investigated by spectroscopic methods and viscosity measurements. Analysis of the electronic absorption spectra indicates that the association of intercalating Ru2 with the triplex RNA is greater than that of Ru1, which is also supported by spectroscopic titrations and viscosity measurements. Thermal denaturation studies reflect that third-strand stabilization depend on the nature of the two complexes and Ru2 is more effective for stabilization of the triplex RNA. Circular dichroism spectra of the triplex RNA in the presence of metal complexes indicate that the binding-induced CD perturbation of the triplex structure is more obvious by Ru2. The main results obtained here suggest that the positions of fluorine substituent in the intercalating ligands have a significant effect on the two complexes stabilizing the third strand.


Assuntos
Complexos de Coordenação/química , Hidrocarbonetos Fluorados/química , Substâncias Intercalantes , Poli A-U/química , Poli U/química , Rutênio/química , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química
16.
Inorg Chem ; 56(15): 9084-9096, 2017 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-28726387

RESUMO

Ruthenium polypyridine complexes have shown promise as agents for photodynamic therapy (PDT) and tools for molecular biology (chromophore-assisted light inactivation). To accomplish these tasks, it is important to have at least target selectivity and great reactive oxygen species (ROS) photogeneration: two properties that are not easily found in the same molecule. To prepare such new agents, we synthesized two new ruthenium complexes that combine an efficient DNA binding moiety (dppz ligand) together with naphthyl-modified (1) and anthracenyl-modified (2) bipyridine as a strong ROS generator bound to a ruthenium complex. The compounds were fully characterized and their photophysical and photochemical properties investigated. Compound 2 showed one of the highest quantum yields for singlet oxygen production ever reported (ΦΔ= 0.96), along with very high DNA binding (log Kb = 6.78). Such photochemical behavior could be ascribed to the lower triplet state involving the anthracenyl-modified bipyridine, which is associated with easier oxygen quenching. In addition, the compounds exhibited moderate selectivity toward G-quadruplex DNA and binding to the minor groove of DNA, most likely driven by the pendant ligands. Interestingly, they also showed DNA photocleavage activity even upon exposure to a yellow light-emitting diode (LED). Regarding their biological activity, the compounds exhibited an exciting antibacterial action, particularly against Gram-positive bacteria, which was enhanced upon blue LED irradiation. Altogether, these results showed that our strategy succeeded in producing light-triggered DNA binding agents with pharmacological and biotechnological potential.


Assuntos
Complexos de Coordenação/farmacologia , DNA/química , Substâncias Intercalantes/farmacologia , Rutênio/química , 2,2'-Dipiridil/síntese química , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacologia , 2,2'-Dipiridil/efeitos da radiação , Antracenos/síntese química , Antracenos/química , Antracenos/farmacologia , Antracenos/efeitos da radiação , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/efeitos da radiação , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , Dano ao DNA , Etídio/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/efeitos da radiação , Ligantes , Luz , Oxigênio/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/efeitos da radiação , Espécies Reativas de Oxigênio/síntese química
17.
Chem Commun (Camb) ; 53(51): 6864-6867, 2017 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-28604852

RESUMO

A novel 2-(furan-2-yl)-4-(pyridin-2-yl)-5H-indeno[1,2-b]pyridin-5-one (TI-1-190) was synthesized using a simple microwave-assisted method and its mode of action was systematically characterized. It is a DNA intercalative human topoisomerase IIα catalytic inhibitor with much stronger activity and less DNA toxicity than etoposide, a topoisomerase II poison. TI-1-190 displays caspase 3-independent anticancer activity, unlike etoposide.


Assuntos
Antineoplásicos/farmacologia , Caspase 3 , Substâncias Intercalantes/farmacologia , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Biocatálise , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Células MCF-7 , Estrutura Molecular , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química
18.
Inorg Chem ; 56(14): 8381-8389, 2017 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-28657712

RESUMO

[Ru(bpy)2(BNIQ)]2+ (BNIQ = Benzo[c][1,7]naphthyridine-1-isoquinoline), which incorporates the sterically expansive BNIQ ligand, is a highly selective luminescent probe for DNA mismatches and abasic sites, possessing a 500-fold higher binding affinity toward these destabilized regions relative to well-matched base pairs. As a result of this higher binding affinity, the complex exhibits an enhanced steady-state emission in the presence of DNA duplexes containing a single base mismatch or abasic site compared to fully well-matched DNA. Luminescence quenching experiments with Cu(phen)22+ and [Fe(CN)6]3- implicate binding of the complex to a mismatch from the minor groove via metalloinsertion. The emission response of the complex to different single base mismatches, binding preferentially to the more destabilized mismatches, is also consistent with binding by metalloinsertion. This work shows that high selectivity toward destabilized regions in duplex DNA can be achieved through the rational design of a complex with a sterically expansive aromatic ligand.


Assuntos
Complexos de Coordenação/química , DNA/química , Corantes Fluorescentes/química , Rutênio/química , Pareamento Incorreto de Bases , Sequência de Bases , Complexos de Coordenação/síntese química , Corantes Fluorescentes/síntese química , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Ligantes , Luminescência , Naftiridinas/síntese química
19.
Bioorg Med Chem Lett ; 27(11): 2369-2376, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28431881

RESUMO

A series of new 1,2,3-triazolo-phenanthrene hybrids has been synthesized by employing Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. These compounds were evaluated for their in vitro cytotoxic potential against various human cancer cell lines viz. lung (A549), prostate (PC-3 and DU145), gastric (HGC-27), cervical (HeLa), triple negative breast (MDA-MB-231, MDA-MB-453) and breast (BT-549, 4T1) cells. Among the tested compounds, 7d displayed highest cytotoxicity against DU145 cells with IC50 value of 1.5±0.09µM. Further, the cell cycle analysis shown that it blocks G0/G1 phase of the cell cycle in a dose dependent manner. In order to determine the effect of compound on cell viability, phase contrast microscopy, AO/EB, DAPI, DCFDA and JC-1 staining studies were performed. These studies clearly indicated that the compound 7d inhibited the cell proliferation of DU145 cells. Relative viscosity measurements and molecular docking studies indicated that these compounds bind to DNA by intercalation.


Assuntos
Antineoplásicos/farmacologia , Naftalimidas/farmacologia , Fenantrenos/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Reação de Cicloadição , Corantes Fluorescentes , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Indóis , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microscopia de Contraste de Fase , Simulação de Acoplamento Molecular , Naftalimidas/síntese química , Fenantrenos/síntese química , Espécies Reativas de Oxigênio/metabolismo , Triazóis/síntese química , Viscosidade
20.
Bioorg Med Chem ; 25(9): 2625-2634, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28342691

RESUMO

DNA intercalating agents are a consolidated therapeutic option in the treatment of tumor diseases. Starting from previous findings in the antiproliferative efficacy of a series of indeno[1,2-c]cinnoline-11-one derivatives, we performed a suitable decoration of this scaffold by means of a simple and straightforward chemistry, aiming to a) enlarge the planar core to a pentacyclic benzo[h]indeno[1,2-c]cinnoline-13-one and b) introduce a basic head tethered through a simple polymethylene chain. In fluorescence melting and fluorescence intercalator displacement assays, these new compounds displayed fair to very good intercalating properties on different nucleic acid strands, with preference for G-quadruplex sequences. Inhibition of human topoisomerase IIα and antiproliferative assays on HeLa and MCF7 tumor cell lines outlined a multitarget antiproliferative profile for tetracyclic 6 and pentacyclic derivative 20, both bearing a N,N-dimethylamine as the protonatable moiety. Particularly, compound 6 displayed a very potent inhibition of tumor cell proliferation, while 20 returned the highest thermal stabilization in melting experiments. In summary, these results outlined a potential of such highly planar scaffolds for nucleic acid binding and antiproliferative effects.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Quadruplex G , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Substâncias Intercalantes/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/síntese química , Benzotiazóis/química , DNA Topoisomerase IV/antagonistas & inibidores , Células HeLa , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Humanos , Substâncias Intercalantes/síntese química , Ligantes , Células MCF-7 , Quinolinas/química , Inibidores da Topoisomerase II/síntese química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA