Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Chemistry ; 2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33871121

RESUMO

Human telomeric DNA,in G-quadruplex (G4) conformation, is characterized by a remarkable structural stability that confers it the capacity to resist to oxidative stress producing one or even clustered 8-oxoguanine (8oxoG) lesions. We present a combined experimental/computational investigation, by using circular dichroism in aqueous solutions, cellular immunofluorescence assays and molecular dynamics simulations, that identifies the crucial role of the stability of G4s to oxidative lesions, related also to their biological role as inhibitors of telomerase, an enzyme overexpressed in most cancers associated to oxidative stress.

2.
J Proteome Res ; 19(11): 4291-4315, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-33119313

RESUMO

The emergence in late 2019 of the coronavirus SARS-CoV-2 has resulted in the breakthrough of the COVID-19 pandemic that is presently affecting a growing number of countries. The development of the pandemic has also prompted an unprecedented effort of the scientific community to understand the molecular bases of the virus infection and to propose rational drug design strategies able to alleviate the serious COVID-19 morbidity. In this context, a strong synergy between the structural biophysics and molecular modeling and simulation communities has emerged, resolving at the atomistic level the crucial protein apparatus of the virus and revealing the dynamic aspects of key viral processes. In this Review, we focus on how in silico studies have contributed to the understanding of the SARS-CoV-2 infection mechanism and the proposal of novel and original agents to inhibit the viral key functioning. This Review deals with the SARS-CoV-2 spike protein, including the mode of action that this structural protein uses to entry human cells, as well as with nonstructural viral proteins, focusing the attention on the most studied proteases and also proposing alternative mechanisms involving some of its domains, such as the SARS unique domain. We demonstrate that molecular modeling and simulation represent an effective approach to gather information on key biological processes and thus guide rational molecular design strategies.


Assuntos
Antivirais , Infecções por Coronavirus , Desenho de Fármacos , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral , Glicoproteína da Espícula de Coronavírus , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Humanos , Simulação de Dinâmica Molecular , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Internalização do Vírus
3.
J Am Chem Soc ; 142(42): 17989-17996, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-32941015

RESUMO

We report herein on a NMR-based enantiospecific response for a family of optically active metal-organic frameworks. Cross-polarization of the 1H-13C couple was performed, and the intensities of the 13C nuclei NMR signals were measured to be different for the two enantiomers. In a direct-pulse experiment, which prevents cross-polarization, the intensity difference of the 13C NMR signals of the two nanostructured enantiomers vanished. This result is due to changes of the nuclear spin relaxation times due to the electron spin spatial asymmetry induced by chemical bond polarization involving a chiral center. These experiments put forward on firm ground that the chiral-induced spin selectivity effect, which induces chemical bond polarization in the J-coupling, is the mechanism responsible for the enantiospecific response. The implications of this finding for the theory of this molecular electron spin polarization effect and the development of quantum biosensing and quantum storage devices are discussed.

4.
Angew Chem Int Ed Engl ; 59(39): 17130-17136, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32633820

RESUMO

AuIII complexes with N-heterocyclic carbene (NHC) ligands have shown remarkable potential as anticancer agents, yet their fate in vivo has not been thoroughly examined and understood. Reported herein is the synthesis of new AuIII -NHC complexes by direct oxidation with radioactive [124 I]I2 as a valuable strategy to monitor the in vivo biodistribution of this class of compounds using positron emission tomography (PET). While in vitro analyses provide direct evidence for the importance of AuIII -to-AuI reduction to achieve full anticancer activity, in vivo studies reveal that a fraction of the AuIII -NHC prodrug is not immediately reduced after administration but able to reach the major organs before metabolic activation.

5.
J Phys Chem Lett ; 11(14): 5661-5667, 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32536162

RESUMO

Coronaviruses may produce severe acute respiratory syndrome (SARS). As a matter of fact, a new SARS-type virus, SARS-CoV-2, is responsible for the global pandemic in 2020 with unprecedented sanitary and economic consequences for most countries. In the present contribution we study, by all-atom equilibrium and enhanced sampling molecular dynamics simulations, the interaction between the SARS Unique Domain and RNA guanine quadruplexes, a process involved in eluding the defensive response of the host thus favoring viral infection of human cells. Our results evidence two stable binding modes involving an interaction site spanning either the protein dimer interface or only one monomer. The free energy profile unequivocally points to the dimer mode as the thermodynamically favored one. The effect of these binding modes in stabilizing the protein dimer was also assessed, being related to its biological role in assisting the SARS viruses to bypass the host protective response. This work also constitutes a first step in the possible rational design of efficient therapeutic agents aiming at perturbing the interaction between SARS Unique Domain and guanine quadruplexes, hence enhancing the host defenses against the virus.


Assuntos
Betacoronavirus/química , Betacoronavirus/genética , Infecções por Coronavirus/virologia , Quadruplex G/efeitos dos fármacos , Pneumonia Viral/virologia , RNA Viral/química , RNA Viral/genética , Betacoronavirus/efeitos dos fármacos , Dimerização , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Pandemias , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética
6.
Bioorg Chem ; 99: 103778, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32229347

RESUMO

Despite the huge success of tyrosine kinase inhibitors as anticancer agents, severe side effects are a major problem. In order to overcome this drawback, the first hypoxia-activatable 2-nitroimidazole-based prodrugs of the clinically approved ALK and c-MET inhibitor crizotinib were developed. The 2-aminopyridine functionality of crizotinib (essential for target kinase binding) was considered as ideal position for prodrug derivatization. Consequently, two different prodrugs were synthesized with the nitroimidazole unit attached to crizotinib either via carbamoylation (A) or alkylation (B) of the 2-aminopyridine moiety. The successful prodrug design could be proven by docking studies and a dramatically reduced ALK and c-MET kinase-inhibitory potential. Furthermore, the prodrugs showed high stability in serum and release of crizotinib in an enzymatic nitroreductase-based cleavage assay was observed for prodrug A. The in vitro activity of both prodrugs was investigated against ALK- and c-MET-dependent or -overexpressing cells, revealing a distinct hypoxia-dependent activation for prodrug A. Finally, inhibition of c-MET phosphorylation and cell proliferation could also be proven in vivo. In summary of the theoretical, chemical and biological studies, prodrug derivatization of the 2-aminopyridine position can be considered as a promising strategy to reduce the side effects and improve the anticancer activity of crizotinib.

7.
Antioxidants (Basel) ; 8(10)2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658666

RESUMO

The DNA-binding of the natural benzophenanthridine alkaloid chelerythrine (CHE) has been assessed by combining molecular modeling and optical absorption spectroscopy. Specifically, both double-helical (B-DNA) and G-quadruplex sequences-representative of different topologies and possessing biological relevance, such as telomeric or regulatory sequences-have been considered. An original multiscale protocol, making use of molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations, allowed us to compare the theoretical and experimental circular dichroism spectra of the different DNA topologies, readily providing atomic-level details of the CHE-DNA binding modes. The binding selectivity towards G-quadruplexes is confirmed by both experimental and theoretical determination of the binding free energies. Overall, our mixed computational and experimental approach is able to shed light on the interaction of small molecules with different DNA conformations. In particular, CHE may be seen as the building block of promising drug candidates specifically targeting G-quadruplexes for both antitumoral and antiviral purposes.

8.
Dalton Trans ; 48(32): 12040-12049, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31292575

RESUMO

Quadruplex nucleic acids - DNA/RNA secondary structures formed in guanine rich sequences - proved to have key roles in the biology of cancers and, as such, in recent years they emerged as promising targets for small molecules. Many reports demonstrated that metal complexes can effectively stabilize quadruplex structures, promoting telomerase inhibition, downregulation of the expression of cancer-related genes and ultimately cancer cell death. Although extensively explored as anticancer agents, studies on the ability of ruthenium arene complexes to interact with quadruplex nucleic acids are surprisingly almost unknown. Herein, we report on the synthesis and characterization of four novel Ru(ii) arene complexes with 1,3-dioxoindan-2-carboxamides ligands bearing pendant naphthyl-groups designed to bind quadruplexes by both stacking and coordinating interactions. We show how improvements on the hydrolytic stability of such complexes, by substituting the chlorido leaving ligand with pyridine, have a dramatic impact on their interaction with quadruplexes and on their cytotoxicity against ovarian cancer cells.


Assuntos
Antineoplásicos/farmacologia , Calixarenos/farmacologia , Complexos de Coordenação/farmacologia , Quadruplex G , Rutênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Calixarenos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Estrutura Molecular , Rutênio/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
9.
Int J Mol Sci ; 20(14)2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31315181

RESUMO

Oxadizoles are heterocyclic ring systems that find application in different scientific disciplines, from medicinal chemistry to optoelectronics. Coordination with metals (especially the transition ones) proved to enhance the intrinsic characteristics of these organic ligands and many metal complexes of oxadiazoles showed attractive characteristics for different research fields. In this review, we provide a general overview on different metal complexes and polymers containing oxadiazole moieties, reporting the principal synthetic approaches adopted for their preparation and showing the variety of applications they found in the last 40 years.


Assuntos
Metais/química , Compostos Organometálicos/química , Oxidiazóis/química , Anti-Inflamatórios/química , Antineoplásicos/química
10.
J Am Chem Soc ; 141(26): 10205-10213, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31244182

RESUMO

The proto-oncogene KIT encodes for a tyrosine kinase receptor, which is a clinically validated target for treating gastrointestinal stromal tumors. The KIT promoter contains a G-rich domain within a relatively long sequence potentially able to form three adjacent G-quadruplex (G4) units, namely, K2, SP, and K1. These G4 domains have been studied mainly as single quadruplex units derived from short truncated sequences and are currently considered promising targets for anticancer drugs, alternatively to the encoded protein. Nevertheless, the information reported so far does not contemplate the interplay between those neighboring G4s in the context of the whole promoter, possibly thwarting drug-discovery efforts. Here we report the structural and functional study of the KIT promoter core sequence, in both single- and double-stranded forms, which includes all three predicted G4 units. By preventing the formation of alternatively one or two G4 units and by combining biophysical techniques and biological assays, we show for the first time that these quadruplexes cannot be analyzed independently, but they are correlated to each other. Our data suggest that, while K2 and K1 G-rich sequences retain the ability to fold into parallel G4 motifs within a long sequence, the SP G-rich domain contributes to G4 structure only together with K2. Remarkably, we have found that, in the context of a dynamic equilibrium between the three G4 units, the G4 formed by K1 has the most significant influence on the structure stability and on the biological role of the whole promoter.


Assuntos
Quadruplex G , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-kit/genética , Humanos
11.
Angew Chem Int Ed Engl ; 58(24): 8007-8012, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31002438

RESUMO

Metal-driven self-assembly afforded a multitude of fascinating supramolecular coordination complexes (SCCs) with applications as catalysts, host-guest, and stimuli-responsive systems. However, the interest in the biological applications of SCCs is only starting to emerge and thorough characterization of their behavior in biological milieus is still lacking. Herein, we report on the synthesis and detailed in-cell tracking of a Pt2 L2 metallacycle. We show that our hexagonal supramolecule accumulates in cancer cell nuclei, exerting a distinctive blue fluorescence staining of chromatin resistant to UV photobleaching selectively in nucleolar G4-rich regions. SCC co-localizes with epitopes of the quadruplex-specific antibody BG4 and replaces other well-known G4 stabilizers. Moreover, the photophysical changes accompanying the metallacycle binding to G4s in solution (fluorescence quenching, absorption enhancement) also take place intracellularly, allowing its subcellular interaction tracking.


Assuntos
DNA/química , Quadruplex G , Compostos Organoplatínicos/química , Linhagem Celular Tumoral , DNA/metabolismo , Fibroblastos/metabolismo , Humanos , Queratinócitos/metabolismo , Células MCF-7 , Modelos Moleculares , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/farmacocinética , Espectrofotometria Ultravioleta
12.
Chemistry ; 25(27): 6651-6660, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30681213

RESUMO

Catalysis has strongly emerged in the field of medicinal inorganic chemistry as a suitable tool to deliver new drug candidates and to overcome drawbacks associated to metallodrugs. In this Concept article, we discuss representative examples of how catalysis has been applied in combination with metal complexes to deliver new therapy approaches. In particular, we explain key achievements in the design of catalytic metallodrugs that damage biomolecular targets and in the development of metal catalysis schemes for the activation of exogenous organic prodrugs. Moreover, we discuss our recent discoveries on the flavin-mediated bioorthogonal catalytic activation of metal-based prodrugs; a new catalysis strategy in which metal complexes are unconventionally employed as substrates rather than catalysts.


Assuntos
Química Farmacêutica , Compostos Inorgânicos/química , Antineoplásicos/química , Catálise , Complexos de Coordenação/química , Humanos , Pró-Fármacos/química
13.
Chem Rev ; 119(2): 1519-1624, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30489072

RESUMO

The immune system deploys a multitude of innate and adaptive mechanisms not only to ward off pathogens but also to prevent malignant transformation ("immune surveillance"). Hence, a clinically apparent tumor already reflects selection for those malignant cell clones capable of evading immune recognition ("immune evasion"). Metal drugs, besides their well-investigated cytotoxic anticancer effects, massively interact with the cancer-immune interface and can reverse important aspects of immune evasion. This topic has recently gained intense attention based on combination approaches with anticancer immunotherapy (e.g., immune checkpoint inhibitors), a strategy recently delivering first exciting results in clinical settings. This review summarizes the promising but still extremely fragmentary knowledge on the interplay of metal drugs with the fidelity of anticancer immune responses but also their role in adverse effects. It highlights that, at least in some cases, metal drugs can induce long-lasting anticancer immune responses. Important steps in this process comprise altered visibility and susceptibility of cancer cells toward innate and adaptive immunity, as well as direct impacts on immune cell populations and the tumor microenvironment. On the basis of the gathered information, we suggest initiating joint multidisciplinary programs to implement comprehensive immune analyses into strategies to develop novel and smart anticancer metal compounds.


Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Metais/química , Neoplasias/terapia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Imunoterapia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/imunologia
14.
Sci Rep ; 8(1): 17198, 2018 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-30464209

RESUMO

We have recently demonstrated that riboflavin (Rf) functions as unconventional bioorthogonal photocatalyst for the activation of PtIV prodrugs. In this study, we show how the combination of light and Rf with two PtIV prodrugs is a feasible strategy for light-mediated pancreatic cancer cell death induction. In Capan-1 cells, which have high tolerance against photodynamic therapy, Rf-mediated activation of the cisplatin and carboplatin prodrugs cis,cis,trans-[Pt(NH3)2(Cl)2(O2CCH2CH2CO2H)2] (1) and cis,cis,trans-[Pt(NH3)2(CBDCA)(O2CCH2CH2CO2H)2] (2, where CBDCA = cyclobutane dicarboxylate) resulted in pronounced reduction of the cell viability, including under hypoxia conditions. Such photoactivation mode occurs to a considerable extent intracellularly, as demonstrated for 1 by uptake and cell viability experiments. 195Pt NMR, DNA binding studies using circular dichroism, mass spectrometry and immunofluorescence microscopy were performed using the Rf-1 catalyst-substrate pair and indicated that cell death is associated with the efficient light-induced formation of cisplatin. Accordingly, Western blot analysis revealed signs of DNA damage and activation of cell death pathways through Rf-mediated photochemical activation. Phosphorylation of H2AX as indicator for DNA damage, was detected for Rf-1 in a strictly light-dependent fashion while in case of free cisplatin also in the dark. Photochemical induction of nuclear pH2AX foci by Rf-1 was confirmed in fluorescence microscopy again proving efficient light-induced cisplatin release from the prodrug system.


Assuntos
Antineoplásicos/metabolismo , Luz , Compostos Organoplatínicos/metabolismo , Processos Fotoquímicos , Pró-Fármacos/metabolismo , Riboflavina/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos
15.
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
16.
Biochemistry ; 57(30): 4391-4394, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-30011196

RESUMO

The G-quadruplex (G4) is a four-stranded DNA structure identified in vivo in guanine-rich regions located in the promoter of a number of genes. Intriguing evidence suggested that small molecules acting as G4-targeting ligands could potentially regulate multiple cellular processes via either stabilizing or disruptive effects on G4 motifs. Research in this field aims to prove the direct role of G4 ligands and/or structures on a specific biological process in a complex living organism. In this study, we evaluate in vivo the effects of a nickel(II)-salnaphen-like complex, named Nisaln, a potent G4 binder and stabilizer, during embryogenesis of the sea urchin embryo. We describe developmental defects inflicted by Nisaln and correlate them with variation in the expression of several regulatory genes. It is worth mentioning that we show that Nisaln binds a G4 structure in the promoter of hbox12-a, a gene lying at the top of the developmental regulatory hierarchy, inducing overexpression of this gene.


Assuntos
Complexos de Coordenação/efeitos adversos , Quadruplex G/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Níquel/efeitos adversos , Ouriços-do-Mar/efeitos dos fármacos , Ouriços-do-Mar/embriologia , Animais , Complexos de Coordenação/química , DNA/genética , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/embriologia , Embrião não Mamífero/metabolismo , Redes Reguladoras de Genes/efeitos dos fármacos , Ligantes , Níquel/química , Regiões Promotoras Genéticas/efeitos dos fármacos , Ouriços-do-Mar/genética
18.
J Exp Clin Cancer Res ; 36(1): 122, 2017 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-28882160

RESUMO

BACKGROUND: Studying the intracellular distribution of pharmacological agents, including anticancer compounds, is of central importance in biomedical research. It constitutes a prerequisite for a better understanding of the molecular mechanisms underlying drug action and resistance development. Hyperactivated fibroblast growth factor receptors (FGFRs) constitute a promising therapy target in several types of malignancies including lung cancer. The clinically approved small-molecule FGFR inhibitor nintedanib exerts strong cytotoxicity in FGFR-driven lung cancer cells. However, subcellular pharmacokinetics of this compound and its impact on therapeutic efficacy remain obscure. METHODS: 3-dimensional fluorescence spectroscopy was conducted to asses cell-free nintedanib fluorescence properties. MTT assay was used to determine the impact of the lysosome-targeting agents bafilomycin A1 and chloroquine combined with nintedanib on lung cancer cell viability. Flow cytometry and live cell as well as confocal microscopy were performed to analyze uptake kinetics as well as subcellular distribution of nintedanib. Western blot was conducted to investigate protein expression. Cryosections of subcutaneous tumor allografts were generated to detect intratumoral nintedanib in mice after oral drug administration. RESULTS: Here, we report for the first time drug-intrinsic fluorescence properties of nintedanib in living and fixed cancer cells as well as in cryosections derived from allograft tumors of orally treated mice. Using this feature in conjunction with flow cytometry and confocal microscopy allowed to determine cellular drug accumulation levels, impact of the ABCB1 efflux pump and to uncover nintedanib trapping into lysosomes. Lysosomal sequestration - resulting in an organelle-specific and pH-dependent nintedanib fluorescence - was identified as an intrinsic resistance mechanism in FGFR-driven lung cancer cells. Accordingly, combination of nintedanib with agents compromising lysosomal acidification (bafilomycin A1, chloroquine) exerted distinctly synergistic growth inhibitory effects. CONCLUSION: Our findings provide a powerful tool to dissect molecular factors impacting organismal and intracellular pharmacokinetics of nintedanib. Regarding clinical application, prevention of lysosomal trapping via lysosome-alkalization might represent a promising strategy to circumvent cancer cell-intrinsic nintedanib resistance.


Assuntos
Indóis/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Receptores de Fatores de Crescimento de Fibroblastos/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Fluorescência , Humanos , Indóis/farmacocinética , Pulmão/efeitos dos fármacos , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Macrolídeos/administração & dosagem , Camundongos , Fosforilação/efeitos dos fármacos , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Free Radic Biol Med ; 106: 134-147, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28189848

RESUMO

Landomycin E (LE) is an angucycline antibiotic produced by Streptomyces globisporus. Previously, we have shown a broad anticancer activity of LE which is, in contrast to the structurally related and clinically used anthracycline doxorubicin (Dx), only mildly affected by multidrug resistance-mediated drug efflux. In the present study, cellular and molecular mechanisms underlying the anticancer activity of landomycin E towards Jurkat T-cell leukemia cells were dissected focusing on the involvement of radical oxygen species (ROS). LE-induced apoptosis distinctly differed in several aspects from the one induced by Dx. Rapid generation of both extracellular and cell-derived hydrogen peroxide already at one hour drug exposure was observed in case of LE but not found before 24h for Dx. In contrast, Dx but not LE induced production of superoxide radicals. Mitochondrial damage, as revealed by JC-1 staining, was weakly enhanced already at 3h LE treatment and increased significantly with time. Accordingly, activation of the intrinsic apoptosis pathway initiator caspase-9 was not detectable before 12h exposure. In contrast, cleavage of the down-stream caspase substrate PARP-1 was clearly induced already at the three hour time point. Out of all caspases tested, only activation of effector caspase-7 was induced at this early time points paralleling the LE-induced oxidative burst. Accordingly, this massive cleavage of caspase-7 at early time points was inhibitable by the radical scavenger N-acetylcysteine (NAC). Additionally, only simultaneous inhibition of multiple caspases reduced LE-induced apoptosis. Specific scavengers of both H2O2 and OH• effectively decreased LE-induced ROS production, but only partially inhibited LE-induced apoptosis. In contrast, NAC efficiently blocked both parameters. Summarizing, rapid H2O2 generation and a complex caspase activation pattern contribute to the antileukemic effects of LE. As superoxide generation is considered as the main cardiotoxic mechanism of Dx, LE might represent a better tolerable drug candidate for further (pre)clinical development.


Assuntos
Aminoglicosídeos/administração & dosagem , Antibióticos Antineoplásicos/administração & dosagem , Células Jurkat/metabolismo , Leucemia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Acetilcisteína/administração & dosagem , Apoptose/efeitos dos fármacos , Caspase 7/metabolismo , Caspase 9/metabolismo , Doxorrubicina/administração & dosagem , Humanos , Peróxido de Hidrogênio/toxicidade , Células Jurkat/efeitos dos fármacos , Células Jurkat/patologia , Leucemia/metabolismo , Leucemia/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Streptomyces/química , Superóxidos/toxicidade
20.
ChemMedChem ; 12(3): 214-225, 2017 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-27997743

RESUMO

Naphthalimide-based N-heterocyclic carbene (NHC) complexes of the type [(1,5-cyclooctadiene)(NHC)RhCl)] (4 a-c), [(p-cymene)(NHC)RuCl2 )] (5 a-c), and [(NHC)CuBr] (6 a-c) were synthesized and investigated as antiproliferative agents that target DNA. The cytotoxic effects were largely driven by the naphthalimide structure, which is a DNA-intercalating moiety. Regarding the metal center, the highest activities were observed with the rhodium complexes, and cytotoxic activity was significantly lower for the ruthenium derivatives. The stable coordination of the NHC ligands of selected complexes 4 b and 5 b in solution was confirmed, and their DNA binding properties were studied by UV/Vis spectroscopy, mass spectrometry, and circular dichroism. Stable intercalative binding into the DNA for all selected naphthalimide-based complexes is indicated by high DNA binding constants. Particularly efficient binding was observed in the case of the rhodium complex 4 b. More detailed biological studies on 4 b showed promising activities against multidrug-resistant Nalm-6 cells and confirmed an important role for mitochondrial pathways in 4 b-induced apoptosis.


Assuntos
Complexos de Coordenação/química , DNA/química , Substâncias Intercalantes/química , Metano/análogos & derivados , Naftalimidas/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dicroísmo Circular , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Cristalografia por Raios X , Cimenos , DNA/metabolismo , Estabilidade de Medicamentos , Células HT29 , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/toxicidade , Ligantes , Células MCF-7 , Metano/química , Conformação Molecular , Monoterpenos/química , Ródio/química , Rutênio/química , Espectrofotometria Ultravioleta
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...