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1.
J Med Chem ; 65(3): 2532-2547, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35073076

RESUMO

Currently, cancer patients with microbial infection are a severe challenge in clinical treatment. To address the problem, we synthesized hemiprotonic compounds based on the unique structure of hemiprotonic nucleotide base pairs in a DNA i-motif. These compounds were produced from phenanthroline (ph) dimerization with phenanthroline as a proton receptor and ammonium as a donor. The biological activity shows that the compounds have a selective antitumor effect through inducing cell apoptosis. The molecular mechanism could be related to specific inhibition of transcription factor PLAGL2 of tumor cells, assessed by transcriptomic analysis. Moreover, results show that the hemiprotonic ph-ph+ has broad-spectrum antibacterial and antifungal activities, and drug-resistant bacteria, including methicillin-resistant Staphylococcus aureus, are sensitive to the compound. In animal models of liver cancer with fungal infection, the ph-ph+ retards proliferation of hepatoma cells in tumor-bearing mice and remedies pneumonia and encephalitis caused by Cryptococcus neoformans. The study provides a novel therapeutic candidate for cancer patients accompanied by infection.


Assuntos
Anti-Infecciosos/uso terapêutico , Antineoplásicos/uso terapêutico , Encefalite/tratamento farmacológico , Neoplasias/tratamento farmacológico , Fenantrolinas/uso terapêutico , Pneumonia/tratamento farmacológico , Animais , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/toxicidade , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/toxicidade , Antifúngicos/síntese química , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Antifúngicos/toxicidade , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Encefalite/complicações , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Neoplasias/complicações , Fenantrolinas/síntese química , Fenantrolinas/farmacologia , Fenantrolinas/toxicidade , Pneumonia/complicações , Prótons , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo
2.
Eur J Pharmacol ; 895: 173880, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33476654

RESUMO

Classic glucocorticoids have been prescribed for various inflammatory diseases, such as rheumatoid arthritis, due to their outstanding anti-inflammatory effects. However, glucocorticoids cause numerous unwanted side effects, including osteoporosis and diabetes. Hence, selective glucocorticoid receptor modulators (SGRMs), which retain anti-inflammatory effects with minimized side effects, are among the most anticipated drugs in the clinical field. The assumption is that there are two major mechanisms of action via glucocorticoid receptors, transrepression (TR) and transactivation (TA). In general, anti-inflammatory effects of glucocorticoids are largely due to TR, while the side effects associated with glucocorticoids are mostly mediated through TA. We previously reported that JTP-117968, a novel SGRM, maintained partial TR activity while remarkably reducing the TA activity. In this study, we investigated the anti-inflammatory effect of JTP-117968 on a lipopolysaccharide (LPS) challenge model and collagen-induced arthritis (CIA) model in mice. Meanwhile, we tested the effect of JTP-117968 on the bone mineral density (BMD) in mouse femur to evaluate the side effect. Based on the evaluation, JTP-117968 reduced the plasma levels of tumor necrosis factor α induced by LPS challenge in mice significantly. Remarkably, CIA development was suppressed by JTP-117968 comparably with prednisolone and PF-802, an active form of fosdagrocorat that has been developed clinically as an orally available SGRM. Strikingly, the side effect of JTP-117968 on mouse femoral BMD was much lower than those of PF-802 and prednisolone. Therefore, JTP-117968 has attractive potential as a new therapeutic option against inflammatory diseases with minimized side effects compared to classic glucocorticoids.


Assuntos
Aminopiridinas/farmacologia , Anti-Inflamatórios/farmacologia , Artrite Experimental/prevenção & controle , Densidade Óssea/efeitos dos fármacos , Glucocorticoides/farmacologia , Articulações/efeitos dos fármacos , Fenantrolinas/farmacologia , Receptores de Glucocorticoides/agonistas , Aminopiridinas/toxicidade , Animais , Anti-Inflamatórios/toxicidade , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Feminino , Glucocorticoides/toxicidade , Humanos , Mediadores da Inflamação/sangue , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Articulações/metabolismo , Articulações/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Fenantrolinas/toxicidade , Receptores de Glucocorticoides/metabolismo , Fator de Necrose Tumoral alfa/sangue
3.
J Inorg Biochem ; 198: 110727, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31195153

RESUMO

Zinc(II) complexes bearing N-salicylideneglycinate (Sal-Gly) and 1,10-phenanthroline (phen) or phenanthroline derivatives [NN = 5-chloro-1,10-phenanthroline, 5-amine-1,10-phenanthroline (amphen), 4,7-diphenyl-1,10-phenanthroline (Bphen) and 5,6-epoxy-5,6-dihydro-1,10-phenanthroline] are synthesized. Complexes formulated as [Zn(NN)2(H2O)2]2+(NN = phen and amphen), are also prepared. The cytotoxicity of the compounds is evaluated towards a panel of human cancer cells: ovarian (A2780), breast (MCF7) and cervical (HeLa), as well as non-tumoral V79 fibroblasts. All compounds display higher cytotoxicity than cisplatin (IC50 = 22.5 ±â€¯5.0 µM) towards ovarian cells, showing IC50values in the low micromolar range. Overall, all compounds show higher selectivity for the A2780 cells than for the non-tumoral cells and higher selectivity indexes (IC50(V79)/IC50(A2780) than cisplatin. [Zn(Sal-Gly)(NN)(H2O)] complexes induce caspase-dependent apoptosis in A2780 cells, except [Zn(Sal-Gly)(Bphen)(H2O)], one of the most cytotoxic of the series. The cellular uptake in the ovarian cells analyzed by Inductively Coupled Plasma mass spectrometry indicates different Zn distribution profiles. Transmission electronic microscopy shows mitochondria alterations and apoptotic features consistent with caspase activation; cells incubated with [Zn(Sal-Gly)(amphen)(H2O)] present additional nuclear membrane alterations in agreement with significant association with the nucleus. The increase of reactive oxygen species and lipid peroxidation forms could be related to apoptosis induction. [Zn(NN)2(H2O)2]2+complexes have high ability to bind DNA through intercalation/groove binding, and circular dichroism data suggests that the main type of species that interact with DNA is [Zn(NN)]2+. Studies varying the % of fetal bovine serum (1-15%) in cell media show that albumin binding decreases the complex activity, indicating that distinct speciation of Zn- and phen-containing species in cell media may affect the cytotoxicity.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Fenantrolinas/farmacologia , Bases de Schiff/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Bovinos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Cricetulus , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Humanos , Ligantes , Peroxidação de Lipídeos/efeitos dos fármacos , Fenantrolinas/síntese química , Fenantrolinas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Bases de Schiff/síntese química , Bases de Schiff/toxicidade , Zinco/química
4.
Anal Chem ; 91(14): 8958-8965, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31251580

RESUMO

Sensitive and specific visualization of cell surface biotin receptors (BRs) a class of clinically important biomarkers, remains a challenge. In this work, a dual-emission ratiometric fluorescent nanoprobe is developed for specific imaging of cell surface avidin, a subtype of BRs. The nanoprobe comprises a dual-emission quantum dot nanohybrid, wherein a silica-encapsulated red-emitting QD (rQD@SiO2) is used as the "core" and green-emitting QDs (gQDs) are used as "satellites", which are further decorated with a new "love-hate"-type BR ligand, a phenanthroline-biotin conjugate with an amino linker. The nanoprobe shows intense rQD emission but quenched gQD emission by the BR ligand. Upon imaging, the rQD emission stays constant and the gQD emission is restored as cell surface avidin accrues. Accordingly, the overlaid fluorescence color collected from red and green emission changes from red to yellow and then to green. We refer to such a color change as a traffic light pattern and the nanoprobe as a fluorescent traffic light nanoprobe. We demonstrate the application of our fluorescent traffic light nanoprobe to characterize cancer cells. By the traffic light pattern, cervical carcinoma and normal cells, as well as different-type cancer cells including BR-negative colon cancer cells, BR-positive hepatoma carcinoma cells, breast cancer cells, and their subtypes, have been visually differentiated. We further demonstrate a use of our nanoprobe to distinguish the G2 phase from other stages in a cell cycle. These applications provide new insights into visualizing cell surface biomarkers with remarkable imaging resolution and accuracy.


Assuntos
Avidina/análise , Corantes Fluorescentes/química , Pontos Quânticos/química , Receptores de Fatores de Crescimento/análise , Biotina/análogos & derivados , Biotina/toxicidade , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Corantes Fluorescentes/toxicidade , Humanos , Ligantes , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Simulação de Acoplamento Molecular , Fenantrolinas/química , Fenantrolinas/toxicidade , Pontos Quânticos/toxicidade , Dióxido de Silício/química , Dióxido de Silício/toxicidade
5.
Eur J Med Chem ; 176: 492-512, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31132480

RESUMO

We report the design, synthesis and biological studies on a group of mixed ligand Fe(III) complexes as anti-cancer drug candidates, namely their interaction with DNA, cytotoxicity and mechanism(s) of action. The aim is to obtain stable, efficient and selective Fe-complexes to be used as anti-cancer agents with less damaging side effects than previously reported compounds. Five ternary Fe(III) complexes bearing a tripodal aminophenolate ligand L2-, H2L = N,N-bis(2-hydroxy-3,5-dimethylbenzyl)-N-(2-pyridylmethyl)amine, and different aromatic bases NN = 2,2'-bipyridine [Fe(L)(bipy)]PF6 (1), 1,10-phenanthroline [Fe(L)(phen)]PF6 (2), or a phenanthroline derivative co-ligand: [Fe(L)(amphen)]NO3 (3), [Fe(L)(amphen)]PF6 (3a), [Fe(L)(Clphen)]PF6 (4), [Fe(L)(epoxyphen)]PF6 (5) (where amphen = 1,10-phenanthroline-5-amine, epoxyphen = 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, Clphen = 5-chloro-1,10-phenanthroline) and the [Fe(L)(EtOH)]NO3 (6) complex are synthesized. The compounds are characterized in the solid state and in solution by elemental analysis, ESI-MS, magnetic susceptibility measurements and FTIR, UV-Vis, 1H and 13C NMR and fluorescence spectroscopies. [Fe(phen)Cl3] and [Fe(amphen)Cl3] were also prepared for comparison purposes. Spectroscopic binding studies indicate groove binding as the main interaction for most complexes with DNA, and for those containing amphen a B- to Z-DNA conformational change is proposed to occur. As determined via MTT analysis all compounds 1-6 are cytotoxic against a panel of three different cell lines (HeLa, H1299, MDA-MB-231). For selected compounds with promising cytotoxic activity, apoptosis was evaluated using cell and DNA morphology, TUNEL, Annexin V/7AAD staining and caspase3/7 activity. The compounds induce oxidative DNA damage on plasmid DNA and in cell culture as assessed by 8-oxo-Guanine and γH2AX staining. Comet assay confirmed the presence of genomic damage. There is also increased reactive oxygen species formation following drug treatment, which may be the relevant mechanism of action, thus differing from that normally assumed for cisplatin. The Fe(III)-complexes were also tested against strains of M. Tuberculosis (MTb), complex 2 depicting higher anti-MTb activity than several known second line drugs. Hence, these initial studies show prospective anti-cancer and anti-MTb activity granting promise for further studies.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Ferro/química , Fenantrolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Antituberculosos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , DNA/química , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Desenho de Fármacos , Estabilidade de Medicamentos , Humanos , Ligantes , Mycobacterium tuberculosis/efeitos dos fármacos , Fenantrolinas/síntese química , Fenantrolinas/química , Fenantrolinas/toxicidade , Estudos Prospectivos , Espécies Reativas de Oxigênio/metabolismo
6.
J Inorg Biochem ; 195: 149-163, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30952084

RESUMO

Five novel silver(I) complexes with 4,7-phenanthroline (4,7-phen), [Ag(NO3-O)(4,7-phen-µ-N4,N7)]n (1), [Ag(ClO4-О)(4,7-phen-µ-N4,N7)]n (2), [Ag(CF3COO-O)(4,7-phen-µ-N4,N7)]n (3), [Ag2(H2O)0.58(4,7-phen)3](SbF6)2 (4) and {[Ag2(H2O)(4,7-phen-µ-N4,N7)2](BF4)2}n (5) were synthesized, structurally elucidated and biologically evaluated. These complexes showed selectivity towards Candida spp. in comparison to the tested bacteria and effectively inhibited the growth of four different Candida species, particularly of C. albicans strains, with minimal inhibitory concentrations (MICs) in the range of 2.0-10.0 µM. In order to evaluate the therapeutic potential of 1-5, in vivo toxicity studies were conducted in the zebrafish model. Based on the favorable therapeutic profiles, complexes 1, 3 and 5 were selected for the evaluation of their antifungal efficacy in vivo using the zebrafish model of lethal disseminated candidiasis. Complexes 1 and 3 efficiently controlled and prevented fungal filamentation even at sub-MIC doses, while drastically increased the survival of the infected embryos. Moreover, at the MIC doses, both complexes totally prevented C. albicans filamentation and rescued almost all infected fish of the fatal infection outcome. On the other side, complex 5, which demonstrated the highest antifungal activity in vitro, affected the neutrophils occurrence of the infected host, failed to inhibit the C. albicans cells filamentation and showed a poor potential to cure candidal infection, highlighting the importance of the in vivo activity evaluation early in the therapeutic design and development process. The mechanism of action of the investigated silver(I) complexes was related to the induction of reactive oxygen species (ROS) response in C. albicans, with DNA being one of the possible target biomolecules.


Assuntos
Antifúngicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Complexos de Coordenação/uso terapêutico , Fenantrolinas/uso terapêutico , Animais , Antifúngicos/síntese química , Antifúngicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Testes de Sensibilidade Microbiana , Fenantrolinas/síntese química , Fenantrolinas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Prata/química , Peixe-Zebra/embriologia
7.
J Biol Inorg Chem ; 24(3): 343-363, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30887122

RESUMO

We report the synthesis, crystal structures and biological activities of two dinuclear Cu(II) complexes [Cu(o-phen)LCu(OAc)] (1) and [Cu(o-phen)LCu(o-phen)](OAc) (2), where o-phen = 1,10-phenanthroline, H3L = o-HOC6H4C(H)=N-NH-C(OH)=N-N=C(H)-C6H4OH-o, and OAc=CH3COO-. Both compounds display strong and broad X-band EPR spectra at RT in their powder state confirming that these are paramagnetic. The intercalative DNA binding of the compounds as revealed from spectrophotometric studies was found to be consistent with the results of fluorescence spectroscopic studies for ethidium bromide displacement assay as well as enhanced viscosity of DNA in the presence of these compounds. The compounds effectively catalyze hydrolytic cleavage of supercoiled pUC19 DNA and show remarkable cytotoxicity toward human lung cancer A549 cell line (IC50 values are 4.34 and 8.46 µM for 1 and 2, respectively) and breast cancer MCF7 cell line (IC50 values are 6.50 and 8.68 µM for 1 and 2, respectively) and are found to be relatively less toxic toward keratinocyte HaCaT normal cell line (IC50 values are 11.19 and 16.01 µM for 1 and 2, respectively). Annexin-V/PI dual staining results analyzed by flow cytometry strongly suggest the induction of apoptotic pathway for the anticancer activity of these complexes. Flow cytometry experiment for cell cycle analysis showed considerable increase in the G2/M phase in both A549 and MCF7 cell lines by these two compounds. On the other hand, compounds 1 and 2 activate reactive oxygen species (ROS) level in A549 cells, but act as scavengers or inhibitors of ROS in MCF7 cell line as analyzed by DCFDA staining using flow cytometry. Two dinuclear Cu(II) complexes exhibit efficient hydrolytic cleavage of DNA and display remarkable cytotoxicity against human lung cancer A549 and breast cancer MCF7cells. The ROS level in A549 cells is activated, but the ROS level in MCF7 cells is decreased in the presence of these complexes. Cell cycle analysis by flow cytometry shows G2/M phase arrest in both these cell lines.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Clivagem do DNA/efeitos dos fármacos , DNA/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Cobre/química , Cristalografia por Raios X , DNA/química , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Hidrazonas/síntese química , Hidrazonas/farmacologia , Hidrazonas/toxicidade , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/farmacologia , Substâncias Intercalantes/toxicidade , Ligantes , Fenantrolinas/síntese química , Fenantrolinas/farmacologia , Fenantrolinas/toxicidade , Espécies Reativas de Oxigênio/metabolismo
8.
J Biomol Struct Dyn ; 37(17): 4437-4449, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30526398

RESUMO

In this study, the interaction of Holmium (Ho) complex including 2, 9-dimethyl-1,10-phenanthroline, also called Neocuproine (Neo), [Ho(Neo)2Cl3.H2O], as fluorescence probe with fish-salmon DNA (FS-DNA) is studied during experimental investigations. Multi-spectroscopic methods are utilized to determine the affinity binding constants (Kb) of complex-FS-DNA. It is found that fluorescence of Ho complex is strongly quenched by the FS-DNA through a static quenching procedure. Under optimal conditions in Tris(trishydroxymethyl-aminomethane)-HCl buffer at 25 °C with pH ≈ 7.2, intrinsic binding constant Kb of Ho complex is 6.12 ± 0.04 × 105 M-1. Also, the binding site number and Stern-Volmer quenching constant are calculated. There are different approaches, including iodide quenching assay, salt effect and thermodynamical assessment to determine the features of the binding mode between Ho complex and FS-DNA. Also, the parent and starch and lipid nanoencapsulated Ho complex, as potent antitumor candidates, were synthesized. The main structure of Ho complex is maintained after encapsulation using starch and lipid nanoparticles. 3-[4,5-Dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method was used to assess the anticancer properties of Ho complex and its encapsulated forms on human cancer cell lines of human lung carcinoma cell line and breast cancer cell line. In conclusion, these compounds could be considered as new antitumor candidates. Communicated by Ramaswamy H. Sarma.


Assuntos
Antibacterianos/farmacologia , DNA/metabolismo , Nanopartículas/química , Fenantrolinas/toxicidade , Absorção Fisico-Química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Etídio/metabolismo , Concentração Inibidora 50 , Iodetos/química , Cinética , Lipídeos/química , Testes de Sensibilidade Microbiana , Nanopartículas/ultraestrutura , Fenantrolinas/química , Salmão , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Amido/química , Temperatura , Termogravimetria , Viscosidade
9.
Toxicol Sci ; 168(2): 339-348, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590774

RESUMO

Chemical pollutants often co-occur and can interact to cause unexpected combined toxic effects. Both pentachlorophenol (PCP) and copper-1,10-phenanthroline [Cu(OP)2], used as wood preservatives, coexist in fluids and tissues of ordinary population. Our previous studies demonstrate that a combination of subtoxic PCP and Cu(OP)2 causes synergistic toxicity on Escherichia coli and hepatocarcinoma cells. However, it is not clear whether this effect also occurs in normal hepatocytes; and if so, what are the differences as compared with the hepatocarcinoma cells. We demonstrate that the combination of low-toxic PCP and Cu(OP)2 (0-1.6 µM; PCP/Cu(OP)2 molar ratio: 2:1) induces a concentration-dependent intracellular copper accumulation, apoptosis, caspase-3/9 activation, depolarization of mitochondrial membrane potential, and oxidative stress (reactive oxygen species increasing and glutathione/oxidized glutathione ratio decreasing) in both normal hepatocytes HL-7702 and hepatocarcinoma HepG2 cells. However, HepG2 cells are more susceptible to the above molecular events as compared with HL-7702 cells. Further data reveal that PCP/Cu(OP)2 markedly decreases X chromosome-linked inhibitor of apoptosis (XIAP), p-ERK-1/2, and p-JNK protein expression in HepG2, but not HL-7702. Overexpression of XIAP gene in HepG2 significantly blocks PCP/Cu(OP)2-induced cytotoxicity, caspase activity, apoptosis, ROS accumulation, and antioxidant genes expression. These results suggest that the combination of low-toxic PCP and Cu(OP)2 preferentially induce synergistic cytotoxicity in human hepatocarcinoma cells by XIAP-ROS-apoptosis pathway, compared with the normal hepatocytes. The present data not only confirm the synergistic toxicity of PCP/Cu(OP)2 combination in normal liver cells, but also suggest a possible opportunity in developing new therapeutic approaches for liver cancer by sensitizing cancer cells to chemotherapy.


Assuntos
Apoptose/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Compostos Organometálicos/toxicidade , Pentaclorofenol/toxicidade , Fenantrolinas/toxicidade , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cobre/metabolismo , Sinergismo Farmacológico , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transcriptoma/efeitos dos fármacos
10.
ChemMedChem ; 13(20): 2229-2239, 2018 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-30157309

RESUMO

As a growing public health concern, the worldwide spread of antimicrobial resistance urges the development of new therapies. Antibacterial photodynamic therapy (a-PDT) may be an alternative to conventional antibiotic therapy. Herein we report the synthesis and characterization of seven original reactive oxygen species (ROS)-producing ruthenium(II) polypyridyl complexes. These are part of a collection of 17 derivatives varying in terms of the nature of the substituent(s), molecular symmetry, electrical charge, and counterions. They were characterized by considering 1) their physical properties (absorption coefficient at irradiation wavelength, 1 O2 generation quantum yield, luminescence) and 2) their antibacterial activity in a series of photodynamic assays using Gram-positive and Gram-negative bacteria of clinical relevance. The results unveiled some structure-activity relationships: one derivative that combines multiple beneficial features for a-PDT was effective against all the bacteria considered, regardless of their Gram status, species, or antibiotic resistance profile. This systematic study could guide the design of next-generation ruthenium-based complexes for enhanced antibacterial photodynamic strategies.


Assuntos
Antibacterianos/farmacologia , Complexos de Coordenação/farmacologia , Fenantrolinas/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Rutênio/química , Antibacterianos/síntese química , Antibacterianos/efeitos da radiação , Antibacterianos/toxicidade , Complexos de Coordenação/síntese química , Complexos de Coordenação/efeitos da radiação , Complexos de Coordenação/toxicidade , Escherichia coli/efeitos dos fármacos , Ligantes , Luz , Luminescência , Medições Luminescentes , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Estrutura Molecular , Fenantrolinas/síntese química , Fenantrolinas/efeitos da radiação , Fenantrolinas/toxicidade , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Fármacos Fotossensibilizantes/toxicidade , Pseudomonas aeruginosa/efeitos dos fármacos , Oxigênio Singlete/metabolismo , Relação Estrutura-Atividade
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