RESUMO
By screening a drug library comprising FDA approved compounds, we discovered a potent interaction between the antifungal agent haloprogin and the experimental organometallic drug RAPTA-T, to synergistically induce cancer cell killing. The combination of these two small molecules, even at low doses, elicited an improved therapeutic response on tumor growth over either agent alone or the current treatment used in the clinic in the highly aggressive syngeneic B16F10 melanoma tumor model, where classical cytotoxic chemotherapeutic agents show little efficacy. The combination with the repurposed chemodrug haloprogin provides the basis for a new powerful treatment option for cutaneous melanoma. Importantly, because synergistic induction of tumor cell death is achieved with low individual drug doses, and cellular targets for RAPTA-T are different from those of classical chemotherapeutic drugs, a therapeutic strategy based on this approach could avoid toxicities and potentially resistance mechanisms, and could even inhibit metastatic progression.
Assuntos
Antifúngicos/uso terapêutico , Reposicionamento de Medicamentos/métodos , Melanoma/tratamento farmacológico , Compostos Organometálicos/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Animais , Antifúngicos/química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organometálicos/química , Éteres Fenílicos/uso terapêutico , Melanoma Maligno CutâneoRESUMO
Chemotherapeutics for the treatment of tumorigenic conditions that feature novel modes of action are highly sought after to overcome the limitations of current chemotherapies. Herein, we report the conjugation of the alkylating agent chlorambucil to the RAPTA scaffold, a well-established pharmacophore. While chlorambucil is known to alkylate DNA, the RAPTA complexes are known to coordinate to amino acid side chains of proteins. Therefore, such a molecule combines DNA and protein targeting properties in a single molecule. Several chlorambucil-tethered RAPTA derivatives were prepared and tested for their cytotoxicity, stability in water and reactivity to protein and DNA substrates. The anticancer activity of the complexes is widely driven by the cytotoxicity of the chlorambucil moiety. However, especially in the cisplatin-resistant A2780R cells, the chlorambucil-functionalized RAPTA derivatives are in general more cytotoxic than chlorambucil and also a mixture of chlorambucil and the parent organoruthenium RAPTA compound. In a proof-of-principle experiment, the cross-linking of DNA and protein fragments by a chlorambucil-RAPTA derivative was observed.
Assuntos
Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacologia , Clorambucila/química , Complexos de Coordenação/química , DNA/química , Proteínas/química , Alquilação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Clorambucila/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cimenos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Cinética , Células MCF-7 , Compostos Organometálicos/química , Proteínas/metabolismo , Ubiquitina/química , Ubiquitina/metabolismoRESUMO
New triruthenium-carbonyl clusters derivatized with glucose-modified bicyclophosphite ligands have been synthesized. These compounds were found to have cytostatic and cytotoxic activity and depending on the number of bicyclophosphite ligands, and could be tuned for either anti-cancer or specific anti-angiogenic activity. While some compounds had a broad cellular toxicity profile in several cell types others showed endothelial cell specific dose-dependent anti-proliferative and anti-migratory efficacy. A profound inhibition of angiogenesis was also observed in the in vivo chicken chorioallantoic membrane (CAM) model, and consequently, these new compounds have considerable potential in drug design, e.g. for the treatment of cancer.
Assuntos
Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Rutênio/química , Inibidores da Angiogênese/síntese química , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Embrião de Galinha , Células Endoteliais/efeitos dos fármacos , Humanos , Estrutura Molecular , Neovascularização Fisiológica/efeitos dos fármacosRESUMO
A new BODIPY-phosphane was synthesized and proved to be a versatile tool for imaging organometallic complexes. It also led to easy access to a new family of theranostics, featuring gold, ruthenium and osmium complexes. The compounds' cytotoxicity was tested on cancer cells, and their cell uptake was followed by fluorescence microscopy in vitro.
Assuntos
Compostos de Boro/química , Metais/química , Fosfinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Ouro/química , Humanos , Microscopia Confocal , Osmio/química , Rutênio/químicaRESUMO
A series of cationic dinuclear p-cymene ruthenium trithiophenolato complexes of the type [(η(6)-p-MeC(6)H(4)Pr(i))(2)Ru(2)(SC(6)H(4)-p-X)(3)](+) (1 X is H, 2 X is Me, 3 X is Ph, 4 X is Br, 5 X is OH, 6 X is NO(2), 7 X is OMe, 8 X is CF(3), 9 X is F, 10 X is Pr(i), 11 X is Bu(t)) have been synthesized from the reaction of [(η(6)-p-MeC(6)H(4)Pr(i))RuCl(2)](2) with the corresponding thiol, isolated as the chloride salts, and further studied for their electrochemical properties, cytotoxicity towards human ovarian cancer cells, and catalytic activity for glutathione (GSH) oxidation. Complex 1 was also compared with the benzene and hexamethylbenzene analogues [(η(6)-C(6)H(6))(2)Ru(2)(SC(6)H(5))(3)](+) (12) and [(η(6)-C(6)Me(6))(2)Ru(2)(SC(6)H(5))(3)](+) (13). The most active compound [11]Cl was structurally studied by single-crystal X-ray diffraction analysis. The concentrations corresponding to 50 % inhibition of cancer cell growth (IC(50) values) in the A2780 and A2780cisR cell lines of these complexes except for 6 were in the submicromolar range, complex 11 showing an IC(50) value of 0.03 µM in both cell lines. The high in vitro anticancer activity of these complexes may be at least partially due to their catalytic potential for the oxidation of GSH, although there is no clear correlation between the IC(50) values and the turnover frequencies at about 50 % conversion. However, the cytotoxicity is tentatively correlated to the physicochemical properties of the compounds determined by the electronic influence of the substituents X (Hammett constants σ(p)) and the lipophilicity of the thiols p-XC(6)H(4)SH (calculated log P parameters).
Assuntos
Antineoplásicos/farmacologia , Glutationa/química , Compostos Organometálicos/farmacologia , Rutênio/química , Compostos de Sulfidrila/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Eletroquímica , Humanos , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Oxirredução , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Three generations of pyrenyl bis-MPA dendrimers with two different end-groups, acetonide (pyr(Gn)) or alcohol (pyr(Gn-OH)) (n = 1-3), were synthesized, and the pyrenyl group of the dendritic molecules was encapsulated in the arene ruthenium metallacages, [Ru(6)(p-cymene)(6)(OOâ©OO)(3)(tpt)(2)](6+) (OOâ©OO = 5,8-dioxydo-1,4-naphtaquinonato (donq) [1](6+) and 6,11-dioxydo-5,12-naphtacenedionato (dotq) [2](6+); tpt =2,4,6-tri(pyridin-4-yl)-1,3,5-triazine). The host-guest properties of [guestâ1](6+) and [guestâ2](6+) were studied in solution by NMR and UV-vis spectroscopic methods, thus allowing the determination of the affinity constants. Moreover, the cytotoxicity of these water-soluble host-guest systems and the pyrenyl-dendrimers was evaluated on human ovarian cancer cells.
Assuntos
Antineoplásicos/farmacologia , Dendrímeros/química , Compostos Organometálicos/farmacologia , Pirenos/química , Rutênio/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dendrímeros/síntese química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Solubilidade , Relação Estrutura-AtividadeRESUMO
Anthracene derivatives of ruthenium(II) arene compounds with 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (pta) or a sugar phosphite ligand, viz., 3,5,6-bicyclophosphite-1,2-O-isopropylidene-α-d-glucofuranoside, were prepared in order to evaluate their anticancer properties compared to the parent compounds and to use them as models for intracellular visualization by fluorescence microscopy. Similar IC(50) values were obtained in cell proliferation assays, and similar levels of uptake and accumulation were also established. The X-ray structure of [{Ru(η(6)-C(6)H(5)CH(2)NHCO-anthracene)Cl(2)(pta)] is also reported.
Assuntos
Antracenos/química , Antineoplásicos/química , Compostos Organometálicos/química , Compostos de Rutênio/química , Ligação de Hidrogênio , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Microscopia de Fluorescência , Modelos Moleculares , Espectrometria de Fluorescência , Espectrometria de Massas por Ionização por Electrospray , Difração de Raios XRESUMO
The self-assembly of 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine (tpt) triangular panels with p-cymene (pPr(i)C(6)H(4)Me) ruthenium building blocks and 2,5-dioxydo-1,4-benzoquinonato (dobq) or 5,8-dioxydo-1,4-naphthoquinonato (donq) bridges, in the presence of a pyrenyl-nucleoside derivatives (pyreneR), affords the triangular prismatic host-guest compounds [(pyrene-R)âRu(6)(pPr(i)C(6)H(4)Me)(6)(tpt)(2)(dobq)(3)](6+) ([(pyrene-R)â1](6+)) and [(pyrene-R)âRu(6)(pPr(i)C(6)H(4)Me)(6)(tpt)(2)(donq)(3)](6+) ([(pyrene-R)â2](6+)), respectively. The inclusion of six monosubstitutedpyrenyl-nucleosides (pyrene-R1 = 5'-(1-pyrenyl butanoate)-2'-deoxyuridine, pyrene-R2 = 5-fluoro-5'-(1-pyrenyl butanoate)-2'-deoxyuridine, pyrene-R3 = 5'-{N-[1-oxo-4-(1-pyrenyl)butyl]-glycyl}-2'-deoxyuridine, pyrene-R4 = 5-fluoro-5'-{N-[1-oxo-4-(1-pyrenyl)butyl]-glycyl}-2'-deoxyuridine, pyrene-R5 = 5-fluoro-5'-{N-[1-oxo-4-(1-pyrenyl)butyl]-phenylalanyl}-2'-deoxyvuridine, pyrene-R6 = 5-fluoro-5'-{N-[1-oxo-4-(1-pyrenyl)butyl]-phenylalanyl}-2'-deoxyuridine) has been accomplished. The carceplex nature of [(pyrene-R)â1](6+) with the pyrenyl moiety firmly encapsulated in the hydrophobic cavity of the cage with the nucleoside groups pointing outward was confirmed by NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS), while the host-guest nature of [(pyrene-R)â2](6+) was studied in solution by NMR techniques. In contrast to the floxuridine compounds used in the clinic, the host-guest complexes are highly water-soluble. Consequently, the cytotoxicities of these water-soluble compounds have been established using human ovarian A2780 and A2780cisR cancer cells. All the host-guest systems are more cytotoxic than the empty cages alone [1][CF(3)SO(3)](6) (IC(50) = 23 µM) and [2][CF(3)SO(3)](6) (IC(50) = 10 µM), the most active compound [pyrene-R4â1][CF(3)SO(3)](6)being 2 orders of magnitude more cytotoxic (IC(50) = 0.3 µM) on these human ovarian cancer cell lines (A2780 and A2780cisR).
Assuntos
Antineoplásicos/administração & dosagem , Floxuridina/administração & dosagem , Neoplasias/tratamento farmacológico , Antineoplásicos/uso terapêutico , Floxuridina/uso terapêutico , Humanos , Espectroscopia de Ressonância Magnética , Neoplasias/patologia , Solubilidade , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Água/químicaRESUMO
An unprecedented series of titanocene-gold bi- and trimetallic complexes of the general formula [[(η(5)-C(5)H(5))(µ-η(5):κ(1)-C(5)H(4)(CH(2))(n)PPh(2))TiCl(2)](m)AuCl(x)](q+) (n = 0, 2, or 4; m = 1, x = 1, q = 0 or m = 2, x = 0, q = 1) have been prepared and characterized spectroscopically. The luminescence spectroscopy and photophysics of one of the compounds, [[(η(5)-C(5)H(5))(µ-η(5):κ(1)-C(5)H(4)PPh(2))TiCl(2)](2)Au]PF(6), have been investigated in 2MeTHF solution and in the solid state at 77 and 298 K. Evidence for interfragment interactions based on the comparison of electronic band positions and emission lifetimes, namely, triplet energy transfer (ET) from the Au- to the Ti-containing chromophores, is provided. The cytotoxicity of the complexes was evaluated on A2780 ovarian cancer cells and on their cisplatin-resistant cell line A2780cisR; the compounds showed activity in the low micromolar range that was markedly more active than the corresponding titanocene-phosphine precursors [(η(5)-C(5)H(5))(η(5)-C(5)H(4)(CH(2))(n)PPh(2))TiCl(2)], cisplatin, and, for some of them, the gold analogue [(PPh(3))AuCl]. In an attempt to draw preliminary structure-activity relationships, cell uptake measurements and interaction studies with plasmid DNA and the model protein ubiquitin (Ub) have been undertaken on some of the compounds.
Assuntos
Antineoplásicos/química , Ouro/química , Compostos Organometálicos/química , Titânio/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ouro/farmacologia , Humanos , Luminescência , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade , Titânio/farmacologiaRESUMO
A series of large cationic hexanuclear metalla-prisms, [Ru(6)(p-iPrC(6)H(4)Me)(6)(tpt)(2)(donq)(3)](6+), [Ru(6)(p-iPrC(6)H(4)Me)(6)(tpt)(2)(doaq)(3)](6+) and [Ru(6)(p-iPrC(6)H(4)Me)(6)(tpt)(2)(dotq)(3)](6+), composed of p-cymene-ruthenium building blocks bridged by OOâ©OO ligands (donq=5,8-dioxido-1,4-naphthoquinonato; doaq=5,8-dioxido-1,4-anthraquinonato, dotq=6,11-dioxido-5,12-naphthacenedionato) and connected by two 2,4,6-tripyridin-4-yl-1,3,5-triazine (tpt) panels, which encapsulate the guest molecules 1-(4,6-dichloro-1,3,5-triazin-2-yl)pyrene and Pd(acac)(2), have been prepared. The host-guest properties of these water-soluble delivery systems were studied in solution by NMR and fluorescence spectroscopy, providing the stability constants (K) for these host-guest systems. Moreover, the ability of the hosts to deliver the guests into cancer cells was evaluated and the uptake mechanism studied; the rate of release of the guest molecule was found to depend on the portal size of the host.
Assuntos
Antineoplásicos/química , Antineoplásicos/síntese química , Monoterpenos/química , Monoterpenos/síntese química , Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Pirenos/síntese química , Rutênio/química , Triazinas/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cimenos , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pirenos/química , Triazinas/química , Água/químicaRESUMO
Two generations of lipophilic pyrenyl functionalized poly(benzyl ether) dendrimers (P(1) and P(2)) have been synthesized. The thermal properties of the two functionalized dendrimers have been investigated, and the pyrenyl group of the dendritic molecules encapsulated in the arene-ruthenium metalla-cage, [Ru(6)(p-cymene)(6)(tpt)(2)(donq)(3)](6+) ([1](6+)) (tpt=2,4,6-tri(pyridin-4-yl)-1,3,5-triazine; donq=5,8-dioxydo-1,4-naphthoquinonato). The host-guest properties of [P(1)â1](6+) and [P(2)â1](6+) were studied in solution by NMR and UV/Vis spectroscopic methods, thus allowing the determination of the affinity constants. Moreover, the cytotoxicity of these water-soluble host-guest systems was evaluated on human ovarian cancer cells.
Assuntos
Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacologia , Clorambucila/análogos & derivados , Clorambucila/farmacologia , Flúor/química , Flúor/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Hipertermia Induzida , Neoplasias Ovarianas/terapiaRESUMO
The cellular uptake and subcellular distribution including adduct formation with genomic DNA and uptake into mitochondria of two ruthenium(iii)-based drugs in clinical trials, KP1019 and NAMI-A, and cisplatin, was investigated in cisplatin sensitive and resistant A2780 human ovarian carcinoma cells. These data indicate that reduced metal uptake into mitochondria in combination with increased binding towards low molecular weight components involved in detoxification mechanisms is essential for cisplatin resistance. The ruthenium drugs show distinct differences with respect to cisplatin, especially in the cisplatin resistant cells; in comparison to the sensitive cells, KP1019 exhibits higher cytotoxicity and an only slightly changed metabolism of the drug, whereas NAMI-A treatment results in increased intracellular ruthenium levels and a higher number of ruthenium-DNA adducts. In addition, size exclusion-inductively coupled mass spectrometry indicates that adduct formation with high molecular weight components in the particulate and nuclear fractions is crucial for the therapeutic effect of KP1019 in both cisplatin resistant and sensitive cell lines.
Assuntos
Cisplatino/farmacocinética , Dimetil Sulfóxido/análogos & derivados , Indazóis/farmacocinética , Compostos Organometálicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Citosol/metabolismo , DNA/química , Adutos de DNA/química , Dimetil Sulfóxido/química , Dimetil Sulfóxido/farmacocinética , Dimetil Sulfóxido/farmacologia , Humanos , Indazóis/química , Indazóis/farmacologia , Concentração Inibidora 50 , Espectrometria de Massas/métodos , Mitocôndrias/metabolismo , Estrutura Molecular , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Rutênio/química , Rutênio/farmacocinética , Rutênio/farmacologia , Compostos de Rutênio , Fatores de TempoRESUMO
The self-assembly of 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine (tpt) triangular panels with p-cymene-ruthenium building blocks and 5,8-dioxido-1,4-naphthoquinonato (donq) bridges, in the presence of pyrenyl-containing dendrimers of different generations (P(0), P(1) and P(2)), affords the triangular prismatic host-guest compounds [P(n)âRu(6)(p-cymene)(6)(tpt)(2)(donq)(3)](6+) ([P(n)â1](6+)). The host-guest nature of these systems, with the pyrenyl moiety being encapsulated in the hydrophobic cavity of the cage and the dendritic functional group pointing outwards, was confirmed by NMR spectroscopy ((1)H, 2D and DOSY). The host-guest properties of these systems were studied in solution by NMR and UV/Vis spectroscopic methods, allowing the determination of their affinity constants (K(a)). Moreover, the ability of these water-soluble host-guest systems to carry the pyrenyl-containing dendrimers into cancer cells was evaluated on human ovarian cancer cells. The host-guest systems are all more cytotoxic than the empty cage [1][CF(3)SO(3)](6) (IC(50)≈4 µM), with the most active compound, [P(0)â1][CF(3)SO(3)](6), being an order of magnitude more cytotoxic.
Assuntos
Antineoplásicos/síntese química , Dendrímeros/química , Dendrímeros/síntese química , Compostos Organometálicos/síntese química , Pirenos/síntese química , Rutênio/química , Triazinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Dendrímeros/farmacologia , Sistemas de Liberação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Pirenos/química , Pirenos/farmacologia , Triazinas/química , Triazinas/farmacologiaRESUMO
New cationic diruthenium complexes of the type [(arene)(2)Ru(2)(SPh)(3)](+), arene being C(6)H(6), p-(i)PrC(6)H(4)Me, C(6)Me(6), C(6)H(5)R, where R = (CH(2))(n)OC(O)C(6)H(4)-p-O(CH(2))(6)CH(3) or (CH(2))(n)OC(O)CH=CHC(6)H(4)-p-OCH(3) and n = 2 or 4, are obtained from the reaction of the corresponding precursor [(arene)RuCl(2)](2) and thiophenol and isolated as their chloride salts. The complexes have been fully characterised by spectroscopic methods and the solid state structure of [(C(6)H(6))(2)Ru(2)(SPh)(3)](+), crystallised as the hexafluorophosphate salt, has been established by single crystal X-ray diffraction. The complexes are highly cytotoxic against human ovarian cancer cells (cell lines A2780 and A2780cisR), with the IC(50) values being in the submicromolar range. In comparison the analogous trishydroxythiophenolato compounds [(arene)(2)Ru(2)(S-p-C(6)H(4)OH)(3)]Cl (IC(50) values around 100 µM) are much less cytotoxic. Thus, it would appear that the increased antiproliferative effect of the arene ruthenium complexes is due to the presence of the phenyl or toluyl substituents at the three thiolato bridges.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Rutênio/química , Enxofre/química , Alcenos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Compostos Organometálicos/síntese químicaRESUMO
A series of bimetallic titanium-ruthenium complexes of general formula [(η(5)-C(5)H(5))(µ-η(5):κ(1)-C(5)H(4)(CR(2))(n)PR'R'')TiCl(2)](η(6)-p-cymene)RuCl(2) (n = 0, 1, 2 or 4; R = H or Me; R' = H, Ph, or Cy; R'' = Ph or Cy) have been synthesized, including two novel compounds as well as two cationic derivatives of formula [(η(5)-C(5)H(5))(µ-η(5):κ(1)-C(5)H(4)(CH(2))(n)PPh(2))TiCl(2)] [(η(6)-p-cymene)RuCl](BF(4)) (n = 0 or 2). The solid state structure of two of these compounds was also established by X-ray crystallography. The complexes showed a cytotoxic effect on human ovarian cancer cells and were markedly more active than their Ti or Ru monometallic analogues titanocene dichloride and RAPTA-C, respectively. Studies of cathepsin B inhibition, an enzyme involved in cancer progression, showed that enzyme inhibition by the bimetallic complexes is influenced by the length of the alkyl chain in between the metal centers. Complementary ESI-MS studies provided evidence for binding of a Ru(II) fragment to proteins.
Assuntos
Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Rutênio , Titânio , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Catepsina B/antagonistas & inibidores , Bovinos , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The self-assembly of 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine (tpt) triangular panels with p-cymene (p-Pr(i)C(6)H(4)Me) ruthenium building blocks and 2,5-dioxydo-1,4-benzoquinonato (dobq) bridges, in the presence of a functionalised pyrenyl derivative (pyrene-R), affords the triangular prismatic host-guest compounds [(pyrene-R) [symbol: see text] Ru(6)(p-Pr(i)C(6)H(4)Me)(6)(tpt)(2)(dobq)(3)](6+) ([(pyrene-R) [symbol: see text] 1](6+)). The inclusion of eight mono-substituted pyrenyl derivatives including biologically relevant structures (a = 1-pyrenebutyric acid, b = 1-pyrenebutanol, c = 1-pyrenemethylamine, d = 1-pyrenemethylbutanoate, e = 1-(4,6-dichloro-1,3,5-triazin-2-yl)pyrene, f = N-hexadecylpyrene-1-sulfonamide, g = pyrenyl ethacrynic amide and h = 2-(pyren-1-ylmethylcarbamoyl) phenyl acetate), and a di-substituted pyrenyl derivative (i = 1,8-bis(3-methyl-butyn-1-yl-3-ol)pyrene), has been accomplished. The carceplex nature of these systems with the pyrenyl moiety being firmly encapsulated in the hydrophobic cavity of the cage with the functional groups pointing outwards was confirmed by NMR ((1)H, 2D, DOSY) spectroscopy and electrospray ionization mass spectrometry (ESI-MS). The cytotoxicities of these water-soluble compounds have been established using human ovarian A2780 cancer cells. All the host-guest systems are more cytotoxic than the empty cage itself [1][CF(3)SO(3)](6) (IC(50) = 23 microM), the most active carceplex [f [symbol: see text] 1][CF(3)SO(3)](6) is an order of magnitude more cytotoxic.
Assuntos
Antineoplásicos/química , Pirenos/química , Antineoplásicos/administração & dosagem , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Pirenos/administração & dosagem , Pirenos/toxicidade , Rutênio/química , Espectrometria de Massas por Ionização por Electrospray , Água/químicaRESUMO
Cationic tetranuclear and hexanuclear opened metalla-assemblies incorporating 5,15-bis(4-pyridyl)-10,20-diphenylporphyrin (bpp) or 5,10,15-tris(4-pyridyl)-20-phenylporphyrin (tpp) panels and dinuclear arene ruthenium clips [(p-cymene)(2)Ru(2)(OO[intersection]OO)(2)](2+) (OO[intersection]OO = oxalato, 2,5-dioxydo-1,4-benzoquinonato (dobq)) have been assembled in the presence of silver triflate. All complexes were characterised by NMR, IR and UV-visible spectroscopy and electrospray ionisation mass spectrometry. The cytotoxicities of the tetranuclear and hexanuclear ruthenium complexes have been established on ovarian A2780 and A2780cisR cancer cell lines. The compounds are quite cytotoxic, the most active metalla-assembly being [Ru(6)(p-cymene)(6)(dobq)(3)(tpp)(2)](6+), with IC(50) values of 2.1 microM and 3.8 microM against A2780 and A2780cisR cells, respectively.
Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , Rutênio/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Mesilatos/química , Conformação Molecular , Porfirinas/química , Espectrofotometria UltravioletaRESUMO
The reaction of copper(II) chloride or copper(II) acetate with 6-N-(2-N',N'-dimethylaminoethylamino)-7,12-dihydroindolo-[3,2-d][1]benzazepine (HL(1)), 9-bromo-6-N-(2-N',N'-dimethylaminoethylamino)-7,12-dihydroindolo[3,2-d][1]benzazepine (HL(2)), N-(9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-yliden-N'-(1-pyridin-2-yl-methylidene)azine (HL(3)), or N-(9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-yliden-N'-(1-pyridin-2-yl-ethylidene)azine (HL(4)) in methanol affords the novel copper(II) complexes [Cu(HL(1))Cl(2)] (1), [Cu(HL(2))Cl(2)] (2), [Cu(HL(3))Cl(2)] (3), [Cu(HL(4))Cl(2)] (4), and [Cu(L(4))(CH(3)COO)(CH(3)OH)] (5). The new ligands (HL(2) and HL(3)) and the complexes 1-5 were characterized by (1)H and (13)C NMR, IR and electronic absorption spectroscopy, ESI mass spectrometry, and X-ray crystallography. Two ligands, HL(1) and HL(2), and complexes 1-4 were tested for cytotoxicity in three human cancer cell lines, namely, CH1 (ovarian carcinoma), A549 (non-small cell lung cancer), and SW480 (colon carcinoma). Additionally, complexes 1, 2, and 4 were assayed in an isogenic pair of ovarian cancer cell lines, one being sensitive to cisplatin (A2780) and the other having acquired cisplatin resistance (A2780cisR). All of the compounds evaluated are cytotoxic, with complexes 3 and 4 exhibiting IC(50) values in the nanomolar range.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cobre/química , Cobre/farmacologia , Compostos Organometálicos/química , Benzazepinas/química , Carcinoma/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Estrutura Molecular , Neoplasias Ovarianas/tratamento farmacológicoRESUMO
Gold(I) complexes bearing water-soluble phosphine ligands, including 1,3,5-triaza-7-phosphaadamantane (PTA), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA), and sodium triphenylphosphine trisulfonate (TPPTS), in combination with thionate ligands, were screened for their antiproliferative activities against human ovarian cancer cell lines A2780 either sensitive or resistant to cisplatin. In addition, the compounds were screened for their inhibition of mammalian thioredoxin reductases (TrxR), enzymes that are overexpressed in many tumor cells and contribute to drug resistance. The gold(I)-phosphine complexes efficiently inhibited cytosolic and mitochondrial TrxRs at concentrations that did not affect the related oxidoreductase glutathione reductase (GR). Additional complementary information on the enzyme metallation process and potential gold binding sites was obtained through the application of a specific biochemical assay using a thiol-tagging reagent, BIAM (biotin-conjugated iodoacetamide).