RESUMEN
Multinuclear platinum anticancer complexes are a proven option to overcome resistance of established anticancer compounds. Transferring this concept to ruthenium complexes led to the synthesis of dinuclear Ru(II)-arene compounds containing a bis(pyridinone)alkane ligand linker. A pronounced influence of the spacer length on the in vitro anticancer activity was found, which is correlated to the lipophilicity of the complexes. IC(50) values in the same dimension as for established platinum drugs were found in human tumor cell lines. No cross-resistance to oxoplatin, a cisplatin prodrug, was observed for the most active complex in three resistant cell lines; in fact, a 10-fold reversal of sensitivity in two of the oxoplatin-resistant lines was found. (Bio)analytical characterization of the representative examples showed that the ruthenium complexes hydrolyze rapidly, forming predominantly diaqua species that exhibit affinity toward transferrin and DNA, indicating that both proteins and nucleobases are potential targets.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Organometálicos/farmacología , Rutenio/farmacología , Antineoplásicos/química , Antineoplásicos/metabolismo , Línea Celular Tumoral , ADN/metabolismo , Resistencia a Antineoplásicos , Humanos , Hidrólisis , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Ligandos , Compuestos Organometálicos/química , Compuestos Organometálicos/metabolismo , Compuestos de Platino/farmacología , Rutenio/química , Rutenio/metabolismo , Relación Estructura-Actividad , Transferrina/metabolismoRESUMEN
The antiproliferative properties of the osmium(II) complexes cis,fac-[Os(II)Cl(2)(DMSO)(3)(L)] and trans,cis,cis-[Os(II)Cl(2)(DMSO)(2)(L)(2)] (L = 1H-pyrazole, 1H-imidazole) were studied in three human cancer cell lines, namely 41M (ovary), SK-BR-3 (breast), and SW480 (colon). Their activities were compared with those of osmium(III) and ruthenium(III) NAMI-A type complexes on HT-29 (colon) and SK-BR-3 cancer cell lines. While IC(50) values of all the Os(II) complexes were found to be >1000 microM in all cell lines, Os and Ru-NAMI-A type complexes showed remarkable antiproliferative activity. The marginal in vitro cytotoxicity of the Os(II) compounds is presumably attributed to their resistance to hydrolysis. However, the Os-NAMI-A complexes, which are also kinetically stable in aqueous solution, showed reasonable antiproliferative activity in vitro when compared with the analogous Ru compounds and with the Os(II)-DMSO-azole species, indicating that hydrolysis might be not a prerequisite for the antitumor activity of Os-NAMI-A type complexes.
Asunto(s)
Azoles/toxicidad , Dimetilsulfóxido/toxicidad , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Osmio/toxicidad , Azoles/química , Proliferación Celular/efectos de los fármacos , Dimetilsulfóxido/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidrólisis/efectos de los fármacos , Ligandos , Conformación Molecular , Compuestos Organometálicos/síntesis química , Osmio/química , Rutenio/química , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Three chalcogensemicarbazones, viz., 2-acetylpyridine N,N-dimethylsemicarbazone (HL(1)), 2-acetylpyridine N,N-dimethylthiosemicarbazone (HL(2)) and 2-acetylpyridine N,N-dimethylselenosemicarbazone (HL(3)), their corresponding gallium(III) complexes [Ga(L(1-3))(2)]PF(6) and the ruthenium(III) compound [Ru(L(2))(2)]PF(6) have been prepared and characterised by X-ray crystallography and spectroscopic techniques (IR, UV/vis, (1)H, (13)C, (15)N, (77)Se NMR) in order to elucidate the effect of metal ion complexation and chalcogen donor identity on the cytotoxicity of chalcogensemicarbazones in two human tumour cell lines 41M (ovarian carcinoma) and SK-BR-3 (mammary carcinoma).
Asunto(s)
Calcógenos/química , Metales/química , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Tiosemicarbazonas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Galio/química , Humanos , Estructura Molecular , Compuestos Organometálicos/síntesis química , Rutenio/químicaRESUMEN
The osmium(III) complex [(DMSO)2H][trans-OsIIICl4(DMSO)2] (1) has been prepared via stepwise reduction of OsO4 in concentrated HCl using N2H(4).2HCl and SnCl(2).2H2O in DMSO. 1 reacts with a number of azole ligands, namely, indazole (Hind), pyrazole (Hpz), benzimidazole (Hbzim), imidazole (Him), and 1H-1,2,4-triazole (Htrz), in organic solvents, affording novel complexes (H2ind)[OsIIICl4(Hind)(DMSO)] (2), (H2pz)[OsIIICl4(Hpz)(DMSO)] (3), (H2bzim)[OsIIICl4(Hbzim)(DMSO)] (4), (H2im)[OsIIICl4(Him)(DMSO)] (6), and (H2trz)[OsIIICl4(Htrz)(DMSO)] (7), which are close analogues of the antimetastatic complex NAMI-A. Metathesis reaction of 4 with benzyltriphenylphosphonium chloride in methanol led to the formation of (Ph3PCH2Ph)[OsIIICl4(Hbzim)(DMSO)] (5). The complexes were characterized by IR, UV-vis, ESI mass spectrometry, 1H NMR spectroscopy, cyclic voltammetry, and X-ray crystallography. In contrast to NAMI-A, 2-4, 6, and 7 are kinetically stable in aqueous solution and resistant to hydrolysis. Surprisingly, they show reasonable antiproliferative activity in vitro in two human cell lines, HT-29 (colon carcinoma) and SK-BR-3 (mammary carcinoma), when compared with analogous ruthenium compounds. Structure-activity relationships and the potential of the prepared complexes for further development are discussed.
Asunto(s)
Antineoplásicos/química , Dimetilsulfóxido/análogos & derivados , Compuestos Organometálicos/química , Compuestos de Osmio/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dimetilsulfóxido/química , Dimetilsulfóxido/farmacología , Estabilidad de Medicamentos , Humanos , Estructura Molecular , Compuestos Organometálicos/farmacología , Compuestos de Osmio/síntesis química , Compuestos de Osmio/farmacología , Compuestos de Rutenio , Análisis Espectral , Relación Estructura-ActividadRESUMEN
Imidazolium [trans-tetrachloro(1H-imidazole)(S-dimethylsulfoxide)ruthenate(III)] (NAMI-A) and indazolium [trans-tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) are the most promising ruthenium complexes for anticancer chemotherapy. In this study, the azole ligand of NAMI-A was systematically varied (from imidazole of NAMI-A to indazole, 1,2,4-triazole, 4-amino-1,2,4-triazole, and 1-methyl-1,2,4-triazole), and the respective complexes were evaluated with regard to the rate of aquation and protein binding, redox potentials, and cytotoxicity by means of capillary zone electrophoresis, electrospray ionization mass spectrometry, cyclic voltammetry, and colorimetric microculture assays. Stability studies demonstrated low stability of the complexes at pH 7.4 and 37 degrees C and a high reactivity toward proteins (binding rate constants in the ranges of 0.02-0.34 and 0.01-0.26 min-1 for albumin and transferrin, respectively). The redox potentials (between 0.25 and 0.35 V) were found to be biologically accessible for activation of the complexes in the tumor, and the indazole-containing compound shows the highest antiproliferative activity in vitro.
Asunto(s)
Antineoplásicos/síntesis química , Dimetilsulfóxido/análogos & derivados , Imidazoles/síntesis química , Compuestos Organometálicos/síntesis química , Rutenio , Triazoles/síntesis química , Albúminas/química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Colorimetría , Cristalografía por Rayos X , Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/química , Dimetilsulfóxido/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Estabilidad de Medicamentos , Electroforesis Capilar , Humanos , Concentración de Iones de Hidrógeno , Imidazoles/química , Imidazoles/farmacología , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Oxidación-Reducción , Potenciometría , Unión Proteica , Compuestos de Rutenio , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad , Transferrina/química , Triazoles/química , Triazoles/farmacología , Agua/químicaRESUMEN
A series of gallium(III) and iron(III) complexes with five different 4N-substituted alpha-N-heterocyclic thiosemicarbazones, viz., 2-acetylpyridine N,N-dimethylthiosemicarbazone (1), 2-acetylpyridine N-pyrrolidinylthiosemicarbazone (2), acetylpyrazine N,N-dimethylthiosemicarbazone (3), acetylpyrazine N-pyrrolidinylthiosemicarbazone (4), and acetylpyrazine N-piperidinylthiosemicarbazone (5), with the general formula [GaLCl2] (HL = 1 and 2) and [ML2][Y] (M = Ga, HL = 1-5, Y = PF6; M = Fe, HL = 1-5, Y = FeCl4 and PF6) were synthesized and characterized by elemental analysis, a number of spectroscopic methods (NMR, IR, UV-vis), mass spectrometry, and X-ray crystallography. The in vitro antitumor potency was studied in two human cancer cell lines (41M and SK-BR-3). The central metal ions exert pronounced effects in a divergent manner: gallium(III) enhances, whereas iron(III) weakens the cytotoxicity of the ligands. The capacity of ligand 1 and its Ga(III) and Fe(III) complexes to destroy the tyrosyl radical of the presumed target ribonucleotide reductase is reported.
Asunto(s)
Antineoplásicos/síntesis química , Quelantes/síntesis química , Galio , Hierro , Compuestos Organometálicos/síntesis química , Ribonucleótido Reductasas/química , Tiosemicarbazonas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Quelantes/química , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Radicales Libres/química , Humanos , Ligandos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Estructura Molecular , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Relación Estructura-Actividad , Tiosemicarbazonas/química , Tirosina/químicaRESUMEN
The microtubule-associated proteins MAP1A and MAP1B are related but distinct multi-subunit protein complexes that consist of heavy and light chains. The predominant forms of these complexes are homotypic, i.e. they consist of a MAP1A heavy chain associated with MAP1A light chains or a MAP1B heavy chain associated with MAP1B light chains, respectively. In addition, MAP1A and MAP1B can exchange subunits and form heterotypic complexes consisting of a MAP1A heavy chain associated with MAP1B light chains which might play a role in a transition period of neuronal differentiation. Here we extend previous findings by confirming that heterotypic MAP1B heavy chain-MAP1A light chain complexes also exist in the developing murine brain. We show that these complexes form through interaction of homologous domains conserved in heavy and light chains of MAP1A and MAP1B. Likewise, conserved domains of the MAP1A and MAP1B light chains account for formation of light chain heterodimers. By yeast 2-hybrid analysis we located the light chain binding domain on the heavy chain to amino acids 211-508, thereby defining a new functional subdomain.
Asunto(s)
Proteínas Asociadas a Microtúbulos/química , Proteínas Asociadas a Microtúbulos/metabolismo , Microtúbulos/metabolismo , Subunidades de Proteína/química , Animales , Línea Celular , Secuencia Conservada , Dimerización , Unión Proteica , Ratas , Relación Estructura-Actividad , TransfecciónRESUMEN
The microtubule-associated proteins 1A (MAP1A) and 1B (MAP1B) are distantly related protein complexes consisting of heavy and light chains and are thought to play a role in regulating the neuronal cytoskeleton, MAP1B during neuritogenesis and MAP1A in mature neurons. To elucidate functional differences between MAP1B and MAP1A and to determine the role of the light chain in the MAP1A protein complex, we chose to investigate the functional properties of the light chain of MAP1A (LC2) and compare them with the light chain of MAP1B (LC1). We found that LC2 binds to microtubules in vivo and in vitro and induces rapid polymerization of tubulin. A microtubule-binding domain in its NH(2) terminus was found to be necessary and sufficient for these activities. The analysis of LC1 revealed that it too bound to microtubules and induced tubulin polymerization via a crucial but structurally unrelated NH(2)-terminal domain. The two light chains differed, however, in their effects on microtubule bundling and stability in vivo. Furthermore, we identified actin filament binding domains located at the COOH terminus of LC2 and LC1 and obtained evidence that binding to actin filaments is attributable to direct interaction with actin. Our findings establish LC2 as a crucial determinant of MAP1A function, reveal LC2 as a potential linker of neuronal microtubules and microfilaments, and suggest that the postnatal substitution of MAP1B by MAP1A leads to expression of a protein with an overlapping but distinct set of functions.