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Described here is the development of gadolinium(III) texaphyrin-platinum(IV) conjugates capable of overcoming platinum resistance by 1) localizing to solid tumors, 2) promoting enhanced cancer cell uptake, and 3) reactivating p53 in platinum-resistant models. Side by side comparative studies of these Pt(IV) conjugates to clinically approved platinum(II) agents and previously reported platinum(II)-texaphyrin conjugates demonstrate that the present Pt(IV) conjugates are more stable against hydrolysis and nucleophilic attack. Moreover, they display high potent antiproliferative activity in vitro against human and mouse cell cancer lines. Relative to the current platinum clinical standard of care (SOC), a lead Gd(III) texaphyrin-Pt(IV) prodrug conjugate emerging from this development effort was found to be more efficacious in subcutaneous (s.c.) mouse models involving both cell-derived xenografts and platinum-resistant patient-derived xenografts. Comparative pathology studies in mice treated with equimolar doses of the lead Gd texaphyrin-Pt(IV) conjugate or the US Food and Drug Administration (FDA)-approved agent oxaliplatin revealed that the conjugate was better tolerated. Specifically, the lead could be dosed at more than three times (i.e., 70 mg/kg per dose) the tolerable dose of oxaliplatin (i.e., 4 to 6 mg/kg per dose depending on the animal model) with little to no observable adverse effects. A combination of tumor localization, redox cycling, and reversible protein binding is invoked to explain the relatively increased tolerability and enhanced anticancer activity seen in vivo. On the basis of the present studies, we conclude that metallotexaphyrin-Pt conjugates may have substantial clinical potential as antitumor agents.
Assuntos
Antineoplásicos/administração & dosagem , Metaloporfirinas/administração & dosagem , Oxaliplatina/administração & dosagem , Células A549 , Animais , Antineoplásicos/farmacocinética , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HCT116 , Humanos , Metaloporfirinas/farmacocinética , Camundongos Nus , Oxaliplatina/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Distribuição Tecidual , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The NIR absorptivity of the metallotexaphyrin derivatives MMn, MGd, and MLu for photoacoustic (PA)-based imaging is explored in this study. All three complexes demonstrated excellent photostabilities; however, MMn provided the greatest PA signal intensities in both doubly distilled water and RAW 264.7 cells. In vivo experiments using a prostate tumor mouse model were performed. MMn displayed no adverse toxicity to major organs as inferred from hematoxylin and eosin (H&E) staining and cell blood count testing. MMn also allowed for PA-based imaging of tumors with excellent in vivo stability to provide 3D tumor diagnostic information. Based on the present findings and previous magnetic resonance imaging (MRI) studies, we believe MMn may have a role to play either as a stand-alone PA contrast agent or as a single molecule dual modal (PA and MR) imaging agent for tumor diagnosis.
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Meios de Contraste/química , Manganês/química , Técnicas Fotoacústicas , Porfirinas/química , Neoplasias da Próstata/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Humanos , Raios Infravermelhos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/diagnóstico por imagem , Células RAW 264.7RESUMO
Porphyrin and related pyrrole-containing macrocycles, collectively porphyrinoids, are versatile ligands that allow access to a multitude of coordination modes. Judicious modification of the porphyrin core as well as the pendant substituents has extended the coordination chemistry of porphyrinoids to include systems that are able to stabilize f-block element complexes with possible utility. This review focuses on our group's efforts to prepare expanded porphyrin and porphyrinogen ligands that can serve as tools to study and apply f-element metal coordination chemistry: it covers the background of the topic, selected syntheses, and application of these species in the chemical and medical sciences.
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The peroxidase activity of hemin-peptide complexes remains a potential factor in oxidative damage relevant to neurodegeneration. Here, we present the effect of temperature, ionic strength, and pH relevant to pathophysiological conditions on the dynamic equilibrium between high-spin and low-spin hemin-Aß40 constructs. This influence on peroxidase activity was also demonstrated using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and dopamine (DA) oxidation rate analyses with increasing ratios of Aß16 and Aß40 (up to 100 equivalents). Interaction and reactivity studies of aggregated Aß40-hemin revealed enhanced peroxidase activity versus hemin alone. Comparison of the results obtained using Aß16 and Aß40 amyloid beta peptides revealed marked differences and provide insight into the potential effects of hemin-Aß on neurological disease progression.
Assuntos
Peptídeos beta-Amiloides/química , Benzotiazóis/química , Dopamina/química , Hemina/química , Fragmentos de Peptídeos/química , Peroxidases/química , Ácidos Sulfônicos/química , Humanos , OxirreduçãoRESUMO
The reaction between dipyriamethyrin and copper(II) acetate [Cu(OAc)2] afforded what is, to our knowledge, the first transition metal-dipyriamethyrin complex. Molecular and electronic characterization of this binuclear Cu(II) complex via EPR, UV-vis, and single crystal X-ray diffraction analysis revealed marked differences between the present constructs and previously reported binuclear copper(II) hexaphyrin species. UV-vis titration analyses provided evidence for a homotropic positive allosteric effect, wherein the binuclear species is formed without significant intermediacy of a monomeric complex.
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Complexos de Coordenação , Cobre/química , Modelos Moleculares , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Estrutura MolecularRESUMO
Reported here are new platinum(IV) (Pt(IV)) complexes bearing ferrocene (Fc) moieties. These systems differ from one another only by the nature of the functional group (ester vs amide) connecting the linker to the Fc subunits. This minor structural variation (one atom difference) leads to major differences in solubility, stability, and antiproliferative activity against lung (A549) cancer cells. The host-guest chemistry of these complexes was investigated in an aqueous medium in the presence of ß-cyclodextrins (ß-CD), either free or in the form of a covalently linked Fc-Pt-ß-CD hybrid. An inclusion complex between Fc and ß-CD is formed in aqueous media, presumably as a result of hydrophobic interactions involving the Fc and the inner ß-CD cavity. Consequently, it proved possible to use a ß-CD-based strategy to purify the Pt-Fc conjugates in this study under aqueous conditions (by means of C18 silica gel columns). The use of a ß-CD adjuvant also allowed dimethyl sulfoxide (DMSO) to be avoided as an organic cosolvent in cell studies. The amide version reported here (2) proved to be more soluble, more stable, and more active than the ester analogue (11) in A549 cells. The use of a ß-CD functionalized with a fluorescent probe allowed intracellular Pt-Fc localization to be visualized by confocal fluorescence microscopy.
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Here, we report the use of gadolinium(III)-, lutetium(III)-, and lanthanum(III)-texaphyrins as bioinspired photocatalysts that promote a novel approach to the degradation of curcumin, a 1,3-diketo-containing natural product. Complexation of curcumin to the lanthanide centers of the texaphyrins yields stable species that display limited reactivity in the dark or under anaerobic conditions. However, upon exposure to mWatt intensity light (pocket flashlight) or simply under standard laboratory illumination in the presence of atmospheric oxygen, substrate oxidation occurs readily to generate curcumin-derived cleavage products. These latter species were identified on the basis of spectroscopic and mass spectrometric analyses. The mild nature of the activation conditions serves to highlight a potential new role for photoactive lanthanide complexes.
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The reaction between a naphthylbipyrrole-containing hexaphyrin-type expanded porphyrin and copper acetate affords a bench-stable dicopper(II) complex. UV-vis spectroscopy, cyclic voltammetry, and X-ray crystallographic analysis measurements provide support for the conclusion that this complex displays aromatic features. A weak antiferromagnetic exchange interaction between the binuclear copper(II) ions is evidenced by variable-temperature electron paramagnetic resonance and by fitting of the bulk magnetic susceptibility to a dimer model, yielding J = -5.1 cm-1.
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Water-soluble platinum(IV) prodrugs, which proved kinetically stable to reduction in the presence of physiological concentration of ascorbate, were quickly reduced to their active form, oxaliplatin, when co-incubated with a macrocycle metallotexaphyrin (i.e., Motexafin Gadolinium (MGd)). The reduction of Pt(IV) to Pt(II) promoted by MGd occurs in cell culture as well, leading to an increase in the antiproliferative activity of the Pt(IV) species in question. The mediated effect is proportional to the concentration of MGd and gives rise to an enhancement when the prodrug is relatively hydrophilic. MGd is known to localize/accumulate preferentially in tumor tissues. Thus, the present "activation by reduction" approach may allow for the cancer-selective enhancement in the cytotoxicity of Pt(IV) prodrugs.
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Antineoplásicos/química , Metaloporfirinas/química , Platina/química , Pró-Fármacos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas Eletroquímicas , Humanos , Oxirredução , Platina/farmacologia , Pró-Fármacos/farmacologiaRESUMO
In an effort to increase the stability and control the platinum reactivity of platinum-texaphyrin conjugates, two Pt(IV) conjugates were designed, synthesized, and studied for their ability to form DNA adducts. They were also tested for their anti-proliferative effects using wild-type and platinum-resistant human ovarian cancer cell lines (A2780 and 2780CP, respectively). In comparison to an analogous first-generation Pt(II) chimera, one of the new conjugates provided increased stability in aqueous environments. Using a combination of (1) Hâ NMR spectroscopy and FAAS (flameless atomic-absorption spectrometry), it was found that the Pt(IV) center within this conjugate undergoes photoinduced reduction to Pt(II) upon exposure to glass-filtered daylight, resulting in an entity that binds DNA in a controlled manner. Under conditions in which the Pt(IV) complex is reduced to the corresponding Pt(II) species, these new conjugates demonstrated potent anti-proliferative activity in both test ovarian cancer cell lines.
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Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Compostos Organoplatínicos/química , Neoplasias Ovarianas/tratamento farmacológico , Porfirinas/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , DNA/metabolismo , Desenho de Fármacos , Feminino , Humanos , Luz , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Oxirredução , Porfirinas/farmacologiaRESUMO
The concentrations of reactive oxygen species (ROS), e.g., H2O2, are often elevated in diseased tissue microenvironments. Therefore, the selective detection of ROS could enable new diagnostic methods or tools for chemical biology. Here, we report the synthesis of boronic ester-bis-norbornene core-cross-linked brush-arm star polymers (BASPs) with polyethylene glycol (PEG) or PEG-branch-spirocyclohexyl nitroxide (chex) shells. Size exclusion chromatography (SEC) and dynamic light scattering (DLS) showed that these BASPs have narrowly dispersed molar masses and average hydrodynamic diameters of 23 ± 2 nm, respectively. Moreover, due to their core-shell structures, these BASPs disassemble into bottlebrush fragments with improved selectivity for H2O2 over ROS such as peroxynitrite (ONOO-) and hypochlorite (-OCl). Finally, H2O2 induced disassembly of chex-containing BASPs induces a change in transverse magnetic relaxivity that can be detected via magnetic resonance imaging (MRI). Chex-BASPs may represent a valuable new diagnostic tool for H2O2 sensing.
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Peróxido de Hidrogênio , Polímeros , Espécies Reativas de Oxigênio , Polietilenoglicóis/química , Imageamento por Ressonância MagnéticaRESUMO
The ability to monitor intracellular calcium concentrations using fluorescent probes has led to important insights into biological signaling processes at the cellular level. An important challenge is to relate such measurements to broader patterns of signaling across fields of view that are inaccessible to optical techniques. To meet this need, we synthesized molecular probes that couple calcium-binding moieties to lanthanide texaphyrins, resulting in complexes endowed with a diverse complement of magnetic and photophysical properties. We show that the probes permit intracellular calcium levels to be assessed by fluorescence, photoacoustic, and magnetic resonance imaging modalities and that they are detectable by multimodal imaging in brain tissue. This work thus establishes a route for monitoring signaling processes over a range of spatial and temporal scales.
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Cálcio , Porfirinas , Imageamento por Ressonância Magnética/métodos , Imagem Multimodal/métodosRESUMO
The ipso-nitration of calix[6]arene-based molecular receptors is a important synthetic pathway for the elaboration of more sophisticated systems. This reaction has been studied for a variety of capped calixarenes, and a general trend for the regioselective nitration of three aromatic units out of six in moderate to high yield has been observed. This selectivity is, in part, attributed to the electronic connection between the protonated cap at the small rim and the reactive sites at the large rim. In addition, this work highlights the fact that subtle conformational properties can drastically influence the outcome of this reaction.
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The coupling of electron and proton transfers is currently under intense scrutiny. This Communication reports a new kind of proton-coupled electron transfer within a homodinuclear first-row transition-metal complex. The triply-bridged complex [Fe(III)(µ-OPh)(µ(2)-mpdp)Fe(II)(NH(2)Bn)] (1; mpdp(2-) = m-phenylenedipropionate) bearing a terminal aminobenzyl ligand can be reversibly deprotonated to the anilinate complex 2 whose core [Fe(II)(µ-OPh)(µ(2)-mpdp)Fe(III)(NHBn)] features an inversion of the iron valences. This observation is supported by a combination of UV-visible, (1)H NMR, and Mössbauer spectroscopic studies.
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Compostos Férricos/química , Compostos Ferrosos/química , Cristalografia por Raios X , Elétrons , Ligantes , Modelos Moleculares , Conformação Molecular , Prótons , EstereoisomerismoRESUMO
We report here a water-soluble metal cation sensor system based on the as-prepared or reduced form of an expanded porphyrin, texaphyrin. Upon metal complexation, a change in the redox state of the ligand occurs that is accompanied by a color change from red to green. Although long employed for synthesis in organic media, we have now found that this complexation-driven redox behavior may be used to achieve the naked eye detectable colorimetric sensing of several number of less-common metal ions in aqueous media. Exposure to In(III), Hg(II), Cd(II), Mn(II), Bi(III), Co(II), and Pb(II) cations leads to a colorimetric response within 10 min. This process is selective for Hg(II) under conditions of competitive analysis. Furthermore, among the subset of response-producing cations, In(III) proved unique in giving rise to a ratiometric change in the ligand-based fluorescence features, including an overall increase in intensity. The cation selectivity observed in aqueous media stands in contrast to what is seen in organic solvents, where a wide range of texaphyrin metal complexes may be prepared. The formation of metal cation complexes under the present aqueous conditions was confirmed by reversed phase high-performance liquid chromatography, ultra-violet-visible absorption and fluorescence spectroscopies, and high-resolution mass spectrometry.
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The complex etiology of neurodegeneration continues to stifle efforts to develop effective therapeutics. New agents elucidating key pathways causing neurodegeneration might serve to increase our understanding and potentially lead to improved treatments. Here, we demonstrate that a water-soluble manganese(II) texaphyrin (MMn) is a suitable magnetic resonance imaging (MRI) contrast agent for detecting larger amyloid beta constructs. The imaging potential of MMn was inferred on the basis of in vitro studies and in vivo detection in Alzheimer's disease C. elegans models via MRI and ICP-MS. In vitro antioxidant- and cellular-based assays provide support for the notion that this porphyrin analog shows promise as a therapeutic agent able to mitigate the oxidative and nitrative toxic effects considered causal in neurodegeneration. The present report marks the first elaboration of an MRI-active metalloantioxidant that confers diagnostic and therapeutic benefit in Alzheimer's disease models without conjugation of a radioisotope, targeting moiety, or therapeutic payload.
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The control of metal-ligand exchange in a confined environment is of primary importance for understanding thermodynamics and kinetics of the electron transfer process governing the reactivity of enzymes. This study reveals an unprecedented change of the Cu(II)/Cu(I) binding and redox properties through a subtle control of the access to the labile site by a protein channel mimic. The cavity effect was estimated from cyclic voltammetry investigations by comparison of two complexes displaying the same coordination sphere (tmpa) and differing by the presence or absence of a calix[6]arene cone surrounding the metal labile site L. Effects on thermodynamics are illustrated by important shifts of E(1/2) toward higher values for the calix complexes. This is ascribable to the protection of the labile site of the open-shell system from the polar medium. Such a cavity control also generates specific stabilizations. This is exemplified by an impressively exalted affinity of the calixarene system for MeCN, and by the detection of a kinetic intermediate, a noncoordinated DMF guest molecule floating inside the cone. Kinetically, a unique dissymmetry between the Cu(I) and Cu(II) ligand exchange capacity is highlighted. At the CV time scale, the guest interconversion is only feasible after reduction of Cu(II) to Cu(I). Such a redox-switch mechanism results from the blocking of the associative process at the Cu(II) state, imposed by the calixarene funnel. All of this suggests that the embedment of a reactive redox metal ion in a funnel-like cavity can play a crucial role in catalysis, particularly for metallo-enzymes associating electron transfer and ligand exchange.
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Cobre/química , Compostos Organometálicos/química , Proteínas/química , Cinética , Ligantes , Mimetismo Molecular , Oxirredução , TermodinâmicaAssuntos
Peptídeos beta-Amiloides/química , Hemina/química , Nitratos/química , Fragmentos de Peptídeos/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Dimerização , Humanos , Cinética , Oxirredução , Fragmentos de Peptídeos/metabolismo , Tirosina/químicaRESUMO
Functionality of enzymes is strongly related to water dynamic processes. The control of the redox potential for metallo-enzymes is intimately linked to the mediation of water molecules in the first and second coordination spheres. Here, we report a unique example of supramolecular control of the redox properties of a biomimetic monocopper complex by water molecules. It is shown that the copper complex based on a calix[6]arene covalently capped with a tetradentate [tris(2-methylpyridyl)amine] (tmpa) core, embedding the metal ion in a hydrophobic cavity, can exist in three different states. The first system displays a totally irreversible redox behaviour. It corresponds to the reduction of the 5-coordinate mono-aqua-CuII complex, which is the thermodynamic species in the +II state. The second system is detected at a high redox potential. It is ascribed to an "empty cavity" or "water-free" state, where the CuI ion sits in a 4-coordinate trigonal environment provided by the tmpa cap. This complex is the thermodynamic species in the +I state under "dry conditions". Surprisingly, a third redox system appears as the water concentration is increased. Under water-saturation conditions, it displays a pseudo-reversible behaviour at a low scan rate at the mid-point from the water-free and aqua species. This third system is not observed with the Cu-tmpa complex deprived of a cavity. In the calix[6]cavity environment, it is ascribed to a species where a pair of water molecules is hosted by the calixarene cavity. A molecular mechanism for the CuII/CuI redox process with an interplay of (H2O) x (x = 0, 1, 2) hosting is proposed on the basis of computational studies. Such an unusual behaviour is ascribed to the unexpected stabilization of the CuI state by inclusion of the pair of water molecules. This phenomenon strongly evidences the drastic influence of the interaction between water molecules and a hydrophobic cavity on controlling the thermodynamics and kinetics of the CuII/CuI electron transfer process.