RESUMO
Glycoconjugation is a powerful tool to improve the anticancer activity of metal complexes. Herein, we modified commercial arylphosphanes with carbohydrate-derived fragments for the preparation of novel glycoconjugated ruthenium(II) p-cymene complexes. Specifically, d-galactal and d-allal-derived vinyl epoxides (VEß and VEα) were coupled with (2-hydroxyphenyl)diphenylphosphane, affording the 2,3-unsaturated glycophosphanes 1ß and 1α. Ligand exchange with [Ru(C2O4)(η6-p-cymene)(H2O)] gave the glycoconjugated complexes Ru1ß and Ru1α which were subsequently dihydroxylated with OsO4/N-methylmorpholine N-oxide to Ru2ß and Ru2α containing O-benzyl d-mannose and d-gulose units respectively. Besides, aminoethyl tetra-O-acetyl-ß-d-glucopyranoside was condensed with borane-protected (4-diphenylphosphanyl)benzoic acid by HATU/DIPEA under MW heating, to afford the amide 3âBH3. Zemplén deacylation with MeONa/MeOH gave the deprotected d-glucopyranoside derivative 4âBH3. The glycoconjugated phosphane complexes Ru3 and Ru4 were obtained by reaction of the phosphane-boranes 3âBH3 and 4âBH3 with [Ru(C2O4)(η6-p-cymene)(H2O)]. The employed synthetic strategies were devised to circumvent unwanted phosphine oxidation. The compounds were purified by silica chromatography, isolated in high yield and purity and characterized by analytical and spectroscopic (IR and multinuclear NMR) techniques. The behaviour of the six glycoconjugated Ru complexes in aqueous solutions was assessed by NMR and MS measurements. All compounds were screened for their in vitro cytotoxicity against A2780/A2780R human ovarian and MCF7 breast cancer cell lines, revealing a significant cytotoxicity for complexes containing the 2,3-unsaturated glycosyl unit (Ru1ß, Ru1α). Additional studies on five other human cancer cells, as well as time-dependent toxicity and cell-uptake analyses on ovarian cancer cells, confirmed the prominent activity of these two compounds - higher than cisplatin - and the better performance of the ß anomer. However, Ru1ß, Ru1α did not show preferential activity against cancer cells with respect to fetal lung fibroblast and human embryonic kidney cells as models of normal cells. The effects of the two ruthenium glycoconjugated compounds in A2780 ovarian cancer cells were further investigated by cell cycle analysis, induction of apoptosis, intracellular ROS production, activation of caspases 3/7 and disruption of mitochondrial membrane potential. The latter is a relevant factor in the mechanism of action of the highly cytotoxic Ru1ß, inducing cell death by apoptosis.
Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias Ovarianas , Rutênio , Antineoplásicos/química , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Feminino , Humanos , Ligantes , Fosfinas , Rutênio/química , Rutênio/farmacologiaRESUMO
Four propargyl O-glycosides derivatized with mannose, glucose, and fructose moieties were synthesized and then incorporated within a diiron structure as part of a vinyliminium ligand. Hence, six glycoconjugated diiron complexes, [2-5]CF3SO3 (see Scheme 1) and the nonglycosylated analogues [6a-b]CF3SO3, were obtained in high yields and unambiguously characterized by elemental analysis, mass spectrometry, and IR and multinuclear NMR spectroscopies. All compounds exhibited a significant stability in DMSO-d 6/D2O solution, with 63-89% of the complexes unaltered after 72 h at 37 °C and also in the cell culture medium. The cytotoxicity of [2-6]CF3SO3, as well as that of previously reported 7 and 8, was assessed on CT26 (mouse colon carcinoma), U87 (human glioblastoma), MCF-7 (human breast adenocarcinoma), and RPE-1 (human normal retina pigmented epithelium) cell lines. In general, the IC50 values correlate with the hydrophobicity of the compounds (measured as octanol-water partition coefficients) and do not show an appreciable level of selectivity against cancer cells with respect to the nontumor ones.
RESUMO
The possibility of selectively delivering metal complexes to a defined cohort of cells on the basis of their metabolic features is a highly challenging goal, which may be extremely useful for a series of purposes, including diagnosis and therapy of pathological states, such as cancer. Tumor cells display augmented requests for carbohydrates and, in particular, for glucose in order to sustain their high proliferation rate, which causes an increased glycolytic process (Warburg effect). Since several metal complexes display diagnostic and/or therapeutic properties, their conjugation to carbohydrate portions often induce their preferential accumulation in cancer cells, similarly to what is observed with fluorodeoxyglucose (FDG). In this review we have considered the latest developments of glycoconjugates containing metal complexes in their structures. These compounds are classified as diagnostic or therapeutic agents and are further systematically discussed on the basis of the metal atom they contain. Several diagnostic techniques are possible with these probes, since, depending on the metal species included in their structures, they may be employed in nuclear medicine (PET, SPECT), magnetic resonance imaging, luminescence and phosphorescence. At the same time, the lack of selective cytotoxicity displayed by several metal-based chemotherapeutic agents, may also be solved by the conjugation of these agents to carbohydrate portions. Overall, data so far available reveal the great potential of this chemical class in the early detection and in the cure of severe neoplastic diseases, which still needs to be fully explored in the clinic.
Assuntos
Antineoplásicos/química , Carboidratos/química , Complexos de Coordenação/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Humanos , Metais/química , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Tomografia/métodosRESUMO
The development of lanthanide-based luminescent probes with a long emission lifetime has the potential to revolutionize imaging-based diagnostic techniques. By a rational design strategy taking advantage of computational predictions, a novel, water-soluble Eu3+ complex from a cyclen-based ligand bearing 1,3-disubstituted benzo[h]isoquinoline arms was realized. The ligand has been obtained overcoming the lack of reactivity of position 3 of the isoquinoline moiety. Notably, steric hindrance of the heteroaromatic chromophore allowed selective and stoichiometry-controlled insertion of two or three antennas on the cyclen platform without any protection strategy. The complex bears a fourth heptanoic arm for easy conjugation to biomolecules. This new chromophore allowed the sensitization of the metal center either with one or two photons excitation. The suitability as a luminescent bioprobe was validated by imaging BMI1 oncomarker in lung carcinoma cells following an established immunofluorescence approach. The use of a conventional epifluorescence microscope equipped with a linear structured illumination module disclosed a simple and inexpensive way to image confocally Ln-bioprobes by single photon excitation in the 350-400 nm window, where ordinary confocal systems have no excitation sources.
Assuntos
Ciclamos/química , Isoquinolinas/química , Algoritmos , Técnicas de Química Sintética , Ciclamos/síntese química , Európio , Isoquinolinas/síntese química , Ligantes , Luminescência , Medições Luminescentes , Modelos Moleculares , Modelos Teóricos , Estrutura Molecular , Processos FotoquímicosRESUMO
Intracellular pH is a critical parameter involved in cell machinery, and its dysregulation can either cause or signal pathologic states. Currently described fluorescent pH probes are based on single acid-base equilibria, and for this reason are intrinsically unable to capture the wide range of cell pH, usually spanning over more than four units. Here we describe a fluorescent pH biosensor based on a conjugated coumarin-triazine scaffold that is excitable in the visible range, shows pseudo-linear ratiometric response over more than 6 pH units with a single fluorogenic unit, and allows imaging of the whole endo-lysosomal pH landscape of living cells with a single acquisition. The probe can discriminate, on the basis of intracellular acidity, between physiologic and tumor cells, being potentially suitable in perspective as diagnostic tool.
Assuntos
Técnicas Biossensoriais , Cumarínicos/química , Corantes Fluorescentes/química , Triazinas/química , Células Cultivadas , Cumarínicos/síntese química , Corantes Fluorescentes/síntese química , Humanos , Concentração de Íons de Hidrogênio , Imagem Óptica , Espectrometria de Fluorescência , Triazinas/síntese químicaRESUMO
Conjugation of known biologically active molecules to carbohydrate frameworks represents a valuable option for the preparation of hybrid, structurally-related families of compounds with the aim of modulating their biological response. Therefore, we present here a study on the preparation of d-galacto, d-manno, d-gluco, and d-lactose glycoconjugates of an established N-hydroxyindole-based (NHI) inhibitor of lactated dehydrogenase (LDH). Structural variations involved the sugar stereochemistry and size as well as the anchoring point of the NHI on the carbohydrate frame (either C-1 or C-6). In the case of the galactose anomeric glycoconjugate (C-1), intriguing solvent-dependent effects were observed in the glycosylation stereochemical outcome. The biological activity of the deprotected glycoconjugates in contrasting lactate formation and cancer cell proliferation are described.