RESUMEN
In the search of new cymantrenyl- and ferrocenyl-sulfonamides as potencial inhibitors of human carbonic anhydrases (hCAs), four compounds based on N-ethyl or N-methyl benzenesulfonamide units have been obtained. These cymantrenyl (1a-b) and ferrocenyl (2a-b) derivatives were prepared by the reaction between aminobenzene sulfonamides ([NH2-(CH2)n-(C6H4)-SO2-NH2)], where n = 1, 2) with cymantrenyl sulfonyl chloride (P1) or ferrocenyl sulfonyl chloride (P2), respectively. All compounds were characterized by conventional spectroscopic techniques and cyclic voltammetry. In the solid state, the molecular structures of compounds 1a, 1b, and 2b were determined by single-crystal X-ray diffraction. Biological evaluation as carbonic anhydrases inhibitors were carried out and showed derivatives 1b y 2b present a higher inhibition than the drug control for the Human Carbonic Anhydrase (hCA) II and IX isoforms (KI = 7.3 nM and 5.8 nM, respectively) and behave as selective inhibition for hCA II isoform. Finally, the docking studies confirmed they share the same binding site and interactions as the known inhibitors acetazolamide (AAZ) and agree with biological studies.
Asunto(s)
Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Simulación del Acoplamiento Molecular , Sulfonamidas , Humanos , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Anhidrasas Carbónicas/metabolismo , Anhidrasas Carbónicas/química , Anhidrasa Carbónica II/antagonistas & inhibidores , Anhidrasa Carbónica II/metabolismo , Anhidrasa Carbónica II/química , Anhidrasa Carbónica IX/antagonistas & inhibidores , Anhidrasa Carbónica IX/metabolismo , Antígenos de Neoplasias/metabolismo , Antígenos de Neoplasias/química , Anhidrasa Carbónica I/antagonistas & inhibidores , Anhidrasa Carbónica I/metabolismo , Bencenosulfonamidas , Compuestos Organometálicos/química , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacología , Cristalografía por Rayos XRESUMEN
Antimicrobial resistance (AMR) has been emerging as a major global health threat and calls for the development of novel drug candidates. Metal complexes have been demonstrating high efficiency as antibacterial agents that differ substantially from the established types of antibiotics in their chemical structures and their mechanism of action. One strategy to exploit this potential is the design of metal-based hybrid organometallics that consist of an established antibiotic and a metal-based warhead that contributes an additional mechanism of action different from that of the parent antibiotic. In this communication, we describe the organometallic hybrid antibiotic 2c, in which the drug metronidazole is connected to a gold(I) N-heterocyclic carbene warhead that inhibits bacterial thioredoxin reductase (TrxR). Metronidazole can be used for the treatment with the obligatory anaerobic pathogen Clostridioides difficile (C. difficile), however, resistance to the drug hampers its clinical success. The gold organometallic conjugate 2c was an efficient inhibitor of TrxR and it was inactive or showed only minor effects against eucaryotic cells and bacteria grown under aerobic conditions. In contrast, a strong antibacterial effect was observed against both metronidazole-sensitive and -resistant strains of C. difficile. This report presents a proof-of-concept that the design of metal-based hybrid antibiotics can be a viable approach to efficiently tackle AMR.
Asunto(s)
Antibacterianos , Clostridioides difficile , Farmacorresistencia Bacteriana , Oro , Metano , Metronidazol , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Clostridioides difficile/efectos de los fármacos , Metronidazol/farmacología , Metronidazol/química , Metano/análogos & derivados , Metano/química , Metano/farmacología , Oro/química , Farmacorresistencia Bacteriana/efectos de los fármacos , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Compuestos Organometálicos/farmacología , Compuestos Organometálicos/química , Compuestos Organometálicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Estructura Molecular , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis químicaRESUMEN
The antibacterial activity of silver species is well-established; however, their mechanism of action has not been adequately explored. Furthermore, issues of low-molecular silver compounds with cytotoxicity, stability, and solubility hamper their progress to drug leads. We have investigated silver N-heterocyclic carbene (NHC) halido complexes [(NHC)AgX, X = Cl, Br, and I] as a promising new type of antibacterial silver organometallics. Spectroscopic studies and conductometry established a higher stability for the complexes with iodide ligands, and nephelometry indicated that the complexes could be administered in solutions with physiological chloride levels. The complexes showed a broad spectrum of strong activity against pathogenic Gram-negative bacteria. However, there was no significant activity against Gram-positive strains. Further studies clarified that tryptone and yeast extract, as components of the culture media, were responsible for this lack of activity. The reduction of biofilm formation and a strong inhibition of both glutathione and thioredoxin reductases with IC50 values in the nanomolar range were confirmed for selected compounds. In addition to their improved physicochemical properties, the compounds with iodide ligands did not display cytotoxic effects, unlike the other silver complexes. In summary, silver NHC complexes with iodide secondary ligands represent a useful scaffold for nontoxic silver organometallics with improved physicochemical properties and a distinct mechanism of action that is based on inhibition of thioredoxin and glutathione reductases.
Asunto(s)
Antibacterianos , Glutatión Reductasa , Bacterias Gramnegativas , Plata , Reductasa de Tiorredoxina-Disulfuro , Humanos , Antibacterianos/química , Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glutatión Reductasa/antagonistas & inhibidores , Glutatión Reductasa/metabolismo , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Plata/química , Plata/farmacología , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidoresRESUMEN
Toxicology based on a deductive approach is called "deductive toxicology," which attempts to explain clinical and pathological findings by collecting all scientific information about the chemical substance under study and relating them to the essence of toxicity. We have introduced the method of signal toxicology into the deductive toxicology of metal and have shown that signal toxicity exists in heavy metals. Based on the results, we have proposed a new research strategy called "bioorganometallics," in which organic-inorganic hybrid molecules are used as molecular probes to analyze biological systems. This review outlines our research that has evolved from "deductive toxicology" to "bioorganometallics."
Asunto(s)
Metales Pesados , Toxicología , Toxicología/métodosRESUMEN
A series of new ferrocenyl nitroheterocyclic sulfonylhydrazones (1a-4a and 1b-2b) were prepared by the reaction between formyl (R = H) or acetyl (R = CH3) nitroheterocyclic precursors [4/5-NO2(C5H2XCOR), where X = O, S)] and ferrocenyl tosyl hydrazine [(η5-C5H5)Fe(η5-C5H4SO2-NH-NH2)]. All compounds were characterized by conventional spectroscopic techniques. In the solid state, the molecular structures of compounds 1a, 2b, and 3a were determined by single-crystal X-ray diffraction. The compounds showed an E-configuration around the C=N moiety. Evaluation of trypanocidal activity, measured in vitro against the Trypanosoma cruzi and Trypanosoma brucei strains, indicated that all organometallic tosyl hydrazones displayed activity against both parasite species with a higher level of potency toward T. brucei than T. cruzi. Moreover, the biological evaluation showed that the 5-nitroheterocyclic derivatives were more efficient trypanocidal agents than their 4-nitroheterocyclic counterparts.
Asunto(s)
Enfermedad de Chagas , Tripanocidas , Trypanosoma cruzi , Humanos , Metalocenos , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitologíaRESUMEN
The 3-chymotrypsin-like protease 3CLpro from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a potential target for antiviral drug development. In this work, three organometallic ferrocene-modified quinolinones and coumarins were compared to their benzoic acid ester analogues with regard to inhibition of 3CLpro using an HPLC-based assay with a 15mer model peptide as the substrate. In contrast to FRET-based assays, this allows direct identification of interference of buffer constituents with the inhibitors, as demonstrated by the complete abolishment of ebselen inhibitory activity in the presence of dithiothreitol as a redox protectant. The presence of the organometallic ferrocene moiety significantly increased the stability of the title compounds towards hydrolysis. Among the studied compounds, 4-ferrocenyloxy-1-methyl-quinol-2-one was identified as the most stable and potent inhibitor candidate. IC50 values determined for ebselen and this sandwich complex compound are (0.40 ± 0.07) and (2.32 ± 0.21) µM, respectively.
Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Metalocenos , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , Cisteína Endopeptidasas/química , Cumarinas/farmacología , Simulación del Acoplamiento MolecularRESUMEN
Half-sandwich MII(cym)Cl (cym = η6-p-cymene; M = Ru, Os) complexes of pyridinecarbothioamide (PCA) ligands have demonstrated potential as orally active anticancer agents. In order to investigate the impact of the substitution of the labile chlorido ligand with phosphorous donor ligands on the antiproliferative properties, the triphenylphosphine (PPh3) and 1,3,5-triaza-7-phophaadamantane (pta) analogues were prepared and characterized by spectroscopic techniques and the molecular structures of several complexes were determined by X-diffraction analysis. Interestingly, the molecular structures contained the PCA ligand deprotonated, presumably driven by the reduction in overall charge of the complex. Density Functional Theory (DFT) calculations suggested minor energy differences between the protonated and deprotonated forms. The aqueous stability and the reactivity with the amino acids l-histidine and l-cysteine were investigated by 1H NMR spectroscopy of representative examples. The most potent anticancer agents featured Ru or Os centers and a PPh3 ligand and showed IC50 values in the submicromolar range against four cancer cell lines. This suggests that the antiproliferative activity was mainly dependent on the lipophilic properties of the phosphine ligand with PPh3 having a significantly higher clog P value than pta.
Asunto(s)
Antineoplásicos , Ligandos , Estructura Molecular , Antineoplásicos/químicaRESUMEN
Bis-arene sandwich complexes are generally prepared by the Fischer-Hafner reaction, which conditions are incompatible with most O- and N- functional groups. We report a new way for the synthesis of sandwich type complexes [Re(η6 -arene)2 ]+ and [Re(η6 -arene)(η6 -benzene)]+ from [Re(η6 -napht)2 ]+ and [Re(η6 -napht)(η6 -benzene)]+ , with functionalized arenes and pharmaceuticals. N-methylpyrrolidine (NMP) facilitates the substitution of naphthalene with the incoming arene. A series of fully characterized rhenium sandwich complexes with simple arenes, such as aniline, as well as with active compounds like lidocaine and melatonin are presented. With these rhenium compounds in hand, the radioactive sandwich complexes [99m Tc(η6 -pharm)2 ]+ (pharm=pharmaceutical) can be unambiguously confirmed. The direct labelling of pharmaceuticals with 99m Tc through η6 -coordination to phenyl rings and the confirmation of the structures with the rhenium homologues opens a path into molecular theranostics.
Asunto(s)
Preparaciones Farmacéuticas , Renio , Naftalenos , TecnecioRESUMEN
Multimetallic complexes have been shown in several examples to possess greater anticancer activity than their monometallic counterparts. The increased activity has been attributed to altered modes of action. We herein report the synthesis of a series of heterodimetallic compounds based on a ditopic ligand featuring 2-pyridylimine chelating motifs and organometallic half-sandwich moieties. The complexes were characterized by a combination of 1H NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis and single crystal X-ray diffraction. Investigations into the stability of representative complexes in DMSO-d 6 and 10% DMSO-d 6 /D2O revealed the occurrence of solvent-chlorido ligand exchange. Proliferation assays in four human cancer cell lines showed that the Os-Rh complex possessed minimal activity, while all other complexes were inactive.
RESUMEN
Among organic-inorganic hybrid molecules consisting of organic structure(s) and metal(s), only few studies are available on the cytotoxicity of nucleophilic molecules. In the present study, we investigated the cytotoxicity of a nucleophilic organotellurium compound, diphenyl ditelluride (DPDTe), using a cell culture system. DPDTe exhibited strong cytotoxicity against vascular endothelial cells and fibroblasts along with high intracellular accumulation but showed no cytotoxicity and had less accumulation in vascular smooth muscle cells and renal epithelial cells. The cytotoxicity of DPDTe decreased when intramolecular tellurium atoms were replaced with selenium or sulfur atoms. Electronic state analysis revealed that the electron density between tellurium atoms in DPDTe was much lower than those between selenium atoms of diphenyl diselenide and sulfur atoms of diphenyl disulfide. Moreover, diphenyl telluride did not accumulate and exhibit cytotoxicity. The cytotoxicity of DPDTe was also affected by substitution. p-Dimethoxy-DPDTe showed higher cytotoxicity, but p-dichloro-DPDTe and p-methyl-DPDTe showed lower cytotoxicity than that of DPDTe. The subcellular distribution of the compounds revealed that the compounds with stronger cytotoxicity showed higher accumulation rates in the mitochondria. Our findings suggest that the electronic state of tellurium atoms in DPDTe play an important role in accumulation and distribution of DPDTe in cultured cells. The present study supports the hypothesis that nucleophilic organometallic compounds, as well as electrophilic organometallic compounds, exhibit cytotoxicity by particular mechanisms.
Asunto(s)
Derivados del Benceno/farmacología , Células Endoteliales/efectos de los fármacos , Compuestos Organometálicos/farmacología , Compuestos de Organoselenio/farmacología , Telurio/farmacología , Animales , Derivados del Benceno/química , Derivados del Benceno/metabolismo , Bovinos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Células Endoteliales/citología , Células Endoteliales/metabolismo , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Células LLC-PK1 , Modelos Químicos , Estructura Molecular , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Compuestos Organometálicos/química , Compuestos Organometálicos/metabolismo , Compuestos de Organoselenio/química , Compuestos de Organoselenio/metabolismo , Porcinos , Telurio/químicaRESUMEN
A library of eleven cationic gold(III) complexes of the general formula [(C C)Au(N N)]+ when C C is either biphenyl or 4,4'-ditertbutyldiphenyl and N N is a bipyridine, phenanthroline or dipyridylamine derivative have been synthesized and characterized. Contrasting effects on the viability of the triple negative breast cancer cells MDA-MB-231 was observed from a preliminary screening. The antiproliferative activity of the seven most active complexes were further assayed on a larger panel of human cancer cells as well as on non-cancerous cells for comparison. Two complexes stood out for being either highly active or highly selective. Eventually, reactivity studies with biologically meaningful amino acids, glutathione, higher order DNA structures and thioredoxin reductase (TrxR) revealed a markedly different behavior from that of the well-known coordinatively isomeric [(C N C)Au(NHC)]+ structure. This makes the [(C C)Au(N N)]+ complexes a new class of organogold compounds with an original mode of action.
Asunto(s)
Antineoplásicos , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Oro/farmacología , Humanos , Compuestos Orgánicos de Oro/farmacología , Reductasa de Tiorredoxina-DisulfuroRESUMEN
We report investigations on the anticancer activity of organometallic [MII/III (η6 -p-cymene/η5 -pentamethylcyclopentadienyl)] (M=Ru, Os, Rh, and Ir) complexes of N-heterocyclic carbenes (NHCs) substituted with a triazolyl moiety. Depending on the precursors, the NHC ligands displayed either mono- or bidentate coordination via the NHC carbon atom or as N,C-donors. The metal complexes were investigated for their stability in aqueous solution, with the interpretation supported by density functional theory calculations, and reactivity to biomolecules. In vitro cytotoxicity studies suggested that the nature of both the metal center and the lipophilicity of the ligand determine the biological properties of this class of compounds. The IrIII complex 5 d bearing a benzimidazole-derived ligand was the most cytotoxic with an IC50 value of 10⠵M against NCI-H460 non-small cell lung carcinoma cells. Cell uptake and distribution studies using X-ray fluorescence microscopy revealed localization of 5 d in the cytoplasm of cancer cells.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Compuestos Heterocíclicos/farmacología , Metano/análogos & derivados , Triazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Teoría Funcional de la Densidad , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Heterocíclicos/química , Humanos , Metano/química , Metano/farmacología , Estructura Molecular , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
RuII(cym)Cl (cym = η6-p-cymene) complexes of pyridinecarbothioamides have shown potential for development as orally active anticancer metallodrugs, underlined by their high selectivity towards plectin as the molecular target. In order to investigate the impact of the metal center on the anticancer activity and their physicochemical properties, the Os(cym), Rh- and Ir(Cp*) (Cp* = pentamethylcyclopentadienyl) analogues of the most promising and orally active compound plecstatin 2 were prepared and characterized by spectroscopic techniques and X-ray diffraction analysis. Dissolution in aqueous medium results in quick ligand exchange reactions; however, over time no further changes in the 1H NMR spectra were observed. The Rh- and Ir(Cp*) complexes were investigated for their reactions with amino acids, and while they reacted with Cys, no reaction with His was observed. Studies on the in vitro anticancer activity identified the Ru derivatives as the most potent, independent of their halido leaving group, while the Rh derivative was more active than the Ir analogue. This demonstrates that the metal center has a significant impact on the anticancer activity of the compound class.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Piridinas/química , Tioamidas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Rutenio/química , Relación Estructura-ActividadRESUMEN
The complex [99m Tc(OH2 )3 (CO)3 ]+ has become a versatile building block in radiopharmaceutical chemistry, applied by many groups worldwide. However, despite widespread efforts, only one compound has made it right the way through clinical trials. Along the way from its discovery to its development into an eventual product, the author experienced issues that he would handle differently in retrospect. In this article, these experiences are turned into "lessons" that might be helpful for young researchers finding themselves in similar situations. Beside issues with patenting and company strategies, the carbonyl story has provided scientific implications beyond its own story, and insights from which any future 99m Tc-based chemistry for radiopharmacy or molecular imaging might benefit.
Asunto(s)
Complejos de Coordinación/química , Radiofármacos/química , Tecnecio/química , Complejos de Coordinación/síntesis química , Desarrollo de Medicamentos , Humanos , Estructura Molecular , Radiofármacos/síntesis química , InvestigadoresRESUMEN
As toxic substances can enter the circulating blood and cross endothelial monolayers to reach parenchymal cells in organs, vascular endothelial cells are an important target compartment for such substances. Reactive sulfur species protect cells against oxidative stress and toxic substances, including heavy metals. Reactive sulfur species are produced by enzymes, such as cystathionine γ-lyase (CSE), cystathionine ß-synthase, 3-mercaptopyruvate sulfurtransferase, and cysteinyl-tRNA synthetase. However, little is known about the regulatory mechanisms underlying the expression of these enzymes in vascular endothelial cells. Bio-organometallics is a research field that analyzes biological systems using organic-inorganic hybrid molecules (organometallic compounds and metal coordinating compounds) as molecular probes. In the present study, we analyzed intracellular signaling pathways that mediate the expression of reactive sulfur species-producing enzymes in cultured bovine aortic endothelial cells, using copper diethyldithiocarbamate (Cu10). Cu10 selectively upregulated CSE gene expression in vascular endothelial cells independent of cell density. This transcriptional induction of endothelial CSE required both the diethyldithiocarbamate scaffold and the coordinated copper ion. Additionally, the present study revealed that ERK1/2, p38 MAPK, and hypoxia-inducible factor (HIF)-1α/HIF-1ß pathways mediate transcriptional induction of endothelial CSE by Cu10. The transcription factors NF-κB, Sp1, and ATF4 were suggested to act in constitutive CSE expression, although the possibility that they are involved in the CSE induction by Cu10 cannot be excluded. The present study used a copper complex as a molecular probe to reveal that the transcription of CSE is regulated by multiple pathways in vascular endothelial cells, including ERK1/2, p38 MAPK, and HIF-1α/HIF-1ß. Bio-organometallics appears to be an effective strategy for analyzing the functions of intracellular signaling pathways in vascular endothelial cells.
Asunto(s)
Cistationina gamma-Liasa/genética , Ditiocarba/farmacología , Animales , Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Translocador Nuclear del Receptor de Aril Hidrocarburo/metabolismo , Bovinos , Células Cultivadas , Cobre/química , Cistationina gamma-Liasa/metabolismo , Ditiocarba/química , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Endotelio Vascular/citología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Azufre/metabolismoRESUMEN
Thiones have been investigated as ligands in metal complexes with catalytic and biological activity. We report the synthesis, characterization, and biological evaluation of a series of MII/III complexes of the general formulae [MII(cym)(L)Cl]X (cym = η6-p-cymene) or [MIII(Cp*)(L)Cl]X (Cp* = η5-pentamethylcyclopentadienyl), where X = Cl- or PF6-, and L represents heterocyclic derivatives of thiourea. The thiones feature a benzyl-triazolyl pendant and they act as bidentate ligands via N,S-coordination to the metal centers. Several derivatives have been investigated by single-crystal X-ray diffraction analysis. NMR investigations showed a counterion-dependent shift of several protons due to the interaction with the counterions. These NMR investigations were complemented with X-ray diffraction analysis data and the effects of different counterions on the secondary coordination sphere were also investigated by DFT calculations. In biological studies, the Ir benzimidazole derivative was found to accumulate in the cytoplasm and it was the most cytotoxic derivative investigated.
Asunto(s)
Antineoplásicos/farmacología , Quelantes/química , Complejos de Coordinación/química , Neoplasias/tratamiento farmacológico , Compuestos Organometálicos/farmacología , Tiourea/química , Antineoplásicos/química , Supervivencia Celular , Humanos , Modelos Moleculares , Estructura Molecular , Neoplasias/patología , Compuestos Organometálicos/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
The combination of more than one bioactive moiety in a multitargeted anticancer agent may result in synergistic activity of its components. Using this concept, bioorganometallic compounds were designed to feature a metal center, a 2-pyridinecarbothioamide (PCA), and a hydroxamic acid, which is found in the anticancer drug vorinostat (SAHA). The organometallics showed inhibitory activity in the nanomolar range against histone deacetylases (HDACs) as the key target for SAHA. In particular, the Rh complex was a potent inhibitor of HDAC6 over HDAC1 and HDAC8. Whereas this complex was highly cytotoxic in human cancer cells, it showed low toxicity in hemolysis studies and zebrafish, demonstrating the role of the metal center. For this complex a slightly reduced expression of vascular endothelial growth factor receptor 2 (VEGFR2) was established, which was upregulated by SAHA. This finding indicates that the new organometallics display different modes of action than their bioactive components.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Compuestos Organometálicos/farmacología , Rodio/farmacología , Vorinostat/farmacología , Línea Celular Tumoral , HumanosRESUMEN
The design and first enantioselective synthesis of a series of chiral ferrocifens and ferrociphenols was realised by enantioselective palladium-catalysed intramolecular direct C-H bond activation followed by McMurry coupling. Biological evaluation revealed moderate anticancer activities on breast cancer cells and evidence of chiral discrimination between enantiomers. Treatment of the novel ferrocifens with Ag2 O revealed that these systems are unable to form a neutral quinone methide, yet still demonstrate marked antiproliferative properties against both the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 cell lines. This bioactivity arises from two mechanisms: Fenton-type chemistry and the anti-estrogenic activity associated with the tamoxifen-like structure.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Compuestos Ferrosos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/patología , Catálisis , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Compuestos Ferrosos/síntesis química , Compuestos Ferrosos/química , Humanos , Estructura Molecular , Paladio/química , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
The conjugation of organometallic groups to current ß-lactam antibiotics is a field of increasing study due to the ability of certain organometallic groups to enhance the antibiotic potency of these drugs. Herein, we report the antibacterial properties of two metallocenyl (ferrocenyl and ruthenocenyl) 7-aminocephalosporanic acid (7-ACA) antibiotic conjugates. Continuing a trend we found in our previous studies, the ruthenocenyl conjugate showed greater antibacterial activity than its ferrocenyl counterpart. Compared with the previously published 7-aminodesacetoxycephalosporanic acid (7-ADCA) conjugates, the 3-acetyloxymethyl group significantly improved the compounds' activity. Furthermore, the Rc-7-ACA compound was more active against clinical Staphylococcus aureus isolates than the ampicillin reference. Noticeably, neither of the two new compounds showed an undesirable toxic effect in HeLa and L929 cells at the concentrations at which they displayed strong antibacterial effects. The antibacterial activity of the two metallocenyl 7-ACA derivatives was further confirmed by scanning electron microscopy (SEM). SEM micrographs showed that bacteria treated with metallocenyl 7-ACA derivatives feature cell wall damage and morphology changes. Using a CTX-M-14 ß-lactamase competition assay based on nitrocefin hydrolysis, we showed that the Rc-7-ACA bound more favorably to CTX-M-14 than its ferrocenyl counterpart, again confirming the superiority of the ruthenocenyl moiety over the ferrocenyl one in interacting with proteins. We also report a 1.47 Å resolution crystal structure of Rc-7-ACA in complex with the CTX-M-14 E166A mutant, an enzyme sharing a similar active site configuration with penicillin-binding proteins, the molecular target of ß-lactam antibiotics. These results strengthen the case for the antibacterial utility of the Rc and Fc groups.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Cefalosporinas/química , Cefalosporinas/farmacología , beta-Lactamasas/química , Antibacterianos/metabolismo , Cefalosporinas/metabolismo , Cristalografía por Rayos X , Células HeLa , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Proteica , beta-Lactamasas/metabolismoRESUMEN
The abundance and evolving pathogenic behavior of bacterial microorganisms give rise to antibiotic tolerance and resistance which pose a danger to global public health. New therapeutic strategies are needed to keep pace with this growing threat. We propose a novel approach for targeting bacteria by harnessing formate, a cell metabolite found only in particular bacterial species, to activate an antibacterial prodrug and selectively inhibit their growth. This strategy is premised on transfer hydrogenation reaction on a biorthogonal substrate utilizing native formate as the hydride source as a means of uncaging an antibacterial prodrug. Using coordination-directed 3-component assembly to prepare a library of 768 unique Ru-Arene Schiff-base complexes, we identified several candidates that efficiently reduced sulfonyl azide functional group in the presence of formate. This strategy paves the way for a new approach of targeted antibacterial therapy by exploiting unique bacterial metabolites.