RESUMEN
Ovarian cancer has the worst case-to-fatality ratio of all gynecologic malignancies. The main reasons for the high mortality rate are relapse and the development of chemoresistance. In this paper, the cytotoxic activity of two new multiaction platinum(IV) derivatives of cisplatin and oxaliplatin in a panel of ovarian cancer cells is reported. Cis,cis,trans-[Pt(NH3)2Cl2(IPA)(DCA)] (1) and trans-[Pt(DACH)(OX)(IPA)(DCA)] (2) (IPA = indole-3-propionic acid, DCA = dichloroacetate, DACH = 1R,2R-1,2-diaminocyclohexane, OX = oxalate) were synthesized and characterized by elemental analysis, ESI-MS, FT-IR, and 1H, 13C, and195Pt NMR spectroscopy. The biological activity was evaluated in A2780, PEA1, PEA2, SKOV3, SW626, and OVCAR3 cells. Both complexes are potent cytotoxins. Remarkably, complex 2 is 14 times more active in OVCAR3 cells than cisplatin and is able to overcome cisplatin resistance in PEA2 and A2780cis cells, which are models of post-treatment patient-developed and laboratory-induced resistance. This complex also shows activity in 3D cancer models of the A2780 cells. Mechanistic studies revealed that the complexes induce apoptosis via DNA damage and ROS generation.
Asunto(s)
Antineoplásicos , Apoptosis , Ensayos de Selección de Medicamentos Antitumorales , Neoplasias Ováricas , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Femenino , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/química , Compuestos Organoplatinos/síntesis química , Especies Reactivas de Oxígeno/metabolismo , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Relación Estructura-Actividad , Relación Dosis-Respuesta a DrogaRESUMEN
Synthetic anticancer catalysts offer potential for low-dose therapy and the targeting of biochemical pathways in novel ways. Chiral organo-osmium complexes, for example, can catalyse the asymmetric transfer hydrogenation of pyruvate, a key substrate for energy generation, in cells. However, small-molecule synthetic catalysts are readily poisoned and there is a need to optimise their activity before this occurs, or to avoid this occurring. We show that the activity of the synthetic organometallic redox catalyst [Os(p-cymene)(TsDPEN)] (1), which can reduce pyruvate to un-natural D-lactate in MCF7 breast cancer cells using formate as a hydride source, is significantly increased in combination with the monocarboxylate transporter (MCT) inhibitor AZD3965. AZD3965, a drug currently in clinical trials, also significantly lowers the intracellular level of glutathione and increases mitochondrial metabolism. These synergistic mechanisms of reductive stress induced by 1, blockade of lactate efflux, and oxidative stress induced by AZD3965 provide a strategy for low-dose combination therapy with novel mechanisms of action.
Asunto(s)
Ácido Láctico , Neoplasias , Ácido Láctico/química , Ácido Láctico/farmacología , Piruvatos/química , Piruvatos/farmacología , CatálisisRESUMEN
Four new bis-substituted ferrocene derivatives containing either a hydroxyalkyl or methoxyalkyl group and either a thyminyl or methylthyminyl group have been synthesised and characterised by a range of spectroscopic and analytical techniques. They were included in a structure-activity-relationship (SAR) study probing anticancer activities in osteosarcoma (bone cancer) cell lines and were compared with a known lead compound, 1-(S,Rp ), a nucleoside analogue that is highly toxic to cancer cells. Biological studies using the MTT assay revealed that a regioisomer of ferronucleoside 1-(S,Rp ), which only differs from the lead compound in being substituted on two cyclopentadienyl rings rather than one, was over 20â times less cytotoxic. On the other hand, methylated derivatives of 1-(S,Rp ) showed comparable cytotoxicities to the lead compound. Overall these studies indicate that a mechanism of action for 1-(S,Rp ) cannot proceed through alcohol phosphorylation and that its geometry and size, rather than any particular functional group, are crucial factors in explaining its high anticancer activity.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Óseas/tratamiento farmacológico , Compuestos Ferrosos/farmacología , Metalocenos/farmacología , Nucleósidos/farmacología , Compuestos Organometálicos/farmacología , Osteosarcoma/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias Óseas/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Ferrosos/química , Humanos , Metalocenos/química , Metilación , Modelos Moleculares , Estructura Molecular , Nucleósidos/química , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Osteosarcoma/patología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
We report the synthesis and characterization of novel pentamethylcyclopentadienyl (Cp*) iridium(III) complexes [(Cp*)Ir(4-methyl-4'-carboxy-2,2'-bipyridine)Cl]PF6 (Ir-I), the product (Ir-II) from amide coupling of Ir-I to dibenzocyclooctyne-amine, and its conjugate (Ir-CP) with the cyclic nona-peptide c(CRWYDENAC). The familiar three-legged 'piano-stool' configuration for complex Ir-I was confirmed by its single crystal X-ray structure. Significantly, copper-free click strategy has been developed for site-specific conjugation of the parent complex Ir-I to the tumour targeting nona-cyclic peptide. The approach consisted of two steps: (i) the carboxylic acid group of the bipyridine ligand in complex Ir-I was first attached to an amine functionalized dibenzocyclooctyne group via amide formation to generate complex Ir-II; and (ii) the alkyne bond of dibenzocyclooctyne in complex Ir-II underwent a subsequent strain-promoted copper-free cycloaddition with the azide group of the modified peptide. Interestingly, while complex Ir-I was inactive towards A2780 human ovarian cancer cells, complex Ir-II exhibited moderate cytotoxic activity. Targeted complexes such as Ir-CP offer scope for enhanced activity and selectivity of this class of anticancer complexes.
RESUMEN
A gene cluster encoding a cryptic trans-acyl transferase polyketide synthase (PKS) was identified in the genomes of Burkholderia gladioli BCC0238 and BCC1622, both isolated from the lungs of cystic fibrosis patients. Bioinfomatics analyses indicated the PKS assembles a novel member of the glutarimide class of antibiotics, hitherto only isolated from Streptomyces species. Screening of a range of growth parameters led to the identification of gladiostatin, the metabolic product of the PKS. NMR spectroscopic analysis revealed that gladiostatin, which has promising activity against several human cancer cell lines and inhibits tumor cell migration, contains an unusual 2-acyl-4-hydroxy-3-methylbutenolide in addition to the glutarimide pharmacophore. An AfsA-like domain at the C-terminus of the PKS was shown to catalyze condensation of 3-ketothioesters with dihydroxyacetone phosphate, thus indicating it plays a key role in polyketide chain release and butenolide formation.
Asunto(s)
Antibacterianos/farmacología , Antineoplásicos/farmacología , Burkholderia gladioli/química , Piperidonas/farmacología , Sintasas Poliquetidas/química , Antibacterianos/química , Antibacterianos/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Burkholderia gladioli/genética , Burkholderia gladioli/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Familia de Multigenes , Piperidonas/química , Piperidonas/metabolismo , Sintasas Poliquetidas/genética , Sintasas Poliquetidas/metabolismoRESUMEN
An organoruthenium(II) complex with pyrithione (2-mercaptopyridine N-oxide) 1 a has previously been identified by our group as a compound with promising anticancer potential without cytotoxicity towards non-cancerous cells. To expand the rather limited research on compounds of this type, an array of novel chlorido and 1,3,5-triaza-7-phosphaadamantane (pta) organoruthenium(II) complexes with methyl-substituted pyrithiones has been prepared. After thorough investigation of the aqueous stability of these complexes, their modes of action have been elucidated at the cellular level. Minor structural alterations in the ruthenium-pyrithionato compounds resulted in fine-tuning of their cytotoxicities. The best performing compounds, 1 b and 2 b, with a chlorido or pta ligand bound to ruthenium, respectively, and a methyl group at the 3-position of the pyrithione scaffold, have been further investigated. Both compounds trigger early apoptosis, induce the generation of reactive oxygen species and G1 arrest in A549 cancer cells, and show no strong interaction with DNA. However, only 1 b also inhibits thioredoxin reductase. Wound healing assays and mitochondrial function evaluation have revealed differences between these two compounds at the cellular level.
Asunto(s)
Antineoplásicos/química , Complejos de Coordinación/química , Piridinas/química , Rutenio/química , Tionas/química , Adamantano/análogos & derivados , Adamantano/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Complejos de Coordinación/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Compuestos Organofosforados/química , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Fourteen novel arene RuII , and cyclopentadienyl (Cpx ) RhIII and IrIII complexes containing an N,N'-chelated pyridylimino- or quinolylimino ligand functionalized with the antimalarial drug sulfadoxine have been synthesized and characterized, including three by X-ray crystallography. The rhodium and iridium complexes exhibited potent antiplasmodial activity with IC50 values of 0.10-2.0â µm in either all, or one of the three Plasmodium falciparum assays (3D7 chloroquine sensitive, Dd2 chloroquine resistant and NF54 sexual late stage gametocytes) but were only moderately active towards Trichomonas vaginalis. They were active in both the asexual blood stage and the sexual late stage gametocyte assays, whereas the clinical parent drug, sulfadoxine, was inactive. Five complexes were moderately active against Mycobacterium tuberculosis (IC50 <6.3â µm), while sulfadoxine showed no antitubercular activity. An increase in the size of both the Cpx ligand and the aromatic imino substituent increased hydrophobicity, which resulted in an increase in antiplasmodial activity.
RESUMEN
Functional drug carrier systems have potential for increasing solubility and potency of drugs while reducing side effects. Complex polymeric materials, particularly anisotropic structures, are especially attractive due to their long circulation times. Here, we have conjugated cyclic peptides to the biocompatible polymer poly(2-hydroxypropyl methacrylamide) (pHPMA). The resulting conjugates were functionalized with organoiridium anticancer complexes. Small angle neutron scattering and static light scattering confirmed their self-assembly and elongated cylindrical shape. Drug-loaded nanotubes exhibited more potent antiproliferative activity toward human cancer cells than either free drug or the drug-loaded polymers, while the nanotubes themselves were nontoxic. Cellular accumulation studies revealed that the increased potency of the conjugate appears to be related to a more efficient mode of action rather than a higher cellular accumulation of iridium.
Asunto(s)
Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Nanotubos/química , Compuestos Organometálicos/administración & dosificación , Péptidos Cíclicos/química , Polímeros/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Humanos , Espectroscopía de Resonancia Magnética , Neutrones , Compuestos Organometálicos/farmacocinética , Dispersión del Ángulo Pequeño , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
A series of dinuclear octahedral PtIV complexes trans, trans, trans-[{Pt(N3)2(py)2(OH)(OC(O)CH2CH2C(O)NH)}2R] containing pyridine (py) and bridging dicarboxylate [R = -CH2CH2- (1), trans-1,2-C6H10- (2), p-C6H4- (3), -CH2CH2CH2CH2- (4)] ligands have been synthesized and characterized, including the X-ray crystal structures of complexes 1·2MeOH and 4, the first photoactivatable dinuclear PtIV complexes with azido ligands. The complexes are highly stable in the dark, but upon photoactivation with blue light (420 nm), they release the bridging ligand and mononuclear photoproducts. Upon irradiation with blue light (465 nm), they generate azidyl and hydroxyl radicals, detected using a 5,5-dimethyl-1-pyrroline N-oxide electron paramagnetic resonance spin trap, accompanied by the disappearance of the ligand-to-metal charge-transfer (N3 â Pt) band at ca. 300 nm. The dinuclear complexes are photocytotoxic to human cancer cells (465 nm, 4.8 mW/cm2, 1 h), including A2780 human ovarian and esophageal OE19 cells with IC50 values of 8.8-78.3 µM, whereas cisplatin is inactive under these conditions. Complexes 1, 3, and 4 are notably more photoactive toward cisplatin-resistant ovarian A2780cis compared to A2780 cells. Remarkably, all of the complexes were relatively nontoxic toward normal cells (MRC5 lung fibroblasts), with IC50 values >100 µM, even after irradiation. The introduction of an aromatic bridging ligand (3) significantly enhanced cellular uptake. The populations in the stages of the cell cycle remained unchanged upon treatment with complexes in the dark, while the population of the G2/M phase increased upon irradiation, suggesting that DNA is a target for these photoactivated dinuclear PtIV complexes. Liquid chromatography-mass spectrometry data show that the photodecomposition pathway of the dinuclear complexes results in the release of two molecules of mononuclear platinum(II) species. As a consequence, DNA binding of the dinuclear complexes after photoactivation in cell-free media is, in several respects, qualitatively similar to that of the photoactivated mononuclear complex FM-190. After photoactivation, they were 2-fold more effective in quenching the fluorescence of EtBr bound to DNA, forming DNA interstrand cross-links and unwinding DNA compared to the photoactivated FM-190.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Organoplatinos/farmacología , Fármacos Fotosensibilizantes/farmacología , Profármacos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/efectos de la radiación , Bovinos , Línea Celular Tumoral , ADN/química , ADN/metabolismo , Humanos , Ligandos , Luz , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Compuestos Organoplatinos/efectos de la radiación , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/efectos de la radiación , Profármacos/síntesis química , Profármacos/química , Profármacos/efectos de la radiación , EstereoisomerismoRESUMEN
The organometallic "half-sandwich" compound [Os(η(6)-p-cymene)(4-(2-pyridylazo)-N,N-dimethylaniline)I]PF6 is 49× more potent than the clinical drug cisplatin in the 809 cancer cell lines that we screened and is a candidate drug for cancer therapy. We investigate the mechanism of action of compound 1 in A2780 epithelial ovarian cancer cells. Whole-transcriptome sequencing identified three missense mutations in the mitochondrial genome of this cell line, coding for ND5, a subunit of complex I (NADH dehydrogenase) in the electron transport chain. ND5 is a proton pump, helping to maintain the coupling gradient in mitochondria. The identified mutations correspond to known protein variants (p.I257V, p.N447S, and p.L517P), not reported previously in epithelial ovarian cancer. Time-series RNA sequencing suggested that osmium-exposed A2780 cells undergo a metabolic shunt from glycolysis to oxidative phosphorylation, where defective machinery, associated with mutations in complex I, could enhance activity. Downstream events, measured by time-series reverse-phase protein microarrays, high-content imaging, and flow cytometry, showed a dramatic increase in mitochondrially produced reactive oxygen species (ROS) and subsequent DNA damage with up-regulation of ATM, p53, and p21 proteins. In contrast to platinum drugs, exposure to this organo-osmium compound does not cause significant apoptosis within a 72-h period, highlighting a different mechanism of action. Superoxide production in ovarian, lung, colon, breast, and prostate cancer cells exposed to three other structurally related organo-Os(II) compounds correlated with their antiproliferative activity. DNA damage caused indirectly, through selective ROS generation, may provide a more targeted approach to cancer therapy and a concept for next-generation metal-based anticancer drugs that combat platinum resistance.
Asunto(s)
Neoplasias Glandulares y Epiteliales/metabolismo , Compuestos Organometálicos/farmacología , Compuestos de Osmio/farmacología , Neoplasias Ováricas/metabolismo , Apoptosis/efectos de los fármacos , Carcinoma Epitelial de Ovario , Línea Celular Tumoral , Cromosomas Humanos/genética , Daño del ADN/genética , ADN Mitocondrial/genética , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Mitocondrias/genética , Mutación/genética , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/patología , Compuestos Organometálicos/química , Compuestos Organometálicos/uso terapéutico , Compuestos de Osmio/química , Compuestos de Osmio/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Análisis de Secuencia de ARN , Factor de Transcripción AP-1/metabolismoRESUMEN
A photoactivatable dopamine-conjugated platinum(IV) anticancer complex (Pt-DA) has been incorporated into G-quadruplex G4K+ borate hydrogels by using borate ester linkages (Pt-G4K+B hydrogel). These were characterized by 11B NMR, attenuated total reflection Fourier transform infrared spectroscopy, circular dichroism, scanning electron microscopy and transmission electron microscopy. Microscopy investigations revealed the transformation of an extended fiber assembly into discrete flakes after incorporation of Pt-DA. Pt-DA showed photocytotoxicity against cisplatin-resistant A2780Cis human ovarian cancer cells (IC50 74 µM, blue light) with a photocytotoxic index <2, whereas Pt-G4K+B hydrogels exhibited more potent photocytotoxicity (IC50 3 µM, blue light) with a photocytotoxic index >5. Most notably, Pt-DA and Pt-G4K+B hydrogels show selective phototoxicity for cancer cells versus normal fibroblast cells (MRC5).
Asunto(s)
Antineoplásicos/farmacología , Boratos/farmacología , Cisplatino/farmacología , Hidrogeles/farmacología , Compuestos Organoplatinos/farmacología , Antineoplásicos/química , Boratos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cisplatino/química , Dopamina/química , Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Fibroblastos/efectos de los fármacos , Humanos , Hidrogeles/química , Sustancias Macromoleculares/química , Sustancias Macromoleculares/farmacología , Estructura Molecular , Compuestos Organoplatinos/química , Tamaño de la Partícula , Procesos Fotoquímicos , Relación Estructura-Actividad , Propiedades de SuperficieRESUMEN
An antimicrobial activity screen of Burkholderia gladioli BCC0238, a clinical isolate from a cystic fibrosis patient, led to the discovery of gladiolin, a novel macrolide antibiotic with potent activity against Mycobacterium tuberculosis H37Rv. Gladiolin is structurally related to etnangien, a highly unstable antibiotic from Sorangium cellulosum that is also active against Mycobacteria. Like etnangien, gladiolin was found to inhibit RNA polymerase, a validated drug target in M. tuberculosis. However, gladiolin lacks the highly labile hexaene moiety of etnangien and was thus found to possess significantly increased chemical stability. Moreover, gladiolin displayed low mammalian cytotoxicity and good activity against several M. tuberculosis clinical isolates, including four that are resistant to isoniazid and one that is resistant to both isoniazid and rifampicin. Overall, these data suggest that gladiolin may represent a useful starting point for the development of novel drugs to tackle multidrug-resistant tuberculosis. The B. gladioli BCC0238 genome was sequenced using Single Molecule Real Time (SMRT) technology. This resulted in four contiguous sequences: two large circular chromosomes and two smaller putative plasmids. Analysis of the chromosome sequences identified 49 putative specialized metabolite biosynthetic gene clusters. One such gene cluster, located on the smaller of the two chromosomes, encodes a trans-acyltransferase (trans-AT) polyketide synthase (PKS) multienzyme that was hypothesized to assemble gladiolin. Insertional inactivation of a gene in this cluster encoding one of the PKS subunits abrogated gladiolin production, confirming that the gene cluster is responsible for biosynthesis of the antibiotic. Comparison of the PKSs responsible for the assembly of gladiolin and etnangien showed that they possess a remarkably similar architecture, obfuscating the biosynthetic mechanisms responsible for most of the structural differences between the two metabolites.
Asunto(s)
Antibacterianos/farmacología , Burkholderia gladioli/química , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Antibacterianos/biosíntesis , Antibacterianos/química , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , ARN Polimerasas Dirigidas por ADN/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Mycobacterium tuberculosis/metabolismo , Relación Estructura-ActividadRESUMEN
A variety of transition metal complexes exhibit anticancer activity, but their target sites in cells need to be identified and mechanisms of action elucidated. Here, it was found that the sub-cellular distribution of [Os(η6 -p-cym)(Azpy-NMe2 )I]+ (p-cym=p-cymene, Azpy-NMe2 =2-(p-[dimethylamino]phenylazo)pyridine) (1), a promising drug candidate, can be mapped in human ovarian cancer cells at pharmacological concentrations using a synchrotron X-ray fluorescence nanoprobe (SXRFN). SXRFN data for Os, Zn, Ca, and P, as well as TEM and ICP analysis of mitochondrial fractions suggest localization of Os in mitochondria and not in the nucleus, accompanied by mobilization of Ca from the endoplasmic reticulum, a signaling event for cell death. These data are consistent with the ability of 1 to induce rapid bursts of reactive oxygen species and especially superoxide formed in the first step of O2 reduction in mitochondria. Such metabolic targeting differs from the action of Pt drugs, offering promise for combatting Pt resistance, which is a current clinical problem.
Asunto(s)
Antineoplásicos/química , Complejos de Coordinación/química , Colorantes Fluorescentes/química , Nanoestructuras/química , Osmio/química , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Complejos de Coordinación/síntesis química , Complejos de Coordinación/toxicidad , Cimenos , Femenino , Humanos , Microscopía Fluorescente , Mitocondrias/metabolismo , Monoterpenos/química , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Especies Reactivas de Oxígeno/metabolismo , SincrotronesRESUMEN
The family of iodido OsII arene phenylazopyridine complexes [Os(η6 -p-cym)(5-R1 -pyridylazo-4-R2 -phenyl))I]+ (where p-cym=para-cymene) exhibit potent sub-micromolar antiproliferative activity towards human cancer cells and are active in vivo. Their chemical behavior is distinct from that of cisplatin: they do not readily hydrolyze, nor bind to DNA bases. We report here a mechanism by which they are activated in cancer cells, involving release of the I- ligand in the presence of glutathione (GSH). The X-ray crystal structures of two active complexes are reported, 1-I (R1 =OEt, R2 =H) and 2-I (R1 =H, R2 =NMe2 ). They were labelled with the radionuclide 131 I (ß- /γ emitter, t1/2 8.02â d), and their activity in MCF-7 human breast cancer cells was studied. 1-[131 I] and 2-[131 I] exhibit good stability in both phosphate-buffered saline and blood serum. In contrast, once taken up by MCF-7 cells, the iodide ligand is rapidly pumped out. Intriguingly, GSH catalyzes their hydrolysis. The resulting hydroxido complexes can form thiolato and sulfenato adducts with GSH, and react with H2 O2 generating hydroxyl radicals. These findings shed new light on the mechanism of action of these organo-osmium complexes.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Organometálicos/farmacología , Osmio/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Fraccionamiento de la Dosis de Radiación , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Modelos Moleculares , Conformación Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Osmio/química , Relación Estructura-ActividadRESUMEN
Novel half-sandwich hydrosulfidoiridium(III) complexes [(η(5)-Cp*)Ir(phen)(SH)]PF6 (1), [(η(5)-Cp*)Ir(bpy)(SH)]PF6 (2), [(η(5)-Cp(biph))Ir(phen)(SH)]PF6 (3), and [(η(5)-Cp(biph))Ir(bpy)(SH)]PF6 (4) were prepared from the chlorido complexes by dechlorination and treatment with excess NaSH·xH2O; phen = 1,10-phenanthroline, bpy = 2,2'-bipyridine, Cp* = 1,2,3,4,5-pentamethylcyclopentadienyl, and Cp(biph) = 1,2,3,4-tetramethyl-5-biphenylcyclopentadienyl. Complexes 1-4 were characterized by various techniques including electrospray ionization mass spectrometry, NMR spectroscopy (δ(SH) ca. -2 ppm), and a single-crystal X-ray analysis. Complex [(η(5)-Cp*)Ir(phen)(SH)]BPh4 (1') shows a typical piano-stool geometry with Ir-S bond length of 2.388(2) Å. Cp(biph) complexes 3 (IC50 = 0.98 µM) and 4 (IC50 = 0.61 µM) showed significantly higher (p < 0.005) in vitro antiproliferative activity against A2780 human ovarian cancer cells, as compared with their Cp* analogues 1 (IC50 = 49.5 µM) and 2 (IC50 = 48.4 µM), and potency similar to the anticancer drug cisplatin. The complexes were relatively stable in aqueous solution toward hydrolysis and reactions with reduced glutathione (GSH), 9-ethylguanine, or 9-methyladenine. Interestingly, GSH was readily oxidized to glutathione disulfide in the presence of Cp(biph) complexes 3 and 4, as judged by (1)H NMR, perhaps indicative of a possible redox-linked mechanism of action.
Asunto(s)
Antineoplásicos/química , Complejos de Coordinación/química , Sulfuro de Hidrógeno/química , Iridio/química , Compuestos Orgánicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Femenino , HumanosRESUMEN
Platinum complexes are the most widely used anticancer drugs; however, new generations of agents are needed. The organoiridium(III) complex [(η(5) -Cp(xbiph) )Ir(phpy)(Cl)] (1-Cl), which contains π-bonded biphenyltetramethylcyclopentadienyl (Cp(xbiph) ) and C^N-chelated phenylpyridine (phpy) ligands, undergoes rapid hydrolysis of the chlorido ligand. In contrast, the pyridine complex [(η(5) -Cp(xbiph) )Ir(phpy)(py)](+) (1-py) aquates slowly, and is more potent (in nanomolar amounts) than both 1-Cl and cisplatin towards a wide range of cancer cells. The pyridine ligand protects 1-py from rapid reaction with intracellular glutathione. The high potency of 1-py correlates with its ability to increase substantially the level of reactive oxygen species (ROS) in cancer cells. The unprecedented ability of these iridium complexes to generate H2 O2 by catalytic hydride transfer from the coenzyme NADH to oxygen is demonstrated. Such organoiridium complexes are promising as a new generation of anticancer drugs for effective oxidant therapy.
Asunto(s)
Antineoplásicos/química , Cisplatino/química , Iridio/química , Compuestos Organometálicos/química , Catálisis , Humanos , Modelos Moleculares , Especies Reactivas de Oxígeno , Relación Estructura-ActividadRESUMEN
Platinum complexes are widely used anticancer drugs. New generations of metal chemotherapeutics offer the prospect of combating platinum resistance and expanding the range of treatable cancers. Such new complexes might be effective if they form distinctly different lesions on DNA. In this Forum Article, we discuss the possibility that targeting the redox balance in cancer cells may also be a highly effective strategy, especially because it is a multiple-site approach and offers selectivity over normal cells. Metal complexes can interfere in cellular redox chemistry in several ways: directly through metal or ligand redox centers or indirectly by binding to biomolecules involved in cellular redox pathways. We illustrate that a surprisingly large number of active metal anticancer agents have a potential redox arm to their mechanism of action. For such complexes, the possibility arises of using combination therapy together with redox modulators to increase the anticancer potency: attractive for lowering the doses of metal complexes that need to be administered. We illustrate that organometallic ruthenium(II) and osmium(II) arene complexes and iridium(III) cyclopentadienyl complexes of the type [(arene/Cp(xPh))M(N,N)Cl/I](n+) can achieve nanomolar potency toward cancer cells in combination with the redox modulator l-buthionine sulfoximine. Our discussion highlights the importance of determining not only the distribution of metal anticancer complexes in cells but also their speciation, the chemical form of the metal complex, including the oxidation state of the metal, the fate of the ligands, and dynamic processes such as efflux. This will be aided in the future by proteomic and genomic analyses but needs to be supplemented by new analytical methods that have the sensitivity and spatial and temporal resolution to reveal such information. To achieve this, major new funding programs are needed that support global research on the design of novel metal-based drugs with new mechanisms of action, tailored to patient needs.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales/métodos , Humanos , Iridio/química , Compuestos Organometálicos/síntesis química , Osmio/química , Oxidación-Reducción , Rutenio/químicaRESUMEN
We have synthesized a series of novel substituted sulfonyl ethylenediamine (en) RuII arene complexes 1-8 of [(η6-arene)Ru(R1-SO2-EnBz)X], where the arene is benzene, HO(CH2)2O-phenyl or biphenyl (biph), X = Cl or I, and R1 is phenyl, 4-Me-phenyl, 4-NO2-phenyl or dansyl. The 'piano-stool' structure of complex 3, [(η6-biph)Ru(4-Me-phenyl-SO2-EnBz)I], was confirmed by X-ray crystallography. The values of their aqua adducts were determined to be high (9.1 to 9.7). Complexes 1-8 have antiproliferative activity against human A2780 ovarian, and A549 lung cancer cells with IC50 values ranging from 4.1 to >50 µM, although, remarkably, complex 7 [(η6-biph)Ru(phenyl-SO2-EnBz)Cl] was inactive towards A2780 cells, but as potent as the clinical drug cisplatin towards A549 cells. All these complexes also showed catalytic activity in transfer hydrogenation (TH) of NAD+ to NADH with sodium formate as hydride donor, with TOFs in the range of 2.5-9.7 h-1. The complexes reacted rapidly with the thiols glutathione (GSH) and N-acetyl-L-cysteine (NAC), forming dinuclear bridged complexes [(η6-biph)2Ru2(GS)3]2- or [(η6-biph)2Ru2(NAC-H)3]2-, with the liberation of the diamine ligand which was detected by LC-MS. In addition, the switching on of fluorescence for complex 8 in aqueous solution confirmed release of the chelated DsEnBz ligand in reactions with these thiols. Reactions with GSH hampered the catalytic TH of NAD+ to NADH due to the decomposition of the complexes. Co-administration to cells of complex 2 [(η6-biph)Ru(4-Me-phenyl-SO2-EnBz)Cl] with L-buthionine sulfoximine (L-BSO), an inhibitor of GSH synthesis, partially restored the anticancer activity towards A2780 ovarian cancer cells. Complex 2 caused a concentration-dependent G1 phase cell cycle arrest, and induced a significant level of reactive oxygen species (ROS) in A2780 human ovarian cancer cells. The amount of induced ROS decreased with increase in GSH concentration, perhaps due to the formation of the dinuclear Ru-SG complex.
Asunto(s)
Antineoplásicos/farmacología , Cisteína/química , Compuestos Organometálicos/farmacología , Compuestos de Sulfhidrilo/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Catálisis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Etilenodiaminas/química , Etilenodiaminas/farmacología , Humanos , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Rutenio/química , Rutenio/farmacologíaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a disease that remains refractory to existing treatments including the nucleoside analogue gemcitabine. In the current study we demonstrate that an organometallic nucleoside analogue, the ferronucleoside 1-(S,Rp), is cytotoxic in a panel of PDAC cell lines including gemcitabine-resistant MIAPaCa2, with IC50 values comparable to cisplatin. Biochemical studies show that the mechanism of action is inhibition of DNA replication, S-phase cell cycle arrest and stalling of DNA-replication forks, which were directly observed at single molecule resolution by DNA-fibre fluorography. In agreement with this, transcriptional changes following treatment with 1-(S,Rp) include activation of three of the four genes (HUS1, RAD1, RAD17) of the 9-1-1 check point complex clamp and two of the three genes (MRE11, NBN) that form the MRN complex as well as activation of multiple downstream targets. Furthermore, there was evidence of phosphorylation of checkpoint kinases 1 and 2 as well as RPA1 and gamma H2AX, all of which are considered biochemical markers of replication stress. Studies in p53-deficient cell lines showed activation of CDKN1A (p21) and GADD45A by 1-(S,Rp) was at least partially independent of p53. In conclusion, because of its potency and activity in gemcitabine-resistant cells, 1-(S,Rp) is a promising candidate molecule for development of new treatments for PDAC.