RESUMEN
Thiopeptides are ribosomally biosynthesized and post-translationally modified peptides (RiPPs) that potently inhibit the growth of Gram-positive bacteria by targeting multiple steps in protein biosynthesis. The poor pharmacological properties of thiopeptides, particularly their low aqueous solubility, has hindered their development into clinically useful antibiotics. Antimicrobial activity screens of a library of Actinomycetota extracts led to discovery of the novel polyglycosylated thiopeptides persiathiacins A and B from Actinokineospora sp. UTMC 2448. Persiathiacin A is active against methicillin-resistant Staphylococcus aureus and several Mycobacterium tuberculosis strains, including drug-resistant and multidrug-resistant clinical isolates, and does not significantly affect the growth of ovarian cancer cells at concentrations up to 400 µM. Polyglycosylated thiopeptides are extremely rare and nothing is known about their biosynthesis. Sequencing and analysis of the Actinokineospora sp. UTMC 2448 genome enabled identification of the putative persiathiacin biosynthetic gene cluster (BGC). A cytochrome P450 encoded by this gene cluster catalyzes the hydroxylation of nosiheptide in vitro and in vivo, consistent with the proposal that the cluster directs persiathiacin biosynthesis. Several genes in the cluster encode homologues of enzymes known to catalyze the assembly and attachment of deoxysugars during the biosynthesis of other classes of glycosylated natural products. One of these encodes a glycosyl transferase that was shown to catalyze attachment of a D-glucose residue to nosiheptide in vitro. The discovery of the persiathiacins and their BGC thus provides the basis for the development of biosynthetic engineering approaches to the creation of novel (poly)glycosylated thiopeptide derivatives with enhanced pharmacological properties.
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
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.
Asunto(s)
Replicación del ADN , Nucleósidos , Neoplasias Pancreáticas , Proteínas de Ciclo Celular/metabolismo , Daño del ADN , Proteínas de Unión al ADN/metabolismo , Humanos , Metalocenos , Nucleósidos/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Fase S , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias PancreáticasRESUMEN
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
We report the synthesis of the organo-osmium anticancer complex [Os(η6-p-cym)(N,N-azpy-NMe2)Br]PF6 (1) containing natural abundance 187Os (1.96%), and isotopically-enriched (98%) [187Os]-1. Complex 1 and [187Os]-1 contain a π-bonded para-cymene (p-cym), a chelated 4-(2-pyridylazo)-N,N-dimethylaniline (azpy-NMe2), and a monodentate bromide as ligands. The X-ray crystal structure of 1 confirmed its half-sandwich 'piano-stool' configuration. Complex 1 is a member of a family of potent anticancer complexes, and exhibits sub-micromolar activity against A2780 human ovarian cancer cells (IC50 = 0.40 µM). Complex [187Os]-1 was analysed by high-resolution ESI-MS, 1D 1H and 13C NMR, and 2D 1H COSY, 13C-1H HMQC, and 1H-187Os HMBC NMR spectroscopy. Couplings of 1H and 13C nuclei from the azpy/p-cym ligands to 187Os were observed with J-couplings (1J to 4J) ranging between 0.6-8.0 Hz. The 187Os chemical shift of [187Os]-1 (-4671.3 ppm, determined by 2D 1H-187Os HMBC NMR) is discussed in relation to the range of values reported for related Os(II) arene and cyclopentadienyl complexes (-2000 to -5200 ppm).
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Osmio/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Osmio/química , Neoplasias Ováricas/tratamiento farmacológicoRESUMEN
Complexes trans,trans,trans-[Pt(N3)2(OH)(OCOR)(py)2] where py = pyridine and where OCOR = succinate (1); 4-oxo-4-propoxybutanoate (2) and N-methylisatoate (3) have been synthesized by derivation of trans,trans,trans-[Pt(OH)2(N3)2(py)2] (4) and characterised by NMR and EPR spectroscopy, ESI-MS and X-ray crystallography. Irradiation of 1-3 with green (517 nm) light initiated photoreduction to Pt(ii) and release of the axial ligands at a 3-fold faster rate than for 4. TD-DFT calculations showed dissociative transitions at longer wavelengths for 1 compared to 4. Complexes 1 and 2 showed greater photocytotoxicity than 4 when irradiated with 420 nm light (A2780 cell line IC50 values: 2.7 and 3.7 µM) and complex 2 was particularly active towards the cisplatin-resistant cell line A2780cis (IC50 3.7 µM). Unlike 4, complexes 1-3 were phototoxic under green light irradiation (517 nm), with minimal toxicity in the dark. A pKa(H2O) of 5.13 for the free carboxylate group was determined for 1, corresponding to an overall negative charge during biological experiments, which crucially, did not appear to impede cellular accumulation and photocytotoxicity.
Asunto(s)
Neoplasias Ováricas , Línea Celular Tumoral , Femenino , Humanos , Compuestos OrganoplatinosRESUMEN
Drug resistance to existing anticancer agents is a growing clinical concern, with many first line treatments showing poor efficacy in treatment plans of some cancers. Resistance to platinum agents, such as cisplatin, is particularly prevalent in the treatment of ovarian cancer, one of the most common cancers amongst women in the developing world. Therefore, there is an urgent need to develop next generation of anticancer agents which can overcome resistance to existing therapies. We report a new series of organoruthenium(II) complexes bearing structurally modified pyrithione ligands with extended aromatic scaffold, which overcome platinum and adriamycin resistance in human ovarian cancer cells. The mechanism of action of such complexes appears to be unique from that of cisplatin, involving G1 cell cycle arrest without generation of cellular ROS, as is typically associated with similar ruthenium complexes. The complexes inhibit the enzyme thioredoxin reductase (TrxR) in a model system and reduce cell motility towards wound healing. Importantly, this work highlights further development in our understanding of the multi-targeting mechanism of action exhibited by transition metal complexes.
RESUMEN
Reaction of dihydroartemisinin (DHA) with 4-methyl-4'-carboxy-2,2'-bipyridine yielded the new ester derivative L1. Six novel organometallic half-sandwich chlorido Rh(III) and Ir(III) complexes (1-6) containing pentamethylcyclopentadienyl, (Cp*), tetramethylphenylcyclopentadienyl (Cpxph), or tetramethylbiphenylcyclopentadienyl (Cpxbiph), and N,N-chelated bipyridyl group of L1, have been synthesized and characterized. The complexes were screened for inhibitory activity against the Plasmodium falciparum 3D7 (sensitive), Dd2 (multi-drug resistant) and NF54 late stage gametocytes (LSGNF54), the parasite strain Trichomonas vaginalis G3, as well as A2780 (human ovarian carcinoma), A549 (human alveolar adenocarcinoma), HCT116 (human colorectal carcinoma), MCF7 (human breast cancer) and PC3 (human prostate cancer) cancer cell lines. They show nanomolar antiplasmodial activity, outperforming chloroquine and artemisinin. Their activities were also comparable to dihydroartemisinin. As anticancer agents, several of the complexes showed high inhibitory effects, with Ir(III) complex 3, containing the tetramethylbiphenylcyclopentadienyl ligand, having similar IC50 values (concentration for 50% of maximum inhibition of cell growth) as the clinical drug cisplatin (1.06-9.23⯵M versus 0.24-7.2⯵M, respectively). Overall, the iridium complexes (1-3) are more potent compared to the rhodium derivatives (4-6), and complex 3 emerges as the most promising candidate for future studies.
Asunto(s)
2,2'-Dipiridil/química , Artemisininas/química , Artemisininas/farmacología , Iridio/química , Compuestos Organometálicos/química , Rodio/química , Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/química , Humanos , Compuestos Organometálicos/farmacología , Plasmodium falciparum/efectos de los fármacos , Trichomonas vaginalis/efectos de los fármacosRESUMEN
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
Twenty-four novel organometallic osmium(II) phenylazopyridine (AZPY) complexes have been synthesised and characterised; [Os(η6-arene)(5-RO-AZPY)X]Y, where arene = p-cym or bip, AZPY is functionalized with an alkoxyl (O-R, R = Me, Et, nPr, iPr, nBu) or glycolic (O-{CH2CH2O}nR*, n = 1-4, R* = H, Me, or Et) substituent on the pyridyl ring para to the azo-bond, X is a monodentate halido ligand (Cl, Br or I), and Y is a counter-anion (PF6-, CF3SO3- or IO3-). X-ray crystal structures of two complexes confirmed their 'half-sandwich' structures. Aqueous solubility depended on X, the AZPY substituents, arene, and Y. Iodido complexes are highly stable in water (X = I â Br > Cl), and exhibit the highest antiproliferative activity against A2780 (ovarian), MCF-7 (breast), SUNE1 (nasopharyngeal), and OE19 (oesophageal) cancer cells, some attaining nanomolar potency and good cancer-cell selectivity. Their activity and distinctive mechanism of action is discussed in relation to hydrophobicity (RP-HPLC capacity factor and Log Po/w), cellular accumulation, electrochemical reduction (activation of azo bond), cell cycle analysis, apoptosis and induction of reactive oxygen species (ROS). Two complexes show ca. 4× higher activity than cisplatin in the National Cancer Institute (NCI) 60-cell line five-dose screen. The COMPARE algorithm of their datasets reveals a strong correlation with one another, as well as anticancer agents olivomycin, phyllanthoside, bouvardin and gamitrinib, but only a weak correlation with cisplatin, indicative of a different mechanism of action.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Azo/farmacología , Complejos de Coordinación/farmacología , Piridinas/farmacología , Antineoplásicos/síntesis química , Compuestos Azo/síntesis química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Éteres/síntesis química , Éteres/farmacología , Humanos , Estructura Molecular , Osmio/química , Piridinas/síntesis química , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-ActividadRESUMEN
Cyclometallated palladium(ii) and platinum(ii) pyrenyl-derived thiosemicarbazone (H2PrR) complexes of the type [M4(µ-S-PrR-κ3-C,N,S)4] (M = PdII, PtII; R = ethyl, cyclohexyl) have been synthesised in good yields and fully characterised. X-ray crystallography showed that the tetranuclear complex [Pt4(µ-S-PrCh-κ3-C,N,S)4](CH3)2COCHCl3 contains an eight-membered ring of alternating M-S atoms. The ethyl derivatives [M4(µ-S-PrEt-κ3-C,N,S)4] exhibit potent antiproliferative activity towards A2780 human ovarian cancer cells, with IC50 values of 1.27 µM (for M = PdII) and 0.37 µM (for M = PtII), the latter being an order of magnitude more potent than the anticancer drug cisplatin (IC50 1.20 µM). These promising complexes had low toxicity towards non-cancerous human MRC5 cells, which points towards an early indication of differential toxicity between cancer and normal cells. Experiments that investigated the effects of these tetranuclear complexes on the cell cycle, integrity of the cell membrane, and induction of apoptosis, suggested that their mechanism of action of does not involve DNA targeting, unlike cisplatin, and therefore could be promising for combatting cisplatin resistance.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Paladio/farmacología , Platino (Metal)/farmacología , Pirenos/farmacología , Tiosemicarbazonas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Estructura Molecular , Paladio/química , Platino (Metal)/química , Pirenos/química , Tiosemicarbazonas/químicaRESUMEN
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
New palladium complexes with thiosemicarbazonate ligands derived from pyrene exhibit potent antiproliferative activity against A2780 and cisplatin-resistant A2780Cis human ovarian cancer cells, which is dependent on substituent groups of the thiosemicarbazone ligands. Cellular accumulation and distribution studies confirmed that palladium enters the cell nucleus. DNA and topoisomerase IB studies show that one complex is a potent TopIB inhibitor, with selectivity for cancer versus normal cells.
Asunto(s)
Antineoplásicos/química , Complejos de Coordinación/química , Paladio/química , Pirenos/química , Tiosemicarbazonas/química , Inhibidores de Topoisomerasa/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Cisplatino/farmacología , Complejos de Coordinación/farmacología , Resistencia a Antineoplásicos , Humanos , Cinética , Inhibidores de Topoisomerasa/farmacologíaRESUMEN
The organo-osmium half-sandwich complex [(η6-p-cymene)Os(Ph-azopyridine-NMe2)I]+ (FY26) exhibits potent antiproliferative activity towards cancer cells and is active in vivo. The complex is relatively inert, but rapidly activated in cells by displacement of coordinated iodide. Here, we study time-dependent accumulation of FY26 in A2780 human ovarian cancer cells at various temperatures in comparison with the chlorido metabolite [(η6-p-cymene)Os(Ph-azopyridine-NMe2)Cl]+ (FY25). Mathematical models described the time evolution of FY26 and FY25 intracellular and extracellular concentrations taking into account both cellular transport (influx and efflux) and the intracellular conversion of FY26 to FY25. Uptake of iodide complex FY26 at 37 °C was 17× faster than that of chloride complex FY25, and efflux 1.4× faster. Osmium accumulation decreased markedly after 24 h of exposure. Modelling revealed that this phenomenon could be explained by complex-induced reduction of osmium uptake, rather than by a model involving enhanced osmium efflux. The intracellular osmium concentration threshold above which reduction in drug uptake was triggered was estimated as 20.8 µM (95% confidence interval [16.5, 30]). These studies provide important new insight into the dynamics of transport of this organometallic anticancer drug candidate.
Asunto(s)
Antineoplásicos/farmacocinética , Complejos de Coordinación/farmacocinética , Osmio/farmacocinética , Neoplasias Ováricas/tratamiento farmacológico , Profármacos/farmacocinética , Línea Celular Tumoral , Femenino , Humanos , Cinética , Compuestos Organometálicos/farmacocinética , Neoplasias Ováricas/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
A conjugate of cancer-cell targeting cyclic disulphide nona-peptide c(CRWYDENAC) consisting of nine l-amino acids with the photoactive succinate platinum(iv) complex trans,trans-[Pt(N3)2(py)2(OH)(succinate)] (Pt-cP) has been synthesised and characterised. The conjugate was stable in dark, but released succinate-peptide and Pt(ii) species upon irradiation with visible light, and formed photoproducts with guanine. Conjugate Pt-cP exhibited higher photocytotoxicity than parent complex trans,trans,trans-[Pt(N3)2(OH)2(py)2] (FM-190) towards cancer cells, including ovarian A2780, lung A549 and prostate PC3 human cancer cells upon irradiation with blue light (465 nm, 17.28 J cm-2) with IC50 values of 2.8-22.4 µM and the highest potency for A549 cells. Even though the dark cellular accumulation of Pt-cP in A2780 cells was lower than that of parent FM-190, Pt from Pt-cP accumulated in cancer cells upon irradiation to a level >3× higher than that from FM-190. In addition, the cellular accumulation of Pt from Pt-cP was enhanced ca. 47× after irradiation.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Luz , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacología , Péptidos Cíclicos/química , Línea Celular Tumoral , Humanos , Concentración 50 InhibidoraRESUMEN
Synchrotron nanoprobe X-ray absorption (XAS) studies of a potent organo-osmium arene anticancer complex in ovarian cancer cells at subcellular resolution allow detection and quantification of both OsII and OsIII species, which are distributed heterogeneously in different areas of the cells.
Asunto(s)
Antineoplásicos/análisis , Nanotecnología , Compuestos Organometálicos/análisis , Osmio/análisis , Neoplasias Ováricas/diagnóstico por imagen , Sincrotrones , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Femenino , Humanos , Compuestos Organometálicos/metabolismo , Compuestos Organometálicos/uso terapéutico , Osmio/metabolismo , Osmio/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Oxidación-Reducción , Espectroscopía de Absorción de Rayos XRESUMEN
BACKGROUND: Chemical imaging of the human brain has great potential for diagnostic and monitoring purposes. The heterogeneity of human brain iron distribution, and alterations to this distribution in Alzheimer's disease, indicate iron as a potential endogenous marker. The influence of iron on certain magnetic resonance imaging (MRI) parameters increases with magnetic field, but is under-explored in human brain tissues above 7 T. NEW METHOD: Magnetic resonance microscopy at 9.4 T is used to calculate parametric images of chemically-unfixed post-mortem tissue from Alzheimer's cases (n = 3) and healthy controls (n = 2). Iron-rich regions including caudate nucleus, putamen, globus pallidus and substantia nigra are analysed prior to imaging of total iron distribution with synchrotron X-ray fluorescence mapping. Iron fluorescence calibration is achieved with adjacent tissue blocks, analysed by inductively coupled plasma mass spectrometry or graphite furnace atomic absorption spectroscopy. RESULTS: Correlated MR images and fluorescence maps indicate linear dependence of R2, R2* and R2' on iron at 9.4 T, for both disease and control, as follows: [R2(s-1) = 0.072[Fe] + 20]; [R2*(s-1) = 0.34[Fe] + 37]; [R2'(s-1) = 0.26[Fe] + 16] for Fe in µg/g tissue (wet weight). COMPARISON WITH EXISTING METHODS: This method permits simultaneous non-destructive imaging of most bioavailable elements. Iron is the focus of the present study as it offers strong scope for clinical evaluation; the approach may be used more widely to evaluate the impact of chemical elements on clinical imaging parameters. CONCLUSION: The results at 9.4 T are in excellent quantitative agreement with predictions from experiments performed at lower magnetic fields.