RESUMO
The biological activity of Pd(II) and Pt(II) complexes toward three different cancer cell lines as well as inhibition of selenoenzyme thioredoxin reductase (TrxR) was modulated in an unexpected way by the introduction of triazolate as a "protective group" to the inner metal coordination sphere using the iClick reaction of [M(N3)(terpy)]PF6 [M = Pd(II) or Pt(II) and terpy = 2,2':6',2â³-terpyridine] with an electron-poor alkyne. In a cell proliferation assay using A549, HT-29, and MDA-MB-231 human cancer cell lines, the palladium compound was significantly more potent than the isostructural platinum analogue and exhibited submicromolar activity on the most responsive cell line. This difference was also reflected in the inhibitory efficiency toward TrxR with IC50 values of 0.1 versus 5.4 µM for the Pd(II) and Pt(II) complexes, respectively. UV/Vis kinetic studies revealed that the Pt compound binds to selenocysteine faster than to cysteine [k = (22.9 ± 0.2)·10-3 vs (7.1 ± 0.2)·10-3 s-1]. Selective triazolato ligand exchange of the title compounds with cysteine (Hcys) and selenocysteine (Hsec)âbut not histidine (His) and 9-ethylguanine (9EtG)âwas confirmed by 1H, 77Se, and 195Pt NMR spectroscopy. Crystal structures of three of the four ligand exchange products were obtained, including [Pt(sec)(terpy)]PF6 as the first metal complex of selenocysteine to be structurally characterized.
RESUMO
AuI -carbene and PtIV -AuI -carbene prodrugs display low to sub-µM activity against several cancer cell lines and overcome cisplatin (cisPt) resistance. Linking a cisPt-derived PtIV (phenylbutyrate) complex to a AuI -phenylimidazolylidene complex 2, yielded the most potent prodrug. While in vivo tests against Lewis Lung Carcinoma showed that the prodrug PtIV (phenylbutyrate)-AuI -carbene (7) and the 1 : 1 : 1 co-administration of cisPt: phenylbutyrate:2 efficiently inhibited tumor growth (≈95 %), much better than 2 (75 %) or cisPt (84 %), 7 exhibited only 5 % body weight loss compared to 14 % for 2, 20 % for cisPt and >30 % for the co-administration. 7 was much more efficient than 2 at inhibiting TrxR activity in the isolated enzyme, in cells and in the tumor, even though it was much less efficient than 2 at binding to selenocysteine peptides modeling the active site of TrxR. Organ distribution and laser-ablation (LA)-ICP-TOFMS imaging suggest that 7 arrives intact at the tumor and is activated there.
Assuntos
Antineoplásicos , Pró-Fármacos , Antineoplásicos/química , Fenilbutiratos , Pró-Fármacos/química , Linhagem Celular Tumoral , Cisplatino/químicaRESUMO
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.
Assuntos
Antineoplásicos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Ouro/farmacologia , Humanos , Compostos Organoáuricos/farmacologia , Tiorredoxina Dissulfeto RedutaseRESUMO
The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has called for an urgent need for dedicated antiviral therapeutics. Metal complexes are commonly underrepresented in compound libraries that are used for screening in drug discovery campaigns, however, there is growing evidence for their role in medicinal chemistry. Based on previous results, we have selected more than 100â structurally diverse metal complexes for profiling as inhibitors of two relevant SARS-CoV-2 replication mechanisms, namely the interaction of the spike (S) protein with the ACE2 receptor and the papain-like protease PLpro . In addition to many well-established types of mononuclear experimental metallodrugs, the pool of compounds tested was extended to approved metal-based therapeutics such as silver sulfadiazine and thiomersal, as well as polyoxometalates (POMs). Among the mononuclear metal complexes, only a small number of active inhibitors of the S/ACE2 interaction was identified, with titanocene dichloride as the only strong inhibitor. However, among the gold and silver containing complexes many turned out to be very potent inhibitors of PLpro activity. Highly promising activity against both targets was noted for many POMs. Selected complexes were evaluated in antiviral SARS-CoV-2 assays confirming activity for gold complexes with N-heterocyclic carbene (NHC) or dithiocarbamato ligands, a silver NHC complex, titanocene dichloride as well as a POM compound. These studies might provide starting points for the design of metal-based SARS-CoV-2 antiviral agents.
Assuntos
Antivirais/farmacologia , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2 , SARS-CoV-2/efeitos dos fármacosRESUMO
The success of nanoparticle-mediated delivery of antioxidant and antiinflammatory-based neuroprotectants to the brain to improve neuronal functions in neurodegenerative diseases has demonstrated lesser impact instead of achieving its full potential. We hypothesized that these failures were due to a combination of parameters, such as: (i) unavailability of a delivery vehicle, which can reproducibly and efficiently transport through the brain capillary endothelium; (ii) inefficient uptake of therapeutic nanoparticles in the neuronal cell population; and (iii) limited ability of a single nanoparticle to cross the two most-impermeable biological barriers, the blood-brain barrier and mitochondrial double membrane, so that a nanoparticle can travel through the brain endothelial barrier to the mitochondria of target cells where oxidative damage is localized. Herein, we demonstrate optimization of a biodegradable nanoparticle for efficient brain accumulation and protection of astrocytes from oxidative damage and mitochondrial dysfunctions to enhance the neuroprotection ability of astrocytes toward neurons using neurodegeneration characteristics in SOD1G93A rats. This biodegradable nanomedicine platform with the ability to accumulate in the brain has the potential to bring beneficial effects in neurodegenerative diseases by modulating the stars, astrocytes in the brain, to enhance their neuroprotective actions.
Assuntos
Barreira Hematoencefálica/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Nanotecnologia/métodos , Animais , Astrócitos/metabolismo , Encéfalo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Nanomedicina , Nanopartículas/metabolismo , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Neuroproteção/fisiologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos TransgênicosRESUMO
We report on the synthesis, structure, and physicochemical characterization of the first three examples of neutral palladium-oxo clusters (POCs). The 16-palladium(II)-oxo cluster [Pd16 O24 (OH)8 ((CH3 )2 As)8 ] (Pd16 ) comprises a cyclic palladium-oxo unit capped by eight dimethylarsinate groups. The chloro-derivative [Pd16 Na2 O26 (OH)3 Cl3 ((CH3 )2 As)8 ] (Pd16 Cl) was also prepared, which forms a highly stable 3D supramolecular lattice via strong intermolecular interactions. The 24-palladium(II)-oxo cluster [Pd24 O44 (OH)8 ((CH3 )2 As)16 ] (Pd24 ) can be considered as a bicapped derivative of Pd16 with a tetra-palladium-oxo unit grafted on either side. The three compounds were fully characterized 1)â in the solid state by single-crystal and powder XRD, IR, TGA, and solid-state 1 H and 13 Câ NMR spectroscopy, 2)â in solution by 1 H, 13 Câ NMR and 1 H DOSY spectroscopic methods, and 3)â in the gas phase by electrospray ionization mass spectrometry (ESI-MS).
RESUMO
Gold complexes have a long tradition in medicine and for many examples antirheumatic, anticancer or anti-infective effects have been confirmed. Herein, we evaluated the lead compound Auranofin and five selected gold organometallics as inhibitors of two relevant drug targets of severe acute respiratory syndrome coronaviruses (SARS-CoV). The gold metallodrugs were effective inhibitors of the interaction of the SARS-CoV-2 spike protein with the angiotensin converting enzyme 2 (ACE2) host receptor and might thus interfere with the viral entry process. The gold metallodrugs were also efficient inhibitors of the papain-like protease (PLpro) of SARS-CoV-1 and SARS-CoV-2, which is a key enzyme in the viral replication. Regarding PLpro from SARS-CoV-2, the here reported inhibitors are among the very first experimentally confirmed examples with activity against this target enzyme. Importantly, the activity of the complexes against both PLpro enzymes correlated with the ability of the inhibitors to remove zinc ions from the labile zinc center of the enzyme. Taken together, the results of this pilot study suggest further evaluation of gold complexes as SARS-CoV antiviral drugs.
Assuntos
Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Auranofina/farmacologia , Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus/antagonistas & inibidores , Ouro/química , Compostos Organometálicos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/farmacologia , Auranofina/química , COVID-19/virologia , Proteases 3C de Coronavírus/metabolismo , Ouro/farmacologia , Humanos , Terapia de Alvo Molecular , Compostos Organometálicos/química , SARS-CoV-2/enzimologia , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
The anticancer drug candidates 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative exhibited nanomolar in-vitro activity against prostate cancer cells advanced prostate cancer (PC3) and micromolar inhibition of mammalian thioredoxin reductase. Encouraging maximum tolerable dose experiments led to human prostate cancer subcutaneous xenograft experiments; 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative were applied twelve times at two doses in groups of n = 5 PC3 to tumor-bearing NMRI:nu/nu mice. 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative at the dose of 10 and 20 mg/kg showed good tolerability, while no significant body weight loss was seen in both groups. In particular, for the drug 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate the tumor growth inhibition suggested to be dose dependent, reflected by the respective optimal T/C values of 0.45 at the dose of 10 mg/kg and of 0.31 at the dose of 20 mg/kg. By contrast, the 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative treated groups showed no indication for dose-dependent antitumoral activity, as reflected by the optimal T/C values of 0.44 for the 10 mg/kg and for the 20 mg/kg treated mice. Immunohistochemical experiments involving Ki67 staining of tumor tissue showed that both compounds reduced PC3 cell proliferation against the difficult to treat advanced human prostate tumors derived from PC3.
Assuntos
Ouro/farmacologia , Compostos Organometálicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Tiocarbamatos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Transportador de Glucose Tipo 1/química , Transportador de Glucose Tipo 1/metabolismo , Ouro/química , Humanos , Masculino , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Distribuição Aleatória , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Tiocarbamatos/síntese química , Tiocarbamatos/química , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The use of photodynamic therapy (PDT) to treat cancer has received increasing attention over the last years. However, the clinically used photosensitisers (PSs) have some limitations that include poor aqueous solubility, hepatotoxicity, photobleaching, aggregation, and slow clearance from the body, so the design of new classes of PSs is of great interest. We present the use of bis(dipyrrinato)zinc(II) complexes with exceptionally long lifetimes as efficient PDT PSs. Based on the heavy-atom effect, intersystem crossing of these complexes changes the excited state from singlet to a triplet state, thereby enabling singlet oxygen generation. To overcome the limitation of quenching effects in water and improve water solubility, the lead compound 3 was encapsulated in a polymer matrix. It showed impressive phototoxicity upon irradiation at 500â nm in various monolayer cancer cells as well as 3D multicellular tumour spheroids, without observed dark toxicity.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Estrutura Molecular , Imagem Óptica , Tamanho da Partícula , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Polímeros/química , Polímeros/farmacologia , Pirróis/química , Pirróis/farmacologia , Células Tumorais Cultivadas , Zinco/química , Zinco/farmacologiaRESUMO
Cisplatin is a major chemotherapeutic that continues to have a significant impact in the treatment of more than 50% of all cancers. Since its Food and Drug Administration approval in 1978 for the treatment of advanced ovarian and bladder cancer, this chemotherapeutic has made significant strides and its application has been extended to a large variety of other cancers. However, the vast majority of patients who receive cisplatin therapy often suffer from nephrotoxicity, neurotoxicity, nausea, and ototoxicity. Numerous methods currently exist for overcoming nephrotoxicity- and nausea-related side effects, but there is no clear prevention to fight ototoxicity and neurotoxicity. In this work, we examined Platin- A, a prodrug of cisplatin and aspirin, using preclinical mouse- and guinea pig-based models and demonstrated its efficacy with reduced ototoxicity. In addition, in vitro studies documented that when Platin- A is used in combination with a clinically relevant dose of radiation, its efficacy can further be improved by attacking cellular bioenergetic profiles, producing multiple modes of DNA damage, and delaying repair of damaged DNA. These studies demonstrated novel properties of the prodrug, Platin- A, highlighting its superior efficacy with reduced toxicity.
Assuntos
Cisplatino/farmacologia , Otopatias/prevenção & controle , Doenças do Sistema Nervoso/prevenção & controle , Neoplasias Ovarianas/tratamento farmacológico , Pró-Fármacos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Apoptose , Aspirina/farmacologia , Proliferação de Células , Feminino , Cobaias , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Iron(III) complexes of pyridoxal (vitamin B6, VB6) or salicylaldehyde Schiff bases and modified dipicolylamines, namely, [Fe(B)(L)](NO3) (1-5), where B is phenyl-N,N-bis((pyridin-2-yl)methyl)methanamine (phbpa in 1), (anthracen-9-yl)-N,N-bis((pyridin-2-yl)methyl)methanamine (anbpa in 2, 4) and (pyren-1-yl)-N,N-bis((pyridin-2-yl)methyl)methanamine (pybpa in 3, 5) (H2L(1) is 3-hydroxy-5-(hydroxymethyl)-4-(((2-hydroxyphenyl)imino)methyl)-2-methylpyridine (1-3) and H2L(2) is 2-[(2-hydroxyphenyl-imino)methyl]phenol), were prepared and their uptake in cancer cells and photocytotoxicity were studied. Complexes 4 and 5, having a non-pyridoxal Schiff base, were prepared to probe the role of the pyridoxal group in tumor targeting and cellular uptake. The PF6 salt (1a) of complex 1 is structurally characterized. The complexes have a distorted six-coordinate FeN4O2 core where the metal is in the +3 oxidation state with five unpaired electrons. The complexes display a ligand to metal charge transfer band near 520 and 420 nm from phenolate to the iron(III) center. The photophysical properties of the complexes are explained from the time dependent density functional theory calculations. The redox active complexes show a quasi-reversible Fe(III)/Fe(II) response near -0.3 V vs saturated calomel electrode. Complexes 2 and 3 exhibit remarkable photocytotoxicity in various cancer cells with IC50 values ranging from 0.4 to 5 µM with 10-fold lower dark toxicity. The cell death proceeded by the apoptotic pathway due to generation of reactive oxygen species upon light exposure. The nonvitamin complexes 4 and 5 display 3-fold lower photocytotoxicity compared to their VB6 analogues, possibly due to preferential and faster uptake of the vitamin complexes in the cancer cells. Complexes 2 and 3 show significant uptake in the endoplasmic reticulum, while complexes 4 and 5 are distributed throughout the cells without any specific localization pattern.
Assuntos
Compostos Férricos/metabolismo , Compostos Férricos/farmacologia , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Piridoxal/metabolismo , Bases de Schiff/metabolismo , Bases de Schiff/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Compostos Férricos/síntese química , Compostos Férricos/química , Células HeLa , Humanos , Luz , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Piridoxal/síntese química , Piridoxal/química , Piridoxal/farmacologia , Teoria Quântica , Espécies Reativas de Oxigênio/metabolismo , Bases de Schiff/síntese química , Bases de Schiff/química , Relação Estrutura-AtividadeRESUMO
Glucose-appended photocytotoxic iron(III) complexes of a tridentate Schiff base phenolate ligand [Fe(bpyag)(L)](NO3) (1-3), where bpyag is N,N-bis(2-pyridylmethyl)-2-aminoethyl-ß-D-glucopyranoside and H2L is 3-(2-hydroxyphenylimino)-1-phenylbutan-1-one (H2phap) in 1, 3-(2-hydroxyphenylimino)-9-anthrylbutan-1-one (H2anap) in 2, and 3-(2-hydroxyphenylimino)-1-pyrenylbutan-1-one (H2pyap) in 3, were synthesized and characterized. The complex [Fe(dpma)(anap)](NO3) (4), having bis-(2-pyridylmethyl)benzylamine (dpma), in which the glucose moiety of bpyag is substituted by a phenyl group, was used as a control, and the complex [Fe(dpma)(anap)](PF6) (4a) was structurally characterized by X-ray crystallography. The structure shows a FeN4O2 core in a distorted octahedral geometry. The high-spin iron(III) complexes with magnetic moment value of â¼5.9 µB showed a low-energy phenolate-to-Fe(III) charge-transfer (CT) absorption band as a shoulder near 500 nm with a tail extending to 700 nm and an irreversible Fe(III)-Fe(II) redox couple near -0.6 V versus saturated calomel electrode. The complexes are avid binders to calf thymus DNA and showed photocleavage of supercoiled pUC19 DNA in red (647 nm) and green (532 nm) light. Complexes 2 and 3 displayed significant photocytotoxicity in red light, with an IC50 value of â¼20 µM in HeLa and HaCaT cells, and no significant toxicity in dark. The cell death is via an apoptotic pathway, by generation of reactive oxygen species. Preferential internalization of the carbohydrate-appended complexes 2 and 3 was evidenced in HeLa cells as compared to the control complex 4. A 5-fold increase in the cellular uptake was observed for the active complexes in HeLa cells. The photophysical properties of the complexes are rationalized from the density functional theory calculations.
Assuntos
Carboidratos/química , Complexos de Coordenação/síntese química , Sistemas de Liberação de Medicamentos , Ferro/química , Luz , Teoria Quântica , Carboidratos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , DNA/química , DNA/metabolismo , Eletroforese em Gel de Ágar , Células HeLa , Humanos , Concentração Inibidora 50 , Microscopia ConfocalRESUMO
Tumor cells adapt to diverse survival strategies defying our pursuit of multimodal cancer therapy. Prostate cancer (PCa) is an example that is resistant to one of the most potent chemotherapeutics, cisplatin. PCa cells survive and proliferate using fatty acid oxidation (FAO), and the dependence on fat utilization increases as the disease progresses toward a resistant form. Using a pool of patient biopsies, we validated the expression of a key enzyme carnitine palmitoyltransferase 1 A (CPT1A) needed for fat metabolism. We then discovered that a cisplatin prodrug, Platin-L, can inhibit the FAO of PCa cells by interacting with CPT1A. Synthesizing additional cisplatin-based prodrugs, we documented that the presence of an available carboxylic acid group near the long chain fatty acid linker on the Pt(IV) center is crucial for CPT1A binding. As a result of fat metabolism disruption by Platin-L, PCa cells transition to an adaptive glucose-dependent chemosensitive state. Potential clinical translation of Platin-L will require a delivery vehicle to direct it to the prostate tumor microenvironment. Thus, we incorporated Platin-L in a biodegradable prostate tumor-targeted orally administrable nanoformulation and demonstrated its safety and efficacy. The distinctive FAO inhibitory property of Platin-L can be of potential clinical relevance as it offers the use of cisplatin for otherwise resistant cancer.
RESUMO
[This corrects the article DOI: 10.1021/acscentsci.3c00286.].
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A red light for cancer cells: an iron(III) complex (1, see picture) that contains an anthracenyl fluorophore moiety and a catecholate ligand is a potent, metal-based PDT agent that efficiently photocleaves DNA in near-infrared light, has significant nuclear uptake, and high photocytotoxicity in red light by an apoptotic pathway in HeLa and MCF-7 cancer cells.
Assuntos
Compostos Férricos/química , Raios Infravermelhos , Fármacos Fotossensibilizantes/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , DNA/metabolismo , Clivagem do DNA , Células HeLa , Humanos , Microscopia Confocal , Conformação Molecular , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
"Multi-action" Pt(IV) derivatives of cisplatin with combretastatin A4 (CA4) bioactive ligands that are conjugated to Pt(IV) by carbonate are unique because the ligand (IC50 < 10 nM) is dramatically 1000-folds more cytotoxic than cisplatin in vitro. The Pt(IV)-CA4 prodrugs were as cytotoxic as CA4 itself, indicating that the platinum moiety probably plays an insignificant role in triggering cytotoxicity, suggesting that the Pt(IV)-CA4 complexes act as prodrugs for CA4 rather than as true multi-action prodrugs. In vivo tests (Lewis lung carcinoma) show that ctc-[Pt(NH3)2(PhB)(CA4)Cl2] inhibited tumor growth by 93% compared to CA4 (67%), cisplatin (84%), and 1:1:1 cisplatin/CA4/PhB (85%) while displaying <5% body weight loss compared to cisplatin (20%) or CA4 (10%). In this case, and perhaps with other extremely potent bioactive ligands, platinum(IV) acts merely as a self-immolative carrier triggered by reduction in the cancer cell with only a minor contribution to cytotoxicity.
Assuntos
Antineoplásicos/farmacologia , Anidrase Carbônica IV/metabolismo , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Anidrase Carbônica IV/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cricetulus , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Proibitinas , Relação Estrutura-AtividadeRESUMO
In this work, a pair of gold(III) complexes derived from the analogous tetrapyridyl ligands H2biqbpy1 and H2biqbpy2 was prepared: the rollover, bis-cyclometalated [Au(biqbpy1)Cl ([1]Cl) and its isomer [Au(biqbpy2)Cl ([2]Cl). In [1]+, two pyridyl rings coordinate to the metal via a Au-C bond (Câ§Nâ§Nâ§C coordination) and the two noncoordinated amine bridges of the ligand remain protonated, while in [2]+ all four pyridyl rings of the ligand coordinate to the metal via a Au-N bond (Nâ§Nâ§Nâ§N coordination), but both amine bridges are deprotonated. As a result, both complexes are monocationic, which allowed comparison of the sole effect of cyclometalation on the chemistry, protein interaction, and anticancer properties of the gold(III) compounds. Due to their identical monocationic charge and similar molecular shape, both complexes [1]Cl and [2]Cl displaced reference radioligand [3H]dofetilide equally well from cell membranes expressing the Kv11.1 (hERG) potassium channel, and more so than the tetrapyridyl ligands H2biqbpy1 and H2biqbpy2. By contrast, cyclometalation rendered [1]Cl coordinatively stable in the presence of biological thiols, while [2]Cl was reduced by a millimolar concentration of glutathione into metastable Au(I) species releasing the free ligand H2biqbpy2 and TrxR-inhibiting Au+ ions. The redox stability of [1]Cl dramatically decreased its thioredoxin reductase (TrxR) inhibition properties, compared to [2]Cl. On the other hand, unlike [2]Cl, [1]Cl aggregated into nanoparticles in FCS-containing medium, which resulted in much more efficient gold cellular uptake. [1]Cl had much more selective anticancer properties than [2]Cl and cisplatin, as it was almost 10 times more cytotoxic to human cancer cells (A549, A431, A375, and MCF7) than to noncancerous cells (MRC5). Mechanistic studies highlight the strikingly different mode of action of the two compounds: while for [1]Cl high gold cellular uptake, nuclear DNA damage, and interaction with hERG may contribute to cell killing, for [2]Cl extracellular reduction released TrxR-inhibiting Au+ ions that were taken up in minute amounts in the cytosol, and a toxic tetrapyridyl ligand also capable of binding to hERG. These results demonstrate that bis-cyclometalation is an appealing method to improve the redox stability of Au(III) compounds and to develop gold-based cytotoxic compounds that do not rely on TrxR inhibition to kill cancer cells.
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An Erlotinib triphenylphosphane gold(I) conjugate has been prepared from AuCl(PPh3) and its crystal structure has been established by X-ray diffraction, showing a metallo-helicate formation. IC50 values of the new gold conjugate were calculated towards a panel of human tumor cell lines representative of breast (MCF-7, MDA-MB-231) and colon (HT-29) cancer cells. Overall, the gold conjugate exhibited higher cytotoxic activity than that of Erlotinib against the cancer cells studied. Particularly, the antiproliferative effect of the conjugate demonstrated to be 68-fold higher than Erlotinib in highly metastatic and triple negative MDA-MB-231 cell line. The gold conjugate caused DNA damage, reactive oxygen species (ROS) increase and induced apoptosis. Flow cytometry analysis showed that the conjugate induces significant arrest in S and G2/M phases primarily, whereas Erlotinib, as an inhibitor of epidermal growth factor receptor (EGFR), blocks G1/S transition and increases G1 cell population.
Assuntos
Antineoplásicos/síntese química , Cloridrato de Erlotinib/análogos & derivados , Compostos Organoáuricos/síntese química , Neoplasias de Mama Triplo Negativas/metabolismo , Antineoplásicos/toxicidade , Apoptose , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Ouro/química , Células HT29 , Humanos , Células MCF-7 , Compostos Organoáuricos/toxicidade , Espécies Reativas de Oxigênio/metabolismoRESUMO
Chemotherapy remains one of the dominant treatments to cure cancer. However, due to the many inherent drawbacks, there is a search for new chemotherapeutic drugs. Many classes of compounds have been investigated over the years to discover new targets and synergistic mechanisms of action including multicellular targets. In this work, we designed a new chemotherapeutic drug candidate against cancer, namely, [Ru(DIP)2(sq)](PF6) (Ru-sq) (DIP = 4,7-diphenyl-1,10-phenanthroline; sq = semiquinonate ligand). The aim was to combine the great potential expressed by Ru(II) polypyridyl complexes and the singular redox and biological properties associated with the catecholate moiety. Experimental evidence (e.g., X-ray crystallography, electron paramagnetic resonance, electrochemistry) demonstrates that the semiquinonate is the preferred oxidation state of the dioxo ligand in this complex. The biological activity of Ru-sq was then scrutinized in vitro and in vivo, and the results highlight the promising potential of this complex as a chemotherapeutic agent against cancer.
Assuntos
Antineoplásicos/química , Antineoplásicos/metabolismo , Quinonas/química , Quinonas/metabolismo , Rutênio/química , Rutênio/metabolismo , Animais , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Feminino , Células HeLa , Humanos , Ligantes , Camundongos , Camundongos Nus , Oxirredução/efeitos dos fármacos , Quinonas/farmacologia , Rutênio/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Gold compounds have a long history of use as immunosuppressants, but their precise mechanism of action is not completely understood. Using our recently developed liver-on-a-chip platform we now show that gold compounds containing planar N-heterocyclic carbene (NHC) ligands are potent ligands for the aryl hydrocarbon receptor (AHR). Further studies showed that the lead compound (MC3) activates TGFß1 signaling and suppresses CD4+ T-cell activation in vitro, in human and mouse T cells. Conversely, genetic knockdown or chemical inhibition of AHR activity or of TGFß1-SMAD-mediated signaling offsets the MC3-mediated immunosuppression. In scurfy mice, a mouse model of human immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, MC3 treatment reduced autoimmune phenotypes and extended lifespan from 24 to 58 days. Our findings suggest that the immunosuppressive activity of gold compounds can be improved by introducing planar NHC ligands to activate the AHR-associated immunosuppressive pathway, thus expanding their potential clinical application for autoimmune diseases.