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2.
Chem Commun (Camb) ; 55(54): 7852-7855, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31215553
3.
Inorg Chem ; 58(13): 8800-8819, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247881

RESUMO

Very few inorganic antineoplastic drugs have entered the clinic in the last decades, mainly because of toxicity issues. Because copper is an essential trace element of ubiquitous occurrence, decreased side effects could be expected in comparison with the widely used platinum anticancer compounds. In the present work, two novel hydrazonic binucleating ligands and their µ-hydroxo dicopper(II) complexes were prepared and fully characterized. They differ by the nature of the aromatic group present in their aroylhydrazone moieties: while H3L1 and its complex, 1, possess a thiophene ring, H3L2 and 2 contain the more polar furan heterocycle. X-ray diffraction indicates that both coordination compounds are very similar in structural terms and generate dimeric arrangements in the solid state. Positive-ion electrospray ionization mass spectrometry analyses confirmed that the main species present in a 10% dimethyl sulfoxide (DMSO)/water solution should be [Cu2(HL)(OH)]+ and the DMSO-substituted derivative [Cu2(L)(DMSO)]+. Scattering techniques [dynamic light scattering (DLS) and small-angle X-ray scattering] suggest that the complexes and their free ligands interact with bovine serum albumin (BSA) in a reversible manner. The binding constants to BSA were determined for the complexes through fluorescence spectroscopy. Moreover, to gain insight into the mechanism of action of the compounds, calf thymus DNA binding studies by UV-visible and DLS measurements using plasmid pBR322 DNA were also performed. For the complexes, DLS data seem to point to the occurrence of DNA cleavage to Form III (linear). Both ligands and their dicopper(II) complexes display potent antiproliferative activity in a panel of four cancer cell lines, occasionally even in the submicromolar range, with the complexes being more potent than the free ligands. Our data on cellular models correlate quite well with the DNA interaction experiments. The results presented herein show that aroylhydrazone-derived binucleating ligands, as well as their dinuclear µ-hydroxodicopper(II) complexes, may represent a promising structural starting point for the development of a new generation of highly active potential antitumor agents.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Hidrazonas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Bovinos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Cobre/química , DNA/química , Clivagem do DNA/efeitos dos fármacos , Cães , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Hidrazonas/toxicidade , Isomerismo , Ligantes , Células Madin Darby de Rim Canino , Camundongos , Plasmídeos/química , Multimerização Proteica/efeitos dos fármacos , Soroalbumina Bovina/metabolismo
4.
Eur J Med Chem ; 178: 141-153, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31177074

RESUMO

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for development of various tumor types. In this study, we synthesized a series of novel 2,4-diarylaminopyrimidine derivatives possessing a unique N-(3-pyridinylmethyl)urea moiety as ALK inhibitors. The most promising analog 5m bearing a 3-methoxy-4-morpholinophenyl substituent significantly inhibited proliferation of ALK positive H3122 and Karpas-299 cells with IC50 values about 10 nM, which were comparable with positive control LDK378. Compound 5m suppressed phosphorylation of ALK and its downstream proteins, and showed low cytotoxicity on normal human primary fibroblast cells (BJ cells). The binding mode of 5m was proposed by docking simulation, which explains the important role of N-(3-pyridinylmethyl)urea moiety. Furthermore, compound 5m exhibited favorable liver microsomal stability and significant efficacy in H3122 xenograft mice model. Interestingly, compound 5m also showed broader anti-proliferative activity on other human tumor cell lines, which was different from other ALK inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Quinase do Linfoma Anaplásico/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estabilidade de Medicamentos , Feminino , Fibroblastos/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/toxicidade , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/toxicidade , Piridinas/síntese química , Piridinas/farmacologia , Piridinas/toxicidade , Pirimidinas/síntese química , Pirimidinas/farmacologia , Pirimidinas/toxicidade , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Bratisl Lek Listy ; 120(6): 423-428, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223022

RESUMO

OBJECTIVES: Recent studies reported that oxidative stress is an important mechanism that contributes to cisplatin induced cardiotoxicity. In the present study, the effects of N-acetylcysteine (NAC), which is an antioxidant, on cisplatin induced cardiotoxicity were investigated in a rat model. METHODS: Thirty two rats were separated into 4 equal groups: Control, NAC-250, CP (cisplatin), CP+NAC. Rats in the experimental groups were treated with a single dose of cisplatin intraperitoneally (ip) (10 mg/kg) and NAC (ip, 250 mg/kg) for 3 consecutive days. At the end of the experiment, cardiotoxicity was determined from plasma CK-MB, LDH, cTnI and cardiac myosin light chain-1 (CMLC-1) levels. In the tissue samples, total oxidant capacity (TOC), total antioxidant capacity (TAC), lipid hydroperoxide (ROOH) and thiol levels were measured. The hearts were also analyzed histopathologically. RESULTS: It was determined that cisplatin increased the tissue TOC, ROOH levels and decreased TAC and thiol levels. NAC administration after cisplatin treatment was observed to have ameliorated histological and functional changes in heart. CONCLUSIONS: In conclusion, the results of this experimental study suggested that oxidative stress had a serious effect on cisplatin cardiotoxicity, and NAC could be used as a therapeutic agent in addition to standard cisplatin treatment protocols (Tab. 3, Fig. 1, Ref. 35).


Assuntos
Acetilcisteína , Antineoplásicos , Antioxidantes , Cisplatino , Acetilcisteína/farmacologia , Animais , Antineoplásicos/toxicidade , Antioxidantes/farmacologia , Cardiotoxicidade , Cisplatino/toxicidade , Estresse Oxidativo , Ratos
6.
DNA Cell Biol ; 38(7): 718-724, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31188023

RESUMO

Human lung cancer cell lines A549 and A549/DDP, and ovarian cancer cell lines SKOV3 and SKOV3/DDP were subjected to thioridazine (Thio), cisplatin, or the combination; A549/DDP and SKOV3/DDP were the cisplatin-resistant sublines. Cell viability, apoptosis, and cell cycle were detected; the mitochondrial membrane potential and proteins related to mitochondrial apoptosis were determined. Thio induced cell death, and the combination of Thio and cisplatin led to the highest percentage of dead cells in four cells lines. Thio and the combined modality led to cell apoptosis by inducing G0/G1 arrest. The collapse of mitochondrial membrane potential, activation of caspase 9, upregulation of Bax protein, and downregulation of Bcl-2 protein demonstrated that apoptosis was mitochondria dependent. These data indicated that Thio could be used to modulate cisplatin-based chemotherapeutic regimen in lung and ovary cancers.


Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/metabolismo , Neoplasias Ovarianas/metabolismo , Tioridazina/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos
7.
Eur J Med Chem ; 177: 338-349, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158748

RESUMO

A series of styrylquinolines was designed and synthesized based on the four main quinoline scaffolds including oxine, chloroxine and quinolines substituted with a hydroxyl group or chlorine atom at the C4 position. All of the compounds were tested for their anticancer activity on wild-type colon cancer cells (HCT 116) and those with a p53 deletion. Analysis of SAR revealed the importance of electron-withdrawing substituents in the styryl part and chelating properties in the quinoline ring. The compounds that were more active were also tested on a panel of four cancer cell lines with mutations in TP53 tumor suppressor gene. The results suggest that styrylquinolines induce cell cycle arrest and activate a p53-independent apoptosis. The apparent mechanism of action was studied for the most promising compounds, which produced reactive oxygen species and changed the cellular redox balance.


Assuntos
Antineoplásicos/farmacologia , Quinolinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Estirenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Heme Oxigenase-1/metabolismo , Humanos , Estrutura Molecular , Poli(ADP-Ribose) Polimerase-1/metabolismo , Quinolinas/síntese química , Quinolinas/química , Quinolinas/toxicidade , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Relação Estrutura-Atividade , Estirenos/síntese química , Estirenos/química , Estirenos/toxicidade , Proteína Supressora de Tumor p53/metabolismo
8.
Eur J Med Chem ; 177: 350-361, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158749

RESUMO

The relationship between chemical structure and in vitro cytotoxic activities of a series of azastibocine-framework organoantimony(III) halide complexes against cancerous (HepG2, MDA-MB-231, MCF-7 and HeLa) and nonmalignant (HEK-293) cell lines was studied for the first time. A positive correlation between cytotoxic activity and the length of N→Sb coordinate bond on azastibocine framework of same nitrogen substituent was observed. By comparison, the organoantimony(III) complex 6-cyclohexyl-12-fluoro-5,6,7,12-tetrahydrodibenzo[c,f][1,5]azastibocine (C4) exhibited the highest selectivity index, giving a IC50(nonmalignant)/IC50(cancerous) ratio of up to 8.33. The results of cell cycle analysis indicated that the inhibitory effect of C4 on the cellular viability was caused by cell cycle arrest mainly at the S phase. The necrosis induced by C4 was confirmed by the Trypan blue dye exclusion test and the increase of lactic dehydrogenase (LDH) released in the culture medium. Furthermore, evaluation of the levels of intracellular reactive oxygen species (ROS) in MDA-MB-231 cells, by quantifying the relative fluorescence units (RFU) using spectrofluorometer, indicated that cytotoxic activity of C4 is dependent on the production of ROS. This work established the correlation between cytotoxic activity and N→Sb inter-coordination, a finding that provided theoretical and experimental basis for in-depth design of antimony-based organometallic complexes as potential anticancer agents.


Assuntos
Antimônio/química , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , L-Lactato Desidrogenase/metabolismo , Estrutura Molecular , Necrose/induzido quimicamente , Espécies Reativas de Oxigênio/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Relação Estrutura-Atividade
9.
Inorg Chem ; 58(14): 9135-9149, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31241925

RESUMO

Prospective anticancer metallodrugs should consider target-specific components in their design in order to overcome the limitations of the current chemotherapeutics. The inclusion of vitamins, which receptors are overexpressed in many cancer cell lines, has proven to be a valid strategy. Therefore, in this paper we report the synthesis and characterization of a set of new compounds [Ru(η5-C5H5)(P(C6H4R)3)(4,4'-R'-2,2'-bpy)]+ (R = F and R' = H, 3; R = F and R' = biotin, 4; R = OCH3 and R' = H, 5; R = OCH3 and R' = biotin, 6), inspired by the exceptional good results recently obtained for the analogue bearing a triphenylphosphane ligand. The precursors for these syntheses were also described following modified literature procedures, [Ru(η5-C5H5)(P(C6H4R)3)2Cl], where R is -F (1) or -OCH3 (2). The structure of all compounds is fully supported by spectroscopic and analytical techniques and by X-ray diffraction studies for compounds 2, 3, and 5. All cationic compounds are cytotoxic in the two breast cancer cell lines tested, MCF7 and MDA-MB-231, and much better than cisplatin under the same experimental conditions. The cytotoxicity of the biotinylated compounds seems to be related with the Ru uptake by the cells expressing biotin receptors, indicating a potential mediated uptake. Indeed, a biotin-avidin study confirmed that the attachment of biotin to the organometallic fragment still allows biotin recognition by the protein. Therefore, the biotinylated compounds might be potent anticancer drugs as they show cytotoxic effect in breast cancer cells at low dose dependent on the compounds' uptake, induce cell death by apoptosis and inhibit the colony formation of cancer cells causing also less severe side effects in zebrafish.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Biotina/química , Ciclopentanos/química , Compostos de Rutênio/síntese química , Animais , Antineoplásicos/toxicidade , Biotina/farmacologia , Biotinilação , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Cristalografia por Raios X , Ciclopentanos/farmacologia , Humanos , Estrutura Molecular , Compostos de Rutênio/química , Compostos de Rutênio/farmacologia , Testes de Toxicidade , Peixe-Zebra
10.
Int. j. morphol ; 37(2): 509-514, June 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1002252

RESUMO

Cisplatin is an antineoplastic agent with neuropathy as one of its major side effect. However, effective treatment is lacking. Increasing evidence suggests that cisplatin might damage nerve capillaries leading to impaired functions of blood-nerve barrier (BNB) and neuropathy. This study was aimed to examine the effects of cisplatin on pericytes. Rats were either treated with intraperitoneal injection of cisplatin 2 mg/kg twice a week for five continuous weeks. Cisplatin-treated rats showed reduced body weight, thermal hypoalgesia and slow sciatic motor nerve conduction velocity, indicating neuropathy. The density of pericytes in the distal sciatic nerves determined by immunohistochemistry to desmin was significantly reduced in the cisplatin compared with that of the control groups. Electron microscopic analysis demonstrated the detachment of pericytes from endothelial cells including the disruption of shared basement membrane in the sciatic nerves from cisplatin-treated rats. These data indicate the pericyte loss and detachment caused by cisplatin. Future studies of the BNB components and functions after cisplatin treatment are needed and will be essential for the development of effective treatments against cisplatin-induced neuropathy.


El cisplatino es un agente antineoplásico y presenta como uno de sus principales efectos secundarios, la neuropatía. Sin embargo, falta un tratamiento eficaz. La creciente evidencia sugiere que el cisplatino podría dañar los capilares nerviosos, lo que puede provocar una alteración de las funciones de la barrera hematoencefálica (BHE) y neuropatía. Este estudio tuvo como objetivo examinar los efectos del cisplatino en los pericitos. Las ratas se trataron con inyección intraperitoneal de cisplatino (2 mg/kg) dos veces por semana durante 5 semanas seguidas. Las ratas tratadas con cisplatino mostraron una reducción del peso corporal, hipoalgesia térmica y una velocidad de conducción del nervio ciático lenta, lo que indicaría neuropatía. La densidad de los pericitos en los nervios ciáticos distales determinada por inmunohistoquímica para desmina se redujo significativamente en el grupo cisplatino en comparación con la de los grupos controles. El análisis al microscopio electrónico demostró el desprendimiento de pericitos de las células endoteliales, incluida la ruptura de la membrana basal compartida en los nervios ciáticos de ratas tratadas con cisplatino. Estos datos indican la pérdida de pericitos y el desprendimiento causado por el cisplatino. Se necesitan estudios futuros de los componentes y funciones del BHE después del tratamiento con cisplatino y serán esenciales para el desarrollo de tratamientos efectivos contra la neuropatía inducida por el cisplatino.


Assuntos
Animais , Masculino , Ratos , Cisplatino/toxicidade , Pericitos/efeitos dos fármacos , Doenças do Sistema Nervoso/patologia , Antineoplásicos/toxicidade , Peso Corporal/efeitos dos fármacos , Imuno-Histoquímica , Ratos Wistar , Pericitos/patologia , Microscopia Eletrônica de Transmissão , Doenças do Sistema Nervoso/induzido quimicamente
11.
Artif Cells Nanomed Biotechnol ; 47(1): 1746-1757, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31062618

RESUMO

To evaluate the safety and efficacy of novel cobalt complex with sulindac (Co-SLD), the zebrafish and oral squamous cell carcinoma CAL27 were investigated in the present study. The developmental toxicity of Co-SLD ranging from 5 to 20 µM was determined by exposure to 3-144-h post-fertilization (hpf) zebrafish. Our data showed that Co-SLD did not cause to the appreciable toxicity at low concentration (5 and 10 µM). A remarkable toxicity was observed at high concentration (20 µM), including increased mortality and malformation, delayed hatchability, reduced heart rate as well as suppressed behaviour. With regard to the antitumor activity of Co-SLD, inhibited cell growth and migration capability were outstandingly observed in oral squamous cell carcinoma treated with 10 and 20 µM Co-SLD, which could be mainly attributed to the Co-SLD-elicited mitochondrial damage as marked by the depression of mitochondrial membrane potential, ROS accumulation and ATP depletion. Furthermore, administration of 10 µM Co-SLD was an optimal concentration not only to avoid the normal tissue toxicity, but also to enhance the killing of cancer cells via disrupting mitochondrial dysfunction. Taken together the above results demonstrated the desirable response of oral squamous cell carcinoma to Co-SLD.


Assuntos
Carcinoma de Células Escamosas/patologia , Cobalto/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Mitocôndrias/efeitos dos fármacos , Neoplasias Bucais/patologia , Sulindaco/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/toxicidade , Relação Dose-Resposta a Droga , Humanos , Locomoção/efeitos dos fármacos , Mitocôndrias/patologia , Peixe-Zebra
12.
Eur J Med Chem ; 176: 492-512, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31132480

RESUMO

We report the design, synthesis and biological studies on a group of mixed ligand Fe(III) complexes as anti-cancer drug candidates, namely their interaction with DNA, cytotoxicity and mechanism(s) of action. The aim is to obtain stable, efficient and selective Fe-complexes to be used as anti-cancer agents with less damaging side effects than previously reported compounds. Five ternary Fe(III) complexes bearing a tripodal aminophenolate ligand L2-, H2L = N,N-bis(2-hydroxy-3,5-dimethylbenzyl)-N-(2-pyridylmethyl)amine, and different aromatic bases NN = 2,2'-bipyridine [Fe(L)(bipy)]PF6 (1), 1,10-phenanthroline [Fe(L)(phen)]PF6 (2), or a phenanthroline derivative co-ligand: [Fe(L)(amphen)]NO3 (3), [Fe(L)(amphen)]PF6 (3a), [Fe(L)(Clphen)]PF6 (4), [Fe(L)(epoxyphen)]PF6 (5) (where amphen = 1,10-phenanthroline-5-amine, epoxyphen = 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, Clphen = 5-chloro-1,10-phenanthroline) and the [Fe(L)(EtOH)]NO3 (6) complex are synthesized. The compounds are characterized in the solid state and in solution by elemental analysis, ESI-MS, magnetic susceptibility measurements and FTIR, UV-Vis, 1H and 13C NMR and fluorescence spectroscopies. [Fe(phen)Cl3] and [Fe(amphen)Cl3] were also prepared for comparison purposes. Spectroscopic binding studies indicate groove binding as the main interaction for most complexes with DNA, and for those containing amphen a B- to Z-DNA conformational change is proposed to occur. As determined via MTT analysis all compounds 1-6 are cytotoxic against a panel of three different cell lines (HeLa, H1299, MDA-MB-231). For selected compounds with promising cytotoxic activity, apoptosis was evaluated using cell and DNA morphology, TUNEL, Annexin V/7AAD staining and caspase3/7 activity. The compounds induce oxidative DNA damage on plasmid DNA and in cell culture as assessed by 8-oxo-Guanine and γH2AX staining. Comet assay confirmed the presence of genomic damage. There is also increased reactive oxygen species formation following drug treatment, which may be the relevant mechanism of action, thus differing from that normally assumed for cisplatin. The Fe(III)-complexes were also tested against strains of M. Tuberculosis (MTb), complex 2 depicting higher anti-MTb activity than several known second line drugs. Hence, these initial studies show prospective anti-cancer and anti-MTb activity granting promise for further studies.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Ferro/química , Fenantrolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Antituberculosos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , DNA/química , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Desenho de Drogas , Estabilidade de Medicamentos , Humanos , Ligantes , Mycobacterium tuberculosis/efeitos dos fármacos , Fenantrolinas/síntese química , Fenantrolinas/química , Fenantrolinas/toxicidade , Estudos Prospectivos , Espécies Reativas de Oxigênio/metabolismo
13.
J Drugs Dermatol ; 18(5): 468-469, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141856

RESUMO

Sorafenib is an oral multikinase inhibitor approved by the United States Food and Drug Administration for the treatment of advanced hepatocellular and renal cell carcinoma. Cases of sorafenib-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome have been reported in the literature. DRESS syndrome is a potentially fatal, drug-induced hypersensitivity reaction that occurs 2-8 weeks after drug exposure. DRESS syndrome presents with generalized morbilliform eruption, facial edema, eosinophilia, and end-organ damage. We present the first reported case of sorafenib toxicity mimicking DRESS syndrome in a patient with metastatic adrenocortical carcinoma presenting with fever, morbilliform rash, and transaminitis in the absence of eosinophilia three days following initiation of sorafenib therapy. It is critical that clinicians are equipped to accurately diagnose DRESS syndrome due to its high mortality rate and the morbidity associated with prolonged steroid therapy. J Drugs Dermatol. 2019;18(5):468-469.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Sorafenibe/toxicidade , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/secundário , Diagnóstico Diferencial , Síndrome de Hipersensibilidade a Medicamentos/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica
14.
Eur J Med Chem ; 177: 32-46, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129452

RESUMO

A series of 2,4-diarylaminopyrimidine derivatives containing dithiocarbamate moiety were designed by molecular hybridization strategy and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most of these compounds exhibit significant antiproliferative activities on human cancer cell lines expressing high levels of FAK at nanomolar concentrations. The compound 14z was identified as the most potent FAK inhibitor among these candidates. 14z has excellent anti-proliferative effect with IC50 values from 0.001 µM to 0.06 µM on HCT116, PC-3, U87-MG and MCF-7 cell lines and relatively less cytotoxicity to a nonmalignant cell line MCF-10A compared with MCF-7 cells (SI value > 10). 14z also exhibits significant FAK inhibitory activity (IC50 = 0.07 nM). In addition, compound 14z causes cell cycle arrest at G2/M and prompted apoptosis in both HCT116 and MCF-7 cells in a dose-dependent manner. Further studies show that compound 14z inhibits migration of MCF-7 and has anti-angiogenesis effect on HUVEC cells.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Quinase 1 de Adesão Focal/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Tiocarbamatos/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/toxicidade , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/toxicidade , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/toxicidade , Relação Estrutura-Atividade , Tiocarbamatos/síntese química , Tiocarbamatos/química , Tiocarbamatos/toxicidade
15.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052347

RESUMO

High-risk human papilloma virus (HPV) infection is directly associated with cervical cancer development. Arsenic trioxide (ATO), despite inducing apoptosis in HPV-infected cervical cancer cells in vitro, has been compromised by toxicity and poor pharmacokinetics in clinical trials. Therefore, to improve ATO's therapeutic profile for HPV-related cancers, this study aims to explore the effects of length of ligand spacers of folate-targeted liposomes on the efficiency of ATO delivery to HPV-infected cells. Fluorescent ATO encapsulated liposomes with folic acid (FA) conjugated to two different PEG lengths (2000 Da and 5000 Da) were synthesised, and their cellular uptake was examined for HPV-positive HeLa and KB and HPV-negative HT-3 cells using confocal microscopy, flow cytometry, and spectrophotometer readings. Cellular arsenic quantification and anti-tumour efficacy was evaluated through inductively coupled plasma-mass spectrometry (ICP-MS) and cytotoxicity studies, respectively. Results showed that liposomes with a longer folic acid-polyethylene glycol (FA-PEG) spacer (5000 Da) displayed a higher efficiency in targeting folate receptor (FR) + HPV-infected cells without increasing any inherent cytotoxicity. Targeted liposomally delivered ATO also displayed superior selectivity and efficiency in inducing higher cell apoptosis in HPV-positive cells per unit of arsenic taken up than free ATO, in contrast to HT-3. These findings may hold promise in improving the management of HPV-associated cancers.


Assuntos
Antineoplásicos/toxicidade , Trióxido de Arsênio/toxicidade , Ácido Fólico/análogos & derivados , Lipossomos/química , Neoplasias do Colo do Útero/metabolismo , Apoptose/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Papillomaviridae , Polietilenoglicóis/química , Neoplasias do Colo do Útero/virologia
16.
Eur J Med Chem ; 176: 50-60, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096118

RESUMO

New sulfonamides 5/6 derived from 4-methoxyacetophenone 1 were synthesized by N-sulfonation reaction of ammonia (3) and aminopyrimidinone (4) with its sulfonyl chloride derivative 2. Sulfonamides 5 and 6 were used as precursors of two new series of chalcones 8a-f and 9a-f, which were obtained through Claisen-Schmidt condensation with aromatic aldehydes 7a-f. Compounds 5/6, 8a-d, 8f, 9a-d, and 9f were screened by the US National Cancer Institute (NCI) at 10 µM against sixty different human cancer cell lines (one-dose trial). Chalcones 8b and 9b satisfied the pre-determined threshold inhibition criteria and were selected for screening at five different concentrations (100, 10, 1.0, 0.1, and 0.01 µM). Compound 8b exhibited remarkable GI50 values ranging from 0.57 to 12.4 µM, with cytotoxic effects being observed in almost all cases, especially against the cell lines K-562 of Leukemia and LOX IMVI of Melanoma with GI50 = 0.57 and 1.28 µM, respectively. Moreover, all compounds were screened against Mycobacterium tuberculosis H37Rv, chalcones 8a-c and 9a-c were the most active showing MIC values between 14 and 42 µM, and interestingly they were devoid of antibacterial activity against Mycobacterium smegmatis and Staphylococcus aureus. These antituberculosis hits showed however low selectivity, being equally inhibitory to M. tuberculosis and mammalian T3T cells. The chalcone-sulfonamide hybrids 8a-f and 9a-f resulted to be appealing cytotoxic agents with significant antituberculosis activity.


Assuntos
Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Chalconas/farmacologia , Sulfonamidas/farmacologia , Células 3T3 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/toxicidade , Linhagem Celular Tumoral , Chalconas/síntese química , Chalconas/química , Chalconas/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/toxicidade
17.
Eur J Med Chem ; 176: 135-148, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31102934

RESUMO

Angiogenesis plays an essential role in tumourigenesis and tumour progression, and anti-angiogenesis therapies have shown promising antitumour effects in solid tumours. 2-Methoxyestradiol (2ME2), an endogenous metabolite of estradiol, has been regarded as a potential antitumour agent mainly targeting angiogenesis. Here we synthesized a novel series of chalcones based on 2-methoxyestradiol and evaluated their potential activities against tumours. Compound 11e was demonstrated to have potent antiangiogenic activity. Further studies showed that 11e suppressed tumour growth in human breast cancer (MCF-7) xenograft models without obvious side effects. Evaluation of the mechanism revealed that 11e targeted the epithelial to mesenchymal transition (EMT) process in MCF-7 cells and inhibited HUVEC migration and then contributed to hindrance of angiogenesis. Thus, 11e may be a promising antitumour agent with excellent efficacy and low toxicity.


Assuntos
2-Metoxiestradiol/análogos & derivados , 2-Metoxiestradiol/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Chalconas/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , 2-Metoxiestradiol/síntese química , 2-Metoxiestradiol/toxicidade , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/toxicidade , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalconas/síntese química , Chalconas/química , Chalconas/toxicidade , Galinhas , Membrana Corioalantoide/efeitos dos fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos Nus , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Estereoisomerismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Eur J Med Chem ; 176: 195-207, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103900

RESUMO

Previously, we focused on a series of 2-aminobenzamide-based histone deacetylase (HDAC) inhibitors, compound 9 of which displayed potent HDAC inhibitory activity against HDAC1 and HDAC2, and moderate anti-proliferative activity against several cancer cell lines. In the current study, we have designed and synthesized a series of novel HDAC inhibitors based on thioether moiety with 9 as a lead compound. Representative compounds12 g and 12 h showed apparently potent anti-proliferative activities against five solid cancer cell lines: A549, HCT116, Hela, A375 and SMMC7721, and low cytotoxicity against NIH 3T3 normal cells. Especially, 12 g and 12 h also revealed potent HDAC inhibitory activity against HDAC1, 2 and 3. In addition, the two compounds could arrest cell cycle in G2/M phase and promote cell apoptosis. Moreover, they showed extended inhibition of colony formation and effectively blocked cell migration towards A549 cancer cells. Furthermore, 12 g and 12 h possessed better pharmacokinetic properties than the lead compound 9. Benefiting from these results, we also explored 12 g and 12 h in the A549 xenografts model for in vivo antitumor activity. The in vivo experiment indicated that 12 g and 12 h could evidently augment antitumor activity (TGI = 56.9% and 62.7% respectively).


Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Sulfetos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Benzamidas/síntese química , Benzamidas/farmacocinética , Benzamidas/toxicidade , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Histona Desacetilases/toxicidade , Humanos , Camundongos , Simulação de Acoplamento Molecular , Células NIH 3T3 , Sulfetos/síntese química , Sulfetos/farmacocinética , Sulfetos/toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Eur J Med Chem ; 176: 248-267, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103903

RESUMO

FLT3 mutation is among the most common genetic mutations in acute myeloid leukemia (AML), which is also related with poor overall survival and refractory in AML patients. Recently, FLT3 inhibitors have been approved for AML therapy. Herein, a series of new compounds with pyrazole amine scaffold was discovered, which showed potent inhibitory activity against FLT3-ITD and significant selectivity against both FLT3-ITD and AML cells expressing FLT3-ITD. Compound 46, possessing the most promising cellular activity, blocked the autophosphorylation of FLT3 pathway in MV4-11 cell line. Furthermore, the apoptosis and downregulation of P-STAT5 were also observed in tumor cells extracted from the MV4-11 cell xenografts model upon compound 46 treatment. Compound 46 was also metabolically stable in vitro and suppressed tumor growth significantly in MV4-11 xenografts model in vivo. Compound 46 showed no toxicity to the viscera of mice and caused no decrease in body weight of mice. In conclusion, the results of this study could provide valuable insights into discovery of new FLT3 inhibitors, and compound 46 was worthy of further development as potential drug candidate to treat AML.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/toxicidade , Pirazóis/síntese química , Pirazóis/química , Pirazóis/toxicidade , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms/química , Tirosina Quinase 3 Semelhante a fms/genética
20.
Eur J Med Chem ; 176: 117-128, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31108261

RESUMO

A series of novel xanthine/NO donor hybrids containing 1,3,8-trisubstituted or 1,8-disubstituted xanthine derivatives were designed and synthesized. The synthesized compounds were tested in a cell viability assay using human mammary gland epithelial cell line (MCF-10A) where all the compounds exhibited no cytotoxic effects and more than 90% cell viability at a concentration of 50 µM. The oxime containing compounds 7a-b and 17-24 were more active as antiproliferative agents than their non-oxime congeners 6a-b and 9-16. Hydroxyimino-phenethyl scaffold compounds 17-24 were more active than the hydroxyimino-ethyl phenyl acetamide 7a-b derivatives. Compounds 18-20 and 22-24 exhibited inhibition of EGFR with IC50 ranging from 0.32 to 2.88 µM. Compounds 18-20 and 22-24 increased the level of active caspase 3 by 4-8 folds, compared to the control cells in Panc-1 cell lines compared to doxorubicin as a reference drug. Compounds 18, 22 and 23 were the most caspase-3 inducers. Compounds 22 and 23 increased the levels of caspase-8 and 9 indicating activation of both intrinsic and extrinsic pathways and showed potent induction of Bax, down-regulation of Bcl-2 protein levels and over-expression of cytochrome c levels in Panc-1 human pancreas cancer cells. Compound 23 exhibited mainly cell cycle arrest at the Pre-G1 and G2/M phases in the cell cycle analysis of Panc-1 cell line. The drug likeness profiles of compounds 18-20 and 22-24 were predicted to have good to excellent drug likeness profiles specially compounds 18-20 and 23. Finally molecular docking study was performed at the EGFR active site to suggest thier possible binding mode. The hydroxyimino-phenethyl scaffold compounds 17-24 represent an interesting starting point to optimize their pharmacokinetics and pharmacodynamics profiles.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Oximas/farmacologia , Xantinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Oximas/síntese química , Oximas/química , Oximas/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Xantinas/síntese química , Xantinas/química , Xantinas/toxicidade , Proteína X Associada a bcl-2/metabolismo
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