RESUMO
New securinine analogues have been prepared by semisynthesis. Two series were developed using either Suzuki or Sonogashira cross coupling reactions. The in vitro cytotoxicity of the compounds was assayed against HCT-116 colon cancer cells. The most potent derivatives showed promising growth inhibition on four tumoral cell lines giving a valuable insight on the structure-activity relationship (SAR) of securinine. Moreover, high antiproliferative effect against A-375 (melanoma) was observed with IC50 up to 60 nM.
RESUMO
A series of new securinine analogues was prepared by Heck reaction from readily accessible securinine and commercially available iodoarenes. The in vitro cytotoxicity of the prepared compounds was assayed against a panel of four cancer cell lines: A375, A549, HCT-116 and HL-60 showing promising growth inhibition with excellent IC50 values in the nanomolar range. The plasmatic stability of the most potent analogue was also investigated demonstrating that they might serve as valuable leads for the development of anticancer drugs.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Azepinas/química , Azepinas/farmacologia , Compostos Heterocíclicos de Anel em Ponte/química , Compostos Heterocíclicos de Anel em Ponte/farmacologia , Lactonas/química , Lactonas/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Azepinas/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Euphorbiaceae/química , Compostos Heterocíclicos de Anel em Ponte/síntese química , Humanos , Lactonas/síntese química , Neoplasias/tratamento farmacológico , Piperidinas/síntese químicaRESUMO
DNA methylation is a mammalian epigenetic mark that is involved in defining where and when genes are expressed, both in normal cells and in the context of diseases. Like other epigenetic marks, it is reversible and can be modulated by chemical agents. Because it plays an important role in cancer by silencing certain genes, such as tumor suppressor genes, and by reactivating other regions, such as repeated elements, it is a promising therapeutic target. Two compounds are already approved to treat hematological cancers. Many efforts have been carried out to discover new molecules that are able to efficiently inhibit DNA methylation in cancer cells. We will briefly overview the foremost of these efforts by focusing on what we have learned to this point on non-nucleoside inhibitors and on what we consider to be the features of an ideal inhibitor.
Assuntos
Metilação de DNA/efeitos dos fármacos , Metilases de Modificação do DNA/antagonistas & inibidores , Descoberta de Drogas/métodos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Metilases de Modificação do DNA/química , Metilases de Modificação do DNA/metabolismo , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Modelos Moleculares , Terapia de Alvo Molecular/métodos , Neoplasias/enzimologia , Neoplasias/genética , Nucleosídeos/química , Nucleosídeos/farmacologiaRESUMO
INTRODUCTION: DNA methylation is an epigenetic modification that modulates gene expression without altering the DNA base sequence. It plays a crucial role in cancer by silencing tumor suppressor genes (TSG). The DNA methyltransferases (DNMT) are the enzymes that catalyze DNA methylation and they are interesting therapeutical targets since DNA methylation is reversible such that an aberrant hypermethylation of DNA can be reverted by inhibition of DNMTs. Today, two drugs are on the market for the treatment of myelodysplastic syndrome, azacitidine and decitabine. AREAS COVERED: Here, we present a review of the patents describing the chemistry and biological activities of novel DNMT inhibitors and discuss select clinical studies. EXPERT OPINION: DNMT inhibitors have shown efficacy in clinics. However, highly efficient and specific DNMT inhibitors have not yet been identified. Improving methods will certainly lead to the prediction of novel directly binding inhibitors in the future.
Assuntos
Antineoplásicos/farmacologia , Metilases de Modificação do DNA/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Patentes como Assunto , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular , Metilação de DNA/efeitos dos fármacos , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Estrutura Molecular , Conformação Proteica , Relação Estrutura-Atividade , TransfecçãoRESUMO
This review presents the different human DNA methyltransferases (DNMTs), their biological roles, their mechanisms of action and their role in cancer. The description of assays for detecting DNMT inhibitors (DNMTi) follows. The different known DNMTi are reported along with their advantages, drawbacks and clinical trials. A discussion on the features of the future DNMT inhibitors will conclude this review.
Assuntos
Metilação de DNA/efeitos dos fármacos , Neoplasias/genética , Animais , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferases/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologiaRESUMO
The anaplastic lymphoma kinase (ALK) is a validated target for the therapy of different malignancies. Aberrant expression of constitutively active ALK chimeric proteins has been implicated in the pathogenesis of anaplastic large-cell lymphoma (ALCL) and has been detected in other cancers such as inflammatory myofibroblastic tumors, diffuse large B-cell lymphomas, certain non-small-cell lung cancers, rhabdomyosarcomas, neuroblastomas and glioblastomas. In the course of a screening program aimed at identifying kinase inhibitors with novel scaffolds, the two pyridoisoquinoline derivatives F91873 and F91874, were identified as multikinase inhibitors with activity against ALK in a biochemical screen. F91873 and F91874 also inhibited nucleophosmin-ALK and signal transducer and activator of transcription 3 phosphorylation in the ALCL cell line COST with the same potency. Both F91873 and F91874 behaved as ATP noncompetitive inhibitors and inhibited cell proliferation of the ALK(+) ALCL cell lines COST, PIO, and Karpas299 ALCL. This growth inhibition effect was associated with a G1-phase cell cycle arrest. Furthermore, administration of F91874 to severe combined immunodeficient mice bearing COST tumor xenografts resulted in a significant antitumor efficacy at 15 mg/kg/day, illustrating the potential utility of such compounds in the treatment of ALK-related pathologies.
Assuntos
Antineoplásicos/uso terapêutico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinolizinas/uso terapêutico , Tiazóis/uso terapêutico , Quinase do Linfoma Anaplásico , Animais , Antineoplásicos/síntese química , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/enzimologia , Feminino , Fase G1/efeitos dos fármacos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Linfoma Anaplásico de Células Grandes/enzimologia , Linfoma Anaplásico de Células Grandes/patologia , Camundongos , Camundongos Endogâmicos ICR , Camundongos SCID , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia , Inibidores de Proteínas Quinases/síntese química , Estrutura Terciária de Proteína , Quinolizinas/síntese química , Receptores Proteína Tirosina Quinases , Proteínas Recombinantes de Fusão/antagonistas & inibidores , Tiazóis/síntese química , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Antineoplásicos Fitogênicos/química , Microtúbulos/efeitos dos fármacos , Vimblastina/análogos & derivados , Antineoplásicos Fitogênicos/síntese química , Ensaios Clínicos como Assunto , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Humanos , Vimblastina/síntese química , Vimblastina/químicaRESUMO
Vinca alkaloids vinblastine and vincristine and some of their derivatives such as vinorelbine are widely used in therapy of leukemia and several solid tumors. Their action is associated with alterations of the mitotic spindle functions that prevent the cell cycle progression and lead to mitotic block. A number of studies show that some Vinca alkaloids inhibit CaM-target interaction. The newest microtubule inhibitor, vinflunine (Javlor), currently in clinical trials, is remarkably more active than vinblastine against a number of tumors. Moreover, vinflunine is significantly less toxic than other Vinca alkaloids. The high antitumor activity of this molecule is not well understood since it binds to tubulin with an overall affinity several-fold lower than that of vinblastine or vincristine. In this study, we examined the interaction of Ca2+-CaM with vinflunine, vinblastine, and stable tubule only polypeptide (STOP) by using a combination of thermodynamic and mass spectrometric approaches. We characterized the influence of Vinca alkaloids on Ca2+-CaM-STOP complex formation. Our results revealed different binding modes to Ca2+-CaM for vinflunine and vinblastine, highlighting that adding fluorine atoms on the cleavamine moiety of the Vinca alkaloid molecule is critical for the localization of the drug on calmodulin. We demonstrate that vinflunine is a better inhibitor for STOP binding to calmodulin than vinblastine. We suggest that vinflunine action on calmodulin can have an effect on microtubule dynamics. These data may contribute to a better understanding of the superior antitumor efficiency and lower toxicity of vinflunine.
Assuntos
Calmodulina/metabolismo , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Vimblastina/análogos & derivados , Animais , Calmodulina/química , Calorimetria , Modelos Moleculares , Estrutura Molecular , Peptídeos/metabolismo , Ligação Proteica , Desnaturação Proteica , Espectrometria de Massas por Ionização por Electrospray , Temperatura , Termodinâmica , Vimblastina/química , Vimblastina/farmacologiaRESUMO
The binding of two antitumour alkaloids, vinorelbine and vinflunine, to the alpha/beta-tubulin dimer has been investigated at equilibrium by nuclear magnetic resonance (NMR) spectroscopy. Tubulin stability and assembly induced by these drugs has been checked under NMR experimental conditions, and tubulin spirals were found in majority. Then, using increasing ligand concentrations, the alkaloids were titrated against tubulin. A non-specific binding of both compounds to tubulin (K(d)>10(-5)M) was characterised by broad NMR ligand signal at 4 and 30 degrees. The tubulin dimer exhibited also 2.7 (sigma: 0.3) and 2.6 (sigma: 0.6) binding sites with a K(d)<10(-5)M for vinorelbine at 4 and 30 degrees, respectively. In contrast, if the tubulin dimer exhibited 2.7 (sigma: 0.2) binding sites for vinflunine at 4 degrees, these sites were not detected at 30 degrees. This NMR study revealed for the first time the presence of specific binding sites and a clear differential affinity of vinorelbine and vinflunine to the tubulin dimer at physiological temperatures which could possibly account for their differential cytotoxicity.
Assuntos
Tubulina (Proteína)/metabolismo , Vimblastina/análogos & derivados , Vimblastina/metabolismo , Animais , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Sítios de Ligação , Dimerização , Espectroscopia de Ressonância Magnética , Conformação Molecular , Peso Molecular , Ovinos , Vimblastina/farmacologia , VinorelbinaRESUMO
Vinblastine and vinorelbine analogues have been synthesised by reacting new versatile electrophilic vindoline derivatives with various 3-substituted indoles. The resulting compounds have been evaluated for their antimitotic properties, but exhibited less potent activities in comparison with the standard binary Vinca alkaloids.